U.S. patent application number 11/250355 was filed with the patent office on 2006-04-13 for diagnosis and treatment system for "reward deficiency syndrome" (rds) and related behaviors.
Invention is credited to Kenneth Blum.
Application Number | 20060079495 11/250355 |
Document ID | / |
Family ID | 35066116 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060079495 |
Kind Code |
A1 |
Blum; Kenneth |
April 13, 2006 |
Diagnosis and treatment system for "reward deficiency syndrome"
(RDS) and related behaviors
Abstract
The present invention relates to a kit and an intravenously
administrable preparation, both with a signal transmitter
precursor, an enhancer of precursor uptake, and an inhibitor of
neurotransmitter reuptake or signal transmitter catabolism. The kit
also contains an appropriate swab for obtaining oral cells suitable
for allelic analysis. The intravenous formulation contains similar
materials and, in some cases, ethanol. Either the kit composition
or the intravenous formulation may be used as guided by a subjects
allelic analysis. Collections of particular alleles, especially
those relating to neural system are comprehensible in terms of
likelihood of success in the administration of an intraveinous
formulation or ingestion of components of the subject kit.
Inventors: |
Blum; Kenneth; (San Antonio,
TX) |
Correspondence
Address: |
AMIN LAW, LLC
217 N. JEFFERSON ST.
STE. 500
CHICAGO
IL
60661
US
|
Family ID: |
35066116 |
Appl. No.: |
11/250355 |
Filed: |
October 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09632838 |
Aug 4, 2000 |
6955873 |
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11250355 |
Oct 14, 2005 |
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60147229 |
Aug 4, 1999 |
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Current U.S.
Class: |
514/184 ;
514/567; 514/724 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/198 20130101; A61K 31/045 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/045 20130101;
A61K 31/555 20130101; A61K 31/198 20130101; A61K 31/555
20130101 |
Class at
Publication: |
514/184 ;
514/567; 514/724 |
International
Class: |
A61K 31/555 20060101
A61K031/555; A61K 31/198 20060101 A61K031/198; A61K 31/045 20060101
A61K031/045 |
Claims
1. An intravenous formulation comprising at least one
pharmaceutically acceptable carrier and consisting of a signal
transmitter precursor, an enhancer of precursors uptake, and an
inhibitor of neurotransmitter re-uptake or signal-transmitter
catabolism.
2. The intravenous formulation of claim 1 wherein an allelic
analysis of a subject predicts likelihood of positive effects of a
subjects intake of the formulation in effective amounts.
3. The intravenous formulation of claim 1 wherein the enhancer is a
chromium salt.
4. The intravenous formulation of claim 1 wherein the enhancer is
at least one of ethanol or calcium.
5. The intravenous formulation of claim 1 wherein the inhibitor is
D Phenylalanine or DL Phenylalanine.
6. The intravenous formulation of claim 1 where the signal
transmitter is a neurotransmitter, a peptidyl transmitter or
opiate, nitric oxide, or other secondary intercellular
messenger.
7. An intravenous formulation comprising: (a) an opiate
destruction-inhibiting amount of at least one substance which
inhibits the enzymatic destruction of neuropeptidyl opiate, said
substance being selected from the group consisting of amino acids,
peptides, and structural analogues or derivatives thereof: b) a
neurotransmitter synthesis-promoting amount of at least one
neurotransmitter precursor selected from the group consisting of
dopamine precursors L-Tyr, L-Phe and L-dopa, serotonin precursors
L-Trp and 5-hydroxytryptophan, and gamma amino butyric acid (GABA)
precursors L-glutamine, L-glutamic acid, and L-glutamate; and c) a
tryptophan concentration enhancing amount of chromium picolinate or
chromium nicotinate; wherein the amount of said substance and said
neurotransmitter precursor and said chromium compound being
effective in reducing a subject's RDS behaviors.
8. An intravenous formulation of claims 1 or 5 comprising about 16
to 500 mg of D-Phenylalanine.
9. An intravenous formulation comprising ethanol at least one of:
L-Phenylalanine, L-Tyrosine, L-Tryptophan, L-Glutamine,
L-5-Hydroxytryptophan, Pyrodoxal Phosphate, Chromium Picolinate,
Chromium Nicotinate, Tyrosine-D-Ar, Rhodiola Rosea, and Huberzine
A.
10. The intravenous formulation of claim 9 comprising at least one
of: 5 to 5,000 mg of L-Phenylalanine, 5 to 5, 000 mg of L-Tyrosine,
9 to 90,000 mg L-Tryptophan, 0.9 to 9,000 mg L-5-Hydroxytryptophan,
and 3 to 30,000 mg L-Glutamine.
11. The intravenous formulation of claim 9 comprising about 1500 mg
L-Phenylalanine, about 900 mg L-Tyrosine, about 500 mg
L-Tryptophan, about 300 mg L-Glutamine, about 20 mg of Pyrodoxal
Phosphate and about 400 ug Chromium Picolinate or Chromium
Nicotinate.
12. The intravenous formulation of claim 9 comprising about 1500 mg
L-Phenylalanine, about 900 mg L-Tyrosine, about 500 mg
L-Tryptophan, about 300 mg L-Glutamine, about 20 mg of Pyrodoxal
Phosphate, about 400 ug Chromium Picolinate or Chromium Nicotinate,
and about 15 ug of Tyrosine-D-Arg.
13. The intravenous formulation of claim 9 comprising about 1500 mg
L-Phenylalanine, about 900 mg L-Tyrosine, about 500 mg
L-Tryptophan, about 300 mg L-Glutamine, about 20 mg of Pyrodoxal
Phosphate, about 400 ug Chromium Picolinate or Chromium Nicotinate,
about 15 ug of Tyrosine-D-Ar, and about 25 mg Rhodiola Rosea, and
about 10 ug Huberzine A.
14. The intravenous formulation of claim 9 comprising about 1500 mg
L-Phenylalanine, about 900 mg L-Tyrosine, about 500 mg
L-Tryptophan, about 300 mg L-Glutamine, about 20 mg of Pyrodoxal
Phosphate, about 400 ug Chromium Picolinate or Chromium Nicotinate,
about 15 ug of Tyrosine-D-Arg, about 25 mg Rhodiola Rosea, about 10
ug Huberzine A, and about 10% ethanol.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and is a divisional
application of U.S. application Ser. No. 09/632,838, filed on Aug.
4, 2000.
BACKGROUND OF THE INVENTION
[0002] The following pending applications are hereby incorporated
by reference: Ser. Nos. 09/481,426 and 09/069,886 and 09/356,266
and 09/423,040 and PCT US 98/08684.
[0003] SynerGene NutraLife Essentials, which is a division of
CyberPharm Corporation, is a new line of patent protected
nutraceuticals and neutraceuticals. All products in the SynerGene
line provide high quality nutrients consisting of amino acids,
trace minerals, vitamins, minerals, and herbals. When combined into
numerous blends they have demonstrable therapeutic health benefits.
The uniqueness of this particular line is that each product is
specifically formulated to achieve synergistic activity from the
active ingredient which has been shown by specific studies as well
as functional combinations which have not been previously
available. The products are backed up by double blind, placebo,
controlled open label research studies on humans as well as other
rigorous studies (including both human and animal studies) and
extensive anecdotal reports.
[0004] Another aspect contributing to the uniqueness of the
SynerGene products is the fact that the origin of action of all the
products is in the central nervous system. Some of the products
ultimately affect the peripheral nervous system and some of them
ultimately affect the central nervous system. However, all are
formulated to affect the health of the central and peripheral
nervous system.
[0005] The Reward Deficiency Syndrome (RDS) results from a
dysfunction in the Brain Reward Cascade which directly links
abnormal craving behavior with a deficit in the DRD2 Dopamine
Receptor Gene. Dopamine is a very powerful neurotransmitter in the
brain which controls feelings of well being. This sense of well
being is produced through the interaction of dopamine and
neurotransmitters such as serotonin, the opioids, and other
powerful brain chemicals. Low serotonin levels are associated with
depression. High levels of the opioids (the brain's opium) are
associated with a sense of well being. The complex interactions of
these powerful neurotransmitters ultimately regulating the
Dopaminergic Activity in the Reward Center of the Brain has been
termed "The Brain Reward Cascade".
[0006] In individuals possessing an abnormality in the DRD2
Dopamine Receptor Gene, the brain lacks enough Dopamine receptor
sites to use the normal amount of Dopamine in the Reward Center of
the brain and thus reduces the amount of Dopamine produced in this
area of the brain. In individuals not possessing the variant in the
Dopamine Receptor Gene who lived certain lifestyles (heavy cocaine
abuse, extremely low caloric diet, high levels of stress over an
extend ed period of time, etc.) their brains function as if the
persons have the DRD2 genetic variant.
[0007] Nutraceuticals are nutritional supplements which have been
shown to affect the peripheral nervous system or other systems of
the body. These include products for symptoms such as pain,
inflammation, cardiovascular disorders, immune system responses,
etc. Neutraceuticals are also nutritional supplements which have
been shown to affect the central nervous system of the body. These
products are for disorders such as addictions to alcohol, cocaine,
nicotine, carbohydrates, sex, gambling, etc. and disorders such as
attention deficit hyperactivity disorder, Tourette Disorder,
personality disorders, depression, premenstrual syndrome,
premenstrual dysphoria disorder, etc.
[0008] The overall effect is inadequate Dopaminergic Activity in
the Reward Center of the Brain. This defect drives individuals to
engage in activities which will increase brain Dopamine function.
Consuming large quantities of alcohol or carbohydrates
(carbohydrate binging) stimulate the brain's production of and
utilization of Dopamine. So too does the intake of crack/cocaine
and the abuse of nicotine. Also, it has been found that the genetic
abnormality is associated with aggressive behavior which also
stimulates the brain's use of Dopamine.
[0009] The Reward Deficiency Syndrome involves a form of sensory
deprivation of the brain's reward or pleasure mechanisms. The
Reward Deficiency Syndrome can be manifested in relatively mild or
severe forms that follow as a consequence of an individual's
biochemical inability to derive reward from ordinary, everyday
activities. We believe that we have discovered at least one genetic
aberration that leads to an alteration in the reward pathways of
the brain. It is a variant form of the gene for the dopamine D2
receptor, called the A1 allele. This genetic variant also is
associated with a spectrum of impulsive, compulsive, and addictive
behaviors. The concept of the Reward Deficiency Syndrome unites
those disorders and may explain how simple genetic anomalies give
rise to complex aberrant behavior.
The Biology of Reward
[0010] The pleasure and reward system in the brain was discovered
by accident in 1954. The American psychologist James Olds was
studying the rat brain's alerting process, when he mistakenly
placed the electrodes in a part of the limbic system, a group of
structures deep within the brain that are generally believed to
play a role in emotions (Olds, 1995). When the brain was wired so
that the animal could stimulate this area by pressing a level, Olds
found that the rats would press the lever almost nonstop, as much
as 5,000 times an hour. The animals would stimulate themselves to
the exclusion of everything else except sleep. They would even
endure tremendous pain and hardship for an opportunity to press the
lever. Olds had clearly found an area in the limbic system that
provided a powerful reward for these animals. Research on human
subjects revealed that the electrical stimulation of some areas of
the brain (medial hypothalamus, which is in the limbic system)
produced a feeling of quasi-orgasmic sexual arousal. If certain
other areas of the brain were stimulated, an individual experienced
a type of light-headedness that banished negative thoughts. These
discoveries demonstrated that pleasure is a distinct neurological
function that is linked to a complex reward and reinforcement
system (Hall, eta!. 1977).
[0011] During the past several decades research has been able to
establish some of the brain regions and neurotransmitters involved
in reward. A neuronal circuit deep in the brain involving the
limbic system and two regions called the nucleus accumbens and the
globus pallidus appears to be critical in the expression of reward
for people (Wise and Bozarth, 1984). Although each substance of
abuse (listed above) and each activity of abuse (listed above)
appears to act on different parts of this circuit, the end result
is the same.
[0012] Dopamine is released in the nucleus accumbens and the
hippocampus (Koob and Bloom, 1988). Dopamine appears to be the
primary neurotransmitter of reward at the reinforcement sites. It
is useful to think of the brain's reward system as a cascade in
which one reaction triggers another. At the level of individual
neurons, the Brain Reward Cascade (Blum and Kozlowski, 1990) is
catalyzed by a number of neurotransmitters. Each neurotransmitter
binds to certain types of receptors and serves a specific function.
The binding of the neurotransmitter to a receptor on a neuron
triggers a reaction that is part of the cascade. Disruption of
these intercellular cascades results in one form or another of the
Reward Deficiency Syndrome.
The Cascade Theory of Reward
[0013] During the past decades, considerable attention has been
devoted to the investigation of the neurochemical and
neuroanatomical systems that underlie a variety of substance
seeking behaviors. In a normal person, neurotransmitters (the
messengers of the brain) work together in a pattern of stimulation
or inhibition, the effects spreading downward from complex stimuli
to complex patterns of response like a cascade, leading to feelings
of well being, which is the ultimate reward (Cascade Theory of
Reward) (Cloninger, 1983; Stein and Belluzzi, 1986; Blum and
Koslowski, 1990).
[0014] In the reward areas, the following interactions take place
(Stein and Belluzzi, 1986; Blum, 1989): [0015] 1. serotonin in the
hypothalamus indirectly activates opiate receptors and causes a
release of enkephalins in the ventral tegmental region A.about.The
enkephalins inhibit the firing of GABA which originates in the
substantia nigra A.about.region; [0016] 2. GABAAEs normal role,
acting through GABA B receptors, is to inhibit and control the
amount of dopamine released at the ventral tegmental regions for
action at the nucleus accumbens. When the dopamine is released in
the nucleus accumbens it activates dopamine D2 receptors, a key
reward site. This release is also regulated by enkephalins acting
through GABA. The supply of enkephalin s is controlled by the
amount of the neuropeptidases which destroy them. [0017] 3.
dopamine may also be released into the amygdala. From the amygdala,
dopamine reaches the hippocampus and the CA, cluster cells
stimulates dopamine D2 receptors, another reward site. [0018] 4. an
alternate pathway involves norepinephrinein the locus of ceruleus
whose fibers project into the hippocampus at a reward area
centering around cluster cells which have not been precisely
identified, but which have been designated a CAx. When GABA A
receptors in the hippocampus are stimulated, they cause the release
of norepinephrine at the CAx site. It is to be noted that the
glucose receptor (GR) in the hypothalamus is intricately involved
and "links" the serotonergic system with opioid peptides leading to
the ultimate release of dopamine at the n. accumbens.
[0019] In the Brain Reward Cascade (Blum and Kozlowski, 1990),
these interactions may be viewed as activities of subsystems of a
larger system, taking place simultaneously or in sequence, merging
in cascade fashion toward anxiety, anger, low self-esteem, or other
bad feelings or toward craving or a substance that will make these
bad feelings go away, for example alcohol, carbohydrates, etc.
Genetic anomalies, long-term continuing stress, or long-term abuse
of substances can lead to a self-sustaining pattern of abnormal
craving behavior in both animals and humans. Animal model support
for the cascade theory can be derived from a series of experiments
carried out by T. K. Li et. al., (Russell, Lanin, and Taljaard,
1988; McBride, 1990; Zhou, 1990; McBride, et. al. 1993) upon their
alcohol-preferring (P) and non-preferring (NP) rat lines. They
found that the P rats have the following neurochemical profile:
[0020] 1. lower serotonin neurons in the hypothalamus; [0021] 2.
higher levels of enkephalin in the hypothalamus (due to a lower
release); [0022] 3. more GABA neurons in the nucleus accumbens;
[0023] 4. reduced dopamine supply at the nucleus accumbens; [0024]
5. reduced densities of dopamine D2 receptors in the meso-limbic
areas.
[0025] This suggests a four-part cascade sequence leading to a
reduction of net dopamine release in a key reward area. This was
further confirmed when they found that by administering substances
that increase the serotonin supply at the synapse, or by
stimulating dopamine D2 receptors directly, they could reduce
craving for alcohol (McBride et al. 1994). Specifically, D2
receptor agonists reduce alcohol intake in high alcohol preferring
rats whereas D2 dopamine receptors antagonists increase alcohol
drinking in these inbred animals (Dyr, et al. 1993). Human support
for the Brain Reward Cascade also can be derived from a series of
clinical trials with neuronutrients (precursor amino acid loading
technique and enkephalinase inhibition) indicating reduced craving,
reduced stress rates, facilitated recovery and reduced relapse
rates (Brown et al. 1990; Blum and Tractenberg, 1988; Blum et al.
1989).
[0026] Most recently, the notion of dopamine as the final common
pathways for a number of diverse drugs of abuse such as cocaine,
morphine, and alcohol is supported by Ortiz and associates at Yale
University School of Medicine and University of Connecticut Health
Services Center demonstrating that chronic treatment of either
cocaine, morphine, or alcohol similarly results in several
biochemical adaptations in the meso-limbic dopamine system, which
may underlie prominent changes in the structural and functional
properties of the neuronal pathways related to the above (Also see
Routtenberg, DiChiara, and Inperato, 1988). We propose that the
Reward Deficiency Syndrome gives rise to a wide range of disorders
that can be classified as impulsive-addictive-compulsive disorders.
Impulsive disorders include attention deficit hyperactivity
disorder and Tourette's Disorder. Addictive disorders include
substance-seeking behaviors involving alcohol, drugs, nicotine, and
food. Compulsive diseases include pathological gambling and
excessive sexual activity.
[0027] CyberPharm, Incorporated through an intellectual property
license from 1899 LLC controls the following related art with the
specified limitations:
Anti-Inflammatory, Analgesics
[0028] 1. U.S. Pat. No. 39452, issued Mar. 27, 1984, entitled CLASS
OF ANALGESICS AND/OR ANTI-INFLAMMATORY AGENTS CONSISTING OF
INHIBITORS OF BREAKDOWN OF ENDOGENOUS ENKEPHALIN AND/OR ENDORPHIN,
AND COMBINATIONS OF SAID ANALGESICS WITH ANTIPYRETIC,
ANTI-INFLAMMATORY (ASPIRIN-TYPE) DRUGS refers to a new class of
analgesics provided by substances that inhibit breakdown of
endogenous substance such as enkephalins and/or endorphins. The
analgesic effect of an enkephalin breakdown inhibitor is greatly
enhanced by being combined with an antipyretic, anti-inflammatory
analgesic, herein designated as an aspirin-type drug. Specifically,
both D-phenylalanine and D-leucine, each an enkephalin breakdown
inhibitor, when used separately provides excellent analgesia in
animals and man without developing tolerance or addiction in either
species. Use of a combination of D-phenylalanine and D-leucine
provides a greatly enhanced analgesia approaching the analgesia
achieved by morphine. Analgesia by the latter combination is very
long-lasting in animals. The injection of a combination of
D-phenylalanine and an aspirin-like drug that is antipyretic and
anti-inflammatory in an animal provides a greatly enhanced
analgesia approaching the analgesia achieved by morphine. Analgesia
by D-phenylalanine is very long-lasting in humans. D-phenylalanine
also exhibits anti-inflammatory character, as demonstrated in
animal tests.
[0029] 2. U.S. Pat. No. 4,579,843, issued Apr. 1, 1986, entitled
ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS, describes analgesic
and anti-inflammatory compositions which comprise a therapeutically
effective amount of a first agent selected from the group
consisting of D-phenylalanine, DL-phenylalanine, D-leucine, and
DL-leucine and synergistically effective amount of a second
therapeutic agent selected from the group consisting of aspirin and
an aspirin-type non-steroidal anti-inflammatory, anti-pyretic
agent.
[0030] 3. U.S. Pat. No. 4,687,781, issued Aug. 18, 1987, entitled
ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS, describes analgesic
and anti-inflammatory compositions are provided which comprise a
therapeutically effective amount of a hydrocinnamic acid alone, or
in combination with one or more amino acids selected from the group
consisting of D-phenylalanine, DL-phenylalanine, D-leucine, and
DL-leucine and synergistically effective amount of a second
therapeutic agent selected from the group consisting of aspirin and
an aspirin-type non-steroidal anti-inflammatory, anti-pyretic
agent.
[0031] 4. U.S. Pat. No. 4,730,007, issued Mar. 8, 1988, entitled
NOVEL ANALGESIC COMPOSITIONS describes an analgesic composition
comprising an effective amount of an analgesic, anti-inflammatory
agent selected from the group consisting of D-phenylalanine,
DL-phenylalanine, D-leucine, DL-leucine and hydrocinnamic acid and
a synergistically effective amount of acetaminophen is provided by
the present invention.
[0032] 5. A Canadian application entitled CLASS OF ANALGESICS
AND/OR ANTI-INFLAMMATORY A GENTS CONSISTING OF INHIBITORS OF
BREAKDOWN OF ENDOGENOUS ENKEPHALIN AND/OR ENDORPHIN, AND
COMBINATIONS OF SAID ANALGESICS WITH ANTIPYRETIC, ANTI-INFLAMMATORY
(ASPIRIN-TYPE) DRUGS describes a new class of analgesics provided
by substances that inhibit breakdown of endogenous substance such
as enkephalins and/or endorphins. The analgesic effect of an
enkephalin breakdown inhibitor is greatly enhanced by being
combined with an antipyretic, anti-inflammatory analgesic, herein
designate d as an aspirin-type drug. Specifically, both
D-phenylalanine and D-leucine, each an enkephalin breakdown
inhibitor, when used separately provides excellent analgesia in
animals and man without developing tolerance or addiction in either
species. Use of a combination of D-phenylalanine and D-leucine
provides a greatly enhanced analgesia approaching the analgesia
achieved by morphine. Analgesia by the latter combination is very
long-lasting in animals. The injection of a combination of
D-phenylalanine and an aspirin-like drug that is antipyretic and
anti-inflammatory in an animal provides a greatly enhanced
analgesia approaching the analgesia achieved by morphine. Analgesia
by D-phenylalanine is very long-lasting in humans. D-phenylalanine
also exhibits anti-inflammatory character, as demonstrated in
animal tests.
[0033] 6. Japanese Patent Number 1435284, issued Jul. 8, 1986,
entitled CLASS OF ANALGESICS AND/OR ANTI-INFLAMMATORY A GENTS
CONSISTING OF INHIBITORS OF BREAKDOWN OF ENDOGENOUS ENKEPHALIN
AND/OR ENDORPHIN, AND COMBINATIONS OF SAID ANALGESICS WITH
ANTIPYRETIC, ANTI-INFLAMMATORY (ASPIRIN-TYPE) DRUGS describes a new
class of analgesics provided by substances that inhibit breakdown
of endogenous substance such as enkephalins and/or endorphins. The
analgesic effect of an enkephalin breakdown inhibitor is greatly
enhanced by being combined with an antipyretic, anti-inflammatory
analgesic, herein designated as an aspirin-type drug. Specifically,
both D-phenylalanine and D-leucine, each an enkephalin breakdown
inhibitor, when used separately provides excellent analgesia in
animals and man without developing tolerance or addiction in either
species. Use of a combination of D-phenylalanine and D-leucine
provides a greatly enhanced analgesia approaching the analgesia
achieved by morphine. Analgesia by the latter combination is very
long-lasting in animals. The injection of a combination of
D-phenylalanine and an aspirin-like drug that is antipyretic and
anti-inflammatory, in an animal provides a greatly enhanced
analgesia approaching the analgesia achieved by morphine. Analgesia
by D-phenylalanine is very long-lasting in humans. D-phenylalanine
also exhibits anti-inflammatory character, as demonstrated in
animal tests.
[0034] 7. A U.S. Patent Disclosure dated Mar. 18, 1999, entitled
CLASS OF ANALGESICS AND/OR ANTI-INFLAMMATORY A GENTS CONSISTING OF
INHIBITORS OF BREAKDOWN OF ENDOGENOUS ENKEPHALIN AND COMBINATIONS
OF SAID ANALGESICS WITH GANODERMA LUCIDUM describes a new class of
analgesics provided by substances that inhibit breakdown of
endogenous substance such as enkephalins and/or endorphins. The
analgesic effect of an enkephalin breakdown inhibitor is greatly
enhanced by being combined with an antipyretic, anti-inflammatory
analgesic, herein designated as an aspirin-type drug. Specifically,
both D-phenylalanine and D-leucine, each an enkephalin breakdown
inhibitor, when used separately provides excellent analgesia in
animals and man without developing tolerance or addiction in either
species. Use of a combination of D-phenylalanine and D-leucine
provides a greatly enhanced analgesia approaching the analgesia
achieved by morphine. Analgesia by the latter combination is very
long-lasting in animals. The unique combination of inhibitors of
amino peptidaises and extracts of ganoderma lucidum provides
synergistic analgesic and antiinflammatory effects in both animals
and humans.
RDS Gene Testing
[0035] 8. U.S. Pat. No. 5,210,016, issued May 11, 1993, entitled
ALLELIC ASSOCIATION OF THE HUMAN DOPAMINE (D.about.) RECEPTOR GENE
IN COMPULSIVE DISORDERS SUCH AS ALCOHOLISM relates to a method for
diagnosing compulsive disease predisposition of an individual. The
method comprises initially obtaining a DNA sample of said
individual and then determining the presence or absence of a
particular human D2 receptor gene allele in said sample. Detection
of said allele in the sample is indicative of predilection to
compulsive disease. A most preferred embodiment is to detect
predisposition to alcoholism, particularly because said allele has
been found to be present in a majority of clinically diagnosed
alcoholics. The human D0.2 receptor gene A1 allele is most
preferably detected in said sample.
[0036] 9. U.S. Pat. No. 5,550,343, issued Mar. 19, 1996, entitled
ALLELIC ASSOCIATION OF THE HUMAN DOPAMINE(D.about.) RECEPTOR GENE
IN COMPULSIVE DISORDERS relates to an important embodiment, this
invention concerns a method for detecting compulsive disorder
susceptibility of a human. The method comprises initially obtaining
a DNA sample of said human and then determining the presence or
absence of a particular human D2 receptor gene allele in said
sample. Detection of said allele in the sample is indicative of
susceptibility to compulsive disorder. A most preferred embodiment
is to detect a susceptibility to alcoholism and cocaine dependence,
particularly because said allele has been found to be present in a
majority of clinically diagnosed alcoholics and cocaine users. The
human D2 receptor gene A1 and Bi alleles are most preferably
detected in said sample.
[0037] 10. U.S. Pat. No. 5,550,021, issued Aug. 27, 1996, entitled
ALLELIC ASSOCIATION OF THE HUMAN DOPAMINE (D.about.) RECEPTOR GENE
IN COMPULSIVE DISORDERS SUCH AS ALCOHOLISM describes a method for
diagnosing compulsive disease predisposition of an individual. The
method comprises initially obtaining a DNA sample of said
individual and then determining the presence or absence of a
particular human D2 receptor gene allele in said sample. Detection
of said allele in the sample is indicative of predilection to
compulsive disease. A most preferred embodiment is to detect
predisposition to alcoholism, particularly because said allele has
been found to be present in a majority of clinically diagnosed
alcoholics. The human D2 receptor gene A1 allele is most preferably
detected in said sample.
RDS Genetic Treatment
[0038] 11. Li. U.S. Pat. No. 5,189,064, issued Feb. 23, 1993,
entitled TREATMENT OF COCAINE ADDICTION describes cocaine addiction
treated by administration of an endorphinase or enkephalinase
inhibitor, and optionally, a dopamine precursor, or a serotonin
precursor, a GABA precursor, or an endorphin or enkephalin
releaser. These components promote restoration of normal
neurotransmitter function and are non-addictive. Use of the
dopamine precursors L-phenylalanine or L-tyrosine, the
enkephalinase inhibitor D-patent opinion letters and infringement
judgement).
[0039] 12. U.S. Pat. No. 4,761,429, issued Aug. 2, 1988, entitled
ENKEPHALINASE AND ENDORPHINASE INHIBITORS AS ANTI-CRAVING
COMPOSITIONS, describes a new class of anti-craving compositions
provided by substances which inhibit breakdown of endogenous
substances such as enkephalins and/or endorphins. An anti-alcohol
craving effect is observed with an enkephalin breakdown inhibitor.
Specifically, D-phenylalanine, DL-phenylalanine, D-leucine,
DL-leucine, and hydrocinnamic acid, each an enkephalin breakdown
inhibitor, significantly lowered alcohol intake in animals and
humans. The anti-alcohol desire effect is observed in animals
genetically prone to choose alcohol over water solutions.
[0040] 13. A U.S. patent application filed Apr. 29, 1998, entitled
ALLELIC POLYGENE DIAGNOSIS OF REWARD DEFICIENCY SYNDROME AND
TREATMENT describes enhancement of attentional processing attained
by administration of an endorphinase inhibitor or enkephalinase
inhibitor and optionally, a dopamine precursor, or a serotonin
precursor, a GABA precursor, or an endorphin or enk ephalinase
releaser, or certain herbal compounds including rhodiola rosea
extract (pharmaline) and/or huperzine. These components promote
restoration of normal neurotransmitter function and the components
combined enhance the release of dopamine at the nucleus accumbens
and are non-addictive. Use of the dopamine precursors
L-phenylalanine, or L-Tyrosine, the enkephalinase inhibitor
D-phenylalanine, and/or the serotonin precursor-hydroxytryptophan
and a natural acetylcholenesterase inhibitor and chromium salts
(i.e. picolinate, nicotinate, etc.) is especially preferred, but
not limited to assist in relieving symptoms associated with brain
phenylalanine deficiency.
[0041] 14. A PCT Patent Application filed Apr. 29, 1998, entitled
ALLELIC POLYGENE DIAGNOSIS OF REWARD DEFICIENCY SYNDROME AND
TREATMENT, describes enhancement of attentional processing by
administration of an endorphinase inhibitor or enkephalinase
inhibitor and optionally, a dopamine precursor, or a serotonin
precursor, a GABA precursor, or an endorphin or enkephalinase
releaser, or certain herbal compounds including Rhodiola rosea
extract (Pharmaline) and/or Huperzine. These components promote
restoration of normal neurotransmitter function and the components
combined enhance the release of dopamine at the nucleus accumbens
and are non-addictive. Use of the dopamine precursors
L-phenylalanine, or L-Tyrosine, the enkephalinase inhibitor
D-phenylalanine, and/or the serotonin precursor-hydroxytryptophan
and a natural acetylcholenesterase inhibitor and chromium salts
(i.e. picolinate, nicotinate, etc.) is especially preferred, but
not limited to assist in relieving symptoms associated with brain
phenylalanine deficiency (See Table 4).
[0042] 15. A U.S. Provisional Patent filed Jan. 12, 1999, entitled
NEW CLASS OF ANTI-HYPERTENSIVE AGENTS INCLUDING INHIBITORS OF THE
BREAKDOWN OF ENKEPHALINS AND/OR ENDORPHINS, AND COMBINATIONS OF
SAID ANTI-HYPERTENSIVE AGENTS WITH OTHER ANTI-HYPERTENSIVE DRUGS
AND NATURAL SUBSTANCES, describes the invention involving the
combination of certain inhibitors of Endorphinase or Enkephalinase
or other related inhibitors of enzymes involved in the breakdown of
natural opioid peptides. These inhibitors could be from a group of
D-amino acids and their metabolites (i.e. D-phenylalanine,
Hydrocinnamic acid D-leucine, etc.) and other precursor
amino-acids, especially those which effect dopamine synthesis (i.e.
L-tyrosine) as well as herbal-based natural substances (fairylike
acid, pharmaline, hopers, hawthorn). The addition of chromium salts
(picolinate, nicotinate & poly nicotinate etc.) to promote a
reduced risk for diabetes, reduced cholesterol, and reduced blood
pressure will be most beneficial. Other important nutrients include
Co-enzyme Q and Pycnogenol and D-Ribose. The combination of D-amino
acids or other similar inhibitors of opioid peptidyl degradation
with known anti-hypertensive agents is also considered (See Table
2).
Synergene Nutralife System
[0043] Research into the potential market (See Table 5) prompted
the development of the exclusive SynerGene NutraLife
System.about.natural essentials, which specifically has been
designed to address health issues the natural way. In this regard,
people today are quite concerned with health and well being issues.
TABLE-US-00001 TABLE 5 Health Concerns and Incidence of Illnesses
Americans Concerned with General Well Being 271,800,000 Americans
Over Age 40 Concerned with 250,056,000 General Well Being Americans
Concerned with Mortality or Life 200,000,000 Expectancy Incidence
of Common Cold and Influenza 157,000,000 Americans Concerned with
Cognition/memory/ 92,000,000 focusing Incidence of Battling Obesity
or Being Overweight 91,000,000 Incidence of Hypertension 60,000,000
Incidence of Sexual Dysfunction 56,000,000 Incidence of Arthritis
35,000,000 Incidence of Adult Children of Alcoholics 28,000,000
[0044] Use of the products described herein to address what is
termed dysfunctions of the "The Brain Reward Cascade" through
precursor amino-acid therapy and inhibition of the enzymatic
breakdown of opioid peptides, such as the endogenous endorphins, is
essential to establishing well being and a healthy life-style. If
properly addressed, especially via natural ways, ultimately will
lead to a successful prescription which allows people to achieve
their life goal in better health through the SynerGene life style
change system termed SMART.about.(SynerGene Management Amino-Acid
Replacement Therapy). A principal of this unique approach is the
recognition that well being involves the interaction of both our
genes and the environment.
[0045] In this regard, this is entering a new phase in the search
for answers to the ancient questions: [0046] What causes diseases?
[0047] How can they be Prevented? [0048] How they can be cured?
[0049] The past century has seen breakthroughs that led to an
understanding of bacteria and infections; to extraordinary progress
in the technology of diagnostics and to the art of surgery; to a
new understanding of the role of emotion in disease states; to an
equally extraordinary expansion of the pharmacopeia; and to a new
understanding of the role of nutrition in brain function.
[0050] Now, we are approaching the most exciting period in the
history of the human science. On the one hand, we are watching the
efforts of researchers as they push the investigational envelop:
[0051] 1. viral infections responsible for afflictions such as AIDS
and certain of the cancers; [0052] 2. genetic anomalies that appear
to be determining factors in neurological diseases such as cystic
fibrosis, and impulsive-compulsive-addictive disorders we term
"Reward Deficiency Syndrome" and related behaviors. [0053] 3. the
design and synthesis of drugs that target specific receptor sites
and enzymes; [0054] 4. plants and organisms that manufacture
natural substances with therapeutic value. From earliest times
individuals and sometimes whole societies have self-medicated with
substances such as coca leaves, opium, and fermented sugars to
relieve their fears or discomforts. Now, scientists are carrying
out systematic searches in the forests and the oceans that will
enrich the pharmacopeia. CyberPharm scientists are watching the
development of a new orientation toward the interaction of brain,
emotion, and behavior that may affect us even more profoundly. As
in the years when we watched psychosomatic medicine clarifying the
role of emotions in a variety of illnesses, we are now beginning to
understand that genetic defects leading to deficiencies and
imbalances in neurotransmitters, enzymes, and receptors may give
rise to a wide range of behavioral disturbances. These somatic
syndromes constitute exciting new frontiers in prevention and
treatment of diseases or disorders.
[0055] Just as emotional and mental disturbances cause organic
disturbances leading to physical illness, so somatic
predispositions, deficiencies, or imbalances may cause emotional
and mental disturbances such as "Reward Deficiency Syndrome" (See
Table 6) and related behaviors but also anxiety, hostility,
depression, or reclusive or anti-social attitudes and responses.
TABLE-US-00002 TABLE 6 Reward Deficiency Syndrome Behaviors
Addictive Severe Polysubstance Nicotine Carbo- Behaviors Alcoholism
Abuse Dependence hydrate Bingeing Impulsive Attention Tourette
Autism Behaviors Deficit Disorder Hyperactivity Disorder Compulsive
Aberrant Pathological Behaviors Sexual Gambling Behavior
Personality Conduct Antisocial Aggressive Disorders Disorder
Personality Behavior
[0056] The inventor believes that behavioral as well as certain
physical anomalies may not be primary aberrations, but may
represent instead, the effort of the mind to adapt to the
consequences of defects in genes.
The SynerGene NutraLife SMART Composition
[0057] It is relevant to point out that claim 10 of U.S. Pat. No.
5,189,064, issued Feb. 23, 1993 essentially reads as follows:
A pharmaceutical composition which consists essentially of:
[0058] an opiate destruction-inhibiting amount of at least one
substance which inhibits enzymatic destruction of a neuropeptidyl
opiate, such as a substance being selected from the group
consisting of: [0059] 1 an amino acid [0060] 2 peptides [0061] 3
analogues or derivatives of (1) or (2) above, and a
neurotransmitter synthesis-promoting amount of at least one
neurotransmitter precursor selected from the group consisting of
the dopamine precursors--l-Tyr. I-Phe and I-dopa; the serotonin
precursors--I-Trp and 5-hydroxytryptophan; and the gamma amino
butyric acid (GABA) precursors-1-glutamine, I-glutamic acid, the
amount of said substance and said neurotransmitter precursor being
chosen so that the composition is effective in reducing the
subject's craving.
[0062] The SynerGene NutraLife Essentials have been designed by
utilizing a composition to affect brain chemistry through
amino-acid precursors and opioid peptide enzymatic breakdown
inhibitors and herbals and essential botanicals to promote a health
life style change.
[0063] It should be understood that the SMART blend, based on the
above referenced patent, is used in all the Neutraceutical
products. In this regard each product consists of a SMART blend
composition designed specifically for the disorder in question. The
neutraceuticals which contain a SMART blend include KRA vEx,
STIMEX, NicoEx, PMX and PROCOG. While Table 7 generally describes a
number of these essentials, specific details of a number of
products are presented emphasizing the rationale for basic
activity, animal and clinical research support and active
ingredient list, as well as benefits and features. TABLE-US-00003
TABLE 7 SynerGene .TM. Product Descriptions PRODUCT Type of
NAME.sup.1 Product PURPOSE NEUROTRANSMITTER MECHANISM Dorfamin
Neutraceutical Branded name of racemic formulation CyberPharm's
patented, branded combination of d- (CNS) of dl-phenylalanine
phenylalanine and l-phenylalanine which is the major constituent of
all neutraceuticals. KravEx.sup.2 Neutraceutical Reduces craving in
Severe Alcoholism Designed to increase activity of the opioid
peptide (CNS) system leading to dopamine release at the reward
site. Alcotox Neutraceutical Reduces withdrawal symptoms
Replenishes important electrolytes and enhances (CNS) of alcoholism
during acute phase neurotransmitter balance. of withdrawal
BodySynergy.sup.3 .TM. Neutraceutical Reduces craving in
Carbohydrate Designed to Stimulate the Brain Glucose Receptor (CNS)
Bingeing Leading to Dopamine Release at the Reward Site.
StimEx.sup.3,4 Neutraceutical Reduces craving in Crack/Cocaine
Designed to maintain normal neurotransmitter balance (CNS)
Dependence in brain reward sites while enhances the release of
Dopamine NicoEx.sup.3 .TM. Neutraceutical Reduce craving in
Nicotine Designed to Activate Both the Dopamine Reward Site (CNS)
Dependence and Smoking Behavior and the Anxiety Brain Site
including herbal calming essentials. GamboEx Neutraceutical Reduces
compulsive behavior in Designed to Work Through Serotonergic and
Opioid (CNS) Pathological Gambling Activation, the Neutraceutical
Will Enhance Dopamine Release into the Reward Site of the Brain.
PolyEx Neutraceutical Reduces drug craving and drug Designed to
maintain normal neurotransmitter balance (CNS) seeking behavior in
patients with in brain reward sites while enhances the release of
multiple addictions. Dopamine PMX .TM. Neutraceutical Relieves
symptoms of premenstrual During the luteal phase, PMX enhances the
neurotransmitter (CNS) stress or premenstrual pathways such as
serotonergic, opioidergic, dysphoric disorder GABAergic, and
catecholeminergic including herbal female support essentials.
ProCog .TM. Neutraceutical Attention Deficit Hyperactivity Designed
to Stimulate the D.sub.1 Receptor Sites. Similar to (CNS) Disorder
(ADHD) and Tourette's Ritalin but is Accomplished via Natural
Processes. Includes Disorder herbal cognitive essentials. ProFlex
Nutraceutical Reduces systemic pain, muscle Enhances opioid peptide
activity by inhibiting break- (PNS) and joint inflammation thereby
down of the opioids. Provides synergistic analgesic increasing
joint mobility and and anti-inflammatory properties by combining
dl- reducing pain in intractable pain Phenylalanine and ganoderma
lucidum and other herbs patients working through multiple
mechanisms including prostaglandins CardioPtex Nutraceutical Long
term reduction of high Enhances opioid peptide activity by
inhibiting break- (PNS) blood pressure without affecting down of
the opioids resulting in peripheral dopamine normal blood pressure
release. Includes natural cognitive enhancers and anti-
hypertensive agents. Stress-Ex Neutraceutical Reduces general
background Enhances opioid peptide activity by inhibiting break-
(CNS) stress, anxiety, and depression; down of the opioids
resulting in peripheral dopamine provides symptomatic treatment
release. May affect phenylethylamine activity. Includes of
posttraumatic stress disorder herbal calming essentials. ImunoPro
Nutraceutical Enhance Immune response Enhances opioid peptide
activity by inhibiting break- (PNS) down of the opioids resulting
in peripheral dopamine release including zinc complexes of
dl-Phenylalanine and other immune enhancing herbals. .sup.1Subject
to name search and registration .sup.2The used of our amino acid
formulation in "Alcostat" has resulted in a six fold reduction in
the number of patients leaving treatment Against Medical Advice, or
leaving treatment before completion. .sup.3The amino acid found in
"StimEx" is a patented neutraceutical of CyberPharm's called
Tropamine. Of all commonly used madications for the treatment of
cocaine addiction, Tropamine has been clinically determined to be
the most effective in preventing or reducing detoxification
symptoms. .sup.4The amino acid found in Tropamine has been found to
be the most effective of all commonly used medications for the
treatment of cocaine addiction in preventing relapse and in
providing maintenance after treament.
[0064] SynerGene NutraLife Essentials, Neutraceuticals, is a
selective grouping of products providing unique dietary supplements
comprised of SMART Blend and specific vitamins and minerals
formulated to support healthy brain chemistry balance which
promotes the normal physiological drives of hunger, drinking and
sex. The basic concept of this important category resides in the
understanding that impulsive-compulsive-addictive behaviors
constitute a very significant proportion of the world population.
In the United States alone there are 28 million adult children of
alcoholics, twenty-two million a alcoholics, fifty-four million
smokers, ninety-two million overeaters/obese, ten million cocaine
dependent persons, five to eight million young children with
attention deficit-hyperactivity (ADHD), over three million
pathological gamblers and millions of sex addicts. Over the last
three decades our understanding of this grave societal dilemma has
grown and today in the 90's we are in the decade of the brain.
Certainly, even more rapid advances will come before the
millennium. While the basic pharmacology, biochemistry,
neurochemistry, toxicology, and pharmacogenetics of abusable drugs
have not changed much over the years, the psycho-biology and
molecular genetic aspects of a new discipline known as Addiction
Medicine (supported by the American Medical association), have
significantly increased with better understanding of the meaning of
the addiction process in general.
[0065] One important outcome of the basic understanding of
addiction medicine is "Reward Deficiency Syndrome". In this term
scientists embrace the fact that addictive impulsive compulsive
behaviors including alcoholism, attention deficit disorder, drug
abuse, smoking behavior and food binging--may have a common genetic
root. The SynerGene NutraLife neutraceuticals were designed to
address this dilemma. The inventor foresees the possibility for
promoting a healthier life-style change in those victims carrying
the genetic predisposition to related "reward seeking"
behaviors.
[0066] Scientific evidence reveals the healing powers of
botanicals, herbals and amino-acids. These natural substances have
been associated with stress reduction, anti-hypertension,
enhancement of mood, improved immune response, stimulation of
sexual performance, increased focus and cognition, reduced
carbohydrate binging, and anti-craving action. Herbs and
phyto-medicines are experiencing explosive growth in pharmacies and
other mass-market retail outlets. An estimated 30 percent of
American adults (60 million persons) are reported to be using herbs
and phyto-medicinal products, spending an estimated $3.24 billion
in 1996 and much more in the years to follow. An excellent example
of the mainstream acceptance of well-researched herbs and
phyto-medicines can be seen in a huge increase in sales of St.
John's Wort, Ginko, Ginsing, Garlic, Echinacia and Saw Palmetto.
Granting herbs some legal protection as dietary supplements in the
United States, was clarified in the report from the senate
committee on Labor and Human Resources that accompanied Senate Bill
784, the HatchHarkin bill, eventually passed and became the
DSHEA.
[0067] The natural healing powers of many herbals and botanicals
have been known for thousands of years, and even more profound is
the understanding that brain endogenous mechanisms seed natural
healing processes leading to well being. Therefore, combining
nature's photo-medicines and amino-acid precursors to alter brain
chemistry (affect on the mind), contributes to a powerful healing
approach.
[0068] The SynerGene NutraLife Essentials meet established
standards for purity and all products are subject to testing
through rigorous quality-control methods.
[0069] Nutraceuticals are the category the products address
peripheral disorder that are still influenced by the brain but the
products are a combination of specific herbals and natural patented
substances having very specific uses which have end actions on
organs controlled by the peripheral nervous system. For example,
the uses of D-amino acids such as d-phenylalanine have analgesic
and anti-inflammatory actions as well as the use of water extracts
of gandermalucidum as an anti-inflammatory. Another example of
CyberPharm nutraceutical products involves the anti-hypertensive
properties of enkephalinase inhibitors including d-phenylalanine.
In the area of immune enhancement, CyberPharm has products
involving the combination of zinc-dlphenylalanine and herbals which
promote a positive immune response. The products in this category
include PRoFLEx, CARDIOPLEX, and MuNoPRo (See the Intellectual
Property Section above for a more detailed description of the
science and technology behind these products). The Neutraceutical
Product, KRAVEX, consists of amino-acid precursor amines, natural
enkephalinase inhibitors, minerals, vitamins trace metals, and
herbals. The product is designed to promote normal physiological
drive especially in individuals prone to addictive behavior of the
depressant kind. Based on a number of clinical trials (See Table
4), the KRAVEX essential is designed to affect abnormal cravings
for depressant type abusable substances such as alcohol,
barbiturates and benzodiazepine anti-anxiety agents. TABLE-US-00004
TABLE 4 SUMMARY OF COMPLETED CLINICAL STUDIES WITH 1899 L. L. C.
NEUTRACEUTICAL SUPPLEMENTATION A Literature Review DRUG ABUSED OR
SUPPLEMENT NO. OF NO. OF STUDY DYSFUNCTION USED PTS. DAYS TYPE
SIGNIFICANT RESULTS Alcohol SAAVE 22 28 TOIP 100 Percent Decrease
in BUD Deterification measures: reduction in Bhum. K. . MC.. :
reduction in withdrawn tremors after 12 hours: treatment of the
alcoholic as a reduction in depression international Bhum and
Treatment by SAAVE, 1 neuro Alcohol SAAVE 52 21 DBPCIP Reduction in
stress reaction as measured by SCL. produced Blum et al., 1989
improved physical sccre; six-loid decrease in improves in patient
treatment Poly-drugs after fue days placebo study of 5,491 Cocame
Tropamine 54 30 TOIP Drug hunger significantly reduced in patient
is taking SAAVE as compared to Blum et al 1988. Reduction controls
4.2 percent rate of polloris cn programmes 30 percent for of cocame
30 patients or SAAVE and 37 percent for controls. Tro. Curr. Th.
Alcohol SAAVE 60 379 TOCP At end of year over 50 percent of the
alcholic DUI offenders not using Bet al., 1990 Neuroc And And SAAVE
out of the program where less than 15 percent of those using Cocame
Tropamine SAAVE dropped out For the cocame abusers over 90 percent
of the Non- Troapamine group dropped out but less than 25 percent
Tropamine dropped out Over-Eating PCAL-103 27 90 TOP The PCAL - 33
group last an average at 27 pounds in 93 days compared with Blum et
al., 1990 "Neuro an average loss of C pounds for the control group.
Only 13.2 percent of the in an outpatient PCAL. 100 percent group
relacompared to 12 percent of the patients in the control group.
Over-Eating PCAL-103 247 730 PCOTCP After two years, craving and
eating were increased in group of Blum. K. CJG. Chem, patients on
PCAL-103 as compared to the control patients PCAL-103 group
Bravemar. ER. Bucel. LR. a regained to 7 percent of their lost
weight: compared with 41.7 percent weight Effectof PhenCal .TM.
regained in control patients. 2-year study. Cu Over-Eating Chromium
cci- 40 112 RDBPCGP 21 percent increase p < 0.001; in Rasling
Metapolic Rate (RMR). no change in K= R. et al. 1992. This is (CrP)
lean body (LSM), RMR LBM increased 25 percent (p < 0.001; Body
fat a plan of improved nutrion and increased approximately 5 and
reduction in serum who while Research 51: 261 L-camiene increasing
RIAR with no loss of LBM. Over-Eating Chromium 32 180 DBPC After
six months Crp group had increase of lean body mass and avoided
non- Bahadori. B. Habeack Picolinate OP fat alakaline weight loss.
Difference between groups was significant of p < 0.2001
"Treatment with chromium .- Weight reduction". Over-Eating Chromium
154 72 RDBPC 200 mcg avg 100 mcg of Crp brough: about significancs
charges in Body Kaars GR. Blun, K, Fisher- Picolinate OP
Composition indoes compared with placebo supplementation on
-controlled alloy. Curr Over-Eating Chromium 122 80 RDBPC After
controlling for differences in contents for expenditure and calonc
intake as Kaats. Gr. Slum, K, Plutin Picolinate OP compares with
placebo group. 400 mcg Crp groups loss significantly more weight
Double-masked, placebo-cont (p < 0.001) and body fat (0 =
0.004), had a greater reduction in percent body fat supplementation
on body pgm (p < 0.001) significantly improved Body Composition
Index (p = 0.004) research 59, 379- Over-Eating Chromium 122 90
RDBPC Measures of change in fat weight, charge n body weight,
percent change in Blum K, Kaats G, Eisenberg A, Picolinate OP
weight and body weight change in kgms all were significant: in
A.sub.PA.sub.P group and THJ Wood R. Duccl L. Woe non-significant
in the A,/A, and A,/A, carriers Induces Charges in Body Co Recector
A, Aleles. Submitted Over-Eating Chromium 3 53 ROTPC C-P
supplmentation resloved in significant weight gain, while exercise
training Grant KB. Chandler RM. Cas N colinate OP combined with GrN
supplementation rosulted ir significant weight and training: affect
on obese w Chromium lowered insulin response to art angl glucose
lose, Concluded high levels of CrP Medicine. 23:8 582-598.
Picolinate supplementation and contraundicated for weight loss in
young obese women. Comparison Moreover. results suggest thst
exercise training combined with CrN may be more beneficial than
exercises training alone for modification of certain CAD and NIDDM
risk factors. Healthy Volunteers Tropagen 15 30 DBPC Non supporting
subjects with Tropegon perfort act Deadler on computer memory . L,
Hyme. C,. Trac OP and performance tests as measured with P300 were
shorted potential. Changes attention processing by Ka in P200 wave
evolved potential result in better focusing n ADHD patients. 58-75
ABBREVIATIONS USED: Bud BLsieng us to ennk AMA Against Medical
Advice OP Outpatient MMPI Marine Muth-phase Personality Inventory
DB Double Blent IP Inpatient SOL Skin Conductance Level BESS
Behaviorl, aristocract, surgical, spritual DBPC Double Blird
Placebo-Controlled DUI Dnvirg uncor the influence R Randomized TO
Open Trial
[0070] Our brain chemistry could be compromised either at birth
through genetic variants and/or through environmental elements
resulting in an impaired Brain Reward Cascade and a
hypodopaminergic dysfunction. In fact it is important to realize
that as we get older we tend to lose dopamine function which leads
to craving behavior in our senior citizens. It is for this reason
that many of our older population abuse psychoactive prescription
medication (tranquilizers) and even alcohol. Because of this,
proper nourishment is essential for the health of brain function to
reduce aberrant cravings for certain substances like alcohol or
depressant drugs.
[0071] KRAVEX is a unique, scientifically advanced product that
provides a multi-nutritional approach to normal brain function. It
supplies your brain with a proprietary blend of amino-acids to
mimic the Brain Reward Cascade providing proper balance consisting
of chromium salts to enhance penetration of select precursor
amino-acids (tryptophan to assist in the synthesis of serotonin),
minerals, vitamins, riboflavin and folic acid to act as co-factors
for the production of neurotransmitters, and Kava Kava as a natural
calming substance, as well as both calcium and magnesium to
regulate neurotransmitter release, and Arctic root, known as
Rhodiola rosea (the Russian alpine plant) which promotes healthy
serotonergic and dopaminergic balance, thereby promoting balanced
mood. In this essential, arctic root extract is standardized to 1.0
percent rosavins and 1.0 percent salidrsides. TABLE-US-00005 TABLE
8 BENEFITS FEATURES Formulated to Increase Well Being.* Features
Patented Blend of Amino-acids. Helps Your Body to Adjust to Stress*
Contains Chromium with Active Compounds Such as Riboflavin,
Pantothenic Acid, and Cyanocobalamin. Designed to Balance the
Includes Such Herbals as Kava Kava and Rhodiola Rosea. "Brain
Reward Cascade"* a Russian Alpine Plant with Neurotransmitter
Balancing Activity. Induces the Brain to Have Normal Includes
Patented Natural Endorphin Enhancers. Physiological Urges* Reduces
Craving for Depressant-like Consists of Calcium and Magnesium for
Proper Dopamine Substances* Release. *These statements have not
been evaluated by the Food and Drug Administration. This product is
not intended to diagnose, treat, cure or proven; disease.
[0072] In terms of craving behavior each product developed will
address a specific type of craving. In this regard, KRAVEx, has
been designed to effect addiction to depressant-like drugs such as
alcohol, barbiturates and tranquilizers. The basic pharmacological
principal, is like treats like. Therefore, the ingredients found in
this neutraceutical promotes a feeling of calm and increased well
being. In general, since deficits have been found in brain chemical
functions underlying craving behavior, and since these deficits may
be alleviated by facilitated dopamine release consequent to the use
of drugs such as alcohol, combining amino-acid precursors and
enkephalinase inhibition may simulate the brain's reward system and
compensate for neurotransmitter imbalance (thereby attenuating
craving behavior). In an attempt to understand that depressant-drug
abuse seeking behavior (craving), is a subset of generalized
craving behavior (Reward Deficiency Syndrome), due in part to low
dopamine function (an impaired reward cascade), scientists believe
individuals self-heal through biochemical attempts to alleviate the
low dopaminergic brain activity via drug (alcohol)-reward site
interaction. Since the brain is made up of 200 billion cells and
these cells require good nutrition, which includes minerals,
vitamins, trace metals and amino acids, this neutraceutical
provides these important elements in a special brain stabilizing
blend along with ancient calming herbals (benzodiazepinelike) which
together reduce craving and enhances well being.
[0073] Nutritional Information TABLE-US-00006 TABLE 9 Supplement
Facts Serving Size: 1 Caplet Servings Per Container: 90 Amount per
Serving % Daily Value Blend + Arctic Root Extract (Rhodiola Rosea)
300 mg + Standardized to 1.0% Rosavins, 25 mg Standarized to 1.0%
Salidrosaides Kava Kava (Root) 90 mg + German Chamomile (Flower
Heads) + Hops (Strobiles) + + Minimum Daily Requirements not
established for this ingredient. Important Notes: Do not take this
product if you are pregnant or nursing, if you are taking an MAO
inhibitor type anti-depressant or if you are known to have PKU. Do
not exceed the recommended dose except under the supervision of a
physician. Do not use with other substances that cause drowsiness
(alcohol). Use caution when operating a motor vehicle or machinery.
If you are under a physician's # care or taking medication, consult
your health care practitioner.
[0074] It is important to realize that each product consists of the
SMART.about.Blend, (See Table 10). TABLE-US-00007 TABLE 10 SMART
.TM. Blend Composition in KravEx .TM. and Rationale for Use
(Amounts are for a daily dose of six Caplets) Restorative
Ingredient Amount Action Mechanism Behavioral Change
d-Phenylalanine 750 mg. Enkephalins Enzyme Inhibition Anti-Craving
Anti-Depression l-Phenylalanine 750 mg. Dopamine Precursor Loading
Reward Norepinephrine Anti-Depression l-5-Hydroxytryptophan 20 mg.
Serotonin Precursor Loading Anti-Craving Anti-Depression
Anti-Insomnia l-Glutamine 300 mg. GABA Precursor Loading
Anti-Craving Anti-Stress Vitamin B Complex Neurotransmitter
Synthesis Enzyme Co-Factor in Neurotransmitter Facilitates Action
of Neuro- Synthesis transmitter Thiamin HCL 100 Mg. Vitamin B
Enzyme Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Riboflavin 15 mg. Vitamin B.sub.2 Enzyme
Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Niacinamide 100 mg. Vitamin B.sub.3 Enzyme
Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Pantothenic Acid 90 mg. Vitamin B.sub.5
Enzyme Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Pyridoxal-5-phosphate 20 mg. Vitamin B.sub.5
Active Metabolite Promotes Gastrointestinal Facilitates Action of
Neuro- Absorption of Amino Acids transmitter Cyanocobalamin 6
.mu.g. Facilitates Action of Neuro- transmitter Ascorbate (Calcium)
750 mg. Neurotransmitter Synthesis Enzyme Co-Factor Facilitates
Action of Neuro- transmitter Folic Acid 400 .mu.g. Neurotransmitter
Synthesis Enzyme Co-Factor Facilitates Action of Neuro- transmitter
Zinc (Chelate) 30 mg. Neurotransmitter Syntheis Enzyme Co-Factor
Facilitates Action of Neuro- transmitter Calcium (Chelate) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Facilitates Action of
Neuro- Modulator Release transmitter Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Facilitates Action of Neuro- Modulator Brain Penetration
transmitter
[0075] STIMEX consists of amino-acid precursor amines, natural
enkephalinase inhibitors, minerals, vitamins trace metals, and
herbals. The product is designed to promote normal physiological
drive especially in individuals prone to addictive behavior of the
stimulant kind. Based on a number of clinical trials (See Table 4)
the STIMEX essential is designed to affect abnormal cravings for
stimulant-like drugs (i.e. cocaine).
[0076] Our brain chemistry can be compromised either at birth
through genetic variants and/or through environmental elements
resulting in an impaired Brain Reward Cascade and a
hypodopaminergic dysfunction. It is well known that low dopamine
function induces aberrant cocaine-seeking behavior in both animals
and humans. Blocking dopamine receptors with specific dopamine type
2 receptor antagonists has been shown to induce abnormal cravings
for stimulant-like drugs such amphetamines and cocaine. In the
February 1999 issue of the American Journal of Psychiatry (1999) it
was reported that chronic cocaine abusers have a low number of
total dopamine nerve terminals and a high number of cocaine
metabolizing sites (dopamine transporter binding sites). These
dopaminergic abnormalities contribute to cocaine craving
behavior.
[0077] Because of this, proper nourishment is essential for the
health of brain function to reduce aberrant cravings for substances
that release dopamine from the neurons in the reward sites of the
brain such as certain stimulants like cocaine. STIMEX is a unique,
scientifically advanced product that provides a multi-nutritional
approach to normal brain function. The product supplies your brain
with a proprietary blend of amino-acids to mimic the reward cascade
providing proper balance, chromium salts to enhance penetration of
select precursor amino-acids (tryptophan to assist in the synthesis
of serotonin) minerals, vitamins, riboflavin and folic acid to act
as co-factors for the production of neurotransmitters, certain
stimulant type herbals--Ginger Root, Siberian Ginsing Root, and a
mood enhancer proprietary blend (Gotu Kola Leaf, Cola Nut, and
Mate) as well as both calcium and magnesium to regulate
neurotransmitter release, and Fairylike acid, a natural substance
which promotes brain chemistry balance by its action on the
serotonergic, opioid peptidergic (Endorphins) and dopaminergic
pathways. TABLE-US-00008 TABLE 11 BENEFITS FEATURES Formulated to
Increase Well Being.* Features Patented Blend of Amino-acids. Helps
Your Body to Adjust to Stress* Contains Chromium with Active
Compounds Such as Riboflavin, Pantothenic Acid, and Cyanocobalamin.
Designed to Balance the Includes such herbals as Ferrulic acid,
Ginsing, Ginger, Cola "Brain Reward Cascade"* Nut, Mate, and Gotu
Kola Induces the Brain to Have Normal Includes Patented Natural
Endorphin Enhancers. Physiological Urges* Reduces Craving for
Stimulant-like Consists of Calcium and Magnesium for Proper
Dopamine Substances* Release. *These statements have not been
evaluated by the Food and Drug Administration. This product is not
intended to diagnose, treat, cure or prevent disease.
[0078] STIMEX is designed to affect addiction to stimulant-like
drugs such as cocaine, amphetamines, caffeine The basic
pharmacological principal, is like treats like. Therefore, the
ingredients found this addiction essential promotes a feeling of
well being. In general, since deficits have ben found in brain
chemical functions underlying craving behavior, and since these
deficits may be activated by facilitated dopamine release
consequent to the use of stimulant-type drugs like cocaine and
amphetamines, combining amino acid precursors and enkephalinase
inhibition may simulate the brain's reward system and compensate
for neurotransmitter imbalance (thereby attenuating craving
behavior). It is now understood that stimulant-like drugs induce
dopamine release in the reward sites of the brain and stimulant
drug seeking behavior (craving) is a subset of generalized craving
behavior ("Reward Deficiency Syndrome"), due in part to low
dopamine function (an impaired cascade). Scientists believe that,
for example cocaine addicts, self-heal through biochemical attempts
to alleviate the low dopaminergic brain activity via cocaine-reward
site interaction. Since the brain is made up of 200 billion cells
and these cells require good nutrition, which includes minerals,
vitamins, trace metals and amino acids, this addiction-essential
provides these important elements in a special brain stabilizing
blend along with well-being enhancer herbals (dopaminergic-like)
which reduces craving for stimulants by enhancing dopaminergic
function through natural replacement therapy.
[0079] Nutritional Information TABLE-US-00009 TABLE 12 Supplement
Facts Serving Size: 1 Caplet Servings Per Container: 90 Amount per
Serving % Daily Value Blend + Methionine 60 mg + Octacosinol 2 mg +
Stim Blend 75 mg Ginger Root + Siberian Ginsing + Mood Enhancer
Blend 200 mg Gotu Kola Leaf + Cola Nut + Mate Folium + Ferulic Acid
50 mg + + Minimum Daily Requirements not established for this
ingredient. Important Notes: Do not take this product if you are
pregnant or nursing, if you are taking an MAO inhibitor type
anti-depressant or if you are known to have PKU. Do not exceed the
recommended dose except under the supervision of a physician.
Reduce intake of caffeine if you are under a physician's care or
taking medication, consult your health care practitioner.
[0080] It is important to realize that each product consists of the
SMART blend, which varies with each specific product (See Table
13). TABLE-US-00010 TABLE 13 SMART .TM. Blend Composition in StimEx
.TM. and Rationale for Use (Amounts are for a daily dose of six
Caplets) Restorative Ingredient Amount Action Mechanism Behavioral
Change d-Phenylalanine 750 mg. Enkephalins Enzyme Inhibition
Anti-Craving Anti-Depression l-Phenylalanine 750 mg. Dopamine
Precursor Loading Reward Norepinephrine Anti-Depression l-Tyrosine
900 mg. Dopamine Precursor Loading Reward Norepinephrine
Anti-Depression Anti-Stress l-5-Hydroxytryptophan 20 mg. Serotonin
Precursor Loading Anti-Craving Anti-Depression Anti-Insomnia
l-Glutamine 300 mg. GABA Precursor Loading Anti-Craving Anti-Stress
Vitamin B Complex Neurotransmitter Synthesis Enzyme Co-Factor in
Neurotransmitter Facilitates Action of Neuro- Synthesis transmitter
Thiamin HCL 100 Mg. Vitamin B Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Riboflavin 15
mg. Vitamin B.sub.2 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Niacinamide 100
mg. Vitamin B.sub.3 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Pantothenic Acid
90 mg. Vitamin B.sub.5 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter
Pyridoxal-5-phosphate 20 mg. Vitamin B.sub.4 Active Metabolite
Promotes Gastrointestinal Facilitates Action of Neuro- Absorption
of Amino Acids transmitter Cyanocobalamin 6 .mu.g. Facilitates
Action of Neuro- transmitter Ascorbate (Calcium) 600 mg.
Neurotransmitter Synthesis Enzyme Co-Factor Facilitates Action of
Neuro- transmitter Folic Acid 400 .mu.g. Neurotransmitter Synthesis
Enzyme Co-Factor Facilitates Action of Neuro- transmitter Zinc
(Chelate) 30 mg. Neurotransmitter Syntheis Enzyme Co-Factor
Facilitates Action of Neuro- transmitter Calcium (Chelate) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Facilitates Action of
Neuro- Modulator Release transmitter Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Facilitates Action of Neuro- Modulator Brain Penetration
transmitter
[0081] NICOEX consists of amino-acid precursor amines, natural
enkephalinase inhibitors, minerals, vitamins trace metals, and
herbals. The product is designed to promote normal physiologic
drive especially in individuals prone to addiction to nicotine.
[0082] While there is a paucity of research with regard to NICOEX,
in contrast, there are a number of clinical trials with regard to
the Addiction-Essential Blend and alcoholism (See Table 4).
Scientists are in agreement that both nicotine and alcohol commonly
induce the release of dopamine from reward site neurons. In fact,
there is strong evidence that the increase in dopamine levels in
the brain reward site (n. accumbens) produced by alcohol is
mediated by nicotinic receptors. In the February 1999 issue of
Alcohol it was reported that alterations in the nicotinic system
affects alcohol self-administration in animals. Taken together this
suggests that since the neutraceutical was quite effective in
reducing alcohol craving then other dopamine releasing drugs like
nicotine also would be similarly affected. Because of this, proper
nourishment is essential for the health of brain function to reduce
aberrant cravings for substances that release dopamine from the
neurons in the reward sites of the brain such as nicotine.
[0083] NICOEX is a unique, scientifically advanced product that
provides a multi-nutritional approach to normal brain function. The
product supplies your brain with a proprietary blend of amino-acids
to mimic the Brain Reward Cascade providing proper balance,
chromium salts to enhance penetration of select precursor
amino-acids (tryptophan to assist in the synthesis of serotonin),
minerals, vitamins, riboflavin and folic acid to act as co-factors
for the production of neurotransmitters, certain calming
herbals-Ashwagandha Root Extract, Valerian Root Extract, Kava Kava
(root), Chamomile (flower-head), and Hops (strobiles). Other
ingredients include Lecithin, and Beta-Carotene. This essential
could be part of a NicoEx Quit Kit which will be comprised of a
Life Style Change Plan, and a specially designed anti-nicotine
cigarette filter using an ion exchange resin. The kit also could
include a homeopathic quit smoking blend. TABLE-US-00011 TABLE 14
BENEFITS FEATURES Formulated to reduce nicotine craving* Features
Patented Blend of Amino-acids. Helps Your Body to Adjust to Stress*
Contains Chromium with Active Compounds Such as Riboflavin,
Pantothenic Acid, Cyanocobalamin, Lecithin, and Beta-Carotene.
Designed to Re-Balance the Includes such herbals as Ashwaganda
Root, Valerian Root, "Brain Reward Cascade"* Kava Kava, and
Charmomile Induces the Brain to Have Normal Includes Patented
Natural Endorphin Enhancers. Physiological Urges* Designed to
Offset Weight Gain from Consists of Calcium and Magnesium for
Proper Dopamine Smoking Withdrawal* Release. Formulated to Increase
a Sense of Includes Ascorbic Acid to Assist in Withdrawal Well
Being* *These statements have not been evaluated by the Food and
Drug Administration. This product is not intended to diagnose,
treat, cure or prevent disease.
[0084] Smoking involves far more than physical addiction to
nicotine. The road to stop smoking is not simply a matter of "just
saying no". Similar to other addictive substances(i.e. alcohol,
cocaine, glucose etc.), the most successful approach is to bring
about a life-style change. The SMART approach to quitting corrects
nutritional deficits and emphasizes improved nutritional intake,
exercise and behaviors that will help the smoker become smoke-free.
As a smoker, the body constantly is being robbed of vital
nutrients. Moreover, the 54 million smokers are not only placing
their bodies under the influence of stress-inducing substances like
nicotine, but may indeed be more genetically prone to overreact
toward stressful events. This is based on a number of reports
linking one variant of the dopamine D2 receptor gene to smoking
behavior. This same variant has been linked to alcoholism,
carbohydrate binging, cocaine dependence, pathological gambling and
an inability to cope with stress. In this regard, nicotine is known
to release dopamine from neurons in the brain reward site and this
effect is paramount to its addictive qualities. Scientists believe
that nicotine dependent persons, self-heal through biochemical
attempts to alleviate the low dopaminergic brain activity via
nicotine-reward site interaction. Stress is an inescapable element
in life which can negatively impact your health and is linked to
many disorders such as substance abuse, cancer, cardiovascular
disorders, headaches, ulcers, weakened immune response as well as
other health problems. It is noteworthy, that abuse of nicotine via
smoking is linked to stress and smoking behavior leads to poor
nutrition. Since the brain is made up of 200 billion cells and
these cells require good nutrition, which includes minerals,
vitamins trace metals, and amino acids, this addiction-essential
provides these important elements in a special natural calming
blend along with the anti-craving composition which reduces craving
for nicotine by enhancing dopaminergic function through natural
replacement therapy.
[0085] Nutritional Information TABLE-US-00012 TABLE 15 Supplement
Facts Serving Size: 1 Caplet Servings Per Container: 90 Amount per
Serving % Daily Value Blend + Lecithin 120 mg + Beta Carotine
25,000 I.U. 500 Ashwaganha Root Extract 200 mg + Standarized to
1.5% Withanolides, 3 mg Standarized to 1% Alkaloids, 2 mg Valerian
Root Extract 67 mg + Standardized to 0.8% Valeranic Acid, 0.5 mg
Calming Blend 133 mg + Kava Kava (root) + German Chamomile
(flower-head) + Hops (strobiles) + + Minimum Daily Requirements not
established for this ingredient. Important Notes: Do not take this
product if you are pregnant or nursing, if you are taking an MAO
inhibitor type anti-depressant or if you are known to have PKU. Do
not exceed the recommended dose except under the supervision of a
physician. Do not use with other substances that cause drowsiness
(alcohol). Use caution when operating a motor vehicle or machinery.
If you are under a physician's care or taking medication, consult
your health care practitioner.
[0086] It is important to realize that each product consists of the
SMART Blend, which varies slightly with each specific product (See
Table 16). TABLE-US-00013 TABLE 16 SMART .TM. Blend Composition in
NicoEx .TM. and Rationale for Use (Amounts are for a daily dose of
six Caplets) Restorative Ingredient Amount Action Mechanism
Behavioral Change d-Phenylalanine 750 mg. Enkephalins Enzyme
Inhibition Anti-Craving Anti-Depression t-Phenylalanine 750 mg.
Dopamine Precursor Loading Reward Norepinephrine Anti-Depression
t-Tyrosine 750 mg. Dopamine Precursor Loading Reward Norepinephrine
Anti-Depression Anti-Stress t-5-Hydroxytryptophan 20 mg. Serotonin
Precursor Loading Anti-Craving Anti-Depression Anti-Insomnia
t-Glutamine 400 mg. GABA Precursor Loading Anti-Craving Anti-Stress
Vitamin B Complex Neurotransmitter Synthesis Enzyme Co-Factor in
Neurotransmitter Facilitates Action of Neuro- Synthesis transmitter
Thiamin HCL 100 Mg. Vitamin B Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Riboflavin 15
mg. Vitamin B.sub.2 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Niacinamide 100
mg. Vitamin B.sub.3 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Pantothenic Acid
90 mg. Vitamin B.sub.5 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter
Pyridoxal-5-phosphate 20 mg. Vitamin B.sub.5 Active Metabolite
Promoters Gastrointestinal Facilitates Action of Neuro- Absorption
of Amino Acids transmitter Cyanocobalamin 5 .mu.g. Facilitates
Action of Neuro- transmitter Ascorbate (Calcium) 500 mg.
Neurotransmitter Synthesis Enzymes Co-Factor Facilitates Action of
Neuro- transmitter Folic Acid 600 .mu.g. Neurotransmitter Synthesis
Enzymes Co-Factor Facilitates Action of Neuro- transmitter Zinc
(Chelate) 30 mg. Neurotransmitter Synthesis Enzymes Co-Factor
Facilitates Action of Neuro- transmitter Calcium (Chelate) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Facilitates Action of
Neuro- Modulator Release transmitter Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Facilitates Action of Neuro- Modulator Brain Penetration
transmitter
[0087] PMX consists of amino-acid precursor monoamines, natural
enkephalinase inhibitors, minerals, vitamins, trace metals, and
herbals. The product is designed to promote normal physiologic
drive especially in individuals prone to Premenstrual Dysphoric
Disorder (PMDD). a premenstrual mood disorder that recurs
cyclically during the majority of menstrual cycles.
[0088] While there is a paucity of research with regard to PMX in
contrast there are number of clinical trials with regards to the
neutraceutical and "Reward Deficiency Syndrome" and related
behaviors (See Table 4). It is noteworthy, a former product known
as SAAVE, in which over 100,000 female alcoholics used to reduce
craving, many reported attenuation of PMDD symptoms. The scientific
basis for this effect resides in the affect PMX will have on the
brain's "Brain Reward Cascade". The four pathways involved include
Serotonergic, Opioidergic (endorphins), GABAergic and Adrenergic.
In women with severe premenstrual dysphoria it was found that
compared with asymptomatic controls, symptomatic women have lower
levels of serotonin. It also has been found that during the luteal
phase platelet serotonin uptake is decreased with PMDD as compared
to controls. In addition, depleting the serotonin precursor
tryptophan is significantly more likely to provoke premenstrual
symptoms during both luteal and follicular phases in PMDD patients
compared to asymptomatic women. In four studies it was found that
lower luteal phase Beta-endorphin levels in symptomatic patients
compared with controls. More over, during the premenstrual period,
levels of both endorphin and estrogen change rapidly and there are
reports that narcotic antagonists reduce PMDD symptoms. Others have
found decreases in plasma gamma-aminobutyric acid levels during the
luteal phase in women with PMDD symptoms. Recently, it was found
that plasma methionine-enkephalin and a decrease in plasma
norepinephrine levels on day 22 in menstrual migraine group and an
increase in plasma methionine, norepinephrine during pain.
Moreover, while the above biological evidence does not definitively
implicate any single, neurobiological system, changes in serotonin
levels, endorphinergic activity, GABA levels and adrenergic binding
activity, suggest neurobiological abnormalities associated with an
impaired "Brain Reward Cascade" and subsequent expression of PMD.
Because there is no single-neurotransmitter involved but instead it
is a multi-neurotransmitter phenomenon, proper nourishment is
essential for the health of brain function to reduce PMDD
expression.
[0089] PMX is a unique, scientifically advanced product that
provides a multi-nutritional approach to normal brain function. The
product supplies your body with a patented blend of amino-acids to
mimic the reward cascade providing proper balance, chromium salts
to enhance penetration of select precursor amino-acid (tryptophan
to assist in the synthesis of serotonin), minerals, vitamins,
riboflavin and folic acid to act as co-factors for the production
of neurotransmitters, certain natural patented pain
killers-d-phenylalanine (See U.S. Pat. No. 4,687,781) and
belladonna, a natural anti-anxiety blend--passionflower, hops, and,
Female Support Blend-black cohash root, chaste tree fruit,
ipriflavone, and natural anti-spasmotics-peppermint leaf, Scopolia
root, and licorice root. In the largest study ever conducted on
PMDD, patients administered 1200 mg of calcium reported symptoms at
a rate of fifty percent of those patients on the placebo.
TABLE-US-00014 TABLE 17 BENEFITS FEATURES Formulated to reduce PMDD
and PMS Symptoms* Features Patented Blend of Amino-acids. Helps
Your Body to Adjust to Stress* Includes Patented Natural Pain
Killer Designed to Re-Balance the "Brain Reward Cascade"* Includes
Patented Natural Endorphin Enhancers. Helps Your Body to Reduce
Pain, and Elevate Mood* Contains Chromium with Active Compounds
Such as Riboflavin, Pantothenic Acid, Cyanocobalamin, Calcium and
Magnesium for Both Co-factors and Neurotransmitter Release.
Formulated to Enhance a Sense of Well Being* Consists of
Anti-anxiery, Anti-spasmodic and Female Support Blends. *These
statements have not been evaluated by the Food and Drug
Administration. This product is not intended to diagnose, treat,
cure or prevent disease. SYNOPSIS
These statements have not been evaluated by the Food and Drug
Administration. This product is not intended to diagnose, treat,
cure or prevent disease.
[0090] Premenstrual Dysphoric Disorder (PMDD) is a premenstrual
mood disorder that recurs cyclically during the majority of
menstrual cycles. It is included under the category of Depressive
Disorders not otherwise specified in the American Psychiatric
Association's DSM-IV. However, a number of factors (biological and
cognitive treatment responses) differentiate PMDD from other mood
disorders. Despite the predictability of luteal phase symptom
expression, the etiology of this disorder has not been established.
Theories regarding hormonal and vitamin deficiencies have been
associated with PMDD. Moreover, neither absolute nor relative
deficits of progesterone, estrogen, prostaglandin, insulin, vitamin
B6 or thyroid hormone have been established in patient groups with
PMDD.
[0091] It is noteworthy, that certain drugs have been used to treat
PMDD such as antidepressants (clonipramine, fluoxitine, buprion,
paroxetine, maprotiline, sertraline, and fenfluramine). Most
scientists would agree that one-single drug with only limited
effects on one single or possibly even two individual
neurotransmitters is insufficient to overcome the abnormal state of
the "reward" system which occurs by hormonal shifts in the female
pre-, during, and post-menstrual phase. There is enough literature
to indicate that the function of four neurotransmitter pathways
(serotonergic, opioidergic, GABAergic, and adrenergic) have been
associated with PMDD and related symptoms.
[0092] Therefore, the SMART approach will influence the "Brain
Reward Cascade" causing neurotransmitter release which induces an
enhanced well being. Moreover, the combination of providing pain
relief, anti-spasmodic, anti-anxiety herbal blends will have
significant impact on effecting symptoms associated with PMDD. For
up to 10 days each month, some 25 million women suffer from
bloating, cramping, moodiness, breast tenderness, migraines, acne
and food cravings. TABLE-US-00015 TABLE 18 Supplement Facts Serving
Size: 1 Caplet Servings Per Container: 90 Amount per Serving %
Daily Value Blend Dandelion root 35 mg + Belladonna root 50 mg +
Standardized to 0.125 mg total alkaloids, calculated as
hyoscyamine. Calming Blend 150 mg Passionflower (passiflorae) +
Hops (strobile) + German Chamomile (flower heads) + Female Support
Blend 100 mg Black Cohash (root) + Chaste Tree Fruit + Ipriflavone
+ Anti-Spasmotic Blend Peppermint leaf 50 mg + Scopolia root +
Stanardized to 0.1 mg total alkaloids calculated as hyoscyamine
Licorice root (equivalent to 25 mg glycyrrhizin) + + Minimum Daily
Requirements not established for this ingredient. Important Notes:
Do not take this product if you are nursing, if you are taking an
MAO inhibitor type anti-depressant or if you are known to have PKU.
Do not exceed the recommended dose except under the supervision of
a physician. Do not use with other substances that cause drowsiness
(alcohol). Use caution when operating a motor vehicle or machinery.
If you are under a physician's care or taking medication, consult
your health care practitioner.
[0093] It is important to realize that each consists of the SMART
Blend, which varies slightly with each specific essential (See
Table 19). Below is the recommended formulation of the supplement
for PMS and PMDD; however, this basic formulation can be modified
by the selective addition of Cramp Bark (A Muscle Relaxant),
Lavender Oil (A Topical Analgesic and Muscle Relaxant); Vitex (A
Hormone Balancer That Stimulates Production of Progesterone to
Alleviate Breast Tenderness, Mood Swings, Food Cravings, Acne, and
Constipation); Valerian Root (A Sedative Which Relaxes Muscles and
Reduces Anxiety and Moodiness Through Depressing the Central
Nervous System); Devil's Club (Eliminates Irritability, Fatigue,
and Headaches), Dong Qual (relieves menstrual cramping, Evening
Primrose (reduces breast tenderness), Flaxseed (reduces menstrual
bleeding). TABLE-US-00016 TABLE 19 SMART .TM. Blend Composition in
PMX .TM. and Rationale for Use (Amounts are for a daily dose of six
Caplets) Restorative Ingredient Amount Action Mechanism Behavioral
Change d-Phenylalanine 750 mg. Enkephalins Enzyme Inhibition
Anti-Craving Anti-Depression t-Phenylalanine 750 mg. Dopamine
Precursor Loading Reward Norepinephrine Anti-Depression
t-5-Hydroxytryptophan 20 mg. Serotonin Precursor Loading
Anti-Craving Anti-Depression Anti-Insomnia t-Glutamine 500 mg. GABA
Precursor Loading Anti-Craving Anti-Stress Vitamin B Complex
Neurotransmitter Synthesis Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Thiamin HCL 100
Mg. Vitamin B Enzyme Co-Factor in Neurotransmitter Facilitates
Action of Neuro- Synthesis transmitter Riboflavin 15 mg. Vitamin
B.sub.2 Enzyme Co-Factor in Neurotransmitter Facilitates Action of
Neuro- Synthesis transmitter Niacinamide 100 mg. Vitamin B.sub.3
Enzyme Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Pantothenic Acid 90 mg. Vitamin B.sub.5
Enzyme Co-Factor in Neurotransmitter Facilitates Action of Neuro-
Synthesis transmitter Pyridoxal-5-phosphate 20 mg. Vitamin B.sub.5
Active Metabolite Promotes Gastrointestinal Facilitates Action of
Neuro- Absorption of Amino Acids transmitter Cyanocabalamin 6
.mu.g. Facilitates Action of Neuro- transmitter Ascorbate (Calcium)
750 mg. Neurotransmitter Synthesis Enzyme Co-Factor Facilitates
Action of Neuro- transmitter Folic Acid 400 .mu.g. Neurotransmitter
Synthesis Enzyme Co-Factor Facilitates Action of Neuro- transmitter
Zinc (Chelate) 30 mg. Neurotransmitter Synthesis Enzyme Co-Factor
Facilitates Action of Neuro- transmitter Calcium (Chelate) 1200 mg.
Neurotransmitter Regulates Neuro-transmitter Facilitates Action of
Neuro- Modulator Release transmitter Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Facilitates Action of Neuro- Modulator Brain Penetration
transmitter
[0094] PROCOG consists of amino-acid precursor monoamines, natural
enkephalinase inhibitors, minerals, vitamins, trace metals and
herbals. The product is designed to promote normal physiological
drive, enhance focus and memory and bring about normal behavioral
activity in inattentive, compulsive hyperactive individuals.
[0095] There is clinical evidence that the neutraceutical PROCOG
significantly enhances cognitive event-related potentials
associated with performance. In fact, in young adult healthy
volunteers the SMART Blend amino-acid composition enhanced visual
attention tasks, spacial orientation, contingent continuous
performance and P300 wave magnitude and latency. In terms of
cognition, it is well known that brain electrical activity analysis
has revealed the existence of subtle neurological change in a wide
variety of disorders including depressions, criminal pathology,
Alzheimers, auto-immune-deficiency syndrome (AIDS), drug addictions
and attention deficit hyperactivity disorder (ADHD). With regard to
the latter, a study in the early 70's showed that a major
ingredient in PROCOG, dl-phenylalanine, a natural enhancer of
opioid peptides (endorphins), by preventing the breakdown of these
biologically active peptides, increased the mood and reduced
anxiety in subjects diagnosed with ADHD.
[0096] Our brain is an intricate organ that controls every thought,
every move and every gesture we make moment by moment. In order to
carry out these complex functions the brain depends on oxygen.
Oxygen is vital for nerve cells to properly transmit chemical
messengers. It is noteworthy, that experiments in swine, provide
evidence that the natural opioid methionine-enkephalin when
administered to the swine resulted in enhancement of blood flow in
specific brain sites especially in the basal ganglia, frontal
cortex, and hippocampus, important reinforcement and memory sites.
It is logical that increases of the neurotransmitter enkephalin, by
inhibition of the enzyme enkephalinase, would augment brain
oxygenation via increased blood flow.
[0097] It also is important to point out that cognition is
associated with the chemical messenger dopamine. Recent human
studies reveal substances such as bromocriptine, that mimic
dopamine at its receptor sites, increase short term memory. In this
regard, the neutraceutical provides the brain with precursor
amino-acids leading to the release of dopamine in the reward site.
The product supplies your body with a patented blend of amino-acids
to mimic the reward cascade providing proper balance, chromium
salts to enhance penetration of select precursor amino-acid
(tryptophan to assist in the synthesis of serotonin), minerals,
vitamins, riboflavin, and folic acid to act as co-factors for the
production of neurotransmitters, a natural patented enhancer of
brain blood flow, d-phenylalanine (See U.S. Patent Pending and PCT
application) and certain herbals that effect cognition including;
huperzine, bacopa monalera, ginko biloba, ginsing, gotu kola,
ferulic acid, and rhodiola rosea extract promotes mental sharpness
and alertness. TABLE-US-00017 TABLE 20 BENEFITS FEATURES Improves
Circulation and Oxygenation of the Brain.* Features Patented
Natural Endorphin Enhancer. Helps Promote Memoray Enhancement and
Focus.* Includes Patented Brain Blood Flow Enhancer. Promotes the
Release of Dopamine to Assist in Cognition.* Consists of Memory and
Focus Herbals for Alertness Such as Huperzine, Ferulic Acid and
Pharmaline Designed to Enhance Well Being.* Provides Bacosides from
Bacopa Reduces Hyperactivity.* Contains Ginkosides, Active
Constituents Found in Ginko Biloba Extract Increases Ability to
Cope with Stress* Includes Rosemary and Gotu Kola. *These
statements have not been evaluated by the Food and Drug
Administration. This product is not intended to diagnose, treat,
cure or prevent disease. SYNOPSIS
[0098] These statements have not been evaluated by the Food and
Drug Administration. This product is not intended to diagnose,
treat, cure or prevent disease.
[0099] Attentional processing has been shown to be dependent on
biogenic amine regulation. Since the precursors for synthesizing
the amines are dependent upon dietary intake, it is possible that
dietary supplements can alter available biogenic amine stores in
the brain. This has led to various clinical strategies that target
nutritional improvement of the brain's chemistry for enhancing
memory and focus. Defects in dopamine metabolism have long been
implicated in attentional processing (short-term memory) as well as
ADHD. There are specific reasons for this relationship: studies in
rodents show that destruction of dopaminergic brain nerve cells
results in hyperactivity and poor response to stress; studies in
rodents showing that the chemical destruction of frontal lobe
dopaminergic neurons shortly after birth produces an animal model
of ADHD that responds to stimulants; an association of low levels
of dopamine metabolites in children with ADHD; brain imaging
studies show deficits of dopaminein ADHD subjects; hyperactivity is
produced in mice when dopaminergic genes (dopamine transporter and
dopamine D3 receptor genes) are knocked out; and, effectiveness of
drugs which mimic dopamine in the treatment of poor cognition
including ADHD.
[0100] The brain is one of the most active body tissues. Although
it constitutes only about five percent of body weight and it
consumes 20 percent of the available oxygen, it is indeed the
master organ. PRoCoG is formulated to maintain healthy levels of
oxygen and blood flow as well as enhancing well being. With this
combination of a patented amino-acid composition and
phyto-medicines, the brain is better able to maintain its vitality
and stay alive. Also using a similar formula we could develop a
product for the sports market place. The product, named Endorphin
Boost, would be an endorphin replacement supplement needed after
strenuous exercise. TABLE-US-00018 TABLE 21 Supplement Facts
Serving Size: 1 Caplet Servings Per Container: 90 Amount per
Serving % Daily Value Blend + Ferulic Acid 50 mg + Huperzine 0.15
mg + Arctic Root Extract (Rhodiola rosea) 25 mg + Standardized to
1.0% Rosavins, 0.25 mg + Standardized to 1.0% Salidrosides, 0.25 mg
+ Bacopa Monolera Leaf Extract 100 mg + Standardized to 20% of
active ingredient. Ginko Biloba Leaf extract 40 mg + Standardized
to 24% ginko flavone Glycosides, 14.4 mg Standardized to 6% Terpene
lactones 3.6 mg Panax Ginseng 60 mg + Standardized to 14%
ginsenosides Gotu Kola Leaf 50 mg + Rosemary Leaf 50 mg + + Minimum
Daily Requirements not established for this ingredient. Important
Notes: Do not take this product if you are pregnant or nursing, if
you are taking an MAO inhibitor type anti-depressant, if you have
high blood pressure, or if you are known to have PKU. Do not exceed
the recommended dose except under the supervision of a physician.
Reduce intake of caffeine. If you are under a physician's care or
taking medication, consult your health care practitioner.
[0101] It is important to realize that the SMART Blend, which
varies with each specific essential (See Table 22). TABLE-US-00019
TABLE 22 Composition of ProCog .TM. and Rationale for Use (Amounts
are for a daily dose of six Caplets) Restorative Ingredient Amount
Action Mechanism Behavioral Change d-Phenylalanine 750 mg.
Enkephalins Enzyme Inhibition Anti-Craving Anti-Depression
l-Phenylalanine 750 mg. Dopamine Precursor Loading Reward
Norepinephrine Anti-Depression l-Tyrosine 900 mg. Dopamine
Precursor Loading Reward Norepinephrine Anti-Depression Anti-Stress
l-Glutamine 300 mg. GABA Precursor Loading Anti-Craving Anti-Stress
Vitamin B Complex Neurotransmitter Synthesis Enzyme Co-Factor in
Neurotransmitter Facilitates Action of Neuro- Synthesis transmitter
Thiamin HCL 100 mg. Vitamin B Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Riboflavin 15
mg. Vitamin B.sub.2 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Niacinamide 100
mg. Vitamin B.sub.3 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter Pantothenic Acid
90 mg. Vitamin B.sub.5 Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neuro- Synthesis transmitter
Pyridoxal-5-phosphate 20 mg. Vitamin B.sub.5 Active Metabolite
Promotes Gastrointestinal Facilitates Action of Neuro- Absorption
of Amino Acids transmitter Cyanocobalamin 6 .mu.g. Facilitates
Action of Neuro- transmitter Ascorbate (Calcium) 600 mg.
Neurotransmitter Synthesis Enzyme Co-Factor Facilitates Action of
Neuro- transmitter Folic Acid 600 .mu.g. Neurotransmitter Synthesis
Enzyme Co-Factor Facilitates Action of Neuro- transmitter Zinc
(Chelate) 30 mg. Neurotransmitter Synthesis Enzyme Co-Factor
Facilitates Action of Neuro- transmitter Calcium (Chelate) 1200 mg.
Neurotransmitter Regulates Neuro-transmitter Facilitates Action of
Neuro- Modulator Release transmitter Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neuro-transmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Facilitates Action of Neuro- Modulator Brain Penetration
transmitter
[0102] PROFLEX consists of amino-acid natural enkephalinase
inhibitor, mushroom, minerals, vitamins, and herbals with specific
analgesic and anti-inflammatory effects. The product is designed to
promote mobile joints, rebuild cartilage and maintain connective
tissue. PROFLEX helps provide temporary relief of minor pains from
arthritis.
[0103] While there is a paucity of research with regard to PROFLEX
specifically, there are numerous animal and clinical reports
regarding the pain killing and anti-inflammatory properties of
certain d-amino acids such as d-phenylalanine. The amino acid,
d-phenylalanine, is a natural inhibitor of opioid peptides (i.e.
enkephalins, endorphins, and dynorphins) in both animals and
humans. D-phenylalanine has been shown to enhance the analgesic
effects of acupuncture. In double-blind studies the compound has
induced analgesia in patients reactive to approved analgesic drugs
including opiates. In cross-over studies in humans D-phenylalanine
reduced pain associated with osteo- and rheumatoid arthritis. The
anti-inflammatory mechanism of action of the D-amino acids appears
to involve the prostaglandins via an opioid peptide interaction.
The product also includes ganoderma lucidum extract which has been
shown to have a number of biological actions. In mice the water
extract of ganoderma lucidum was found to be a potent
anti-inflammatory agent. An extracted and characterized compound
was as active as hydrocortisone without the typical side effects
(thymic involution and gastropathy).
[0104] Since the anti-inflammatory effect observed in mice worked
in both the carrageenan and croton oil experiments, indicates that
the mushroom based compound may have multiple mechanisms.
CyberPharm's scientists believe the combination of d-phenylalanine
with ganoderma lucidum could have powerful synergistic actions. The
combination of d-phenylalanine and a number of non-steroidal
substances like aspirin are synergistic in animal carrageenan
experiments. A benefit of this essential is the addition of
glucosamine, a substance known to act as a building block of the
proteoglycons, an essential constituent of collagen, which gives
cartilage its cushioning property. It has been suggested that
glucosamine is required to make the material that binds water in
the cartilage matrix.
[0105] The product supplies your body with patented natural pain
killers having anti-inflammatory properties such as
DL-phenylalanine and an extract of the mushroom ganoderma lucidum,
as well as white willow bark a natural, aspirin-like form of
salicin. The product also consists of a blend of herbals such as
boswellia, bromelian nettle leaf, and a homeopathic osteo-blend
including active ingredients such as monkshood, deadly nightshade,
wild hops, leopard's bane, and poison ivy which support healthy
joint function. PROFLEX also contains calcium and magnesium for
bone density support. TABLE-US-00020 TABLE 23 BENEFITS FEATURES
Reduces Pain Associated with Joint Swelling* Provides a Patented
Natural Pain Killer and Anti-inflammatory Composition. Promotes
Cartilage Repair and Regeneration* Includes a Patent Pending
Natural Anti-inflammatoryAgent. Supports Healthy Joint Function and
Mobility* Features Glucosamine for Healthy Cartilage. Prevents
Muscle Fatigue* Includes Natural Homeopathic ingredients. Provides
Active Natural Anti-inflammatory Supplies the Mobility Action*
Support of Herbals. *These statements have not been evaluated by
the Food and Drug Administration. This product is not intended to
diagnose, treat, cure or prevent disease.
[0106] The PROFLEX SYNERGY PACK is a selective companion system
which consists of natural pain killers, anti-inflammatory agents,
herbals, and homeopathic ingredients which when taken together
supplies the body with active substances known to promote healthy
joint function in a synergistic manner. It is well known that as
our bodies age, connective tissue and cartilage needs important
nutrients to maintain vitality. It is also well known that in
seniors the ability to produce some of these nutrients necessary
for cartilage building declines. Proper nutrients safe guard
against inflammation of all the 143 different joints in the human
body such as hands, feet, fingers, wrists, elbows, neck, shoulders,
knee, back, hip, and ankles. The patented PROFLEX-SYNERGY-SYSTEM is
the most natural scientifically advanced product that provides a
nutritional approach to both reduction of pain and inflammation
through its DL-Phenylalanine (See U.S. Pat. No. 4,730,007) and its
natural (1899 LLC and the University of Texas System) extract of
ganodermalucidum, which has been shown to be a very potent
anti-inflammatory agent. Using gas chromatography and mass spectral
analysis along with NMR and X-ray techniques two isomers were
identified out of several hundred triterpines in the mushroom, both
having significant anti-inflammatory properties. The product
supplies your body with the Indian herb boswellia, known for its
anti-inflammatory effects in humans, glucosamine, a naturally
occurring amino-sugar found in the body, which plays a role in
maintaining and rebuilding cartilage and acts as a "shock
absorber"
[0107] It is anticipated that the gene test will involve a gene
recently discovered by George UHL and colleagues involving one's
sensitivity to pain related to an endogenous opioid. TABLE-US-00021
TABLE 24 Supplement Facts Serving Size: 1 Caplet Servings Per
Container: 90 Amount per Serving % Daily Value dl-Phenylalanine 750
mg + Glucosamine HCL 500 mg + Calcium (Chelate) 225 mg Magnesium
(Oxide) 150 mg White Willow Bark 60 mg + Standardized to 1 percent
total Salicin Ganoderma Lucidum 750 mg + Standardized to Percent of
Isomer X Flex Blend 120 mg Bozwellia serrata Gum Resin + Bromelein
+ Nettle Leaf + HOMEOPATHIC FLEX PACK Aconitum Napellus (Monkshood)
6x Belladonna (Deadly Nightshade) 6x Bryonia Alba (Wild Hops) 6x
Amica Montana (Leopard's Bane) 6x Rhus Toxiconendron (Poison lvy)
6x + Minimum Daily Requirements not established for this
ingredient. Important Notes: Do not use this product in cases with
PKU, if you are pregnant or nursing. If you are under the care of a
physicians or taking medication consult your health professional
before taking product. If you are allergic to shellfish or
mushrooms do not take. For severe pain or if minor pain persists
for seven days consult a health care professional immediately. Take
as directed and keep away from children.
[0108] CARDIOPLEX consists of amino-acid precursor monoamines,
natural enkephalinase inhibitors, minerals, vitamins, trace metals
and herbals. The product is designed to promote healthy
cardiovascular function and normal blood pressure.
[0109] To date, there are no clinical trials on CARDIOPLEX per se,
but certain ingredients have been tested in both animals and
humans. There are a number of classes of drugs which currently are
in use to treat hypertension. These consist of the following: drugs
which modify the adrenergic part of the autonomic nervous system;
drugs which dilate blood vessels; diuretics, drugs that inhibit
angiotensin converting enzyme; drugs that block calcium channels;
and, drugs that block angiotensin receptors. With this in mind, the
inventor has CyberPharm's scientists have discovered a natural
anti-hypertensive substance which by itself lowers blood pressure
in hypertensive individuals without causing blood pressure lowering
in normals. A provisional patent was filed on Jan. 12, 1999
entitled Hypertensive Agents Including Inhibitors of the Breakdown
of Enkephalins and/or Endorphins and Combinations of SAID,
Anti-Hypertensive Agents with other AntiHypertensive Drugs and
Natural Substances. The enkephalins and endorphins are peptides
which are present in blood and in the central nervous system.
Although their main function appears to be control of the pain
response, they have other important actions including lowering
blood pressure in some animal species, but these compounds have
many drawbacks when administered.
[0110] Ehrenpreis discovered the natural enkephalinase inhibitor
d-phenylalanine is highly effective in lowering blood pressure in
animals and in man and is the major ingredient of CARDIOPLEX. In
this regard, our scientists found that D-phenylalanine
significantly lowered both systolic and diastolic blood pressure
with no change in heart rate in genetically bred spontaneously
hypertensive rats (SHR). D-Phenylalanine was able to lower systolic
blood pressure of these rats close to normal (average drop of 36.7
mm Hg). It is noteworthy that this effect is blocked by the
narcotic antagonist and the effect on blood pressure is synergistic
with the beta-blocker popranolol. Even more important is that the
lowering of blood pressure by d-phenylalanine lasted several days.
A single dose of d-phenylalanine lowers blood pressure for one or
more days in human 5 having no effect in normotensive
individuals.
[0111] Because there is no single neurotransmitter involved in
controlling blood pressure, we have designed CARDIOPLEX as a
combination of substances which have been shown in numerous studies
to promote a healthy heart. In fact d-ribose is included, since it
plays a role in myocardial metabolism and post-myocardia schemia.
The product also includes the trace metal chromium nicotinate
because it has been shown to reduce blood pressure in humans.
Moreover the patented SMART composition was found in one study to
reduce blood pressure when given on a chronic basis. Unique to this
product is the addition of certain herbs that enhance cognition
including huperzine, rhodiola rosea extract, and ganoderma lucidum
as well as other natural anti-hypertensive agents like hawthorn
berry, Co-enzyme Q, and Pycogenol. It also is important to supply
the body with two amino-acids, Lysine and Proline, which help in
preventing fat buildup. TABLE-US-00022 TABLE 25 BENEFITS FEATURES
Lowers Blood Pressure* Includes Patented Natural Anti-Hypertensive.
Promotes Oxygenation of Cells* Includes a Chromium as an
Anti-Hypertensive. Enhances Cognition, Especially for Seniors*
Contains Anti-Oxidants and Vitamins. Prevents Free Radical Damage*
Includes Huperzine, Rhodiola Rosea, and Ganoderma Lucidum Helps
Maintain Elasticity of the Arteries* Contains the Patented
Pyncogenol. Stimulates Cell Growth and Healthy Tissue Includes
Patented SMART Composition Reduces Fatty Deposits in Arteries*
Contains Synergistic Amino Acids Stimulates Natural Endorphinergic
Healing Functions Contains d-Ribose *These statements have not been
evaluated by the Food and Drug Administration. This product is not
intended to diagnose, treat, cure or prevent disease.
Stimulates Natural Endorphinergic Healing Functions contains
d-Ribose
[0112] These statements have not been evaluated by the Food and
Drug Administration. This product is not intended to diagnose,
treat, cure or prevent disease.
[0113] Fifteen to 20 percent of adults in the United States have
hypertension. The great majority of cases are presently undetected,
untreated, or inadequately treated, and it is twice as life
threatening if you do not know you have it. High blood pressure
takes years to develop and up to 30 years to do its damage not just
to your heart and arteries, but also to your kidneys, lungs, brain,
and nervous system. Next to old age and obesity, high blood
pressure is the most potent predictor of a shortened life span. Of
the 60 million Americans who are hypertensive, 10 million or more
may be on medication of questionable value or may be on medication
of real danger. Current reports of the American Medical
Association, The American Heart Association and the National
Institutes of Health indicate that treating your high blood
pressure with drugs in current use can reduce sex drive, produce
accelerated aging of all the major organs (the heart, lungs, and
kidneys) and can shorten life expectancy by 16 years. Moreover,
fifty percent of all elderly patients on diuretics show severe
potassium and magnesium deficiencies. Most high blood pressure
medications interfere with normal brain function, decrease
alertness and memory, and can cause premature senility symptoms in
persons over 60 years of age. Finally, certain high blood pressure
medications (e.g. Captopril, Vasotec, etc.) may worsen the quality
of life for 30 to 40 percent of all individuals. Heart attacks can
be caused in-part by the development of cholesterol and fatty
deposits on the walls of the arteries. Lipoproteins are the sticky
molecules that stick to artery walls that make up fatty deposits
beside cholesterol particles. These molecules form a biological
"adhesive tape" around the particles of fat and could lead to the
clogging of blood vessels. L-Lysine and L-Proline prevent and
neutralize the sticky particles and reduce clogging.
[0114] CARDIOPLEX provides a SMART composition which contains
natural blood pressure lowering substances as well as herbs which
enhance cognition. CARDIOPLEX contains the SMART composition of
amino-acids, minerals, and vitamins (See Table 27). TABLE-US-00023
TABLE 26 Supplement Facts Serving Size: 1 Caplet Servings Per
Container: 90 Amount per Serving % Daily Value SMART .TM.
Composition + l-Lysine 150 mg + l-Proline 150 mg + Huperzine 1 mg +
Arctic Root Extract 25 mg + Standardized to 1.0% Rosavins, 0.25 mg.
Standardized to 1.0% Salidrosides, 0.25 mg. Ganoderma Lucidum 750
mg. + Standardized to % of Isomer X d-Ribose 500 mg. + Co-Encyme
Q-10 10 mg + Pycnogenol 10 mg. + + Minimum Daily Requirements not
established for this ingredient. Important Notes: Do not use this
product in cases with PKU, if you are pregnant or nursing. If you
are under the care of a physicians or taking medication consult
your health professional before taking product. Do not exceed the
recommended dose unless directed to do so by your health care
professional. Do not use with other substances which cause
drowsiness (such as alcohol). Take as directed and keep away from
children.
[0115] TABLE-US-00024 TABLE 27 SMART .TM. Blend Composition in
CardioPlex .TM. and Rationale for Use (Amounts are for a daily dose
of six Caplets) Restorative Ingredient Amount Action Mechanism
Behavioral Change d-Phenylalanine 750 mg. Enkephalins Enzyme
Inhibition Anti-Craving Anti-Depression t-Phenylalanine 750 mg.
Dopamine Precursor Loading Reward Nonepinephrine Anti-Depression
t-Tyrosine 900 mg. Dopamine Nonepinephrine Precursor Loading Reward
Anti-Depression Anti-Stress t-5-Hydroxytryptophan 20 mg. Serotonin
Precursor Loading Anti-Craving Anti-Depression Anti-Insomnia
t-Glutamine 400 mg. GABA Precursor Loading Anti-Craving Anti-Stress
Vitamin B Complex Neurotransmitter Synthesis Enzyme Co-Factor in
Neurotransmitter Facilitates Action of Neurotransmitter Synthesis
Thiamin HCL 100 Mg. Vitamin B Enzyme Co-Factor in Neurotransmitter
Facilitates Action of Neurotransmitter Synthesis Riboflavin 15 mg.
Vitamin B.sub.2 Enzyme Co-Factor in Neurotransmitter Facilitates
Action of Neurotransmitter Synthesis Niacinamido 100 mg. Vitamin
B.sub.3 Enzyme Co-Factor in Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Pantothenic Acid 90 mg. Vitamin B.sub.5
Enzyme Co-Factor in Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Pyridoxal-5-phosphato 20 mg. Vitamin
B.sub.6 Active Metabolite Promotes Gastrointestinal Absorption of
Facilitates Action of Neurotransmitter Amino Acids Cyanoccbalamin 6
.mu.g. Facilitates Action of Neurotransmitter Ascorbate (Calcium)
600 mg. Neurotransmitter Synthesis Enzyme Co-Factor Facilitates
Action of Neurotransmitter Folic Acid 400 .mu.g. Neurotransmitter
Synthesis Enzyme Co-Factor Facilitates Action of Neurotransmitter
Zinc (Chelate) 30 mg. Neurotransmittar Synthesis Enzyme Co-Factor
Facilitates Action of Neurotransmitter Calcium (Chelate) 1500 mg.
Neurotransmitter Regulates Neurotransmitter Facilitates Action of
Neurotransmitter Modulator Release Magnesium (Oxide) 150 mg.
Neurotransmitter Regulates Neurotransmitter Calmative Modulator
Release Chromium Picolinate 1500 .mu.g. Neurotransmitter Enhances
Amino Acid Brain Penetration Facilitates Action of Neurotransmitter
Modulator
[0116] TABLE-US-00025 TABLE 28 Additional CardioPlex .TM.
Ingredients* Vitamin C Vitamin C salt with varying molecular
Magnesium Vital to enzyme activity, helps in maintaining (Ascorbic
Acid) components to enhance overall C utilization stable blood
pressure and converting blood sugar to energy, assists n calcium
and potassium intake. Vitamin C A unique, essential vitamin used by
the body Potassium Important for healthy nervous system, to produce
the collagen molecules necessary regular heartbeat, and assists in
maintaining for proper cardiovascular function stable blood
pressure. Vitamin E Important antioxidant that improves
circulation, Phosphate Required for cell growth, contraction of
helps tissue repair, promotes normal the heart muscle, and kidney
function. clotting and healing, and reduces scarring Assists the
body in utilization of vitamins from some wounds. and conversion of
food into energy. Vitamin A Important Antioxidant essential for new
cell Zinc Required for protein synthes is, collagen growth and
healthy tissue development. Beta- formation, and appears necessary
for Carotene is a pro-vitamin which the body tissue repair.
converts into Vitamin A as the body finds it necessary. Vitamin
B.sub.1 Enhances circulation and assists in the production
Manganese Needed for protein and fat metabolism, hydrochloric acid,
blood formation, healthy nerves, blood sugar regulation, and
carbohydrate metabolism. and is needed for energy production.
Vitamin B.sub.2 Necessary for red blood cell formation, antibody
Copper Aids in the formation of bone hemoglobin production, cell
respiration and growth; and red blood cells. Works in balance aids
in the metabolism of carbohydrates, fats, with zinc and vitamin C
to form and proteins. elastin. Involved n the healing process and
energy production. Vitamin B.sub.3 Needed for proper circulation,
and healthy Selenium Antioxidant needed for pancreatic function
skin; aids in the metabolism of carbohydrates, and tissue
elasticity. fats, and proteins. Vitamin B.sub.5 Assists n vitamin
utilization and helps convert Chromium Involved in the metabolism
of glucose carbohydrates, fats, and proteins to energy. for energy
and in the synthesis of fats, cholesterol, and proteins. Vitamin
B.sub.6 Involved in more bodily functions than any Pycnogenol
Antioxidant made from the bark of European other nutrient. Needed
in the production of Marine Pine. This rare patented hydrochloric
acid and in the absorption of fats agent has been thoroughly
studied and and proteins. Aids in maintaining sodium and heralded
for its power to block free potassium balance. Enhances and
promotes radical damage and its ability to be red blood cell
formation. absorbed quickly and enhance activity of other
antioxidants. Vitamin B.sub.12 Promotes red blood cell formation
and cellular t-Proline and Amino acids that have been shown in
longevity. Required for proper digestion, t-Lysine laboratory
studies to limit and reverse absorption of foods, protein
synthesis, and fatty tissue development in artery tissue.
metabolism of fats and carbohydrates. Vitamin D Important for
strong bones. Necessary for t-Carnitine Amino acids required for
optimum cell phosphorus and calcium absorption and t-Arginine
function. utilization. t-Cysteine Folic Acid Needed for energy
production and the formation Inositol Helps maintain elasticity of
the arteries of red blood cells. Important for red blood and helps
remove fats from the liver. cell division and replication, and is
involved in protein metabolism. Biotin Aids n cell growth, fatty
acid production, Coenzyme Q-10 Vital cell fuel and catalyst in the
c reation metabolism of fats, carbohydrates, and proteins, of
energy. and utilization of the B complex vitamins. Calcium
Importance in the maintenance of regular Molybdenum Necessary for
the function of several heartbeat and the transmission of nerve
impulses, enzymes and for iron metabolism. needed for muscle
growth, the formation of strong bones and teeth and is essential in
blood clotting. *SOURCE: REXALL, SHOWCASE INTERNATIONAL
[0117] IMUNOPRO.TM.
[0118] IMUNOPRO consists of amino-acids, trace metals, minerals,
vitamins, and herbals designed to promote a naturally powerful
defense mechanism known as your immune response. It is well known
that certain factors play a role in the immune response which
include genetics, nutrition, stress, and other life-style changes.
(See Table 31).
[0119] The common cold is the most frequent infection in all age
groups in the United States. About $5.5 million are spent annually
on colds in the United States. Persons have more than one billion
colds each year, of which 110 million are disabling: the result is
about 300 million days of restricted activity, about 60 million los
t days of school and about 50 million work day. Although it is well
recognized that most colds are caused by rhinoviruses, at least
$37.5 million worth of antibiotics were prescribed for the common
cold in 1994 in the United States. More than 100 distinct
rhinoviruses exist, making it impossible to produce a useful
vaccine. Therefore, leaders in the pharmaceutical industry have
looked more recently to the nutrition as a possible answer to this
health issue. However, this has not been an easy task, for example
review of six major studies on vitamin C supplementation gave no
evidence that high dose vitamin C supplementation decrease the
incidence of the common cold. In contrast, a look at the trace
metal zinc lead to more definitive conclusions.
[0120] In 1974 it was reported that zinc ions inhibit rhinovirus
replication. A review of published clinical studies on the use of
zinc lozenges in colds found four studies that reported zinc salts
to be beneficial and four were did not do so. One important note is
that the four studies that did not show benefits used zinc lozenges
with substances known to complex zinc ions, where as the four
studies with positive results used an ionizable form of zinc
without such substances. Zinc ions have other benefits that may
shorten the severity and duration of non-viral symptoms associated
with the common cold. In 1998, the CyberPharm scientist, Kenneth
Blum, in conjunction with others in a randomized, double-masked,
placebo controlled study demonstrated the effectiveness of zinc
acetate lozenges on common cold symptoms in allergy tested
subjects. Zinc acetate significantly shortened the duration of
common cold symptoms and relieved symptoms associated with
allergies. Moreover, zinc is an essential element in immune system
functions. The inhibitory effect of zinc on histamine release from
mast cells is attributed to its action on the stabilization of mast
cell membranes.
[0121] Opioids (exogenous opiates and endogenous opioid peptides)
have been found to modulate the immune system by regulating the
function of immunocompetent cells. Several laboratories have
indicated that opioids can operate as cytokinins, the principal
communication signals of the immune system. Chronic activation of
the endogenous opioid system augments the natural immune response.
One important method to increase the activity of endogenous opioid
peptides is to use D-amino acids, like D-phenylalanine, which
inhibits the neuropeptidases known to breakdown the enkephalins,
endorphins, and dynorphins in the brain. This in turn would enhance
the natural immune response.
[0122] Two other important aspects that relate to the design of
IMUNOPRO is that it is well know that catecholamines, like
dopamine, seem to play an important role in the regulation of the
immune function, both after chronic exercise and emotional stress.
The second important aspect relates to the finding that the zinc
ion is a potent inhibitor of one of the opioid peptide degrading
enzymes, specifically aminotripepidase.
[0123] Experimental data available today strongly indicate that
various types of physiological stressors, including physical
exercise and emotional stress, can influence immune function. It is
noteworthy, that natural immunity is strongly influenced by chronic
exercise, and this regulation includes interaction between the
nervous, endocrine, and immune systems as well as a positive effect
on the endogenous opioids.
[0124] Moreover certain herbs are believed to promote immune system
health and may stimulate the production and action of white blood
cells, which are critical to the body's ability to promote cell
repair and health.
[0125] IMUNOPRO also consists of herbs know to have an anti-oxidant
and immune-stimulatory action including curcumin the active
ingredient of spice tumeric which protects the body from
free-radical damage. The product also features the following herbs:
cat's claw, garlic, elderbery, ganoderma lucidum, astralgus, and
echinacea. which are believed to promote immune system health.
TABLE-US-00026 TABLE 29 BENEFITS FEATURES Increases the
Endorphinergic System* Includes Patented SMART Composition. Blocks
the Aminopeptidase Enzymes* Includes d-phenylalanine to Boost
Endorphins. Enhances the Immune System* Contains the Novel
Zinc-dl-phenylalanine Complex. Protects Against Free Radical
Damage* Consists of Zinc Acetate Has Anti-Oxidant Properties
Contains Curcumin of Tumeric Releases Brain Dopamine and
Norepinephrine Provides the Immune Stimulant Echinacea Has
Anti-Viral Activity Includes Other Herbal Immune Stimulants *These
statements have not been evaluated by the Food and Drug
Administration. This product is not intended to diagnose, treat,
cure or prevent disease.
[0126] The body protects itself from infectious organisms and other
harmful invaders through an elaborate network of safeguards called
the host defense system. This system has three lines of defense:
physical, the inflammatory response, and the immune response.
Physical barriers, such as the skin and mucous membranes, prevent
most organisms from invading the body. Organisms tat penetrate this
first barrier simultaneously trigger the inflammatory and immune
response. Both responses involve stem cells in the bone marrow that
form blood cells. Four structures in the body make up the immune
system: lymph nodes, thymus, spleen, and tonsils.
[0127] Certain cells have the ability to distinguish between
foreign matter and what belongs to the body. When foreign
substances invade the body, two types of immune responses are
possible cell mediated and humoral immunity. In cell-mediated
immunity, T cells respond directly to antigens (foreign substances
such as bacteria or toxins that induce antibody formations). This
response involves destruction of target cells--such as
virus-infected cells and even cancer cells--through the secretion
of lymphokines (lymph protein). Eighty percent of blood cells are T
cells. In humoral immunity B cells act in a different way that T
cells are responsible for humoral or immunoglobulin-mediated
immunity. B cells originate in the bone marrow and mature into
plasma cells that produce antibodies (immunoglobin molecules that
interact with a specific antigen). Antibodies destroy bacteria and
viruses, thereby preventing them from entering host cells. There
are still other cells--not lymphocytes--called phagocytes, or "cell
eaters", that digest microbes. IMUNMOPRO is designed to combine
amino acids, vitamins, and minerals which naturally stimulate the
immune system response via enhancement of the opioid peptide and
the catecholamine systems as well as providing herbs that can be a
powerful aid in supporting the body's defense against infections
and when combined with good nutrition and exercise leads to a
healthy lifestyle.
[0128] Nutritional Information TABLE-US-00027 TABLE 30 Supplement
Facts Serving Size: 1 Caplet Servings Per Container: 90 Amount per
Serving % Daily Value SMART .TM. Composition +
Zinc-di-Phenylalanine 100 mg + Zinc Acetate 10 mg + Tumeric Rhizome
Extract 100 mg + Standardized to 85.0% Curcuminoids, 95 mg.
Echinacea Purpurea Extract 100 mg. + Standardized to 4% Phenolic
Compounds, 4 mg. ImunoPro Blend 200 mg. + Garlic Bulb. + Astragalus
Root + Elderberry Fruit + Ganoderma Lucidum + Cats Claw Bark + +
Minimum Daily Requirements not established for this ingredient.
Important Notes: Do not use this product in cases with PKU, if you
are pregnant or nursing.. If you are under the care of a physician
or taking an MAO-inhibitor type anti-depressant medication or a
blood thinner medication consult your health professional before
taking product. Do not exceed the recommended dose unless directed
to do so by your health care professional.. Do not use continuously
for more than eight weeks. Not recommended for individuals with
autoimmune disorders.
[0129] IMUNOPRO contains the SMART composition of amino-acids,
minerals, and vitamins (See Table 32). TABLE-US-00028 TABLE 31
Composition of ImunoPro .TM. and Rationale for Use (Amounts are for
a daily dose of six Caplets) Restorative Ingredient Amount Action
Mechanism Behavioral Change d-Phenylalanine 750 mg. Enkephalins
Enzyme Inhibition Anti-Craving Anti-Depression t-Phenylalanine 750
mg. Dopamine Precursor Loading Reward Anti-Depression
Norepinephrine t-Tyrosina 900 mg. Dopamine Precursor Loading Reward
Anti-Depression Anti-Stress Norepinephrine t-5-Hydroxytryptophan 20
mg. Serotonin Precursor Loading Anti-Craving Anti-Depression
Anti-Insomnia t-Glutamine 300 mg. GABA Precursor Loading
Anti-Craving Anti-Stress Vitamin B Complex Neurotransmitter
Synthesis Enzyme Co-Factor In Neurotransmitter Facilitates Action
of Neurotransmitter Synthesis Thiamin HCL 100 Mg. Vitamin B Enzyme
Co-Factor In Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Riboflavin 15 mg. Vitamin B.sub.2 Enzyme
Co-Factor In Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Niacinamide 100 mg. Vitamin B.sub.3
Enzyme Co-Factor In Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Pantothenic Acid 90 mg. Vitamin B.sub.5
Enzyme Co-Factor In Neurotransmitter Facilitates Action of
Neurotransmitter Synthesis Pyridoxal-5-phosphate 20 mg. Vitamin
B.sub.5 Active Metabolite Promotes Gastrointestinat Facilitates
Action of Neurotransmitter Absorption of Amino Acid 5
Cyanocobalamin 5 .mu.g. Facilitates Action of Neurotransmitter
Ascorbate (Calcium) 600 mg. Neurotransmitter Synthesis Enzyme
Co-Factor Facilitates Action of Neurotransmitter Folic Acid 400
.mu.g. Neurotransmitter Synthesis Enzyme Co-Factor Facilitates
Action of Neurotransmitter Zinc (Chelate) 30 mg. Neurotransmitter
Synthesis Enzyme Co-Factor Facilitates Action of Neurotransmitter
Calcium (Chelate) 150 mg. Neurotransmitter Regulates
Neurotransmitter Facilitates Action of Neurotransmitter Modulator
Release Magnesium (Oxide) 150 mg. Neurotransmitter Regulates
Neurotransmitter Calmative Modulator Release Chromium Picolinate
1500 .mu.g. Neurotransmitter Enhances Amino Acid Brain Penetration
Facilitates Action of Neurotransmitter Modulator
[0130] TABLE-US-00029 TABLE 32 Summary of Studies of the Human
D.sub.2 Receptor Gene and the Deficiency Syndrome Behavior-Obesity
Poly- Inves- mor- tiga- phic Type Population tion Loci Study
Studied Parameter Results Comment Blum, A.sub.1 Association
Morbidly Obese Percent Positive DRD2 A.sub.1 accounted for 45.9
percent of the variance et al. Males and Body Fat associate with
percent body fat as compared with (1999).sup.1 Females "super
controls". Blum, A.sub.1 Association Morbidly Obese Response
Positive Change in fat weight, change in body weight, percent et
al. Males and to Change change in weight, and body weight change in
kgms all (1999).sup.2 Females In Body were significant in
A.sub.2/A.sub.2 group and non-significant in the administered
Composition A.sub.1/A.sub.1 and A.sub.1/A.sub.1 carriers. 400 mcg
of CrP/day Blum, A.sub.1 Association Obese Patients Obesity
Positive Association of the DRD.sub.2 A.sub.1 allele and patients
with a et al. With A Body Mass Body Mass Index over 25. Significant
increase of A.sub.1 percent (1996).sup.3 Index Over 25. prevalence
with increasing severity of substance Risk factors dependence.
Include Co-morbid Substance Abuse Disorder. Blum, A.sub.1
Association Obese and Obesity Positive A.sub.1 allele was present
in 25 percent of probands having et al. control probands and zero
risk factors compared to 66 percent of obese (1994).sup.4 electro-
subjects with risk factors. This work confirms the physiology
association of P300 abnormalities and the A.sub.1 allele in
obesity. Comings, A.sub.1 Association Young Morbidly Obesity
Positive OB and DRD2 genes were additive in their contribution et
al. Obese females to overall variance of BMI. These two genes
accounted (1996).sup.5 for 22.8 percent of BMI variance. Comings,
DRD.sub.2 Association Undifferentiated Obesity Positive
Undifferentiated Obese patients in terms of macro- et al. Haplo-
Overweight selection associated with haplotype IV. (1993).sup.6
types Subjects Intron 6- And Controls Exon 7 Noble, A.sub.1
Association Characterized Obesity/ Positive Prevalence of A.sub.1
allele increases in obese patients et al. Overweight carbo-
compared to controls. While there was no association (1994).sup.7
Obese Patients hydrate with cardiovascular factors, a positive
association was And Non-Obese Bingeing found with parental
alcoholism and carbohydrate bingeing Controls And Associated Risk
Factors .sup.1Blum K, Kaats G, Davis K Sherman M, Eisenberg A, Cull
JG, Chen TJH, Wood R, Braverman E, Bucci L, Quilici-Timmcke. J, and
Comings DE. The Dopamine D.sub.1 Receptor A.sub.1 Allele is A Major
Gene Variant in Morbid Obesity: Strong Association With Percent
Body Fat. Submitted to Molecular Psychiatry. .sup.2Blum K, Kaats G,
Eisenberg A, Sherman M, Davis K, Comings DE, Cull JG, Chen THJ,
Wood R, Bucci L, Wise JA, Braverman ER, and Pullin D. Chromium
Picolinate induces Changes in Body Composition as a Function of the
Taq1 Dopamine D.sub.2 Receptor A.sub.2 Alleles Submitted to Journal
of The American College of Nutrition. .sup.3Blum, K, Braverman,
ER., Wood, RC., G, J., Li, C., Chen, TJH., Taub, M., Montggomery.
AR., Cull, JG and Sheridan, PJ. 1996. Increased prevalence of the
Taq1 A1 allele of the dopamine receptor gene in obesity with
comorbid substance use disorder. Pharmacogenetics 6: 297-305.
.sup.4Blum, K., Braverman, E. R., Wood, R., Sheridan, P. J. DRD2 A1
Allele and P300 abnormalities in obesity [Abstract]. Presented at
the American Society of Human Genetics, Montreal, Canada, October
8th, American Journal of Human Genetics, 1994. .sup.5Comings, DE.,
Gade, R. MacMurray, JP., Munseman. D., Johnson. P., Verde. R., and
Peters, WR. 1996 Genetic variants of the human obesity (OB) gene:
association with body mass index in young women psychiatric
symtoms, and interaction with the dopamine D.sub.2 receptor gene.
Molecular Psychiatry 1: 325-335. .sup.6Comings, DE., Flanapan, SD.,
Diez, G., Muhlman, D., Knell, E., end Gysin, R. 1993. The dopamine
D.sub.2 receptor as a major gene in obesity and height. Biochemical
Medicine and Metabolic Biology 50: 176-185. .sup.7Noble, EP.,
Noble, RE., Ritchie, T., Syndulko, K., St. Jeor, SC., Fitch, RJ.,
Brunner, RL., end Sparkes, RS. 1994. D.sub.2 dopamine receptor gene
end obesity. International Journal Eating Disorders 15:
205-217.
[0131] OBGENEMAP is the New Dopaminergic Genotypic Assessment for
Obesity due to Carbohydrate Binging is now available. As a result
of dramatic new findings in Reward Deficiency Syndrome Behaviors,
CyberPharm, Inc. is pleased to offer the new Dopamine Receptor Gene
DRD2 genotype report for genetic susceptibility to Obesity Due to
Carbohydrate Binging. Genetic research reports (See Table 32):
[0132] A strong genetic correlation between variants of the
dopamine D2 receptor gene, a gene which regulates the protein
(receptors) involved in the reward centers of the brain and
obesity, has been reported by several independent investigators.
[0133] Dopamine D2 receptor densities are lower in brain tissue
obtained from patients carrying the A1 Bi and Intron6-Exon7
Haplotypes of the DRD2 gene. Similar reduced DRD2 densities have
been found in alcohol preferring rodents compared to
alcohol-non-preferring inbred animals. [0134] Variants of the DRD2
gene has been correlated with increased risk of carbohydrate
binging, obesity, attention-deficit/hyperactivity (ADH D), and
Tourettes Disorder. [0135] The association of the variants of the
DRD2 gene with risk in developing compulsive diseases has been
reported. [0136] Results of independent studies suggest that
individuals with two copies of the A1 allele are much more likely
to develop one of the Reward Deficiency Syndrome behaviors than
those who have one or none. The number of receptors are more
greatly reduced in individuals with two copies than in those who
have one or none. [0137] Researchers report that vulnerability to
obesity, carbohydrate binging, and food seeking behavior is likely
to be the result of multiple factors and is polygenic, of which the
DRD2 is one. [0138] The A1 allele associated with almost 70 percent
of deceased severe alcoholics. This value is highly confirmatory of
the computed Bayes Theorem value to measure the predictive power of
the A1 allele in obesity due to carbohydrate binging which is 74
percent. [0139] Studies demonstrate that abnormal dopaminergic
function results in abnormal carbohydrate seeking behavior. The D2
receptors are profoundly involved. Test Results and Test
Interpretation The DRD2 dopamine receptor gene is evaluated by the
DNA Based Multi-Plex OBGeneMap. The report specifies the following
genotypes with greater than 99% accuracy: [0140] DRD2 A1/A1 [0141]
A1/A2 [0142] A2/A2
[0143] Interpretations of the genotype are provided in terms of
offering confirmatory diagnostic data for the Reward Deficiency
Syndrome behavior of obesity due to carbohydrate binging. Reports
provide suggested therapeutic options.
[0144] This genetic diagnostic test requires no special handling or
shipping. The tissue gathering aspects of the test consist of a
non-invasive buccal swab. The consumer is instructed to "swab" the
inside of the cheeks. The swabs then are placed in the provided
mailer and shipped back to our laboratory for analysis and
reporting.
SUMMARY OF INVENTION
[0145] An important aspect of the present invention is a kit
comprising a buccal swab for obtaining a subject's DNA sample
suitable for analysis of alleles associated with signal-transmitter
production, reception or catabolism; and at least one composition
comprising at least one of: a signal-transmitter precursor, an
enhancer of precursor uptake, and an inhibitor of neurotransmitter
reuptake or signal-transmitter catabolism; wherein allelic analysis
predicts a likelihood of positive effects of a subjects intake of
one or more components of the composition in effective amounts.
[0146] In an important aspect, the enhancer is a chromium salt, for
example chromium nicotinate or chromium picolinate. Such chromium
enhances certain neurotransmitter precursor uptake. In certain
important aspects, the present invention involves a signal
transmitter which includes neurotransmitters as a subcategory.
Other signal transmitters may be peptide like substances or
hormones of various sorts. (Although a preferred signal transmitter
is a neurotransmitter). In certain cases the inhibitor of the
present invention may be an inhibitor of neurotransmitter reuptake
or of various signal transmitter catabolisms. The buccal swab of
the present invention is basically a method for a subject to obtain
a DNA sample from the subjects oral cavity and send this DNA sample
to an analytical lab where certain alleles may be determined. One
preferred inhibitor of signal transmitter catabolism is D
phenylanine or as it exists in DL phenylanine. Certain signal
transmitters, in addition to being neurotransmitters, peptidyl
transmitters or peptidyl opiates, may be agents such as nitric
oxide or other secondary intercellular messengers.
[0147] In an important aspect of the present invention alleles are
obtained from DNA samples originating from the subjects buccal
swab. The alleles to be analyzed include alleles from the following
genes: DAT1 (dopamine transporter), dopamine-beta-hydroxylase,
dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,
dopamine D4 receptor, dopamine D5 receptor, serotonin HTT,
serotonin HTRIA, serotonin TDO2, adrenergic ADRA2A, adrenergic
ADRA2C, adrenergic NET, catecholamine metabolizing MAOA,
catecholamine metabolizing COMT, GABA-GABRA3, GABA-GABRB3,
Canabinoid CNRI, NMDA Receptor NMDAR1, Nicotinic Cholinergic
(CHRNA4), enkephalin (PENK), and Adrenergic Receptor (AR).
A kit of the present invention may also include, in addition to a
buccal swab, the following:
[0148] a) an opiate destruction-inhibiting amount of at least one
substance which inhibits the enzymatic destruction of a
neuropeptidyl opiate, said substance being selected from the group
consisting of amino acids, peptides, and structural analogues or
derivatives thereof; [0149] b) a neurotransmitter
synthesis-promoting amount of at least one neurotransmitter
precursor selected from the group consisting of dopamine precursors
L-Tyr, L-Phe and L-dopa, serotonin precursors L-Trp and
5-hydroxytryptophan, and gamma amino butyric acid (GABA) precursors
L-glutamine, L-glutamic acid, and L-glutamate; and [0150] c) a
tryptophan concentration enhancing amount of chromium picolinate or
chromium nicotinate, the amount of said substance and said
neurotransmitter precursor and said chromium compound being
effective in reducing the subject's RDS behaviors.
[0151] An important aspect of the present invention, a tryptophan
concentration-enhancing amount of chromium nicotinate or chromium
picolinate may be present. This combination now being effective in
preventing or reducing a subjects unwanted weight or other RDS
behaviors, such as attention deficits disorder, intentional
processing or memory deficiency. Further RDS behaviors may include
any in the group existing of SUD, Obesity, Smoking, Tourettes
Syndrome, ADHD, Schizoid/Avoidant Behavior, Aggression,
Posttraumatic stress syndrome, PMS or tobacco use. In certain
aspects, composition of the present invention may include a daily
dietary composition comprising 32 to 10,000 mg DL-phenylalanine, 5
to 5,000 mg L-tryptophan, 3 to 30,000 mg L-glutamine, and the
composition further comprises 1-300 mg pyridoxal-5'-phosphate. When
the term excess weight is involved, it is understood that this
indicates obesity. In a preferred aspect, the kit involves a
composition that comprises a daily dietary consumption of about 460
mg DL-phenylalanine, 25 mg L-tryptophan, 25 mg L-glutamine, and the
mixture further comprises 5 mg pyridoxal-5'-phosphate. Allelic
analysis may be confirmed by observation of a family history of
certain RDS behaviors, this involving or confirming an improved
likelihood for successful treatment by consumption of the subject
composition in the kit. Various other RDS behaviors such as binge
eating and cravings for various sensations are also a subject of
the present invention.
[0152] In an important aspect of the present invention analysis of
alleles are involved such alleles may be, for example D.sub.2 TaqI
A1, B1, C1 or exon.sup.6-7 haplotype HTR2A-C allele homozygous
OB-homozygosity for <208 BP alleles of 1875 dinucleotide repeat
polymorphism human chromosome 2 microsatellite polymorphism,
APO-D-TaqI 2.2 or 2.7 BP, or OB gene D7S1875. One most important
allele of the present invention is the DRD2A1 allele. In one
possible embodiment of the present invention, various key
ingredients of the composition may be contained in cyclodextrin,
particularly where an interveineous or bolus injection might be
part of administrating the composition of the present invention. In
certain other aspects, consumption of the composition as described
in the kit may be advised when the subject has at least one of the
following alleles: D1 (homozygosity of Dde A1) D2 (TaqI A1) D4
(VNTR 2) D5 (dinucleotide 13 alleles range 135-159 BP) DAT1 VNTR
(10/10) D_H (TaqI B1 allele). This indicating an improved
likelihood for a successful response to the composition
parenterally or enterally administered.
[0153] Other aspects of RDS behavior include Autism, Tourette's
Syndrome or ADHD. In an important aspect, the addition of effect
amounts of rhodiola or huberzine add an important aspect to the
composition of the present invention. Other RDS behaviors include
Pathological gambling and wherein the presence in a subject of at
least one of the following alleles: D (homozygosity of Dde A), D
(Taq A, B, C), indicates an improved likelihood for a successful
response. Such behaviors may also include pathological violence,
Schizoid/Avoidant (SAB), Aggression, Anger, Hostility, or
Posttraumatic Stress Disorders, wherein the presence in the subject
of at least one of the following alleles D (Taq A, B, C, exon), DAT
(VNTR/), mNOSIa--homozygosity for .ltoreq.BP allele indicates an
improved likelihood for a successful response. In certain cases,
the RDS behavior may be PMS wherein the presence of at least one of
the following alleles DAT1 VNTR (10/10) D.sub.2 TaqI A1, B1, C1,
exon.sup.6-7 haplotype, or alleles from the DRD1, DRD2, DRD4, HTT,
HTRIA, TDO2, D.beta.H, MAO, COMT, GABRAB, GABRB3, PENk, ADRA2A or
ADRA2C genes indicates an improved likelihood for a successful
response. Substance abuse disorder is also an important RDS
behavior, potentially treated by the by the present invention.
[0154] In another important embodiment, the alleles being detected
indicate at least one RDS behavior, and in this case the allele is
at least one of DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, HTT, HTR1A,
TDO2, DBH, ADRA2A, ADRA2C, NET, MAOA, COMT GABRA3, GABRB3, CNR1,
CNRA4, NMDAR1, PENK, AR, CRF, HTR1D_HTR2A, HTR2C, interferon-_CD8A,
or PS1 genes. Various other RDS behaviors are still an aspect of
the present invention. These behaviors include mania, OCD, sexual,
sleep, grade school behavior, gambling, learning, inattention,
ADHD, ADDR, impulsivity, MDE, CD, hyperactivity, phobia, schizoid
behavior, general anxiety, somatization, drugs, IV drugs, read,
ODD, tics, alcohol, or tobacco use. In an important aspect, the
allele being analyzed as pointing to certain RDS behaviors is the
ventr polymorphism of the maoa gene as stated in claim 29. Such RDS
behavior may be schizoid or avoidant.
[0155] Most often important alleles of the present invention
include DRD.sub.2 gene A.sub.1 allele, the DAT.sub.1 gene, VNTR
10/10 allele, or the D.beta.H gene B.sub.1 allele. Another allele
of significance is an increased number of (AAT).sub.n triplet
repeats in the CNR1 gene. Other aspects of the present invention
involve the figment of RDS behavior that includes drug use,
obesity, anxiety, depression, psychoses, hostility, paranoid
ideation, obsessive-compulsive behavior, neuroticism and
over-conscientiousness. In certain important aspects the kit of the
present invention may involve analysis of an allele selected from
the group consisting of an increased number of the D7S1873,
D7S1875, D7S514 or D7S680 dinucleotide repeats in the OB gene. In
an important aspect, the allele detecting is by determining the
existence of the D.sub.2A1 allele of the DRD2 gene and an allele
selected from the group comprising the an increased number of the
D7S1873, D7S1875, D7S514 or D7S680 dinucleotide repeats in the OB
gene.
[0156] In 1999, the present inventor conceived of the idea to
develop a novel approach to both diagnose and treat RDS and related
behaviors via an integrated, systematic approach involving a number
of non-obvious components interacting as a commercially produced
kit. The kit consists of a non-invasive buccal swab to diagnose the
DNA of a suspected RDS proband (a single or multiple genes); an RDS
Diagnostic Inventory Scale; a neutraceutical formula consisting of
two parts (the SMART Formula plus a specific herbal remedy for each
known RDS subtype behavior, i.e. alcoholism, cocaine dependence,
smoking behavior, carbohydrate binging, PMS, PMDD, PTSD, ADD, ADHD,
pathological gambling, episodic dyscontrol, sexual addiction
etc.)
[0157] The invention first provides a composition for the treatment
of Reward Deficiency Syndrome (RDS) behaviors in a subject. In
certain aspects, this composition includes at least one of the
following components: an opiate destruction-inhibiting amount of at
least one substance which inhibits the enzymatic destruction of a
neuropeptidyl opiate, the substance being either amino acids,
peptides, and structural analogues or derivatives thereof; a
neurotransmitter synthesis-promoting amount of at least one
neurotransmitter precursor, the neurotransmitter precursor being
either a dopamine precursor such as L-Tyr, L-Phe and L-dopa, a
serotonin precursor such as L-Trp and 5-hydroxytryptophan, or a
gamma amino butyric acid (GABA) precursor such as L-glutamine,
L-glutamic acid, and L-glutamate; a tryptophan concentration
enhancing amount of chromium picolinate or chromium nicotinate; a
compound that releases enkephaline, the enkephaline releaser being,
but not limited to, a peptide, and preferably a D-amino acid
containing peptide; or an opiate antagonist amount of at least one
compound which blocks the effects of an opiate at either the delta,
mu, kappa, sigma, or epsilon receptors. The type of enkephalinase
inhibitors, the neurotransmitter precursor, opiate
destruction-inhibiting substance, opiate antagonist, and/or the
chromium compound, in addition to the compounds specifically listed
above, are further described herein this application and are
encompassed by this invention. In certain preferred aspects of the
invention, the composition is used in preventing or reducing a
subject's unwanted weight. In certain other aspects of the
invention, the composition is preferably used in the treatment of
Attention Deficits Disorder, attentional processing or memory. In
this embodiment, for the treatment of Attention Deficits Disorder,
Attention-Deficit-Hyperactivity Disorder (ADH D) attentional
processing or memory, the composition more preferably includes a
neurotransmitter synthesis promoting amount of at least one
neurotransmitter promoting substance selected from the group
Rhodila or Hubazine or any substance known to enhance the
functional amount of the neurotransmitter. As used herein,
"derivative" may refer to a chemically modified compound, and
analog refers to a different compound that is similar properties or
structure to the compound it is being compared.
[0158] In certain embodiments of the invention, this composition
may be used in the treatment of all RDS related behaviors disclosed
herein. RDS behaviors are those behaviors related to a chemical
imbalance manifests itself as one or more behavioral disorders
related to an individual's feeling of well-being with anxiety,
anger or a craving for a substance. RDS behaviors include,
alcoholism, SUD, smoking, BMI or obesity, pathological gambling,
carbohydrate binging, axis 11 diagnosis, SAB, ADD/ADHD, CD, TS,
family history of SUD, and Obesity.
[0159] The invention also provides a method of treating a subject
for RDS behaviors, including but not limited to SUD, Obesity,
Smoking, Tourettes Syndrome, ADHD, Schizoid/Avoidant Behavior,
Aggression, Posttraumatic stress syndrome, PMS or tobacco use. RDS
behaviors are not specifically limited to these disorders, as many
types of sub-disorders are encompassed by these conditions. For
example, Attention Deficit Hyperactivity Disorder (ADHD) may
manifest itself as alcohol, drugs, obsessive compulsive behaviors,
learning disorders, reading problems, gambling, manic symptoms,
phobias, panic attacks, oppositional defiant behavior, conduct
disorder, academic problems in grade school, smoking, sexual
behaviors, schizoid, somatization, depression, sleep disorders,
general anxiety, stuttering, and tics disorders. All these
behaviors, and others described herein as associated with RDS
behaviors or genes involved in the neurological pathways related to
RDS, are included as RDS behaviors as part of this invention.
Additionally, many of the clinical terms used herein for many
specific disorders that are RDS disorders are found in the Quick
Reference to the Diagnostic Criteria From DSM-IV.about., The
American Psychiatric Association, Washington, D.C., 1994, 358
pages. Specific disorders whose definitions can be found in this
reference, and their code numbers within the DSM-IV.about. include
Anxiety disorders, include Panic Disorder Without Agoraphobia,
300.01, Panic Disorder With Agoraphobia, 300.21, Agoraphobia
Without History of Panic Disorder, 300.22, Specific Phobia, 300.29,
Social Phobia, 300.23, Obsessive-Compulsive Disorder, 300.3,
Posttraumatic Stress Disorder, 309.81, Acute Stress Disorder,
308.3, Generalized Anxiety Disorder, 300.02, Overanxious Disorder
of Childhood, 300.02, Anxiety Disorder Due to [Indicate general
medical condition], 293.89, Substance Induced Anxiety Disorder,
293.89, Anxiety Disorder NOS, 300.00; Attention Deficit and
Disruptive Behavior Disorders, including
Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive
Type, 314.00, Attention-Deficit/Hyperactivity Disorder,
Predominately Hyperactivity-Impulsive Type, 314.01
Attention-Deficit/Hyperactivity Disorder, Combined Type, 314.01,
Attention-Deficit/Hyperactivity Disorder NOS, 314.9, Conduct
Disorder, 312.8 Oppositional Defiant Disorder, 313.81, Disruptive
Behavior Disorder NOS, 312.9; Bipolar Disorders including Bipolar I
Disorder, 296.0x, 296.40, 296.4x, 296.6x, 296.5x, and 296.7,
Bipolar II Disorder, 296.89, Cyclothymic Disorder, 301.13, Bipolar
Disorder NOS, 296.80; Depressive Disorders including Major
Depressive Disorder, Recurrent, 296.3, Dysthymic Disorder, 300.4,
Depressive Disorder NOS, 311, Major Depressive Disorder, Single
Episode, 296.2; Eating Disorders including Bulimia Nervosa,
Nonpurging Type, 307.51, Bulimia Nervosa, Purging Type, 307.51,
Anorexia Nervosa, 307.1, Eating Disorder NOS 307.50; Impulse
Control Disorders including Intermittent Explosive Disorder,
312.34, Kleptomania, 312.32, Pyromania, 312.23, Pathological
Gambling, 312.31, Trichotillomania, 312.39, Impulse Control
Disorder NOS, 312.30; Personality Disorders including Antisocial
Personality Disorder, 301.7, Avoidant Personality Disorder, 301.82,
Obsessive-Compulsive Personality Disorder, 301.4, Schizoid
Personality Disorder, 301.20; Schizophrenia including Paranoid
Type, 295.30, Disorganized Type, 295.10, Catatonic Type, 295.20,
Undifferentiated Type, 295.90, Residual Type, 295.60,
Schizoaffective Disorder, 295.70, Schizophreniform Disorder,
295.40; Sleep Disorders including Primary Sleep Disorders such as
Dyssomnias, which include Primary Insomnia 307.42, Primary
Hypersomnia 307.44, Narcolepsy 347, Circadian Rhythm Sleep
Disorder, 307.45, Dyssomnia NOS 307.47, Parasomnias which include
Nightmare Disorder 307.47, Sleep Terror Disorder 307.46,
Sleepwalking Disorder 307.46, Parasonmia NOS 307.47, Sleep
Disorders Related to Another Mental Disorder which include insomnia
related to [Indicate Axis I or Axis II disorder] 307.42,
Hypersomnia related to [Indicate Axis I or Axis II disorder]
307.44, Other Sleep Disorders which include Sleep Disorder due to
[Indicate the General Medical Condition] 780.xx, Substance Induced
Sleep Disorder 78o.xx; Substance Use Disorders including Alcohol
Related Disorders such as Alcohol-Induced Psychotic Disorder, with
delusions, 291.5, Alcohol Abuse, 305.00, Alcohol Intoxication,
303.00, Alcohol Withdrawal, 291.8, Alcohol Intoxication Delirium,
291.0, Alcohol Withdrawal Delirium, 291.0, Alcohol-Induced
Persisting Dementia, 291.2, Alcohol-Induced Persisting Amnestic
Disorder, 291.1, Alcohol Dependence, 303.90, Alcohol-Induced
Psychotic Disorder, with hallucinations, 291.3, Alcohol-Induced
Mood Disorder, 291.8, Alcohol-Induced Anxiety Disorder, 291.8,
Alcohol-Induced Sexual Dysfunction, 291.8, Alcohol-Induced Sleep
Disorder, 291.8, Alcohol-Related Disorder NOS, 291.9, Alcohol
Intoxication, 303.00, Alcohol Withdrawal, 291.8, Nicotine Related
Disorders which include Nicotine Dependence, 305.10, Nicotine
Withdrawal, 292.0, Nicotine-Related Disorder NOS, 292.9,
Amphetamine Related Disorders which include Amphetamine Dependence,
304.40, Amphetamine Abuse, 305.70, Amphetamine Intoxication,
292.89, Amphetamine Withdrawal, 292.0, Amphetamine Intoxication
Delirium, 292.81, Amphetamine-Induced Psychotic Disorder with
delusions, 292.11, Amphetamine-Induced Psychotic Disorders with
hallucinations, 292.12, Amphetamine-Induced Mood Disorder, 292.84,
Amphetamine-Induced Anxiety Disorder, 292.89, Amphetamine-Induced
Sexual Dysfunction, 292.89, Amphetamine-Induced Sleep Disorder,
292.89, Amphetamine Related Disorder NOS, 292.9, Amphetamine
Intoxication, 292.89, Amphetamine Withdrawal, 292.0, Cannabis
Related Disorders which include Cannabis Dependence, 304.30,
Cannabis Abuse, 305.20, Cannabis Intoxication, 292.89, Cannabis
Intoxication Delirium, 292.81, Cannabis-Induced Psychotic Disorder,
with delusions, 292.11, Cannabis-Induced Psychotic Disorder with
hallucinations, 292.12, Cannabis-Induced Anxiety Disorder, 292.89,
Cannabis Related Disorder NOS, 292.9, Cannabis Intoxication,
292.89, Cocaine Related Disorders which include Cocaine Dependence,
304.20, Cocaine Abuse, 305.60, Cocaine Intoxication, 292.89,
Cocaine Withdrawal, 292.0, Cocaine Intoxication Delirium, 292.81,
Cocaine-Induced Psychotic Disorder with delusions, 292.11,
Cocaine-Induced Psychotic Disorders with hallucinations, 292.12,
Cocaine-Induced Mood Disorder, 292.84, Cocaine-Induced Anxiety
Disorder, 292.89, Cocaine-Induced Sexual Dysfunction,
[0160] 292.89, Cocaine-Induced Sleep Disorder, 292.89, Cocaine
Related Disorder NOS, 292.9, Cocaine Intoxication, 292.89, Cocaine
Withdrawal, 292.0; Hallucinogen Use Disorders which include
Hallucinogen Dependence, 304.50, Hallucinogen Abuse, 305.30,
Hallucinogen Intoxication, 292.89, Hallucinogen Withdrawal, 292.0,
Hallucinogen Intoxication Delirium, 292.81, Hallucinogen-Induced
Psychotic Disorder with delusions, 292.11, Hallucinogen-Induced
Psychotic Disorders with hallucinations, 292.12,
Hallucinogen-Induced Mood Disorder, 292.84, Hallucinogen-Induced
Anxiety Disorder, 292.89, Hallucinogen-Induced Sexual Dysfunction,
292.89, Hallucinogen-Induced Sleep Disorder, 292.89, Hallucinogen
Related Disorder NOS, 292.9, Hallucinogen Intoxication, 292.89,
Hallucinogen Persisting Perception Disorder (Flashbacks), 292.89;
Inhalant Related Disorders which include Inhalant Dependence,
304.60, Inhalant Abuse, 305.90, Inhalant Intoxication, 292.89,
Inhalant Intoxication Delirium, 292.81, Inhalant-Induced Psychotic
Disorder, with delusions, 292.11, Inhalant-Induced Psychotic
Disorder with hallucinations, 292.12, Inhalant-Induced Anxiety
Disorder, 292.89, Inhalant Related Disorder NOS, 292.9, Inhalant
Intoxication, 292.89; Opioid Related Disorders which include Opioid
Dependence, 304.00, Opioid Abuse, 305.50, Opioid Intoxication,
292.89, Opioid Intoxication Delirium, 292.81, Opioid-induced
Psychotic Disorder, with delusions, 292.11, Opioid-Induced
Psychotic Disorder with hallucinations, 292.12, Opioid-induced
Anxiety Disorder, 292.89, Opioid Related Disorder NOS, 292.9,
Opioid Intoxication, 292.89, Opioid Withdrawal, 292.0;
Polysubstance Related Disorders which include Polysubstance
Dependence, 304.80; Tic Disorders which include Tourettes Disorder,
307.23, Chronic Motor or Vocal Tic Disorder 307.22, Transient Tic
Disorder 307.21, Tic Disorder NOS 307.20, Stuttering 307.0,
Autistic Disorder, 299.00, and Somatization Disorder 300.81.
Additionally, other RDS disorders are defined as would be known to
one of skill in the art, such as Novelty Seeking, defined in
(Clonigen et al., 1993). Other disorders, if not specifically
defined herein, are the same as commonly known to one of skill in
the art, including common abbreviations. The second part of the
invention includes but not limited the following genes: DRD1, DRD2,
DRD5, DATI, HTT HTR IA, TDO2, DBH, ADRA 2A, ADRA2C, NET, MAQA,
COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, DRD3,
DRD4. HTR1DI3, HTR2A, HTR2C, interferon-.about.y, CD8A, PSi, TDO2,
HTT, APOE. The third part of the patent is to include an RDS
Inventory Scale. The fourth part of the patent involves the
SYNERGENE Neutralife product line and includes the following
information which relates to the brain reward cascade, the Reward
Deficiency Syndrome and both nutraceuticals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0161] The following information forms an important basis of the
invention. In an embodiment of the invention, each gene studied
will be specified, and the survey will pinpoint the primary
presenting problem which will dictate the type of neutraceutical to
be employed. It is anticipated the diagnosis and treatment unit
will consist of four parts: four swabs, one scale, a bottle of the
RDS neutraceutical, and a selection of herbal or other remedies to
ameliorate the specific RDS behavior which is the focus of
attention.
The above references do not limit in any shape or form the type of
swab, envelope, survey type, or type of bottles, or caplets,
capsules, liquid, gums, powder, bars or any configuration, size
standard to the art.
Allelic Diagnosis of Susceptibility to Compulsive Disorder
[0162] In an important embodiment, the present invention concerns a
method for diagnosing and detecting compulsive disorder
susceptibility of an individual. The method comprises initially
obtaining a DNA sample of said individual and then determining the
presence or absence of particular human D2 receptor gene alleles in
said sample. Detection of said alleles in the sample are indicative
of predilection to compulsive disorder. A most preferred embodiment
is to detect predisposition to impulsive, addictive, and compulsive
disorders such as, but not limited to, alcoholism, obesity,
smoking, polysubstanceabuse and drug addiction, particularly
because said alleles have been found to be present in a majority of
individuals clinically diagnosed with these compulsive disorders.
The human D2 receptor gene A1, Bi, and .about.haplotype I alleles
are most preferably detected in said sample.
[0163] A preferred embodiment includes a four component unit or kit
comprising of a. the gene test, b. an inventory scale, c. the SMART
formula, d. the SYNERGENE herbal formula. Also, in one form of the
embodiment, the Kit would contain the forms as illustrated in
Tables 1 through 3. TABLE-US-00030 TABLE 1 Self Observation Scale
NAME: AGE: DOB: SEX: ADDRESS: TELEPHONE: FAX: E-MAIL: DATE:
PHYSICAL CHARACTERISTICS: WEIGHT HEIGHT BLOOD PRESSURE / RESTING
HEART RATE MARITAL STATUS: MARRIED , DIVORCED , WIDOWED , SEPARATED
, INDICATE HOW LONG: EDUCATION (CHECK HIGHEST LEVEL): HIGH SCHOOL
DIPLOMA , SOME COLLEGE , BUSINESS OR TECHNICAL SCHOOL , COLLEGE
DEGREE , GR OCCTORATE IN THE BOXES BELOW, PLEASE CHECK ALL OF THE
DESCRIPTIONS WHICH APPLY. THE BOXES RANCE FROM "1" INDICATING NONE
OR NON-APPLICABLE UP TO "5" INDICATING A PROBLEM OF SEVERE
INTENSITY. BEHAVIORS WHICH BEHAVIORS WHICH NOW APPLY OR HAVE
APPLIED TO YOU. APPLY OR HAVE APPLIED TO MEMBERS OF YOU 1 2 3 4 5 1
2 3 Alcoholism Alcoholism Crack/Cocaine Addiction Crack/Cocaine
Addiction Carbohydrate Bingeing Carbohydrate Bingeing Nicotine Use
or Abuse Nicotine Use or Abuse Hyperactivity Hyperactivity Sexual
Hyperactivity Sexual Hyperactivity Pathological Violence
Pathological Violence PATHOLOGICAL GAMBLING PATHOLOGICAL GAMBLING
Tourette's Disorder Tourette's Disorder Autism Autism I chose to
buy this product because of my: Alcoholism or Problem Drinking ,
Crack/Cocaine Addiction , Carbohydrate Bingeing , Smoking History ,
Hyperactivity , , Sexual Hyperactivity , Pathological Violence ,
Pathological Gambling , Tourette's Disorder
[0164] TABLE-US-00031 TABLE 2 a good almost none of a little of
some of part of all of Read each Item carefully, then check the
following boxes to describe yourself the time the time the time the
time the time I crave a substance or activity or behavior. I use
substances such as food, alcohol, etc. to change my mood or to
relax. To adjust to stress or problems I pretend nothing is wrong:
I ignore the problem. I abuse coffee, aspirin, medications to try
to cope better. I have a judgmental attitude; I Complain and
criticize. well well below below above above EMOTIONAL average
average average average average My coping skills are: My resilience
(ability to "bounce back" during times of stress or trouble) is: My
desire or need to control others or situations is: My spontaneity
(ability to act without being "guarded" or defensive) is: My
ability to function "smoothly" and "coolly" is: My ability to
function calmly in times of stress or emergency is: My ability to
function patiently with others in times of stress or emergency is:
My tolerance of surrounding noise and confusion is: My tolerance of
surrounding flashing lights and confusion is: The number of bad
emotional feelings I have is: My ability to concentrate in all
types of environments is: well well below below above above
PHYSICAL average average average average average My ability to fall
asleep is: My ability to sleep throughout the night is: My ability
to sleep soundly and deeply is: The number of pleasant dreams which
I have are: My ability to remember my dreams is: The number of
times in which I awaken refreshed and energetic is: My energy level
throughout the day is: My energy level at the end of the day is: My
sexual energy level is: My sexual drive is: My level of
uncontrollable anger is: My level of calm relaxation is:
[0165] TABLE-US-00032 TABLE 3 My impulsivity is: The number of
headaches I have is: The number of muscle aches, pains, soreness,
joint tenderness is: My overall background level of pain is: My
appetite stability (having an appetite that is roughly the same day
in and day out) is: The number of times I get a nervous stomach is:
My accident proneness is: The amount of bad physical feelings I
have is: well well below below above above SPIRITUAL average
average average average average My sense of emptiness is: My sense
of a Loss of Meaning about life is: My sense of doubt about myself
and the meaning of what I do is: The number of times in which I
feel like a martyr (feeling like a victim) is: The number of times
I find myself wishing for or looking for a "magical" solution is:
The number of times I am somewhat "hard" and unforgiving of others
is: My sense of a Loss of Direction is: My Need to Prove myself is:
My cynicism (distrust, pessimism, skepticism) is: My apathy
(indifference, lack of concern) is: well well below below above
above MEMORY average average average average average My short-term
memory is: My immediate recall (the ability to recall a word, a
name, event, date, etc.) is My ability to concentrate and learn is:
My ability to retain what I have read or heard is: The ease with
which I learn is: My Interest in reading is: My Interest in
studying my schoolwork or for my job is:
[0166] After thousands of years of speculation about the nature of
alcoholism and other impulsive, addictive, compulsive behaviors,
and half a century of intensifying research into their causes, a
consensus is beginning to emerge that is agreed to by most
scientists in the field: craving for abusable substances is a
malfunction of the reward centers of the brain involving the
neurotransmitters the enzymes that control them and that certain
other repetitive behaviors are due to imbalances of
neurotransmitter systems.
[0167] As yet, this information has not led to dependable methods
of prevention or cure. In the area of addiction, abstinence is
still the only sure way to combat addiction to alcohol or drugs.
But we now have adjuncts that make treatment easier. Tests are
under development that will enable us more accurately to identify
individuals at risk. The goal is to diagnose individuals "at risk"
for RDS behaviors sufficiently early to prevent the impulsive,
addictive, or compulsive behavior from becoming established and to
diagnose them accurately enough to help in the removal of the
treatment retarding "denial" phenomenon. An additional goal is to
provide more targeted treatment in tertiary probands either for
alcoholism with bromocryptine as a function of one's genome
(Lawford et al., 1995) or for carbohydrate binging with chromium
response as a function of one's genome (Blum et al., 1999). The
important point to make here is that as we make progress with
regard to understanding the human genome, and as we continue to
identify genetic links to polymorphisms for many disease states the
more refined treatment approaches will be derived from such
knowledge. In fact we believe, a new scientific term will emerge in
this new millennium--Pharmacogenomics. This area of endeavor will
help define the role of our genome in terms of individual
differences with regard to a number of drug responses including
pharmacokinetics and pharmatherapeutics.
[0168] The relationships among a wide range of impulsive,
addictive, compulsive behaviors--from alcoholism to drug addiction
to food abnormalities to attention deficit disorder--are now
beginning to be understood, and the door to effective therapies is
beginning to open wide.
[0169] The first definitive insight grew out of the discovery that
addiction-free behavior is facilitated by an adequate supply of
neurotransmitters; the availability of enzymes to regulate the
supply of such brain chemicals and maintain balance among them; and
the presence of receptors to give neurotransmitters access to the
neurons that determine feelings of well-being. A malfunction in any
of these areas may trigger a biogenic behavioral disorder.
[0170] The second definitive insight was that these various RDS
disorders involve complex interactions of neurotransmitters. In
alcoholism, for example, we may see the progressive involvement of
serotonin, opioid peptides, GABA, dopamine, and--in some
instances--norepinephrine. Each in its turn initiates or promotes
changes in the brain's biochemistry.
[0171] The third definitive insight grew out of the discovery of an
association between a severe form of alcoholism and defects in the
D.sub.2 gene in the reward area of the brain and other dopaminergic
genes (i.e. the dopamine transporter gene and the dopamine
.beta.-hydroxylase gene). This genetic defect leads to such
behavioral disorders, as severe alcoholism, polysubstance
abuse/dependence, attention deficit disorder, and carbohydrate
binging, severe gambling, nicotine abuse among other behavioral
abnormalities.
[0172] The fourth definitive insight was that these physiological
conditions constitute a somatopsychological syndrome: sequential
changes in brain chemistry that cause or trigger changes in
feelings, beliefs, and behaviors. Just as emotional and mental
disturbances can lead to physical illness as in psychosomatic
medical theory, so somatic deficiencies or imbalances can cause
emotional and mental disturbances including compulsive diseases,
anxiety, hostility, depression, or anti-social attitudes. If a
genetic defect is the original cause of the behavioral anomaly,
somatopsychological responses may be the mind's way of coping with
or adapting to the problem in the gene. The recent scientific
literature continues to support this definitive insight (see meta
analyses by Uhl et al., 1993; Blum et al., 1995; and, Noble,
1998).
[0173] The initial work opening the way to an understanding of
common causes underlying compulsive behaviors was carried out by
the present inventor and associates in 1990. A variant of the
D.sub.2 gene was shown to be associated with a severe form of
alcoholism. This sparked numerous studies of similar associations
of gene variants with a wide spectrum of related compulsive
disorders.
[0174] As previously discussed, numerous studies found
significantly high prevalence of the D.sub.2 variant gene in
subjects with ADHD, Tourette's Disorder, conduct disorder, and
posttraumatic stress disorder (PTSD). One striking example was that
59 percent of Vietnam veterans with PTSD carried the D.sub.2 gene
variant, compared with only 5 percent of those who did not. These
results suggest that not only do drug abuse, ADHD, Tourette's
Disorder, conduct disorder, and PTSD have a common genetic origin,
but that the D.sub.2 gene is one of the primary causative
factors.
[0175] Given the widespread prevalence of ADHD in children and the
frequent association of ADHD with substance use disorder and a wide
range of other behavioral disorders, it seems reasonable to suggest
that childhood ADHD may be a predisposing cause in these other
anomalies or at least a pre-existing condition.
[0176] Gittleman (1985), for example, found a significant
correlation between ADHD and adult substance use disorder. Studies
by Comings (1991) showed an intimate relationship between
Tourette's Disorder and ADHD. In his various studies, 50 percent to
80 percent of persons with Tourette's Disorder had ADHD, and 20
percent to 60 percent of their relatives, who themselves had
Tourette's Disorder, also had ADHD.
[0177] While the exact identity of the genes causing ADHD and
Tourette's Disorder are still unknown, mutations of genes affecting
dopamine function have been strongly implicated. Certainly, the
D.sub.2 gene appears to be one of the primary genes involved. One
of its variants seems to lower the number of D.sub.2 receptors,
thereby affecting dopamine function, and perhaps playing the role
of risk factor for ADHD, Tourette's disorder, conduct disorder,
anti-social personality disorder, food binging, smoking behavior,
posttraumatic stress disorder, pathological gambling, and
polysubstance dependence, including severe alcoholism.
[0178] While other genes playing a role in these interrelated
disorders are still to be identified, the concept of a "Reward
Deficiency Syndrome" (RDS), first proposed by KB, unites addictive,
impulsive, and compulsive behaviors and may explain for the first
time the way in which simple genetic anomalies give rise to complex
aberrant behavior.
[0179] As Milam (1992) pointed out in his landmark paper, "The
Alcoholism Revolution", which may serve the addiction field best by
providing a blueprint for action: " - - - meanwhile, the ugly
battle for control will continue in the political arena. The public
has heard the hostile allegations (Fingeratte 1988) that nobody
understands alcoholism, that alcoholism does not exist, that it is
merely willful misbehavior, that since treatment does not work
anyway, only the briefest and least expensive should be funded. " .
. . every word they say chagrins us" . . . because all of these
criticisms are true of the bankrupt psychogenic approach to
alcoholism; none, however, is true of the biogenic approach."
[0180] In a more modern approach to treat or prevent the onset of
RDS behaviors, we know that premorbid behaviors to substance use
disorder, including nicotine dependence, food addiction, violence,
sexual deviancy, acting out in a variety of uncontrollable type
behaviors, potentially could be treated with behavioral therapy,
along with amino acid therapies, pharmaceuticals, electrical
therapies, acupuncture type therapies, subluxation correction,
biofeedback therapies, which all work on the neurophysiological
mechanisms controlled by our brain. This novel approach will short
circuit the genetic roots to this premorbid trait and reduce RDS
behaviors.
[0181] It is the hope of the inventor that, through rigorous
scientific exploration in both animals and humans, still unsolved
mysteries about our "addictive brains" will become less mysterious.
However, at this juncture we believe that great progress already
has been made and it is time to move from the bench to the clinic
and begin to apply our present knowledge base. In this regard we
are working, in different ways, toward the development of standard
diagnosis and treatment of "Reward Deficiency Syndrome".
[0182] The inventor is hopeful that he will find an optimal
amino-acid composition which will constitute the core of the
short-term intravenous bolus therapy similar to what has been
proposed in this provisional application.
[0183] The inventor is convinced that treatment of RDS associated
behaviors should consist of: [0184] physiological and psychological
diagnosis (based on genetic testing, brain electrophysiological
mapping and psychometric testing); [0185] re-balancing the
neurotransmitters (through pharmacotherapies and amino acid based
therapies); [0186] neurotransmitter activation (through
biofeedback, cranial electrostimulation,
acupuncture/auriculotherapy and perhaps chiropractic induced
subluxation); and, [0187] traditional therapies (including
psychotherapy, self-help groups, structured aftercare programs,
etc.).
[0188] They also are convinced the treatment of RDS behaviors in
the future will include the development of a wide variety of
treatment settings which include development of community
outpatient clinics, day hospitals, inpatient treatment programs,
etc. These treatment programs will have programs geared for all the
subtypes of behavioral problems under one-roof similar to the a
one-stop shopping network. All of the RDS behaviors will be treated
together in one location (alcoholism, substance use disorder,
smoking, eating disorders-carbohydrate bingers, pathological
gambling, sex addiction, violent offenders, and attention deficit
hyperactivity disorder).
[0189] It is the goal of the inventors to continue the search for
solutions to the world's oldest dilemia our addictive brains and we
believe through sound scientific exploration as described herein,
we will as humans begin to learn how to ease oue "legacy of
pain".
[0190] In Alcohol and the Addictive Brain (1991) Blum (in
collabration with Payne) stated: "In the remainder of this century
and the early decades of the century to come, I think that we will
see neurobiology, neuropharmacology, biogenetics, psychiatry, and
medicine moving forward in close coordination to reduce the
devastating behavioral and social costs of faulty brain function.
My vision of the future is a world in which the chemical and
electrical functions of the brain are understood; the problem of
chemical imbalances as they affect behavior has been solved; the
role of genetic anomalies in defective brain chemistry is
understood; pharmaceutical and nutritional intervention as an
adjunct to Twelve-Step programs and professional treatment is
precise and effective; and the technique of defective-gene
replacement has been perfected, enabling us to break (or repair)
the genetic chain of inherited addiction. In this world, each
individual will be able to enjoy the inborn legacy of reward and
pleasure without having the need for addictive substances, without
having to pay the price of addiction and pain.
[0191] Currently, due to poorly distributed knowledge regarding the
etiology of the variety of RDS behaviors, all the treatment
categories listed above are treated separately. We the inventors,
believe that with the knowledge base described in this patent
application the rationale of developing standard protocols for the
treatment of all RDS behaviors (Intravenous amino-acid bolus
short-term therapy) in integrated groups is clear and clearly will
be cost effective. This should give all of us involved in the
diagnosis and treatment of impulsive, addictive, compulsive
disorders hope for the future.
[0192] Moreover, it is important to realize that awarding of this
invention is important because the commercialization of this
knowledge will positively benefit millions here in America and
around the globe. For example, in the United States alone there are
18 million alcoholics, 28 million children of alcoholics, 6 million
cocaine adicts, 14.9 million people who abuse other substances, 25
million people addicted to nicotine, 54 million who are at least 20
pounds overweight, 3.5 million school-aged children with ADHD or
Tourette's syndrome, and about 3.7 million compulsive gamblers. The
inventors believe that using amino-acid bolus intravenous therpy on
a short term and repeated basis coupled with genotyping humans for
the alleles of the DRD2 gene as well as other genes (described in
Blum's PCT application) related to psychological disorders in the
present invention is indeed the first steps toward rational
treatment for a devastating problem in society.
[0193] The invention first provides intravenous compositions for
the treatment of RDS behaviors in a subject. In certain aspects
this composition comprises the following:
Composition A.
[0194] A composition comprising of an intravenous amount of any
polar or non-polar substance known to inhibit the
enzymatic-destruction of an opiate/peptidyl opiate or opioid. The
intravenous solution must contain an opiate destruction-inhibiting
amount of at least one substance which inhibits the enzymatic
destruction of a neuropeptidyl opiate, the substance being either
amino acids, peptides, and structural analogues or derivatives
thereof and zinc/zinc complexes. Composition B. [0195] A
composition comprising of an intravenous amount of any polar or
non-polar substance known to act as a neurotransmitter
synthesis-promoting amount of at least one neurotransmitter
precursor, the neurotransmitter precursor being either a dopamine
precursor such as L-Tyr, L-phe and L-dopa, a serotonin precursor
such as 1-Trp and 5-hydroxytrytophan, or a gamma amino butryic acid
(GABA) precursor such as L-glutamine, L-glutamic acid, and
L-glutamate. Composition C. [0196] A composition comprising of an
intravenous tryptophan concentration enhancing amount of the
mineral chromium. The chromium utilized includes but is not limited
to chromium piccolinate or chromium nicotinate or polynicotinate
salts or other chelates. Composition D. [0197] A composition
comprising of an intravenous polar or non-polar compound known to
cause the release of neuronal opiate peptides/peptidyl
opiates/opioid peptides such as enkephaline. The enkephaline
releaser being, but not limited to, a peptide, and preferably a
D-amino acid containing peptide. Composition E. [0198] A
composition comprising of an intravenous polar or non-polar
compound known to promote the synthesis and enhance the functional
activity of serotonin, opioid peptides, and catecholamines
(dopamine and norepinephrine) selected from the group Rhodiola or
huperzine, but not limited to these substances. Composition F
[0199] A composition comprising of a intravenous compound known to
promote neuronal dopamine release in the nucleus accumbens,
selected from the group consisting of ethanol and calcium, but not
limited to these substances.
[0200] The type of enkephalinase inhibitors, the neurotransmitter
precursor, chromium compound, enkephalinase releaser and
neurotransmitter synthesis promoting substance and enhancer of
neurotransmitter functional activity alone or combined (combining
at least one composition A-E), in addition to the compounds
specifically listed above, are further described herein in this
application and are encompassed by this invention. In certain
preferred aspects of the invention, the composition is preferably
used in the treatment of SUD and other preferred embodiments such
as smoking behavior, carbohydrate bingeing and even ADHD,
attentional processing and/or memory, and stress. As used herein
"derivative" may refer to a chemically modified compound, and
"anolog" refers to a different compound that has similar properties
or structure to the compound it is being compared.
[0201] In certain aspects of the invention, these intravenous
compositions which have never been used before as short-term bolus
therapy, may be used in the treatment of all RDS related behaviors
previously disclosed in Blum's published PCT application of Apr.
29, 1998 which has been nationalized in numerous countries on Oct.
29, 1999 and Nov. 29, 1999. RDS behaviors are those behaviors
related to a chemical imbalance which manifests itself as one or
more behavioral disorders related to an individual's feeling of
well-being with anxiety, SUD, smoking, Body Mass Index, Obesity,
carbohydrate binging, pathological gambling, sexual deviancy, axis
II diagnosis, Schizoid avoidant behavioral cluster, ADD/ADHD,
conduct disorder, Tourettes Syndrome, family history of SUD, and
obesity as well others previously defined as well as other non-RDS
disorders as defined herein.
[0202] The inventor believes that various psychological disorders
are linked by a common biological substrate, a "hard-wired" system
in the brain that provides pleasure in the process of rewarding
certain behavior. The inventors propose in this invention that an
inborn chemical inbalance that alters the intracellular signaling
in the nucleus accumbens or other limbic reward regions could
supplant an individual's feeling of well-being with anxiety, anger
or a craving for a substance (i.e. alcohol) that can alleviate the
negative emotions. This chemical inbalance manifests itself as one
or more behavioral disorders for which the term "Reward deficiency
Syndrome" has been coined (Blum et al. 1996a).
[0203] While a major aspect of this invention involves the use of
an intravenous amino-acid based bolus composition for the
short-term treatment of RDS behaviors as well as other non-RDS
behaviors, disorders or diseases, certain aspects of this invention
does involve the coupling of intravenous administration with gene
testing. The gene testing aspect has already been applied for via a
previous PCT application (Apr. 29, 1998). In order to be complete
it is important to realize that in RDS, genetic defects in the
reward pathways is best understood as a polygenic disorder, and
genetic testing would require the testing of multiple genes. The
earlier PCT identified the correlation between predisposition to
RDS and alleles of a number of genes including but not limited to
the dopaminergic genes DRD1, DRD2, DRD3, DRD4, DRD5, dopamine
transporter gene (DAT1), serotonin genes HTT, HTRA, HTRDb, HTRA,
HTRC, HTIA, 5HT2R, tryptophan 2,3-hydroxylase (TDO2);
Norepinephrine genes, DbH, ADRAA, ADRAC, NT, Catecholamine
metabolizing genes, MAOA, COMT, GABA genes, GABRAA, GABRAB,
Canabinoid receptor gene, CNR; Nicotinic cholinergic, CHRNA; NMDA
receptor gene, NMDAR; Enkephalin genes. PENK, Androgen receptor
gene, AR; Interfereron gamma gene, INFG, CDA; Presenilin, PS, CRF
gene, CRF; obesity genes, OB, leptin recteor gene; catechol-0
methyl-transferase (COMT) gene; the neuronal nitric oxide gene
synthase gene (nNOS1a); Apolipo protein-D (APO-D) and, uncoupling
protein (UCPI and UCP2) among others.
[0204] Enkephalins and endorphins are opiate-like substances which
have been found to be endogenous in various animal species and man,
whereby the general term endorphins includes but is not limited to
Beta-endorphin, methionine-enkephalin, leucine-enkephalin and
dynorphins. These substances are peptides or polypeptides which are
normally found in the brain and in the periphery as well.
[0205] As pointed out in U.S. Pat. No. 4,439,452, it has been
observed that both enkephalins and endorphins have an ability to
act as a biologically active pain killer when administered by even
intracerebral injections. However, the major drawbacks of utilizing
the endogenous substances directly for therapeutic purposes,
including intravenous therapy to treat RDS or non-RDS disorders,
are their extremely labile nature and poor penetration into the
brain via oral administration and their ability to induce
addiction. It is known that the destruction of the endognous
enkephalins and or endorphines is due to the actions of certain
enzymes which resemble carboxypeptidase or endopeptidase
(catelepsin), respectively. These and other enzymes which
inactivate enkephalins and endorphins are known collectively as
enkephalins and endorphinases. An enkephalinase inhibitor is a
substance which inhibits a class of enzymes known as enkephalinases
and endophinases known to destroy these neuropeptides in both
animals and humans.
Pharmaceutical Compositions
[0206] Aqueous compositions of the present invention comprise an
effective amount of the various compounds disclosed to treat RDS
related disorders, including substance use disorder, obesity, ADHD,
Tourettes syndrome, PMS, smoking, any other related behavior
described herein, dissolve or dispersed in a pharmaceutically or
pharmacologically acceptable carrier or aqueous medium. The phrases
"pharmaceutically or pharmacologically acceptable" refer to
molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an animal,
or a human, as appropriate.
[0207] A preferred chromium salt, in addition to those previously
mentioned, is chromium niacin-glycerate. Clyclodextrin maybe added
to composition in the kits of the present invention. This
clyclodextrin could aide in the absorption of many of the various
components in the composition. The kits also preferably contain a
reward deficiency syndrome related scale. This scale allows the
patient to gage the degree of his RDS problems.
[0208] Each of the several embodiments of the invention hereinafter
to be described not only reduces intake of alcohol, cocaine,
heroin, nicotine, glucose but reduces all known RDS behaviors. The
following examples of compositions is provided to best describe the
invention herein:
EXAMPLE I
Composition A
[0209] The invention includes the intravenous administration of a
new class of anti-craving compositions provided by substances which
inhibit the breakdown of endogenous substances such as enkephalins
and endorphins. Specifically, D-phenylalanine, DL-phenylalanine,
D-Leucine, DL-Leucine, and hydocinnamic acid, each in an
intravenous solution in sufficient concentration to bring about
enkephalinase inhibition which would significantly lower alcohol
intake in animals and humans. The anti-alcohol desire effect has
been observed in animals genetically prone to choose alcohol over
water, but this effect has never been observed via the intravenous
route. The inventors believe that the intravenous route would be
advantageous since the dose needed would be much less than what is
required by the oral dose. In a series of experiments the exact
dose will be determined in both humans and animals to at least
reduce alcohol or drug intake.
[0210] In this invention only and not in limitation, the term
enkephalin inhibitors includes D-phenylalnine (DPA), DL-PA,
hydrocinnamic acid and D-amino acids such as D-leucine. It is
anticipated that other enkephalinase inhibitors (depending on
ability to place the substance into a safe and effective
intravenous solution) selected from a group consisting of certain
protein synthesis inhibitors (bacitracin, bestatin, and puromycin);
and peptide amino acids (mono free form amino acids in the D-form;
thiol benzyl amino acids
(2-[mercapto-3-phenyl-propanoyl]-L-leucine; carboxyalkyl methyl
esters, N-[(R,S)-2 carbethoxy-3-phenyl propanol]-L-leucine; as well
as a number of other structurally unrelated compounds such as
secobarbital, pyrophosphate, o-phenanthroline, phosphamidon,
Z-leucine-NHOH, and Z-glycine-NHOH.
[0211] The potencies will be determined by trial and error, but a
starting point for the various enkephalinase inhibitors in vitro
range from 10 nM to nM amounts and, therefore, the anticipated
human dosage range is from milligrams to micrograms per kilogram
based on a 80 kilogram man. It is understood that the daily,
recommended dosage is to be sufficient to alter the activity of
enkephalinase and/or opioid receptor function so as to reduce the
craving for euporiants such as alcohol, cocaine, heroin, marijuana,
nicotine, glucose as well as behavioral acts including but not
limited to pathological gambling and sexual deviancy. It is further
anticipated that the broad range of dosage will be provided in the
final application due to both pharmacogenetic and pharmacogenomic
elements. It is also important for this invention, that these
substances alone, in equal dosages are less efficatious
enkephalinase or endorphinase inhibitors in reducing craving but
should be synergistic when used in combination with said inhibitors
and other precursor amino-acids and even when combined with
intravenous ethanol solutions.
[0212] An Intravenous Solution of D-Phenylalanine 16-500 mg
[0213] For example, without testing, it is anticipated, that the
range of the daily dosage of D-amino acid like D-leucine is between
15-5000 mg but a more definitive amount will be determined. The
intravenous solution could be expanded to include any substance
which inhibits enkephalinases, endorphinases and or dynorphinases.
It is also anticipated that intravenous solutions could also
contain the DL-forms as well.
EXAMPLE II
Composition B
[0214] The inventor believes that the substrate for RDS behaviors
is mediated by regions in the brain's "pleasure center" or "reward
centers" which are high in a number of neurotransmitters including
dopamine. These regions include the dopamine-containing nucleus
accumbens, and its projection to limbic structures and frontal
cortex. It has been observed that if dopamine projections to limbic
and cortical areas are lessioned the self-administration of
psychoactive drugs which release dopamine (e.g. alcohol, cocaine,
heroin, nicotine etc) by animals are greatly reduced. Moreover,
selective dopamine receptor antagonists, like haloperidol, atenuate
or block alcohol and cocaine self-administration in animals.
Similarly, in humans, pretreatment with dopamine receptor
antagonits will block stimulant-induced "euphoria". Additionally,
dopamine receptor agonists (e.g. bromocryptine, apomorphine etc)
have rewarding actions. These and other studies suggest that the
lack of "reward" as observed in RDS subjects is due to a deficiency
of certain neurotransmitters involved in the mediation of dopamine
release and function.
[0215] A second step in the invention is to induce restoration and
balance within the limbic structures of important
neurotransmitters. This is accomplished by utilizing the brain's
own natural biochemical mechanisms involved in the synthesis of
individual chemical messengers such as serotonin,
Gamma-amino-butryic acid (GABA) and the catecholamines (dopamine,
norepinephrine and epinephrine). In understanding the chemistry
involved, these neurotransmitters of the monoamine type are derived
via enzymatic actions concerned with known precursor amino
acids.
[0216] Catecholamine are compounds which passes two adjacent
hydroxyl (OH) groups on a benzene ring. In the body, such
substances are synthesized from the aromatic amino acid L-tyrosine,
which is hydroxylated to L-3,4-dihydoxyphenylalanine (L-DOPA) by
the enzyme tyrosine hydroxylase. L-trosine is actively taken up
into noradrenergic nerve terminals. L-phenylalanine is a precursor
of L-Tyrosine. In the cytoplasm, L-DOPA is decarboxylated to
dopamine by L-aromatic amino acid decarboxylase, an enzyme which
requires pyridoxal phosphate (vitamin B6) as a cofactor. The
dopamine is actively taken up into granular storage vesicles in
which the dopamine is hydroxylated to form norepinephrine by the
enzyme dopamine-beta-hydroxylase.
[0217] It is known that dopamine is the precursor of norepinephrine
and epinephrine, and each of these three neurotransmitters have
distinct functions in the central nervous system and at some ganlia
in the autonomic nervous system. Dopamine is stored in storage
granules where the catecholamine is complexed with chromogranins,
divalent metal ions and ATP. Dopamine is believed to be released
into the syneptic cleft by exocytosis. As with norepinephrine, this
is a calcium dependent process and occurs in response to action
potentials reaching nerve terminals or to drugs. The following
drugs/substances can induce a dopamine release--they include:
alcohol, cocaine, amphetamine, methyamphetamine, amantadine,
morphine, heroin, phentermine, nicotine, marijauna, glucose to name
a few.
[0218] The use of these precursors may be supplemented at
appropriate stages of treatment of an RDS subject following the
short-term bolus intravenous therapy. These include dopaminergic
releasers, blockers, agonists or antagonists or agents affecting
the reuptake or degradation of dopamine, norepinephrine or
epinephrine. However, it should be understood that the entire range
of dopaminergic activity including synthesis, and release is
regulated to some degree by certain opioid peptides (e.g.
enkephalins and endorphins). Centrally administered opioid peptides
produce elevations in levels of catecholamines in blood plasma in
animals and humans (Clouet Ann N.Y. Acad. Sci., 398; 130-139,
1982). In fact, blockade of presynaptic dopaminergic receptors
results in an enhancement of B-endorphin release, showing a unique
reciprocal relationship.
[0219] Serotonin (5-HT) is a CNS neurotransmitter. It is also found
in the enterochromaffin system of the intestine, and in blood
platelets. This neurochemical is biosynthesized by first
hydroxylating the precursor amino acid L-Tryptophan to obtain
5-hdroxytryptophan and then decarboxylating the latter to obtain
serotonin. The hydroxylation (the rate limiting step) is performed
by the enxyme tryptophan hydroxylase, while the decarboxylation is
accomplished by the ubiquitous enzyme L-aromatic acid
decarboxylase. This enzyme requires pyridoxal phosphate as
acofactor.
[0220] Unlike tyrosine hydroxylase, tryptophan hydroxylase, under
normal physiological conditions, is not saturated, therefore, the
enzyme is not working to full capacity and thus tryptophan
hydroxylase activity is significantly affected by 1-tryptophan. The
amount of available free tryptophan is dependent on a number of
factors including the concentration of circulating L-tryptophan in
the plasma at the rate of its uptake in the brain and presynaptic
terminals. We contemplate using L-tryptophan or 5-hdroxytryptophan,
to restore the serotonergic system disrupted by either genes or
other environmental elements.
[0221] There is come controversy concerning the usefulness of
another amino acid precursor, 5-hydroxytryptophan, which is about
20 times more potent than L-tryptophan. The rate of entry of
L-tryptophan into the brain depends upon the ratio of free-bound
tryptophan in the plasma, and this ratio is influenced by the
concentration in the blood of neutral amino acids, insulin, glucose
levels, and pharmaceutic agents, which compete for plasma protein
binding sites, as well as for the tryptophan-uptake sites. Also
5-hdroxytryptophan is taken up by neurons other than just
serotoninergic neurons; therefore the increases in serotonin
synthesis are not selectively limited to serotoninergic neurons.
Since the inventors plan to utilize the intravenous compositions
via an FDA approved drug drug, and since in the United States
physicians are allowed to subscribe or utilize L-tryptophan, the
preferred embodiment is the L-tryptophan precursor rather than the
L-5-hydroxytryptophan amino-acid.
[0222] Serotonin can be released into the synaptic cleft by the
process of exocytosis in response to action potentials and to
certain drugs/substances. Facilitation of serotonin release is
accomplished with cocaine, alcohol, amphetamine. metamphetamine,
fenfluramine, chlorimipramine and others.
GABA is an inhibitory neurotransmitter which controls the release
of dopamine (Gessa et al. 4th World Congress on Biological
Psychiatry 459 No. 620: 10 1985).
[0223] The main synthetic pathway to gamma-aminobutyric acid is via
decarboxylation of L-Glutamic acid by glutamic acid decarboxylase
(GAD). Like other amino acid decarboxylases, this enzyme needs
pyridoxal phosphate or vitamin B6. GAD is found exclusively in the
cytoplasm of synaptic GABA nerve terminals. The basic control of
GABA synthesis is GAD, which is the rate limiting step. Saturation
concentrations of L-glutamic acid are present in the presynaptic
neurons: thus, increased substrate concentrations do not normally
affect the rate of GABA synthesis. Therefore, the exogenous
administration of L-glutamic acid may not significantly increase
GABA levels, unless the L-glutamic levels are abnormally low.
However, it has been shown that a 10 day administration of
1-glutamine (@ 500 ng/kg per day) with the drinking water to adult
albino rats resulted in significant increase in the content of
glutamate, GABA and taurine in the brain. Glutamine is an active
intermediate in transport of ammonia from brain and therefore may
greatly affect metabolism of different amino acid acids in nervous
tissue. After deamination, glutamine may become a precursor of
glutamate and, accordingly, GABA. (Thawki et al. J. Neurochem. 41:
611-617, 1983).
[0224] Changes in affinity of GABA receptors for GABA, the
benzodiazepine-binding sites for benzodiazepines and/or barbiturate
binding site for barbiturates is regulated by a protein
"GABA-modulin". No reports have indicated that the use of GABA
precursors can postively affect RDS behaviors in the short-term.
However, the inventors believe, that since in a number of RDS
behaviors there is a significant association of stress and/or
anxiety the addition of L-glutamine may act to increase GABA, which
in turn could stimulate the benzodiazepine-ionophor complex and
reduce anxiety through this mechanism, even on a short time period
for initial interaction via the intravenous route.
[0225] It will also be recognized that while this invention is
directed to the use of a substance which inhibits the destruction
of endogenous neuropeptidyl opiates (as described in Example 1),
especially in combination with dopamine, serotonin and/or GABA
precursors, it may also be beneficial to add certain soluble
neurotransmitter agonists, blockers, antagonists, releasers, or
degradation inhibitors into one intravenous solution if desired or
if proven to effect the efficacy of the base composition.
[0226] There are other substances which could also effect the
activity of neurotransmitters and brain cell dynamics which can be
contemplated as well in this invention. For example, calcium is a
required substance for proper neurotransmitter release and
function. Zinc is essential for protein synthesis and can inhibit
enzymes involved in the destruction of endogenous opiates. Thiamine
promotes the synthesis of niacinamide and enhances oxidative
metabolism of brain cells. Riboflavin is a cofactor which acts as a
hydrogen acceptor and promotes the conversion of tryptophan to
niacinamide. Niacinamide is an essential part of the enzyme system
concerned with the efficient use of oxygen by neurons and promotes
brain cell respiration. Pantothenic acid is a vital substance
involved in cellular metabolism. It is believed that the
combination of riboflavin, niacinamide, and pantothenic acid reduce
irritability, restlessness and fatigue. Cyanocobalamine is a
cofactor/coenzyme for both chemical synthesis and neuronal
electrical activity. Ascorbic acid is involved in the metabolism of
phenylalanine and tyrosine and can reduce drug-induced withdrawal
reactions. Follic acid promotes oxidation in the blood as a
hematopoietic agent. D-Ribose is a cardiac protector and may play a
role in memory.
[0227] An example of the precursor amino-acids in treating RDS
behaviors as an intravenous composition is as follows:
[0228] In an intravenous solution these amino-acid precursors could
be given alone or in any combination with any of the other
precursor amino-acid at the specified dosage range.
L-phenylalanine 5 mg-5,000 mg daily dose.
L-Tyrosine 5 mg-5,000 mg daily dose.
L-Tryptophan 9-90,0000 mg daily dose.
L-5-hydroxytryptophan 0.9-9,000 mg daily dose.
L-Glutamine 3-30,000 mg daily dose.
One preferred embodiment is as follows:
[0229] Amino Acid Precursor Formulation
[0230] Daily Dose TABLE-US-00033 L-Phenylalanine - 1500 mg
L-Tyrosine - 900 mg L-Tryptophan - 500 mg L-Glutamine - 300 mg
Pyridoxal Phosphate 20 mg
Note. While the foregoing doses are preferred, it is contemplated
that the quantities of each ingredient may be varied by an order of
magnitude (10% to 1000%). Because of the interactions of the
various neurotransmitters, an increase in the amount of one
ingredient may facilitate the reduction of another ingredient.
Also, other substances of similar activity, as noted above in the
text of this invention, may be substituted for those of the
Example.
EXAMPLE III
Composition C
In this composition the inventors are including a tryptophan
concentration enhancing amount of all salts and chelates of
chromium (e.g. picolinate, nicotinate, ablion chelate etc.).
Background on Chromium
[0231] Body cells need chromium to keep insulin working properly as
well as a host of other important biological actions. Scientists
agree, that insulin directs the movement of digested food into the
body's cells and affects how that food is used. When insulin
doesn't act as intended, blood glucose and fat aren't stored and
used properly. This malfunction leads to obesity, heart disease, or
diabetes.
[0232] Our diets contain little chromium, and what chromium we do
eat is often in a form that is difficult for the body to absorb.
Therefore, chromium must be combined with a substance that will
allow this substance to enter the bloodstream. A number of forms
include picolinate, polynicotinate as well as Ablion chelate.
Dozens of studies have proven that chromium, in the form of
chromium picolinate, helps control blood fat, blood glucose, body
fat, food cravings, and age-related bone weakening or osteoporosis,
lowers blood pressure and reduces both total and LDL cholesterol,
and induce higher levels of HDL cholesterol.
[0233] Dietary chromium is an essential nutrient whose value in
human nutrition has been conclusively documented. Interest in
chromium stems from the view that because chromium is an essential
trace mineral and a cofacactor to insulin, it could play a role in
glucose, lipid, and amino acid metabolism by it's potentiating
effects on insulin action. Supporting this argument is the
observation that chromium deficiency results in impaired glucose
tolerance, insulin resistance, elevated blood glucose levels, and
symptoms of type II diabetes; in addition, adequate amounts of
physiogically active forms of chromium can reduce insulin
requirements in humans (Kaats et al. 1996).
[0234] The National Academy of Sciences has classified chromium as
an essential trace mineral and recommends daily intakes of 50 to
200 micrograms. However, the most reliable studies report that
among Americans (which is similar for other countries) is
suboptimal--only 40% of the minimum for women and 60% for men.
There are more than 25 human studies documenting the beneficial
effects of supplemental chromium on subjects living at home
including improvements in glucose, insulin, and lipid levels:
impaired glucose tolerance; adults with elevated cholesterol
levels; insulin and hypoglycemic patients (Mertz, 1992).
[0235] To increase the bioavailability of chromium, several studies
have suggested using picolinate acid, a naturally occurring
metabolic derivative of tryptophan. Picolinate acid appears to
combine with trace metal ions in the intestines and blood which
facilitates the collection and use of essential trace metals (Evans
& Brown, 1992). We are in this invention, only interested in
the intravenous use of chromium. We will explore the absorption of
unsalted chromium compared to various salts and chelated forms in
terms of absorption and potency using typical studies involving
glucose sensitivity and tolerance as a measure of biological
activity.
Enhancing Brain Tryptophan
[0236] Because deposition of body fat appears in part by insulin,
improvements in insulin utilization should lead to reductions in
fat deposition. Enhancing the effects of insulin can also have
positive effects on muscle tissue because insulin directs amino
acids into muscle cells; once amino acids enter the muscle cells,
they are assembled into proteins through insulin's effect on the
cell's genetic material, that is, DNA and ribonucleic acid. This
effect of chromium is important for this invention, since by doing
so it reduces required amounts of the amino acid tryptophan
(Wurtman, 1982). By enhancing tryptophan, this will lead to an
enhanced synthesis of serotonin. The newly synthesized serotonin,
will stimulate dopamine release via an indirect action on
enkephalinergic neurons resulting in GABA inhibition, and through
this mechanism enhance dopamine release at the nucleus accumbens.
This would therefore benefit RDS behaviors, including substance use
disorder, carbohydrate binging, pathological gambling, sexual
deviancy, ADHD among other known and defined RDS behavioral
subtypes.
[0237] Moreover, chromium can potentially facilitate the
maintenance or addition of fat-free mass (FFM). It has been
suggested that if chromium can lower insulin resistance it can
improve body composition, as insulin resistance or deficiency
results in impaired entry of glucose and amino acids into muscle
cells, and increased catabolism of muscle protein as well as
insulin deficiency's potential to accelerate lipid disposition
(Kaats et al. 1996). Other references indicate that insulin
resistance may help stabilize body fat in the obese patient, albeit
at an obese level, acting much like a "set point" to prevent
further weight gain (Eckel, 1992).
Why Intravenous
[0238] In general, although animal studies have supported this
contention (Liarn et al, 1993), one human study found positive
changes in body composition with chromium supplements (Hasten et
al. 1992), another reported positive, although not statistically
significant changes in body composition (Hallmark et al. 1993), and
a third failed to find any positive changes in body composition
with chromium supplementation (Clancey et al. 1994). The
controversial nature of the literature reveals that most human
studies used small numbers of subjects, and patients often followed
exercise or conditioning programs that could increase the need for
chromium at amounts higher than amounts provided in these studies.
Previous work observing concurrent chromium supplementation and
exercise training has been restricted to effects on body weight and
composition, with conflicting results (Clancy et al, 1994; Evans et
al 1989; Evans et al, 1993; Hallmark et al. 1996; Hasten et al.
1992). Chromium Picolinate is the most heavily used, studied and
promoted compound, but in vitro work suggests that chromium
nicotinate may be also viable in the area of weight loss and
changes in body composition. In this regard, very recent work by
Grant et al. (1997), suggests that the nicotinate salt may be even
more important than the picolinate salt.
[0239] While there still is controversy regarding the effects of
chromium salts (picolinate and nicotinate) on body composition and
weight loss in general, recent work seems to support the positive
change in body composition in humans. Considering the work of
Lawford, et al. (1995), showing a selective positive effect of
bromocryptine, a D.sub.2 agonist, in reducing relapse rates in
alcoholics as a function of dopamine D.sub.2 receptor genotype, one
of us (KB) embarked on a similar phamacogenomic study with CrP (see
below).
[0240] Recently, there was concern over the demonstration that, at
concentrations thousands of times higher than physiological levels,
trivalent chromium can break chromosomes in cell culture. It is the
inventor's position that this finding is not relevant to
nutritional supplementation. In this regard, a prediction that CrP
will accumulate in tissues to dangerous levels during long-term
supplementation is based on an inappropriate pharmacokinetic model
and is at odds with data from long-term rat feeding studies.
Furthermore, clastgenicity is not equivalent to either mutagenicity
or carcinogenicity and studies in animals reveal that any effects
observed with regard to clastogenicity of trivalent chromium is
only relevant to cell culture studies, not to living animals or
humans. Moreover, the therapeutic-toxic-dose ratio for trivalent
chromium is 1:10,000 and the Environmental Protection Agency in the
United States has established a "Reference Dose" for nutritional
chromium that is 350 times higher than the upper end of the
nutritional range. Considering the wide margin of safety for
trivalent chromium, as well as its picolinate salt, we believe
large scale, worldwide use of CrP is justified as an important
dietary supplement to assist in reducing obesity.
[0241] Thus, it can be seen that effects of chromium
supplementation on different subject populations (obese and lean)
were variable with respect to changes in body composition
regardless of dose. Given the comparable study designs for most
studies, the results taken together suggest that a subset of
responders in each study may account for the observed variability
among studies.
[0242] In order to resolve the issue of non-responders, the
inventor decided to test the hypothesis that typing the obese
patients by genotyping the DRD2 gene prior to treatment with CrP
would result in a differential treatment outcome. This was based on
previous research which indicated that the DRD2 TaqA1 allele
associated with obesity in general; the BMI; carbohydrate binging;
co-morbid substance use disorder; and contributed to the overall
variance of percent body fat in the present population at the high
rate of 45.9 percent (Blum et al. unpublished). One of us (KB)
predicted carriers of the DRD2 A2 allele would retain the positive
metabolic effects of P, but in contrast the DRD2 A1 carriers,
because there is a proclivity to increased carbohydrate binging,
would possibly mask the metabolic effects of CrP on weight loss and
change in body fat attenuating any positive effects. One prophetic
example as described earlier (see page 48):
[0243] The inventor genotyped 130 obese subjects for the dopamine
D.sub.2 receptor gene (DRD2) utilizing standard PCR techniques. The
subjects were assessed for scale weight and for percent body fat
using dual energy X-ray absorptiometry (DEXA.sup.R). The subjects
were divided into matched placebo and chromium picolinate (CrP)
groups (400 ug. per day). The sample was separated into two
independent groups; those with either an A1/A1 or A1/A2 allele and
those with only the A2/A2 allelic pattern. Each of these groups was
tested separately for differences between placebo and treatment
means for a variety of measures of weight change. These measures
consisted of calculations of the percent of fat weight change; the
change in fat weight; the change in body weight; the change in free
mass, the percent change of fat weight; the body composition index;
and the body weight change in kilograms. T-analysis revealed that
carriers of the DRD2 A2 allele were more responsive to the effects
of CrP than were the DRD2 A1 allele carriers. The measures of the
change in fat weight (p<0.041), change in body weight
(p<0.017), the percent change in weight (p<0.044), and the
body weight change in kilograms (p<0.012) were all significant,
whereas no significance was found for any parameter for those
subjects possessing a DRD2 A1 allele.
[0244] These results suggest that the dopaminergic system,
specifically the density of the D.sub.2 receptors, confers a
significant differential therapeutic effect of CrP in terms of
weight loss and change in body fat. Moreover, we propose for the
first time that mixed effects now observed with CrP administration
in terms of body composition, may be resolved by typing the patient
via DRD2 genotyping prior to treatment with chromium salts.
[0245] The point here is that, depending on a number of important
factors, genetic make-up as well as absorption results obtained
with any chromium supplement are equivocal. It is the intent of
this invention to resolve this controversy by administering the
chromium via the intravenous route either alone (25-10,000 ug), or
in combination with Composition B as specified above.
[0246] Amino Acid Precursor Formulation Daily Dose TABLE-US-00034
L-Phenylalanine - 1500 mg L-Tyrosine - 900 mg L-Tryptophan - 500 mg
L-Glutamine - 300 mg Pyridoxal Phosphate 20 mg Chromium
(picolinate, or 400 ug nicotinate)
NOTE: While the foregoing doses are preferred, it is contemplated
that the quantities of each ingredient may be varied by an order of
magnitude (10% to 1000%). Because of the interactions of the
various neurotransmitters, an increase in the amount of one
ingredient may facilitate the reduction of another ingredient.
Also, other substances of similar activity, as noted above in the
text of this invention, may be substituted for those of the
Example.
EXAMPLE IV
Composition D
[0247] In this composition the prime element is the use of an
enkephalinase releasing substance which is known to release
neuronal endorphins or enkephalins, said substance being selected
from the group consisting of polypeptides or amino-acids.
[0248] The inventor believes that an important embodiment is the
inclusion of a opioidergic releasing agent. Therefore, a further
enhancement of the intravenous composition, is to combine an
enkephalinase inhibitor with an enkephalin releasing agent. The
rationale for this is that by doing so we could significantly
enhance the effect of enkephalin on its respective opiate receptor
sites (e.g. delta or mu). To accomplish this aim, we would prefer
to use the peptide Tyr-Arg (Kyotorphin), or its stable analog,
Tyr-D-arg, which has been shown to be analgesic and to enhance
intracellular calcium in synaptosomes in rat brain slices. These
substances appear to be putative methionine-enkephalin releases
acting by an unknown mechanism (Udeda et al. Biochem. Biophy. Res.
Comum. 137:897, 1986).
[0249] To provide both enkephalinase inhibition as well as enhanced
neuronal enkephalinase release the substance Kyotorphin may be used
as a daily dosage range of 15 micrograms-15 milograms orally. In
our experiments to come, the inventors will provide the best dose
for the intravenous composition preferred. (Takagi et al. Eur. J.
Pharm. 55: 109, 1979). The more stable analog Tyr-D-Arg, at a daily
dosage range could be substituted as an enkephalin releaser and it
to will be studied in terms of it's appropriate effective and safe
intravenous dose (Tajima et al. Chem. Pharm, Bull. 28: 1935, 1980);
Ueda, et al. Biochem. Biophys. Res. Commun., 137: 897-902,
1986).
[0250] Thus, an enkephalin releaser may be combined with an
enkephalinase inhibitor to achieve a high degree of enkephalinergic
activity at the synapse to further augment the release of neuronal
dopamime. This will act as a form of bolus short term "replacement
therapy" and produce a surprising long-term reduction in aberrant
craving behavior for a number of addictions.
[0251] Amino Acid Precursor Formulation Daily Dose TABLE-US-00035
L-Phenylalanine- 1500 mg L-Tyrosine- 900 mg L-Tryptophan- 500 mg
L-Glutamine- 300 mg Pyridoxal Phosphate 20 mg Chromium (picolinate,
or 400 ug nicotinate) Tyr-D-Arg 15 ug
NOTE: While the foregoing doses are preferred, it is contemplated
that the quantities of each ingredient may be varied by an order of
magnitude (10% to 1000%). Because of the interactions of the
various neurotransmitters, an increase in the amount of one
ingredient may facilitate the reduction of another ingredient.
Also, other substances of similar activity, as noted above in the
text of this invention, may be substituted for those of the
Example.
EXAMPLE V
Composition E
[0252] A composition comprising of an intravenous polar or
non-polar compound known to promote the synthesis and enhance the
functional activity of serotonin, opioid peptides, and
catecholamines (dopamine and norepinephrine) selected from the
group Rhodiola or huperzine, but not limited to these
substances.
[0253] Rhodiola rosea, or Golden Root, is a perennial herbaceous
plant of the Orpine (Crasssulaceae) family, growing in the Polar
Arctic and Alpine regions. In the altai mountains, in Eastern
Siberia, Tien-sdhein and in the Far East, the cultivation of
Rhodiola rosea has been successfully mastered.
[0254] The rhizomes contain phenolic compounds, among them the most
important are p-oxyphenylethanol (tyrasol) and its glycoside
salidoside determining the biological activity of the Rhodiola
preparations (Saratikav et al. 1968). Rhodiola possess stimulative
and adatogenic characteristics. It is thought that this compound
improves the ability to perform physical work; reduce fatigue;
shorten the recovery period after prolonged muscular workloads; and
normalize cardiovascular activity. During intensive muscular work,
Rhodiola prevents loss of phosphates in brain and muscles by
optimization of the processes of oxidative phosphorylation,
stabilizing the muscular activity of lipids; improving the
indicators of metabolism (activation of aminacyl-t-RNA-synthetase)
in the skeletal muscles, increase of the RNA content, and
increasing the blood supply to the muscles, especially to the
brain.
[0255] Rhodiola can increase attention span, memory; improve mental
work and enhance performed work. The area of the brain involved in
this activity is the thalamocortical and posterior hypothalamus
(Marina et al. 1973). Various other actions have been noted for
Rhodiola and include; prevent development of hyper- and
hypoglycemia, leukocytosis and leukopenia, erythrocytosis and
erythropenia, hypoxia; reduce stress and bring about a
cardio-protective action. The stress-regulative effect of Rhodiola
involves it's normalizing effect on the hypophyso-adrenal and
opioidergic system. It has also been found that Rhodiola increases
the anti-tumor resistance of the organism. It significantly
inhibits the growth of experimental tumors, decreases the frequency
of their metastasises; prolongs the life expectancy of animals with
recidivistic tumors, and decreases the outcome of spontaneous
tumors (Dementyeva and Yaremnko, 1983). There is some evidence that
this compound also reduces neurosis and fights exhaustion
(Saratikov, 1977).
[0256] Salidosid (an extract of Rhodiola) [SAL], at 30 mg/kg
prevented disulfuram-induced decrease of NE in the brain of
animals. SAL influences brain NE by virtue of it's ability to
inhibit the activity of COMT and MAO. SAL does not decrease the
permeability of the Blood Brain Barrier (BBB) for precursors of the
catecholamines and serotonin, and this property makes it useful for
the intravenous composition to treat RDS behaviors. Administration
of rhodosine (which contains SAL, aglycone p-tyrosol and rosavin)
at 2 mg/kg increases the brain concentration of DOPA, dopamine, and
serotonin in the cortex and a decrease of the level of NE in the
caudate nucleus in the brain of the intact mice, 30 min after
subcutaneous injection. Others have shown that SAL did not alter
the levels of epinephrine and DOPA: at a dose of 30 mg/kg, it
decreased the content of NE by 26% and of 5-HT by 15%; at a dose of
100 mg/kg, it decreased the concentration of NE, Dopamine and
serotonin by 20, 28, and 23% respectively. Studies involving the
administration of L-Dopa (50 mg/kg) and 5-HTP (100 mg/kg) to mice
showed that SAL (30 mg/Kg) increases the rise in exogenous DOPA and
serotonin in animals by 26 and 13%, respectively, compared to
saline-dopa-5-HT-controls. These data indicate that the preparation
increased the permeability of the blood-brain barrier for the
catecholamine precursor.
[0257] Moreover, from the research of Petrov (1981) indicates that
SAL decreases MAO activity and inhibits COMT activity thereby,
slowing the inactivity of Catecholamines by o-methylation and
oxidative deamination. Moreover, studies have shown that SAL does
not alter the activity of 5-HTP decarboxylase. Consequently, it
does not influence the synthesis of serotonin from 5-HTP, but may
slow the biotransformation of the amine, by slightly inhibiting
MAO. Evidently the increase in the rise of serotonin in the brain
in studies involving the combined administration of 5-HTP and SAL
is governed by the capacity of the latter to increase the
permeability of the blood brain barrier for 5-HTP.
[0258] The effects of Rhodiola in rats was studied using several
methods of active avoidance with negative and positive
reinforcement (Petrov et al. 1986). Using the maze-method with
negative reinforcement, it has been found that Rhodiola extract in
a single dose of 0.10 ml per rat improves learning and retention
after 24 hours. In terms of the bolus therapy, it is of interest
that significant improvements of the long-term memory is also
established in memory tests after 10 day treatment with the same
dose of the extract. Other work on the positive effects of Rhodiola
on learning and memory has been noted (Lazarova et al. 1986).
[0259] Huperzine is a compound belonging to a class known as
acetlycholinesterase inhibitors. It has been shown to inhibit the
enzyme that is responsible for the breakdown of acetylcholine, an
important neurotransmitter, or brain chemical, which is critical in
not only memory and/or learning but is critical in peripheral
nervous system as well. This could have a beneficial effect in the
disorder known as Myastenia Gravis. Huperzine is a naturally
occurring compound that was originally isolated from the club moss
Huperzine Serrata. It has been used in Chinese folk medicine and
more recently in limited clinical trials conducted in China as a
treatment for age-related memory disorders. Results suggest that it
improves learning and memory in certain patients. However, these
suggested results have not been substantiated by clinical trials.
This natural substance is contemplated for use with the composition
of matter claimed in this patent application (provisional) to
affect attentional processing. In humans the recommended oral dose
to enhance memory is 150 micrograms daily (the therapeutic range is
1.5 to 1,500 mcg daily). We will determine the best intravenous
dose via experimentation alone and in combination with the claimed
compositions.
[0260] Huperzine A, a novel potent, reversible, and selective
acetylcholinesterase (AchE) inhibitor has been expected to be
superior to other AchE inhibitors now known for the treatment of
memory deficits in patients with Alzheimer's disease. The compound
has been studied by a number of investigators including Zhi and
associates (1995) with very positive results. In fact huperzine A
is superior in activity to Cognex.sup.R, the first drug licensed in
the USA for Alzheimer's disease. The drug also blocked
glutamate-induced cellular death of neurons. The duration of action
of Huperzine A at 3 hours is superior to Cognex.sup.R (2 hours) and
physostigmine (30 min.). In behavioral studies of learning and
memory enhancement in animals, the difference between amounts of
the extract effective for memory and learning and the
non-toxic-effect dose was 30-100 fold. These data strongly suggest
that Huperzine A can be useful in treating Alzheimer's disease with
minimal side effects.
[0261] Toxicology and efficacy studies of Huperzine A show it to be
non-toxic even when administered at 50-100 times the human
therapeutic dose. The extract is active for six hours at a dose of
2 micrograms/kg with no remarkable side effects.
[0262] Amino Acid Precursor Formulation Daily Dose TABLE-US-00036
L-Phenylalanine- 1500 mg L-Tyrosine- 900 mg L-Tryptophan- 500 mg
L-Glutamine- 300 mg Pyridoxal Phosphate 20 mg Chromium (picolinate,
or 400 ug nicotinate) Tyr-D-Arg 15 ug Rhodiola rosea 25 mg and/or
Huperzine A 10 ug
NOTE: While the foregoing doses are preferred, it is contemplated
that the quantities of each ingredient may be varied by an order of
magnitude (10% to 1000%). Because of the interactions of the
various neurotransmitters, an increase in the amount of one
ingredient may facilitate the reduction of another ingredient.
Also, other substances of similar activity, as noted above in the
text of this invention, may be substituted for those of the
Example.
EXAMPLE VI
Composition F and Combined Therapy
[0263] In one such example the inventors propose the combination of
utilizing compositions A-E, with the patented method of treating
alcohol dependence by Bonin (U.S. Pat. No. 5,418,225 incorporated
by reference into the present invention) issued in 1995.
[0264] The Bonin invention relates to a treatment for alcohol
dependence involving intravenous infusion of an alcohol solution.
In the present invention, the inventors propose to expand the use
to all RDS behaviors. The rational here is that Bonin never
appreciated the fact that alcohol like other substances of abuse
such as nicotine, heroin, cocaine, marijauna, glucose to name a
few, all release neuronal dopamine at the "reward site" in the
brain. It is anticipated then that by using alcohol to induce
dopamine release, the subject would overcome potential genetic
deficits as outlined in this application and induce, for example,
proliferation of dopamine D2 receptors, thereby reducing
generalized craving behavior as seen in most RDS subjects.
Therefore, this short-term approach may even be useful in ADHD,
Tourettes, pathological gambling and even sexual deviancy.
[0265] It is the intent of the inventor to determine the potential
optimal and wide spread utility of this intravenous approach as
first proposed by Bonin (specific for alcohol dependence). The
inventor will also determine the best composition (A-E) described
herein to combine with the ethanol solution.
[0266] The Bonin invention is a method of treating alcohol
dependence in which an ethanol solution is infused intravenously
into a patient. Typically, for the new patient, the treatment is
continued for ten days, with a steady decrease in the amount of
ethanol infused each day. It is preferred that about 40-50 ml of
ethanol be initially administered in two separate aliquots, and
that the volume of ethanol be decreased by about 2 to 4 ml per day
for the first three days. On the fourth day, the volume of ethanol
is decreased by about 20 ml and this volume is given in only one
aliquot. From the fourth through the tenth day, the volume is again
decreased by about 2 ml per day so that on the final day,
preferably only about 4 ml of ethanol is infused in one
aliquot.
[0267] The preferred concentration of ethanol in solution is about
10 to 20% by volume. However, the concentration and the total
volume of solution infused can vary considerably (5% to 25%),
depending primarily on the tolerance and weight of the patient. One
suitable alcohol solution which is available in prepackaged form is
manufactured by Kendall-McGraw Laboratories, Inc. And contains 5%
dextrose and 10% ethanol in distilled water.
[0268] According to the Bonin patent, it has been found that after
the initial treatment program, the patients who suffer recidivism
(this can be checked against genotyping the individual for multiple
polymorphisms such as the DRD2A1 allele--see tables presented
herein), can often be effectively retreated by a six day course of
alcohol infusion, rather than the full ten day treatment program.
With this shorter program, the same volume of ethanol, i.e. about
40 to 50 ml, is initially administered, and it is then decreased
following the same schedule described above for the ten day
treatment. On the final day treatment, preferably about 12 ml of
ethanol infused.
Initial Test:
[0269] Preferred solution includes the 5% dextrose and 10% ethanol
solution, begins with 220 ml of solution twice daily on the first
day. At least about two and one-half hours rest or waiting period
should be given between successive infusions. Following the
above-described treatment on the first day, the preferred treatment
schedule, using the aforementioned 10% ethanol solution, is as
follows: [0270] Day two: 200 ml, twice daily; [0271] Day Three: 180
ml, twice daily; [0272] Day four: 160 ml, once daily; [0273] Day
five: 140 ml, once daily; [0274] Day six: 120 ml, once daily;
[0275] Day seven: 100 ml, once daily; [0276] Day eight: 80 ml, once
daily; [0277] Day nine: 60 ml, once daily; [0278] Day ten: 40 ml.
Once daily. Recidivists can often be effectively re-treated.
Preferably, if using the preferred 10% ethanol solution, 220 ml is
administered twice on the first day. The amount of solution infused
is then reduced as follows: [0279] Day two: 200 ml, twice daily;
[0280] Day three: 180 ml, twice daily; [0281] Day four: 160 ml,
once daily; [0282] Day five: 140 ml, once daily; [0283] Day six:
120 ml, once daily.
[0284] If the shorter treatment program is not effective, a longer
re-treatment program can be used. Further, the volume of solution,
the rate of infusion, and the concentration can all be varied with
the shorter program in the same manner, and subject to the same
concentrations, in which they are varied in the longer ten day
program.
Is the Preamble of the Bonin Patent Limiting in its Use?
[0285] In terms of expanded use, the inventors point out that Bonin
was very specific in its specified use--alcohol dependence and
alcohol craving. This is stated in the preamble of the claims and
throughout the text. In fact Bonin;'s proposed mechanism is
strictly directed to alcoholism. He states:
[0286] "A proposed explanation for the effectiveness of this
treatment is that alcohol addiction is the result of an immune
response to ethanol antigen. The intestine is lined by a great
number of macrophage. Phagocytization of an antigen by macrophage
is usually the first step in the immune response. Thus, when
alcohol is introduced intravenously, it does not pass through the
macrophage-rich intestine, and the immune response is substantially
ameliorated. At the same time, however, this alcohol is available
in the blood stream to satisfy the needs of the central nervous
system and abate the usual [alcohol induced] withdrawal symptoms.
Because the amount of alcohol administered in gradually decreased,
the patient is desensitized to the alcohol antigen, which caused
the allergic-type reactions. Ultimately, the patient becomes
immunologically non-reactive to alcohol, and the craving for it
diminishes."
[0287] Therefore, if Bonin is correct the use of intravenous
alcohol alone would have no effect on other substances of abuse and
addiction i.e cocaine, heroin, nicotine, glucose, marijauna as well
as other RDS behaviors (ADHD, pathological gambling, sexual
deviancy etc.).
[0288] The inventor expects to find a surprising and unexpected
effect of ethanol infusions to reduce cravings for other drugs of
abuse; this would be indeed a patentable advance. This coupled with
the outlined amino-acid, herbal and mineral combinations would also
provide a novel step in the treatment of RDS behaviors with
short-term bolus intravenous therapy.
[0289] Amino Acid Precursor Formulation Daily Dose TABLE-US-00037
L-Phenylalanine- 1500 mg L-Tyrosine- 900 mg L-Tryptophan- 500 mg
L-Glutamine- 300 mg Pyridoxal Phosphate 20 mg Chromium(picolinate
400 ug or nicotinate) Tyr-D-Arg 15 ug Rhodiola rosea 25 mg and/or
Huperzine A 10 ug Ethanol 10%
[0290] NOTE: While the foregoing doses are preferred, it is
contemplated that the quantities of each ingredient may be varied
by an order of magnitude (10% to 1000%). Because of the
interactions of the various neurotransmitters, an increase in the
amount of one ingredient may facilitate the reduction of another
ingredient. Also, other substances of similar activity, as noted
above in the text of this invention, may be substituted for those
of the Example.
[0291] It is important the inventors will carry out certain
pharmaconetic studies and mass spectrophotometry on the resultant
compositions, especially as it relates to the biochemical
interactions, if any, with ethanol and the amino-acids, herbals and
minerals contained in the final preferred compositions.
[0292] It should be understood that the forgoing terms, expressions
are exemplary only and not limiting, and that the scope of
protection is defined only by the claims which follow and includes
all equivalents of the subject matter of the claims.
REFERENCES
[0293] The following references as well as those cited elsewhere
herein are incorporated by reference herein in pertinent part to
supplement this disclosure.
The &mgr opiate receptor as a candidate gene for pain:
polymorphisms, variations in expression, nociception, and opiate
responses.
[0294] UhI G R, Sora I, Wang Z [0295] Molecular Neurobiology
Branch, Intramural Research Program, National Institute on Drug
Abuse, National Institutes of Health, Baltimore, Md. 21224, USA.
There are differences between human individuals and between mouse
strains in levels of &mgr; opiate receptor (&mgr;OR)
expression, responses to painful stimuli, and responses to opiate
drugs. One of the best candidates for contributing to these
differences is variation at the &mgr;OR gene locus. Support for
this idea comes from analyses of the human and murine &mgr;OR
genes, Assessments of Individual differences in human &mgr;OR
expression add further support. Studies with mice, including
knockout-tranegenle, quahtltativo trait locus, and
strain-comparison studies, also strongly support the possibility
that &mgr;OR gene alleles would be strong candidates for
contributing to individual dIfferences in human nocleeption and
opIate drug responses. This paper reviews current analyses of the
murine and human &mgr;OR genes, their Important variants, and
correlations between these variants and opIate Influences on pain
[0296] McI Phermacol 1999 August; 56(2):434-47 Dopamine
transporter: transmnembrane phenylalanine mutations can selectively
influence dopamine uptake and cocaine analog recognition. [0297]
Lin Z, Wang W, Kopajtic T, Revay R S, UhI G R [0298] Molecular
Neurobiology Branch, National Instltute on Drug Abuse, Intramural
Research Program, National Institutes of Health, Baltimore, Md.
Cocaine blocks the normal role of the dopamine traris.about.porter
(DAT) in terminating doparriine signaling through molecular
interactions that are only partially understood. Cocaine analog
structure-activity studies have suggested roles for both cationic
and aromatic interactions among DAT, dopemine, and cocaine. We
hypothesized that phenylalanine residues lying in putative DAT
tranemombrane (TM) domains wore good candidates to contribute to
aromatic and/or cationic interactions among DAT, dopamine, and
cocaine. To test this idea we characterized the influences of
alanine substitution for each of 29 phenylalanine residues lying in
or near a putative DAT TM domain. Cells express 22 mutartts at near
wild-type levels, manifest by DAT immunohistochemistry and binding
of the radiolabeled cocaine analog
[(3)H](-)-2-beta-carbomethoxy-3-beta-(4.fluoroph5nyl)tropane
.COPYRGT. FT), Seven mutants fail to express at normal levels. Four
mutations selectively reduce cocaine analog affinities. Alanine
substitutions at Phe(76), Phe(98), Phe(390), and Phe(381) located
ln TM domains 1 and 2, the fourth extracelkilar loop near TM 4 and
In TM 7, displayed normal affinities for dopan.about.lne but 3- to
8-fold reductions in affinities for CFT. One TM 3 mutation,
F(155)A, selectively decreased dopamine affinity to less than 3% of
wild-type levels while reducing CPT affinity less than 3-told. In a
current DAT structural model, each of the residues at which alanine
substitution selectivefy reduces cocaine analog or dopamine
affinities faces a central transporter cavity, whereas mutations
that Influence expression levels are more likely to lIe at
potential helixlhellx interfaces. Specific, overlapping sets of
phenylalenine residues contribute selectively to DAT recognition of
dopermlne and cocaine. [0299] J Camp Neural 1999 Jul. 26;
410(2):197-210 Choilnergic axon terminals in the ventral tegrnental
area target a subpopulauon of neurons expressing low levels of the
dopamlne transporter. [0300] Garzon M, Vaughan R A, Uhl G R, Kuhar
M J, Plcl.about.el V M [0301] Department of Neurology and
Neuroscience, Cornell University Medical College, New York, N.Y.
iOO2i, USA. mgarzon-mell.med.comell.edu ChoHnerglc actIvation of
dopen-lnerglc neurons In the ventral tegmental area (VTA) Is
thought to play a major role in .about.ognltive functions and
reward. These dopamlnergic neurons dIfferentIally project to
cortical and limbic forebrain regions, wheretheir.terminsls differ
In levels of expressIon of the plasmalemmal dopamlne transporter
(DAT). This transporter selectively identifies dopaminergic
neurons, Whereas Itie vesicular acetyictioline transporter (yAchT)
is present only In the neurons that store arid release
acetyicholine. We examined Immunogold labeling for DAT and
immunoperoxidase localization of VAchT antipeptlde antisera in
single sections of the rat VTA to determine whether dopaminefgic
someta and dendrites in this region differ In their levels of
expression of DAT and/or input from cholinergic terminals. VAchT
immunoreactivity was prominently localized to membranes .about.f
small synaptic vesIclee In unmyelinated axons and axon terminals.
VAchT-immunoreactive terminals formed almost exclusively
asyrnnietnc synapses with dendrites. Of 159 dendrites that were
Identified as cholinergic targets, 36% contained plasmalemmul DAT,
and 65% were without detectable DAT immunoresetivity. The
DAT-immunoreactive dendrites postsynaptic to VAchT-labeled
terminals contained less than half the density of gold particles as
Seen in other dendrites receiving Input only from unlabeled
termInals. These results suggest selective targeting of cholinergic
afferents in the VTA to non-dopaminergic neurons and a
subpopulation of dopaminergic neurons that have a limited capacity
for plasmalemmal reuptake of dopamine, a characteristic of those
that project to the frontal cortex. [0302] Eur J Phermecol 1999
February.about.366(2-3):R3-5 Visceral chemical nociception in mice
lacking mu-opioid receptors: effects of morphine, SNC80 and
U-50A88. [0303] Sara I, LI X F, Funada M, Kinsey S, UhI G R [0304]
Molecular Neurobiology Branch, Intramural Research Program,
National Inetituta on Drug Abuse, National Institutes of Health,
Baltimore, Md. 21224, USA. Writhing responses to Intraperitoneal
acetic acid administration and their modulation by mu-, kappa- and
delta-oploid receptor agonists were compared in wild-typo and
mu-opioid receptor knockout mice, Unpretreated homozygous knockout
mice displayed less writhing than wildtype mlce. U-50,488
[trans-3,4-dlchloro-N-methyl-N-f2-(1-pyrolldlnyl)cyclohexyIJ-b.about.nze
neacetamide]) reduced writhing responses in wIld-type and
khockouts. Morphine and SNC80
((4)-4-[9.-alpha-R)-alpha-(2S,5RO-4-ellyl-2.about.-dImethyl-I-piperazinyl-
)-3-methoxybenzylj-N,Ndiethylbenzsmide] were effective in wild-type
mice but ineffective in knockouts. Mu-opioid receptors appear to
play Important roles In responses to this visceral nociceptlve
stimulus and rt.about.modulation by mu- and delta-oploid receptor
agonists. [0305] Br J Pharmacol 1999 January; 126(2):451-6 Absence
of Q-protsin activation by mu-opioid receptor agonists in the
spinal cord of mu-opioid receptor knockout mice. [0306] Narita M,
Mlzoguchl H, NarIta M, Sora I, Uhl G R, Teeng L F [0307] Department
of Anesthesiology, Medical College of Wisconsin, Milwaukee, 53226,
USA. 1. The ability of mu-opioid receptor agonists to activate
G-proteins in the spinal cord of muopicici receptor knockout mice
was examined by monitoring the binding to membranes of the
non-hydrolyzable analogue of GTP,
guanoslne-.about.AE-O-(3-t35$1thIo)trIphosphate (t36S1GTPgammaS).
2. In the receptor binding study, Soatchard analysis of
[3H][DAa2,NHPh4,Gly-oflenkephaiin ([3H]DAMGO; mu-opioid receptor
ligand) binding revealed that the heterozygous mu-knockout mice
displayed approximately 40% reduction in the number of mu-receptors
as compared to the wild-type mIce, The homozygous mu-knockout mlc.e
showed no detectable mu-binding sites. 3. The newly Isolated
mu-opioid peptides endomorphln-1 and -2, the synthetic selective
mu-opiold receptor agonist DAMGO and the prototype of mu-oploid
receptor agonist morphine each produced concentration-dependent
Increases In [35S]GrPgammaS binding In wild-type mice. This
stimulatIon was reduced by 55-70% of the wild-type level In
heterozygous, and virtually elIminated in homozygous knockout mica.
4 No differences in the [35S]GTPgammaS binding stimulated b-AE
specific deftal-([D-Pen2,5]enkephalin), delta2-(ED-Ale2ldeltorphin
II) or kappal-(U50,A.about.8t-1) oploid receptor egonlets were
noted In mice of any of the three genotypes. 5. The data clearly
indicate that mu-opioid receptor gene products play a key role in
G-prdtein actru.about.ation by endomorphins, DAMGO and morphine in
the mouse spinal cord, fl..about.y support the idea that mu-op.Oid
receptor densities could be rate-limiting steps in the G-proteln
activation by muoplold receptor agoniats In the spinal cord. These
thus indicate a limited phyelologlcal mureeeptdr reserve.
Furthermore, little change in deital-, delta2-orkappal-oplold
receptor-Gprotein complex appears to accompany mu-opioid receptor
gene deletions in this region. [0308] erain Re,s 1999 Mar. 13;
821(2):480-6 Charactenzation of mechanical withdrawal responses and
effects of mu-, delta- and kappoploid agonists in normal and
mu-opioid receptor knockout mace. [0309] Fuchs P N. Raze C, Sara I.
Uhi G, Rain S N [0310] Oepartment of Neurosurgery, Johns Hopkins
School of Medicine, 600 North Wolfe Stre4 Meyer 5-109, Baltimore,
Md. 21257, USA. fuch.sup.outa.edu Clinical and expenmental
observations suggest that opiates can exert different influences on
the perception of stimuli from distinct sensory modalIties.
Thermally-induced nociception is classically responsive to opiate
ugonists. mu-Opioid receptor-deficient transgenic mice are more
sensitive to thermal noclceptlve stimuli a,.about.d morphine faile
to attenuate the nocloeptive responses to thermal stimulI in these
animals. To enhance our understanding of opIate Influences on
mechanical sensitMty, we have examined withdrawal responses to a
sequence of ascending forces of mechanical stimuli In mice with
normal (wild type), half-normal (heterozygous) and absent
(honiozygous) mu-opioid receptor levels. We report data from mice
examined without drug pretreatment or following pretreatment with
morphine, the selective kappa-oplold agonist, U5048811, end the
selective delta-opio;d agonist, DPOPE. Saline pretreated mice of
e8ch genotype displayed sImIlar, mnonotonlcally increasing
frequency of withdrawal responses to the graded stimuli.
Subcut.aneously adminIstered morphine produced a dose-dependent
reduction in withdrawal responses in wild type and heterozygous
mice, but had no significant effect in homozygous mice.
Intraventricular administration of DPDPE also reduced the frequency
of paw withdrawal (FPW) in wild type mice, but not in homozygous
mice. In contrast, systemic U5Ci488H produced a dose-dependent
attenuation of paw withdrawal in both wild type and horriozygous
mice. These findings suggest that (1) interactions of endogenous
peptides with mu-opioid receptors may not play a significant role
in the response to mechanical stimuli in drug-free animals, and (2)
deficiency of mu-apioid receptors has no functional consequence on
the response to the prototypical kappa-opiold receptor agonist, but
decreases responses to the prototypical mu- and delta-opioicl
receptor agonists. [0311] Neuropsychopharmecolo9y 1.about.99 Jan;
20(1):3-9 Molecular genetics of substance abuse vulnerability: a
vurrent approach. [0312] UhI G R [0313] Molecular Neurobiology
Branch1 NatIonal Institute on Drug Abuse, NIH, Baltimore, Md., USA.
Molecular genetics of substance abuse vulnerability: a current
approach. [0314] Nuropsychopharmacology. 1999 January; 20(1):3-9.
Review. No abstract available. [0315] PMID: 9885780; UI: 99103166.
Publication Types: Review Review, tutorial
REFERENCES
[0316] The following references, to the extent that they provide
exemplary procedural or other details supplementary to those set
forth herein, are specifically incorporated herein by reference.
[0317] U.S. Pat. No. 4,761,429 [0318] U.S. Pat. No. 5,189,064
[0319] Abraham, Brooks, Eylath, "The effects of chromium
supplementation on serum glucose and lipids in patients with and
without non-insulin-dependent diabetes," Metabolism, 41:768-771,
1992. [0320] Abraham and Dufy, "Computed EEG abnormalities in panic
disorder with and without premorbid drug abuse," Biol. Psychiatry,
29:687-690, 1991. [0321] Accili et al., "A new look at D.sub.3
receptors," Mol. Psychiatry, 1:93-94, 1996. [0322] Adams et al.,
"Neuropsychologicla deficits are correlated with frontal
hypometabolism in positron emission tomography studies of older
alcoholic patients," Alcohol Clin. Exp. Res., 17:205-210, 1993.
[0323] Aggleton and Mishkin, The Amygdala: Sensory gateway to the
emotions, In Plutchik and Kellerman (Eds.), Emotion Theory,
Research, and Experience, pp. 281-299, NY Adacemic Press, Inc.,
1986. [0324] Allen and Gorski, Sex differences in the bed nucleus
of the stria terminalis of the human brain, J. Comp. Neurol.,
302:697-706, 1990. [0325] American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders (DSM-II),
Washington, D.C. 1968. [0326] American Psychological Association,
Standards for Educational and Psychological Tests (Rev. Ed.),
Washington, D.C. 1974. [0327] American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders (DSM-III),
Washington, D.C. 1980. [0328] American Psychological Association,
Ethical Principles of Psychologists (Rev.) American Psychologist,
36:633-638, 1981. [0329] American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R),
Washington, D.C. 1987. [0330] American Psychiatric Association Task
Force: Quantitative electroencephalography: a report on the present
state of computerized EEG techniques, Am. J. Psychiatry,
148(7):961-964, 1991. [0331] American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),
Washington, D.C. 1994. [0332] Amit and Brown, "Actions of drugs of
abuse on brain reward systems: A reconsideration with specific
attention to alcohol," Pharmacology Biochemistry and Behavior,
17:233-238, 1982. [0333] Amsterdam et al., Life Sci.,
33(1):109-112, 1983. [0334] Anderson, "Chromium and parental
nutrition," Nutrition, 11(Suppl. 1):83-86, 1995. [0335] Anderson,
Polansky, Bryder, Canary, "Supplemental-chromium effects on
glucose, insulin, glucagon and urinary chromium losses in subjects
consuming controlled low-chromium diets," Am. J. Clin. Nutr.,
54:909-916, 1991. [0336] Aoki, Go, Venkatesan, Kurose, "Perikaryal
and synaptic localization of alpha-2A-adrenergic receptor-like
immunoractivity," Brain Res., 650:181-204, 1994. [0337] Arcot,
Wang, Weber, Deininger, Batzer, "Alu repeats: a source for the
genesis of primate microsatellites," Genomics, 29:136-144, 1995.
[0338] Arden, J. Pharm., Pharmacol 24:905-911, 1972. [0339]
Arinami, Gao, Hamaguchi, Toru, "A functional polymorphism in the
promoter region of the dopamine D.sub.2 receptor gene is associated
with schizophrenia," Human Molecular Genetics, 6:577-582, 1997
[0340] Arndt-Jovin, Udvardy, Garner, Ritter, Jovin, "Z-DNA binding
and inhibition by GTP of Drosophilia topoisomerase II,"
Biochemistry, 32:4862-4872, 1993. [0341] Arnsten, "Catecholamine
regulation of the prefrontal cortex," J. Psychopharmacology, 11:
151-162, 1997. [0342] Arnsten, Steere, Hunt, "The contribution of
a.sub.2-noradrenergic mechanism to prefrontal cortical cognitive
function. Potential significance for Attention-Deficit
Hyperactivity Disorder," Arch. Gen. Psychiatry, 53:448-455, 1996.
[0343] Asghari et al., "Modulation of intercellular cyclic AMP
levels by different human dopamine D.sub.4 receptor variants" J.
Neurochem, 65:1157-1165, 1995. [0344] Ashani, Grunwald, Kronman et
al., "Roles of tyrosine 337 in the binding of Huperzine A to the
active site of human acetylcholinesterase, Mol. Pharmacol.,
45:555-560, 1994. [0345] Ashani, Peggins, Doctor, "Mechanism of
inhibition of cholinesterase by Huperzine A," Biochem. Biophys.
Res. Commun., 184:719-726, 1992. [0346] Aston-Jones et al.,
"Discharge of noradrenergic locus coeruleus neurons in behaving
rats and monkeys suggest a role in vigilance" Progress in Brain
Res., 88:501-520, 1991. [0347] Aston-Jones, Foote, Bloom, "Anatomy
and physiology of locus coeruleus neurons: Functional
implications," M. G. Ziegler (Ed.), In: Frontiers of Clinical
Neuroscience, Vol 2, Baltimore, Williams and Williams, 1984. [0348]
August and Garfinkel, "Behavioral and Cognitive Subtypes of AD-HD,"
J. Am. Acad. Child Adoles. Psychiatry, 28(5):739-748, 1989. [0349]
August et al., "Familial subtypes of childhood hyperactivity" J.
Nerv. Ment. Dis., 171:362-368, 1972. [0350] Bain, et al., "Naloxone
attenuation of the effect of cocaine on rewarding brain
stimulation," Life Sciences, 40:1119-1125, 1986. [0351] Balagot, et
al., In: Advances in pain research and therapy, (Bowica, E U J, et
al., Raven Press, New York, 5:289-293, 1983. [0352] Balfour and
Fagerstrom, "Pharmacology of nicotine and its therapeutic use in
smoking cessation and neurodegenerative disorders," Pharmac. Ther.,
72:51-81, 1996. [0353] Balldin et al., "Further neuroendocrine
evidence for reduced D.sub.2 dopamine receptor function in
alcoholism, Drug Alcoh. Dep., 32:159-162, 1993. [0354] Ballenger et
al, "Carbamazepine in manic-depressive illness: a new treatment,"
Am. J. Psychiatry, 137:782-790, 1980. [0355] Banerjee and
Grunberger, "Enhanced expression of the bacterial chloramphenicol
acetyltransferase gene in mouse cells cotransfected with synthetic
polynucleotides able to form Z-DNA," Proc. Natl. Acad. Sci. USA,
83:4988-4992, 1986. [0356] Banerjee, Carethers, Grunberger,
"Inhibition of the herpes simplex virus thymidine kinase gene
transfection in Ltk-cells by potential Z-DNA forming polymers,"
Nucl. Acids Res., 13:5111-5126, 1985. [0357] Beckmann, et al., J.
Neuronal Trans., 41:123-124, 1977. [0358] Begleiter and Porjesz,
"Potential biological markers in individuals at high risk for
developing alcoholism", Alcohol Clin. Exp. Res., 12:488-493, 1988.
[0359] Begleiter and Porjesz, "Neuroelectric processes in
individuals at risk for alcoholism," Alcohol and Alcoholism,
25:251-256, 1990. [0360] Behnke and Wilmore, In: Evaluation and
Regulation of Body Build and Composition, Englewood Cliffs, N.J.,
Prentice-Hall, 1974. [0361] Benjamin, Li, Patterson, Greenberg,
Murphy, Hamer, "Population and familial association between the D4
dopamine receptor gene and measures of novelty seeking," Nature
Genet., 12:81-84, 1996. [0362] Bennett, Lucassen, Grough, Pewell,
Undlien, Pritchard, Merriman, Kawaguchi, Dronsfeld, Pociot, Nerup,
Bouzekri, Cambon-Thomsen, Ronning, Barnett, Bain, Todd,
"Susceptibility to human type 1 diabetes at IDDM2 is determined by
tandem repeat variation at the insulin gene minisatellite locus,"
Nature Genet., 9:284-292, 1955. [0363] Benuck, et al., Biophys.
Res. Comm., 107:1123-1129, 1982. [0364] Berman et al., "EP reduced
viso-spatial performance in children with the D.sub.2 dopamine
receptor A.sub.1, allele" Behav. Genet., 25:45-58, 1995. [0365]
Bernad, "EEG and pesticides," Electroencephalography and Clinical
Neurophysiology, 20:IX-X, 1989. [0366] Beyer and Feder, Sex
steroids and afferent input: their roles in brain sexual
differentiation, Annu. Rev. Physiol., 49:349-364, 1987. [0367]
Biederman et al., "Evidence of familial association between
attention disorder and major affective disorders" Arch. Gen.
Psychiatry, 48:526-533, 1990a. [0368] Biederman, Faraone, Keenan,
Knee, Tsuang, "Family-genetic and psychosocial risk factors in
DSM-III attention deficit disorder," J. Amer. Acad. Child
Adolescent Psychiat., 29:526-533, 1990b. [0369] Biederman, Newcom,
Sprich, Comorbidity of attention deficit hyperactivity disorder
with conduct, depressive, anxiety, and other disorders, Am. J.
Psychiatry, 148:564-577, 1991. [0370] Biederman, Faraone, Spencer,
Wilens, Norman, Lapey, Mick, Lehman, Doyle, "Patterns of
psychiatric comorbidity, cognition, and psychosocial functioning in
adults with attention deficit hyperactivity disorder," Am. J.
Psychiatry, 150:1792-1798, 1993. [0371] Biggio et al., "Stimulation
of dopamine synthesis in caudate nucleus by intrastriatial
enkephalins and antagonism by naloxone," Science, 200:552-54, 1978.
[0372] Black, Chenz, Craig, Powell, "Dinucleotide repeat
polymorphism at the MAOA locus," Nucleic Acids Res., 19:689, 1991.
[0373] Blackburn and Kanders, eds., In: Obesity Pathophysiology,
Psychology and Treatment, Chapman and Hall Series in Clinical
Nutrition, New York, N.Y., Chapman and Hall, 1994. [0374] Bloom et
al., Proc. Natl. Acad. Sci., USA, 75:1591-1595, 1978. [0375] Bloom,
In: The Pharmacological Basis Of Therapeutics, 247-248, (Goodman,
et al., eds., 1985). [0376] Blum, Wallace, Geller, "Synergy of
ethanol and putative neurotransmitters: Glycine and serine,"
Science, 176:292-294, 1972. [0377] Blum, Hamilton, Wallace, Alcohol
and opiates: A review of common neurochemical and behavioral
mechanisms, Editor: K. Blum, (pp. 203), Academic Press, New York,
1977. [0378] Blum et al., "Methionine enkephalinase as a possible
neuromodulator of regional cerebral blood flow," Experimentia,
41:932-933, 1985. [0379] Blum, Allison, Trachtenberg, Williams,
Loeblich, "Reduction of both drug hunger and withdrawal against
advice rate of cocaine abusers in a 30-day inpatient treatment
program by the neuronutrient Tropamine," Current Therapeutic
Research, 43:1204-1214, 1988. [0380] Blum, "A commentary on
neurotransmitter restoration as a common mode of treatment for
alcohol, cocaine and opiate abuse," Integrative Psychiatry,
6:199-204, 1989a. [0381] Blum, Briggs, Trachtenberg, "Ethanol
ingestive behavior as a function of central neurotransmission
(Review)," Experientia, 45:444-452, 1989b. [0382] Blum,
Trachtenberg, Elliott, Dingler, Sexton, Samuels, Cataldie,
"Enkephalinase inhibition and precursor amino acid loading improves
inpatient treatment of alcohol and polydrug abusers: Double-blind
placebo-controlled study of the nutritional adjunct," SAAVE.
Alcohol, 5:481-493, 1989c. [0383] Blum and Kozlowski, "Ethanol and
neuromodulator interactions: A cascade model of reward," Ollat et
al. (Eds), In: Progress Alcohol Research II (pp. 131-149), VSP
Utrecht, 1990a. [0384] Blum, Noble, Sheridan, Montgomery, Ritchie,
Jagadeeswaren, Nogami, Briggs, Cohns, "Allelic association of human
dopamine D.sub.2 receptor gene in alcoholism," Journal of the
American Medical Association, 263:2055-2060, 1990b. [0385] Blum,
Trachtenberg, Cook, "Neuronutrient effect on weight loss in
carbohydrate bingers: an open clinical trial," Current Therap.
Res., 48:217-223, 1990c. [0386] Blum and Payne, Alcohol and the
Addictive Brain, Free Press, New York, 1991a. [0387] Blum, Noble,
Sheridan, Finley, Montgomery, Ritchie, Ozkavagoz, Fitch, Sadlack,
F., Sheffield, Dahlmann, Halbardier, Nogami, "Association of the A1
allele of the D.sub.2 dopamine receptor gene with severe
alcoholism," Alcohol, 8:407-416, 1991b. [0388] Blum, Noble,
Sheridan, Montgomery, Ritchie, Ozkaragoz, Fitch, Wood, Finley,
Sadlack, "Genetic predisposition in alcoholism: association of the
D.sub.2 dopamine receptor TaqI B.sub.1 RFLP with severe
alcoholism," Alcohol, 10:59-67, 1993. [0389] Blum, Braverman,
Dinardo, Wood, Sheridan, "Prolonged P300 latency in a
neuropsychiatric population with the D.sub.2 dopamine receptor
A.sub.1 allele," Pharmacogenetics, 4:313-322, 1994a. [0390] Blum et
al., "Prolonged P300 latency in a neuropsychiatric polulation with
the D.sub.2 dopamine A.sub.1 allele," Pharmacogenetics, 4:313-322,
1994b. [0391] Blum, Braverman, Wood, et al., "Increased prevalence
of the TaqI A.sub.1 of the dopamine receptor gene (DRD.sub.2) in
obesity with comorbid substance use disorder: a preliminary
report," Pharmacogenetics, 6:297-305, 1995a. [0392] Blum, Sheridan,
Wood, Braverman, Chen, Comings, "Dopamine D.sub.2 receptor gene
variants: Association and linkage studies in
impulsive-addictive-compulsive behaviors," Pharmacogenetics,
5:121-141, 1995b. [0393] Blum, Cull, Braverman, Comings, "Reward
deficiency syndrome," Am. Scientist, 114:132-145, 1996a. [0394]
Blum et al., "Reward deficiency syndrome," American Scientist,
84:132-145, 1996. [0395] Blum et al., "The D.sub.2 dopamine
receptor gene as a determinant of reward deficiency syndrome," J.
Royal Soc. Of Med., 89:396-400, 1996b. [0396] Blum et al.,
"Increased prevalence of the TaqI A.sub.1 allele of the dopamine
receptor gene (DRD2) in obesity with comorbid substance use
disorder: a preliminary report," Pharmacogenetics, 6:297-305,
1996c. [0397] Blum, Braverman, Wu, Cull, et al., "Association of
polymorphisms of dopamine D.sub.2 receptor (DRD2) and dopamine
transporter (DAT1) genes with Schizoid Avoidant behaviors (SAB),"
Molecular Psychiatry, 2:239-246, 1997a. [0398] Blum, Cull, Chen, et
al., "Clinical evidence for effectiveness of Phencal in maintaining
weight loss in an open label controlled 2-year study," Current
Therap. Res., 58:745-763, 1997b. [0399] Blum et al., "Generational
Association Studies of Dopaminigic Genes in
Attention-Deficit-Hyperactivity (ADHD) probands of Multiple Family
Members up to four Generations," J. Neurotherapy [Abstract], 1998.
[0400] Bradford and McClean, Sexual offenders, violence and
testosterone: A clinical study, Can. J. Psychiatry, 29:335-343,
1984. [0401] Braun, Little, Reuter, Muller-Mysok, Koster, "Improved
analysis of microsatellites using mass spectrometry," Genomics,
46:18-23, 1997a. [0402] Braun, Little, Koster, "Detecting CFTR gene
mutations by using primer oligo base extension and mass
spectrometry," Clin. Chem., 43:1151-1158, 1997b. [0403] Braverman,
"Brain electrical activity mapping in treatment resistant
schizophrenics," Journal of Orthomolecular Medicine, 5:46-48,
1990a. [0404] Braverman et al., "A commentary on brain mapping in
60 substance abusers: can the potential for drug abuse be predicted
and prevented by treatment?" Cur. Ther. Res., 48:549-585, 1990b.
[0405] Braverman, Smith, Smayda, Blum, "Modification of P300
amplitude and other electrophysiological parameters of drug abuse
by cranial electrical stimulation," Current Therapeutic Research,
48:586-596, 1990c. [0406] Braverman and Blum, "Substance use
disorder exacerbates brain electrophysiological abnormalities in a
psychiatrically-ill population," Clin. EEG., 27(4 supplement):
1028, 1996a. [0407] Braverman and Blum, "Substance use disorder
exacerbates brain electrophysiological abnormalities in a
psychiatrically ill population" 148 Annual American Psychiatric
Society, New York 1996b (Abstract).
[0408] Brown, Ebert, Goyer, Jimerson, Klein, Bunney, Goodwin,
Aggression, suicide and serotonin relationships to CSF amine
metabolism, Amer. J. Psychiat., 139:741-746, 1982. [0409] Brown,
"Teacher ratings and the assessment of attention deficit disordered
children," J. Learn. Disabil., 19(2):95-100, 1986. [0410] Brown,
Goss, Lubahan, Joseph, Wilson, French, Willard, Androgen receptor
locus on the human X chromosome: regional localizatin to Xq11-12
and description of a DNA polymorphism, Am. J. Hum. Genet.,
44:264-269, 1989. [0411] Brown, Blum, Tractenberg, "Neurodynamics
of release prevention: A neuronutrient approach to outpatient DUI
offenders," J. of Psychoactive Drugs, 22(2), 173-187, 1990. [0412]
Brown et al., "Alcoholism and affective disorder: clinical course
of depressive symptoms," Am. J. Psychiatry, 152:45-52, 1994. [0413]
Bruckner and Hausch, "Amino acids as ubiquitous constituents in
fermented foods, G. Lubec and Rosenthal (Eds.), In. Amino
Acids--Chemistry, Biology and Medicine. (pp. 1172-1182). Leiden:
ESCOM Science Publication. [0414] Brunner, Nelen, van Zandvoort,
Abeling, van Gennip, Wolters, Kuiper, Ropers, van Oost, "X-linked
borderline mental retardation with prominent behavioral
disturbance: phenotype, genetic localization and evidence for
disturbed monoamine metabolism," Am. J. Hum. Genet., 52:1032-1039,
1993. [0415] Brunner, Helen, Breakefield, Ropers, van Oost,
"Abnormal behavior linked to a point mutation in the structural
gene for monamine oxidase A," Psychiat. Genet., 3:122, 1993. [0416]
Buchsbaum, Coursey, Murphy, "The biochemical high-risk paradigm:
behavioral and familial correlates of low platelet monoamine
oxidase activity," Science, 194:339-341, 1976. [0417] Buchsbaum,
Haier, Murphy, "Suicide attempts, platelet monamine oxidase and the
average evoked response," Acta Psychiatr. Scand., 56:69-79, 1977.
[0418] Buchsbaum, Rigal, Coppola, Cappelletti, King, Johnson, "A
new system for gray-level surface distribution maps of electrical
activity," Electroencephalography and Clinical Neurophysiology,
53:237-242, 1982. [0419] Buchsbaum and Wender, "Average evoked
responses in normal and minimally brain dysfunctional children
treated with amphetamine," Archives of General Psychiatry,
29:764-770, 1993. [0420] Bulbulian, Pringle, Liddy, "Chromium
picolinate supplementation in male and female swimmers," Med. Sci.
Sports Exerc., 28:s11 (abstract), 1996. [0421] Burke, Enghild,
Martin, Jou, Myers, Roses, Vance, Strittmatter, "Huntington and
DRPLA proteins selectively interact with the enzyme GAPDH," Nature
Med., 2:347-350, 1996. [0422] Butler et al., "Biogenic amine
metabolism in Tourette syndrome" Ann. Neurol, 37-39, 1979. [0423]
Butzow, Shin, Eichhorn, "Effect of template conversion from the B
to the Z conformation on RNA polymerase activity," Biochemistry,
23:4837-4843, 1984. [0424] Cabot and Serfontein, "Quantitative
electroencephalographic profiles of children with Attention Deficit
Disorder," Biol. Psychiatry, 40:951-963, 1996. [0425] Cadoret et
al., "Psychopathology in adopted away of biological parents with
antisocial behavior," Arch. Gen. Psychiatry, 35:175-184, 1978.
[0426] Cahill, Ernst, Janknecht, Nordheim, "Regulatory squelching,"
FEBS Lett., 344:105-108, 1994. [0427] Campuzano, Montermini, Molt ,
Pianese, Cossee, Cavalcanti, Monros, Rodius, Ducilos, Monticelli,
Zara, Canizares, Koutnikoa, Bidichandani, Gellera, Brice,
Trouillas, Michele, Filla, Frutos, Palau, Patel, DiDonate, Mandel,
Cocozza, Koenig, Pandolfo, "Friedreich's ataxia: autosomal
recessive disease caused by an intronic GAA triplet repeat
expansion," Science, 271:1423-1427, 1996. [0428] Cantwell,
"Psychiatric illness in the families of hyperactive children,"
Arch. Gen. Psychiatry, 27:414-417, 1972. [0429] Capon, Chen,
Levinson, Seeburg, Goeddel, "Complete nucleotide sequences of the
T24 human bladder carcinoma oncogene and its normal homologue,"
Nature, 302:33-37, 1983. [0430] Carenzie, Biasini, Frigeni, Della
Bella, "On the enzymatic degradation of enkephalins:
Pharmacological implications", In: Neural peptides and neuronal
communication, E. Costa and M. Trabucci (Eds)., (pp. 237-246), New
York: Raven press, 1980. [0431] Carey and Williamson, "Linkage
analysis of quantitative traits: increased power by using selected
samples," Am. J. Hum. Genet., 49:786-796, 1991. [0432] Caskey,
Pizzuti, Fu, Fenwick, Nelson, "Triplet repeat mutations in human
disease," Science, 256:784-789, 1992. [0433] Cassel et al.,
"Serotonergic modulation of cholinergic function in the central
nervous system: cognitive implications," Neurosci, 69:1-41, 1995.
[0434] Castellanos et al., "Cerebrospinal fluid homovanillic acid
predicts behavioral response to stimulants in 45 boys with
attention deficit/hyperactivity disorder," Neuropsychopharmacology,
14:125-137, 1996. [0435] Castelli, Garrison, Wilson, Abbott,
Kalousdian, Kannel, "Incidence of coronary heart disease and
lipoprotein cholesterol levels," JAMA, 256:2835-2838, 1986. [0436]
Chamberlain, Driver, Miesdeld, The length and location of CAG
trinucleotide repeats in the androgen receptor N-terminal domain
affect transactivation function, Nucleic Acids Res., 22:3181-3186,
1994. [0437] Cheng, Ren, Tang, "Huperine A, a novel promising
acetylcholinesterase inhibitor," Neuroreport, 8:97-101, 1996.
[0438] Choong, Kemppainen, Zhou, Wilson, Reduced androngen receptor
gene expression with first exon CAG repeat expansion," Molec.
Endocr., 10:1527-1535, 1996. [0439] Christian et al., "Associations
of dopamine D.sub.2 polymorphisms with brain electrophysiology,"
Alcoholism, 18:178, 1994. [0440] Clancy, Clarkson, DeCheke, Nosaka,
Freedson, Cunningham, Valentine, "Effects of chromium picolinate
supplementation on body composition, strength, and urinary chromium
loss in football players," Inter. J. Sport Nutr., 4:142-153, 1994.
[0441] Cloninger et al., "Psychobiological model or temperament and
character," Arch. Gen. Psych., 50:975-990, 1993. [0442] Cloninger,
"Genetic and environmental factors in the development of
alcoholism" J. Psychiat. Treat. Eval., 5:487-496, 1983. [0443]
Cloninger and Gottesman, Genetic and environmental factors in
antisocial behavioral disorders. In Mednick, Moffitt, Stack (Eds.),
The Causes of Crime (pp. 92-109). New York, N.Y., Cambridge Univ.
Press, 1986. [0444] Cloninger, "D.sub.2 dopamine receptor gene is
associated bu not linked with alcoholism," JAMA, 266:1833-1834,
1991. [0445] Clouet, "A biochemical and neurophysicalogical
comparison of opioids and antipsychotics, Annals New York Acad. of
Sci., 398:130-137, 1982. [0446] Clouet et al., "Catecholamine
bisynthesis in brains of rats treated with morphine," Science,
168:854-855, 1970. [0447] Coccaro, Central serotonin and impulsive
aggression, Br. J. Psychiatry, 155 (suppl 8):52-62, 1989. [0448]
Cochran, "Some methods for strengthening the common X.sup.2 tests,"
Biometrics, 10:417-454, 1954. [0449] Coetzee and Ross, Prostate
cancer and the androgen receptor," J. Nat. Cancer Inst.,
86:872-873, 1994. [0450] Coffey, Prostate Cancer. UICC Technical
Report Series Vol 48. Geneva: International Union Against Cancer.
1979. [0451] Coger, Moe, Serafetinides, "Attention deficit disorder
in adults and nicotine dependence: Psychobiological factors in
resistance to recovery," J. Psychoactive Drugs, 28:229-240, 1996.
[0452] Cohen et al., "Central biogenic amine metabolism in children
with the syndrome of chronic multiple tics of Gilles de la
tourette: Norepinephrine, serotonin and dopamine," J. Am. Acad.
Child Psychiatry, 118:320-341, 1979. [0453] Cohen, Semple, Gross,
Nordahl, DeLisi, Holcomb, King, Morihisa, Pickar, "Dysfunction in a
prefrontal substrate of sustained attention in schizophrenia," Life
Sciences., 40:2031-2039, 1987a. [0454] Cohen, Walter, Levinson, "A
repetitive sequence element 3' of the human c-Ha-ras.sub.1 gene has
enhancer activity," J. Cell. Physiol., 5:75-81, 1987b. [0455]
Collick, Dunn, Jeffreys, "Minisatellite binding protein Msbp-1 is a
sequence-specific single-stranded DNA-binding protein," Nucl. Acids
Res., 19:6399-6404, 1991. [0456] Collier, Stober, Li, Heils,
Catalano, DiBella, Arranz, Murray, Vallada, Bengel, Muller,
Roberts, Smeraldi, Kirov, Sham, Lesch, "A novel functional
polymorphism within the promoter of the serotonin transporter gene:
possible role in susceptability to affective disorders," Molecular
Psychiatry, 1:453-460, 1996 [0457] Comings and MacMurray,
"Molecular heterosis," 1977. [0458] Comings and Comings,
"Tourette's syndrome and attention deficit disorder with
hyperactivity: Are they genetically related." J. Am. Acad. Child
Psychiatry, 23:138-146, 1984. [0459] Comings and Comings, "A
controlled study of Tourette syndrome. I-VII," Am. J. Hum. Genet.,
41:701-866, 1987. [0460] Comings and Comings, "A controlled study
of Tourette syndrome. I. Attention-deficit disorder, learning
disorders, and school problems," Am. J. Hum. Genet., 41:701-741,
1987. [0461] Comings and Comings, A controlled family history study
of Tourette syndrome. I. Attention deficit hyperactivity disorder,
learning disorders and dyslexia, J. Clin. Psychiat., 51:275-280,
1990a. [0462] Comings, In: Tourette Syndrome and Human Behavior,
Hope Press: Duarte, Calif., pp 1-828, 1990b. [0463] Comings,
Comings, Tacket, and Li, "The clonidine patch and behavioral
problems," J. Am. Acad. Child. Adolesc. Psychiatry., 29:667-668,
1990c. [0464] Comings, Comings, Muhleman, Dietz, Shahbahrami, Tast,
Knell, Kocsis, Baumgarten, Kovacs, Levy, Smith, Kane, Lieberman,
Klein, MacMurray, Task, Sverd, Gysin, Flanagan, "The dopamine
D.sub.2 receptor locus as a modifying gene in neuropsychiatric
disorders," J. Am. Med. Assn., 266:1793-1800, 1991. [0465] Comings
et al., "Association between Tourett's syndrome and homozygosity at
the dopamine-D.sub.3 receptor gene," Lancet, 341:906, 1993a. [0466]
Comings and Comings, "Comorbid Behavioral Disorders," R. Kurlan
(Ed.), In: Handbook of Tourette's Syndrome and Related Tic and
Behavioral Disorders, pp. 111-147, New York: Marcel-Decker, 1993b.
[0467] Comings, "Genetic factors in substance abuse based on
studies of Tourette syndrome and ADHD probands and relatives. I.
Drug abuse," Drug and Alcohol Dependence, 35:1-16, 1994a. [0468]
Comings, "Genetic factors in substance abuse based on studies of
Tourette syndrome and ADHD probands and relatives. II. Alcohol
abuse," Drug and Alcohol Dependence, 35:17-24, 1994b. [0469]
Comings, The role of genetic factors in human sexual behavior based
on studies of Tourette syndrome and ADHD probands and their
relatives, Am. J. Med. Gen. (Neuropsych. Genet.), 54:227-241,
1994c. [0470] Comings, "Candidate genes and association studies in
psychiatry," (Letter to the editor), Am. J. Med. Gen. (Neuropsych.
Genet.), 54:324, 1994d. [0471] Comings, Muhleman, Ahn, Gysin,
Flanagan, "The dopamine D.sub.2 receptor gene: a genetic risk
factor in substance abuse," Drug Alcohd Depend., 214:175-180,
1994e. [0472] Comings, "The role of genetic factors in conduct
disorder based on studies of Tourette syndrome and ADHD probands
and their relatives," J. Dev. Behav. Pediatr., 16:142-157, 1995a.
[0473] Comings, "Tourette syndrome: A hereditary neuropsychiatric
spectrum disorder," Ann. Clin. Psychiatry, 6:235-247, 1995b. [0474]
Comings, "Genetic factors in depression based on studies of
Tourette syndrome and Attention Deficit Hyperactivity Disorder
probands and relatives, Am. J. Med. Gen. (Neuropsych. Genet.),
60:111-121, 1995c. [0475] Comings, "The haplotype relative risk
technique lacks power in polygenic inheritance," 1995 World
Congress Psychiatric Genetics, 5:103, 1995d. [0476] Comings et al.,
"Susuptability to post-tramatic stress disorder: a study of
replication," Biochmeistry, 40:368-372, 1996a. [0477] Comings et
al, "A study of the dopamine D.sub.2 receptor in pathological
gambling," Pharmacogenetics, 6:223-234, 1996b. [0478] Comings,
Gade, Muhleman, MacMurray, "Role of the HTR1A serotonin receptor
gene in Tourette syndrome and conduct disorder," Psychiat. Genet.,
6:166, 1996c. [0479] Comings, MacMurray, Gade, Muhleman, Peters,
"Genetic variants of the human obesity gene: association with
psychiatric symptoms and body mass index in young women, and
interaction with the dopamine D2 receptor gene," Mol. Psychiatry,
1:325-335, 1996d. [0480] Comings, Muhleman, Gade, Chiu, Wu, Dietz,
Winn-Dean, Ferry, Rosenthal, Lesieur, Rugle, Sverd, Johnson,
MacMurray, "Exon and intron mutations in the human tryptophan
2,3-dioxygenase gene and their potential association with Tourette
syndrome, substance abuse and other psychiatric disorders,"
Pharmacogenetics, 6:307-318, 1996e. [0481] Comings, Wi, Chiu,
Muhleman, Sverd, "Studies of c-Harvey-Ras gene in psychiatric
disorders," Psychiatry Res., 63:25-32, 1996f. [0482] Comings, Wu,
Chiu, Ring, Dietz, and Muhleman, "Polygenic inheritance of Tourette
syndrome, stuttering, ADHD, conduct and oppositional defiant
disorder: The Additive and Subtractive Effect of the three
dopaminergic genes -DRD2, DbH and DAT1," Am. J. Med. Gen.
(Neuropsych. Genet.), 67:264-288, 1996j. [0483] Comings, "Polygenic
inheritance and minisatellites," Psychiat. Genet., 6:157-158,
1996k. [0484] Comings, "Polygenetic inheritance of psychatric
disorders," In. Handbook of Psychiatric Genetics, Blum K., Noble E
P, Sparks R S, Sheridan P J (Eds), CRC Press, Boca Raton, Fla., pp
235-260, 19961. [0485] Comings, In: Search for the Tourette
Syndrome and Human Behavior Genes, Hope Press: Duarte, Calif.,
1996m. [0486] Comings, Gade, Wu, Chiu, Dietz, Muhleman, Saucier,
Ferry, Burchete, Johnson, Verde, MacMurray, "Studies of the
potential role of the dopamine D.sub.1 receptor gene in addictive
behaviors," Mol. Psychiatry, 2:44-56, 1997a. [0487] Comings,
Muhleman, Gade, Johnson, Verde, Saucier, MacMurray, "Cannabinoid
receptor gene (CNR1): association with IV drug use," Mol.
Psychiatry, 2:161-168, 1997b. [0488] Comings, Wu, Gonzalez,
Muhleman, Gade, Blake, MacMurray, McGue, Lykken, "Association of
the normal FRAXA and HTR2A genes with performance IQ in the general
population," 1997. [0489] Comings, "Polygenic inheritance and
micro/minisatellites," Mol. Psychiatry, 3:21-31, 1998. [0490]
Conners, Levin, Sparrow, Hinton, Erhardt, Meck, Rose, March,
"Nicotine and attention in adult attention deficit hyperactivity
disorder (ADHD)," Psychopharmacol. Bull., 32:67-73, 1996. [0491]
Cook, Stein, Krasowski, Cox, Olkon, Kieffer, Leventhal,
"Association of attention-deficit disorder and the dopamine
transporter gene," Am. J. Hum. Genet., 56:993-998, 1995. [0492]
Corbetta, Miezin, Dobmeyer, Shulman, Petersen, "Selective and
divided attention during visual discriminations of shape, color,
and speed: functional anatomy by positron emission tomography,"
Journal of Neuroscience., 11:2383-2402, 1991. [0493] Corrigall and
Coen, "Nicotine maintains robust self-administration in rats on a
limited-access schedule,
" Psychopharmacology (Berlin), 99:473-478, 1989. [0494] Corrigall
and Coen, "Selective Dopamine Antagonists Reduce Nicotine
Self-Administration," Psychopharmacology (Berlin), 104:171-176,
1991. [0495] Corrigall, Coen, Adamson, "Self-administered nicotine
activates the mesolimbic dopamine system through the ventral
tegmental area," Brain Res., 653:278-284, 1994. [0496] Costello, "A
Report on the NIMH Diagnostic Interview Schedule for Children
(DISC)," Paper presented at the Research Forum: Structured
diagnostic instruments in child psychiatry, Am. Acad. Child
Psychiatry, San Francisco, Calif., 1983. [0497] Coy and Kastin, J.
Peptides, 1: 175-177, 1980. [0498] Craddock, Daniels, Roberts,
Rees, McGuffin, Owen, "No evidence for allelic association between
bipolar disorder and monoamine oxidase A gene polymorphisms," Am.
J. Med. Gen. (Neuropsych. Genet.), 60:322-324, 1995. [0499] Crocq
et al., "Association between schizophrenia and homozygosity at the
dopamine D.sub.3 receptor gene," J. Med. Genet., 29:858-860, 1992.
[0500] Curtis, Lehman, Zamore, "Translational regulation in
development," Cell, 81:171-178, 1965. [0501] d'Amato, Leboyer,
Malafosse, Samolyk, Lamouroux, Junien, Mallet, "Two TaqI dimorphic
sites at the human b-hydroxylase locus," Nucleic Acids Res.,
17:5871, 1989. [0502] Davidson, Clinical Diabetes Mellitus, New
York, N.Y., Thieme Medical Publishers, Inc., 1991. [0503] Davis,
Hurt, Morse, O'Brien, "Discriminant analysis of the
self-administered alcoholism screening test," Alcoholism: Clinical
& Experimental Research, 11:269-273, 1987. [0504] DeFrance,
Schweitzer, Sands, Ginsberg, Sharma, "Age-Related Changes of
Cognitive ERPs in Attention, 1995. [0505] DeFrance, Ginsberg,
Rosenberg, Sharma, "Topographical mapping of adolescent affective
disorders," 1995 [0506] DeFrance, Hymel, Degioanni, Kutyna,
Calkins, Estes, Schweitzer, "Evidence of temporal lobe activation
by discriminative spatial orientation," Brain Topography,
6:137-142, 1993. [0507] del Senno, Aguiari, Piva, Dinucleotide
repeat polymorphism in the human estrogen receptor (ESR) gene, Hum.
Mol. Genet., 1:354, 1992. [0508] Della Bella, Carenzie, Frigeni,
"Effect of carboxypeptidase inhibition on in vitro and in vivo
pharmacological properties of morphine enkephalins,"
Neuropharmacology, 18:719-721, 1979. [0509] Dementyeva and
Yaremenko, Bul. Sib. Dep. Of the Academy of Science of the USSR,
6:70-77, 1983. [0510] Devor, Cloninger, Hoffman, Tabakoff,
"Association of monoamine oxidase (MAO) activity with alcoholism
and alcoholic subtypes," Am. J. Med. Genet., 48:209-213, 1994.
[0511] Diagnostic and Statistical Manual of Mental Disorders, 3rd
Ed, revised, American Psychiatric Association: Washington, D.C.,
1987. [0512] Diagnostic and Statistical Manual of the American
Psychiatric Assn. IV. Washington, D.C.: American Psychiatric Assn.,
1994. [0513] DiChiara and Imperato, "Drugs abused by humans
preferentially increase synaptic dopamine concentrations in the
mesolimbic system of freely moving rats," Proc. Natl. Acad. Sci.
USA, 85:5274-5278, 1988. [0514] Dienstbier, "Arousal and
physiological toughness: Implication for mental and physical
health", Psychological Rev., 96:84-100, 1989. [0515] Djordjevic,
Dimitrijevic, Maksimovic, Vivic, Vucetic, "Application of organic
bound chrome in disturbed glycoregulation therapy," Transplant.
Proc., 27:3333-3334, 1995. [0516] Donaldson, Lee, Smith, Rennefl,
"Glucose tolerance and plasma lipid distribution in rats fed a high
sucrose, high cholesterol, low Cr diet," Metabolism, 34:1086-1093,
1985. [0517] Donchin, Callaway, Cooper, Desmedt, Goff, Hillyard,
Suton, "Publication criteria for studies of evoked potentials (EP)
in man. Report of the methodology committee," Desmedt (Ed.), In:
Attention, voluntary contraction and event related cerebral
potentials, Progress in clinical neurophysiology, (pp. 1-11),
Basel, Karger, 1977. [0518] Donnelly, Rapoport, Potter, Oliver,
Keysor, Murphy, "Fenfluramine and dextroamphetamine treatment of
childhood hyperactivity," Arch. Gen. Psychiatry, 46:205-212, 1989.
[0519] Duffy et al., "Status of quantitative EEG (QEEG) in clinical
practice," Clinical EEG, 25(1), 1994. [0520] Duffy, Albert,
McAnulty, "Brain electrical activity in patients with presenile and
senile dementia of the Alzheimer Type," Annals of Neurology,
16:439-448, 1984. [0521] Duffy, Bartels, Burchfield, "Significance
Probability Mapping: An Aid in the Topographical Analysis of Brain
Electrical Activity," Electroencephalography and Clinical
Neurophysiology, 51:455-462, 1981. [0522] Durstine and Haskell,
"Effects of exercise training on plasma lipids and lipoproteins,"
In: Exercise and Sport Sciences Reviews, Volume 22, J. O. Holloszy
(ed), Baltimore, Md., Williams and Wilkins, 1994. [0523] Dykman,
Ackerman, Oglesby, "Selective and sustained attention in
hyperactive learning disabled and normal boys," J. Nerv. Ment.
Dis., 167:288-297, 1979. [0524] Ebstein, Novick, Umansky, Priel,
Osher, Blaine, Bennett, Nemanov, Katz, Belmaker, "Dopamine D4
receptor (D4DR) exon III polymorphism associated with the human
personality trait of novelty seeking," Nature Genet., 12:78-80,
1996. [0525] Eckel, "Insulin resistance: an adaption for weight
maintenance," Lancet, 340:1452-1453, 1992. [0526] Edwards, Hammond,
Jin, Caskey, Chakraborty, Genetic variation at five trimeric and
tetrameric tandem repeat loci in four human population groups,
Genomics, 12:241-253, 1992. [0527] Egger and Flytin, Effects of
electrical stimulation of the amygdala on hyopthalamically elicited
attack behavior in cats, J. Neurophysiol., 26:705-720, 1963. [0528]
Eggers, Kurth, Kurth, "Allele frequencies of dopamine receptors
DRD.sub.1 and DRD.sub.2 in Parkinson's disease populations," Am. J.
Hum. Genet., 57:A162, 1995. [0529] Ehrenpreis et al., In: Advances
in endogenous and exogenous opioids: Proc. Intl. Narcotic Res.
Conf., Kodancha, Tokyo, 279-281, 1981. [0530] Ehrenpreis, Balagot,
Comaty, Myles, "Naloxone reversible analgesia in mice produced by
D-phenylalanine and hydrocinnamic acid, inhibitors of
carboxypeptidase A," Bonica et al. (Eds.), In: Advances in pain and
research therapy (pp 479-488). New York: Raven Press, 1979. [0531]
Ehrenpreis et al., Pharmacologist 20:168, 1978 [0532] Epplen, Kyas,
Maueler, "Genomic simple repetitive DNAs are targets for
differential binding of nuclear proteins," FEBS Lett., 389:92-95,
1996. [0533] Evans, "The role of picolinic acid in mineral
metabolism," Life Chem. Rpts., 1:57-67, 1982. [0534] Evans and
Press "Cholesterol and glucose lowering effect of chromium
picolinate," FASEB. J., 3:A3101, 1989a. [0535] Evans, "The effect
of chromium picolinate on insulin controlled parameters in humans,"
Int. J. Biosoc. Med. Res., 11:163-180, 1989b. [0536] Evans and
Bowman, "Chromium picolinate increases membrane fluidity and rate
of insulin internalization," J. Inorgan. Biochem., 46:243-250,
1992a. [0537] Evans and Meyer, "Chromium picolinate increases
longevity," Age, 15:134, 1992b. [0538] Evans and Pouchnik,
"Composition and biological activity of chromium-pyridine
carboxylate complexes," J. Inorg. Biochem., 49:177-187, 1993a.
[0539] Evans, "Chromium picolinate is an efficacious and safe
supplement," Int. J. Sport Nutr., 3:117-122, 1993b. [0540] Falk and
Rubinstein, "Haplotype relative risks: an easy reliable way to
construct a proper control sample for risk calculations," Ann. Hum.
Genet., 51:227-233, 1987. [0541] Farde et al., "D.sub.2 dopamine
receptors and personality traits" Nature, 385:590, 1997. [0542]
Farone et al., "Evidence for the independent famial transmission of
attention deficit hyperactivity disorder and learning disabilities:
Results from a family genetic study," Am. J. Psychiatry,
150:891-895, 1993a. [0543] Farone et al., "Family-genetic and
psycholsocial risk factors in DSMIII attention deficit disorder,"
Am. J. Psychiatry, 150:1792-1798, 1993b. [0544] Felig, "Amino acid
metabolism in man," Ann. Rev. Biochem., 44:933-955, 1975. [0545]
Felig, "Insulin is the mediator of feeding-related thermogenesis:
Insulin resistance and/or deficiency results in a thermogenic
deficit which contributes to the pathogenesis of obesity," Clin.
Physiol., 4:267-273, 1984. [0546] Fernstrom and Wurtman, Science,
174:1023, 1971. [0547] Fink, Bores, Effland et al., "Synthesis and
evaluation of 5-amino-5,6,7,8-tetrahydroquinolinones as potential
agents for the treatment of Alzheimer's disease," J. Med. Chem.,
38:3645-3651, 1995. [0548] Fitz et al., J. Am. Soc. Pharmacol.
Therap., 271:1574-1582, 1994. [0549] Fowler, Tipton, MacKay,
Youdin, "Human platelet monoamine oxidase--a useful enzyme in the
study of psychiatric disorders," Neuroscience, 7:1577-1594, 1982.
[0550] Friedman, Carson, Larsson, DeMarco, A polymorphism in the
coding region of the vasopressin type 2 receptor (AVPR.sub.2) gene,
Hum. Mol. Genet., 2:1746, 1993. [0551] Gade, Blake, MacMurray,
Muhleman, Johnson, Verde, Comings, "Relationship of the GABRB.sub.3
gene to adult ADHD and personality traits in Caucasian and
African-American samples," Psychiat. Genet., 6:164-165, 1996.
[0552] Gade, Muhleman, Blake, MacMurray, Johnson, Verde, Saucier,
McGue, Lykken, Comings, "Correlation of length of VNTR alleles are
the X-linked MAOA gene and phenotypic effect in Tourette syndrome
and drug abuse," Mol. Psychiatry, 3:50-60, 1997. [0553] Gadow and
Sprafkin, In: Child Symptom Inventories Manual, Checkmate Plus Ltd:
Stony Brook, N.Y., pp 1-115, 1994. [0554] Gail et al., J.
Pharmacol. Exp. Therap., 226:111 33-38, 1983. [0555] Galen and
Gambino, "Beyond Norreality," In: The Predictive Value and The
Efficiency of Medical Diagnosis, NY, Wiley Biomedical, 1975. [0556]
Geib, Tuckmantel, Kozikowski, "Huperzine A-a potent
acetylcholinesterase inhibitor of use in the treatment of
Alzheimer's disease," Acta Crystalogr C., 47:824-827, 1991. [0557]
Gelernter, "Genetic association studies in psychiatry: recent
history. Chapter 2, In Handbook of Psychiatric Genetics (Eds. K.
Blum and E. P. Noble), CRC Press, Boca Raton, pp 25-36, 1997.
[0558] Gelernter, Krazler, Satel, Rao, "Genetic association between
dopemine transporter protein alleles and cocaine-induced paranoia,"
Neuropsychopharmacology, 11:195-200, 1994. [0559] Gelertner et al.,
"Exclusion of close linkage of Tourette's syndrome to D1 dopamine
receptor," Am. J. Psychiatry, 150:449-453, 1993. [0560] Geller et
al, 1970. [0561] Geller, Hartmann, Blum, "The effects of low-dose
combinations of D-amphetamine and cocaine on experimentally induced
conflict in the rat," Current Therapeutic Research, 14:220-224,
1972. [0562] Gessa et al., 4th World Congress on Biological
Psychiatry, 459(620):10, 1985. [0563] Gill, Daly, Heron, Hawi,
Fitzgerald, "Confirmation of association between attention deficit
disorder and a dopamine transporter polymorphism," Molecular
Psychiatry, 2:311-313, 1997. [0564] Gillis, Gigler, Pennington,
DeFries, "Attention deficit disorder in reading-disabled twins:
Evidence for a genetic etiology," J. Abnorm. Child. Psychol.,
20:343-348, 1992. [0565] Gillman et al., J. Neurochem., 37:410,
1981. [0566] Gilman et al., "Cerebellar and frontal hypometabolism
in alcoholic cerebellar degeneration studies with positron emission
tomography," Annals. Neurology, 28:775-785, 1990. [0567]
Giovannucci, Stampfer, Krithivas, Brown, Brufsky, Hennekens,
Kantoff, The CAG repeat within the androgen receptor gene and its
relationship to prostate cancer, Proc. Natl. Acad. Sci. USA,
94:3320-3323, 1997. [0568] Girardi, Shaywitz, Shaywitz, Marchione,
Fleischman, Jones, Tamborlane, "Blunted catecholamine responses
after glucose ingestion in children with attention deficit
disorder," Pediatr. Res., 38:539-542, 1995. [0569] Giros et al.,
"Hyperlocomotion and indifference to cocaine and amphetamine in
mice lacking dopamine transporter," Nature, 379:606-612, 1996.
[0570] Glinsmann and Mertz, "Effect of trivalent chromium on
glucose tolerance," Metabolism, 15:510-515, 1966. [0571]
Goldman-Rakic, "Topolography of cognition: Parallel distributed
networks in primate association cortex," Annu. Rev. Neurosci.,
11:137-156, 1988. [0572] Goldman-Rakie, In: Plum and Mountcasle
(Eds) Handbook of Physiology, The Nervous System V. Bethesda Md.,:
Am. Physiol. Soc., 373-417, 1987. [0573] Goldstein et al.,
"Psychiatric disorders in relatives of probands with panic disorder
and/major depression," Archives Gen. Psychiatry, 51:383-394, 1994.
[0574] Gorski, Critical role for the medial preoptic area in the
sexual differentiation of the brain, Prog. Brain Res., 61:129-146,
1984. [0575] Gottfries, Oreland, Wiberg, Winblad, "Lowered
monoamine oxidase activity in brains from alcoholic suicides," J.
Neurochem., 25:667-673, 1975. [0576] Gottlieb, Trifiro, Lumbroso,
Pinsky, The angroden receptor gene mutation database, Nucleic Acids
Res., 25:158-162, 1977. [0577] Grandy, Marchionni, Makam, Stofko,
Alfano, Frothingham, Fisher, Burke-Howie, Bunzow, Server, Civelli,
"Cloning of the cDNA and gene for a human D.sub.2 dopamine
receptor," Proc. Natl. Acad. Sci. USA, 86:9762-9766, 1989a. [0578]
Grandy, Lilt, Allen, Bunzow, Marchiormi, Makam, Reed, Magenis,
Civelli, The human dopamine D.sub.2 receptor gene is located on
chromosome 11 at q22-q23 and identifies a TaqI RFLP, Am. J. Hum.
Genet., 45:778-785, 1989b. [0579] Granon, Poucet, Thinus-Blanc,
Changeux, Vidal, "Nicotinic and muscarinic receptor in the rat
prefrontal cortex: Differential roles in working memory, response
selection and effortful processing," Psychopharmacology (Berlin),
119:139-144, 1995. [0580] Grant et. al., Med. Sci. Sports Exerc.,
29:992-998, 1997. [0581] Grayson and Carlson, "The utility of a
DSM-III-R based checklist in screening child psychiatric patients,"
J. Am. Acad. Child. Adolesc. Psychiatry, 30:669-673, 1991. [0582]
Green and Krontiris, "Alleleic variations of reporter gene
activation by the HRAS 1 minisatellite," Genomics, 17:429-434,
1993. [0583] Greenberg, Hodge, Vieland, Spence, "Affecteds-only
linkage methods are not a panacea," Am. J. Hum. Genet., 58:892-895,
1996. [0584] Grice, Leekman, Pauls, Kurlan, Kidd, Pakstis, Chang,
Buxbaum, Cohen, Gelermter, "Linkage disequilibrium of an allele at
the dopamine D4 receptor locus with Tourette's syndrome by TDT,"
Am. J. Hum. Genet., 59:644-652, 1996. [0585] Grimsby, Chen, Wang,
Lan, Shih, "Human monamine oxidase A and B genes exhibit identical
exon-intron organization," Proc. Natl. Acad. Sci. USA,
88:3637-3641, 1991. [0586] Grompe, "The rapid detection of unknown
mutations in nucleic acids," Nature Genet., 5:111-117, 1993. [0587]
Grunwald, Raveh, Doctor, et al., "Huperzine A as a pretreatment
candidate drug against nerve agent toxicity," Life Sci.,
54:991-997, 1994. [0588] Guan, Chen, Lu, et al., "Effects of
Huperzine A on eletroencephalography power spectrum in rabbits,"
Chung Kuo Yao Li Hsuch Pao,
10:496-500 (article in Chinese), 1989. [0589] Guipponi,
Baldy-Moulinier, Malafosse, "A fok1 polymorphism in the human
neuronal nicotinic acetylcholine receptor a4 subunit gene," Clin.
Genetics, 51:78-79, 1997. [0590] Halgren and Smith, "Cognitive
evoked potentials as modulatory processes in human memory formation
and retrieval," Human Neurobiology, 6:129-139, 1987. [0591]
Halgren, Squires, Wilson, Rohrbaugh, Babb, Crandall, "Endogenous
potentials generated in the human hippocampal formation and
amygdala by infrequent events," Science, 210:803, 1980. [0592]
Halikas, Nugent, Crosby, Carlson, "1990-1991 survey of
pharmacotherapies used in the treatment of cocaine abuse," J.
Addictive Diseases, 12:129-139, 1993. [0593] Hall et al.,
"Distribution of D.sub.1 and D.sub.2-dopamine receptors, and
dopamine and its metabolites in the human brain,"
Neuropsychopharmacol., 14:245-256, 1994a. [0594] Hall, Antoniou,
Wang, Cheung, Arbus, Olson, Lu, Kau, Marsden, "Structural
organization of the human neuronal nitric oxide synthase gene
(NOS)," J. Biol. Chem., 269:33082-33090, 1994b. [0595] Halliday,
Rosenthal, Naylor, Callaway, "Averaged evoked potential predictors
of clinical improvement in hyperactive children treated with
methyphenidate: an initial study and replication,"
Psychophysiology, 13:429-440, 1976. [0596] Hallmark, Reynolds,
DeSouza, Dotson, Anderson, Rogers, "Effects of chromium and
resistive training on muscle strength and body composition," Med.
Sci. Sports Exerc., 28:139-144, 1996. [0597] Hallmark, Reynolds,
Desouza et al., "Effects of chromium supplementation and resistive
training on musclar strength and lean body mass in untrained men,"
Med. Sci. Sports Exerc., 25 (Suppl. 5) S101 (abstract), 1993.
[0598] Halperin, Newcorn, Koda, Pick, McKay, Knott, "Noradrenergic
mechanisms in ADHD children with and without reading disabilities.
A replication and extension," J. Am. Acad. Child Adolesc.
Psychiatry, 36:1688-1696, 1997. [0599] Halperin, Newcom, Schwartz,
McKay, Bedi, Sharma, "Plasma catecholamine metabolites in ADHD boys
with and without reading disabilities," J. Clin. Child. Psychol.,
22:219-225, 1993. [0600] Hamada and Kakunaga, "Potential Z-DNA
sequences are highly dispersed in the human genome," Molec. Cell
Biol., 4:2610-2621, 1984. [0601] Hamada, Petrino, Kakunaga, A novel
repeated element with Z-DNA-forming potential is widely found in
evolutionarily diverse eukaryotic genomes, Proc. Natl. Acad. Sci.
USA, 79:6465-6469, 1982. [0602] Hammer, Jr. et al., Soci.,
Neuroscience Abstracts, 13(21):85 No. 2710, 1987. [0603]
Hammond-Kosack and Docherty, "A consensus repeat sequence from the
human insulin gene linked polymorphic region adopts multiple
quadriplex DNA structures," FEBS Lett., 301:79-82, 1992. [0604]
Hammond-Kosack, Dobrinski, Lurz, Docherty, Kilpatrick, "The human
insulin gene linked polymorphic region exhibits an altered DNA
structure," Nucl. Acids Res., 20:231-236, 1992. [0605] Haniford and
Pulleybank, "Facile transition of poly[d(TG).d(CA)] into a
left-handed helix in physiological conditions," Nature,
302:632-634, 1983. [0606] Hanin, Tang, Kindel, Kozikowski, "Natural
and synthetic Huperzine. An effect on cholinergic function in vitro
and in vivo," Ann. NY Acad. Sci., 695:304-306, 1993. [0607] Hanna,
Ornitz, Hariharan, "Urinary epinephrine excretion during
intelligence testing in attention-deficit hyperactivity disorder
and normal boys," Biol. Psychiatry, 40:553-555, 1996. [0608] Hao,
Gong, Qin, "Effects of Huperzine A on cholinesterase isoenzymes in
plasma of mice and dogs," Chung Kuo Yao Li Hsuch Pao 9:312-316
(article in Chinese), 1988. [0609] Hardy, Scher, Bodenreider,
Sabbatini, Zhang, Namus, CaRemil, Androgen receptor CAG repeat
lengths in prostate cancer: correlation with age of onset, J. Clin.
Endocrinol. Metab., 81:4400-4405, 1996. [0610] Harley,
"Noradrenergic and Locus modulation of the preforant path-evoked
potential in rat dsentate gyrus supports a role for the locus
coeruleus in attentional procession and memorial processes,"
Progress in Brain Res., 88:307-321, 1988. [0611] Hartruck and
Lipscomb, In: Carboxypeptidase A: in THE ENZYMES, 1-56, Boyer, ed.,
Academic Press, New York, 1971 [0612] Haskell, "The influence of
exercise training on plasma lipids and lipoproteins in health and
disease," Acta. Med. Scan., (Suppl.) 711:25-37, 1986. [0613] Hasten
et. al., Int. J. Sports Nutr., 2:343-350, 1992. [0614] Hasten,
Rome, Franks, Haysted, "Effect of chromium picolinate on beginning
weight training students," Int. J. Sports Nutr., 2:343-350, 1992.
[0615] Hasten, Siver, Fomea, et al., "Dosage effects of chromium
picolinate on body composition," FASEB J., 8(4):A194, 1994. [0616]
Heath, Gavin, Hinderliter, Hagberg, Bloomfield, Holloszy, "Effects
of exercise and lack of exercise on glucose tolerance and insulin
action," J. Appl. Physiol., 55:512-517, 1983. [0617] Hechman,
"Genetic and neurobiological aspects of attention deficit
hyperactivity disorder: a review," J. Psychiatry Neurosci.,
19:193-201, 1994. [0618] Heils, Teufel, Petri, Seeman, Bengel,
Batling, Riederer, Lesch, Functional promoter and polyadenylation
site mapping of the human serotonin (5-HT) transporter gene, J.
Neural. Transm., 102:247-254, 1995. [0619] Heils, Teufel, Petri,
Stober, Riederer, Bengel, Lesch, Allelic variation of human
serotonin transporter gene expression, J. Neurochem., 66:2621-2624,
1996. [0620] Herault, Perrot, Barthelemy, Buchlar, Cherpi, Leboyer,
Sauvage, Lelord, Mallet, Muh, "Possible association of
C-Harvey-Ras-1 (HRAS-1) marker with autism," Psychiatry Res.,
46:261-267, 1993. [0621] Herbert and Rich, "The biology of
left-handed Z-DNA," J. Biol. Chem., 271:11595-11598, 1996. [0622]
Herbert, "RNA editing, introns and evolution," Trends Genet.,
12:6-9, 1996. [0623] Herbert, Lowenhaupt, Spitzner, Rich, "Chicken
double-stranded RNA adenosine deaminase has apparent specificity
for Z-DNA," Proc. Natl. Acad. Sci. USA, 92:7550-7554, 1995. [0624]
Heijanic and Campbell, "Differentiating psychiatrically disturbed
children on the basis of a structured interview," J. Abnorm. Child
Psychology, 5:127-134, 1977. [0625] Hernandez-Rodriquez and
Chagoya, "Brain serotonin synthesis and NA.sup.+, K.sup.+-ATPase
activity are increased post-natally after prenatal administration
of L-tryptophan," Developmental Brain Research, 25:221-226, 1989.
[0626] Hernandez, Lee, Hoebel, "Microdialysis in the nucleus
accumbens during feeding or drugs of abuse: amphetamine, cocaine,
and phencyclidine,". Kalivas and Nemeroff (Eds.), In: The
Mesocorticolimbic Dopamine System (pp. 508-511), New York: New York
Academy of Sciences, 1988. [0627] Hersh, Biochem., 20:2345-2350,
1981. [0628] Hexum et al., Life Sci, 24:1211-1216, 1980. [0629] Hi,
Yi, Xi, "Huperzine A ameliorates the spatial working memory
impairmnents induced by AF64A," Neuroreport, 6:2221-2224, 1995.
[0630] Higuchi, Muramatsu, Matsushita, Arai, Sasaki, "Presenilin-1
polymorphism and Alzheimer's disease," Lancet, 347:1186, 1996
[0631] Hill and Neiswanger, "The value of narrow psychiatric
phenotypes and super normal controls," Chapter 3. In Handbook of
Psychiatric Genetics (Eds. K. Blum and E. P. Noble), CRC Press,
Boca Raton, pp 37-48, 1997. [0632] Hillyard, Hink, Schwent, Picton,
"Electrical signs of selective attention in the human brain,"
Science, 182:177-180, 1973. [0633] Hinds, Hendricks, Craig, Chen,
"Characterization of a highly polymorphic region near the first
exon of the human MAOA gene containing a GT dinucleotide and a
novel VNTR motif," Genomics, 13:896-897, 1992. [0634] Hirschi and
Hindelang, "Intelligence and delinquency: A revisionist review,"
Am. Socialog. Rev., 42:571-587, 1977. [0635] Hodgins and Guebaly,
"More data on the Addiction Severity Index. Reliability and
validity with the mentally ill substance abuser," J. Nerv. Ment.
Dis., 180:197-201, 1992. [0636] Hoge and Biederman, "A case of
Tourette's syndrome with symptorms of attention deficit disorder
treated with desipirame," J. Clin. Psychiatry, 47:478-479, 1986.
[0637] Hosobuchi, et al., In: Neural Peptides and Neuronal
Communications, 563, 1980. [0638] Hotamisligil and Breakefield,
"Human monoamine oxidase A gene determines levels of enzyme
activity," Am. J. Hum. Genet., 49:383-392, 1994. [0639] Hudson,
"Drug abuse increases among U.S. teenagers beliefs about drugs'
dangers soften," Psychiatric Times, 35-36, 1995. [0640] Huhtaniemi,
Haier, Fedio, Buchsbaum, "Neuropsychological characteristics of
college males who show attention dysfunction," Perceptual and Motor
Skills, 57:399-406, 1983. [0641] Hunt, Minderaa, Cohen, "Clonidine
benefits children with attention deficit disorder and
hyperactivity: Report of a double-blind placebo-crossover
therapeutic trial," J. Amer. Acad. Child Psychiat., 24:617-629,
1985. [0642] Huntington's Disease Collaborative Research Group, "A
novel gene containing a trinucleotide repeat that is expanded and
unstable on Huntington's disease chromosomes," Cell, 72:971-983,
1993. [0643] Huston et al., "Sequence-specific effects of
neurokinin substance P on memory, reinforcment, and brain dopamine
activity," Psychopharmacology, 103:143-149, 1991. [0644] Imagawa,
Ishikawa, Shimano, Osada, Nishihara, "CTG triplet repeat in mouse
growth inhibitory factor/metallothionein III gene promoter
represses the transcriptional activity of the heterologous
promoters," J. Biol. Chem., 270:20898-20900, 1995. [0645]
Irenwasser, Jacocks, Rosenberger, Cox, "Nicotine indirectly
inhibits [3H] dopamine uptake at concentrations that do not
directly promote [3H] dopamine release in rat striatum," J.
Neurochemistry, 56:603-610, 1991. [0646] Irvine, Yu, Ross, Coetzee,
The CAG and GGC microsatellites of the androgen receptor gene are
in linkage disequilibrium in men with prostate cancer, Cancer.
Res., 55:1937-1940, 1995. [0647] Iwatsubo, et al., Biochem,
Pharmacol., 24:1495-1503, 1975. [0648] Jasper, "Report to the
committee on methods of clinical examination in
electroencephalography. Appendix: The ten-twenty system of the
International Federation," Electroencephalography and Clinical
Neurophysiology, 102:371-375, 1958. [0649] Jeejeehboy, Chu,
Marliss, Grun, Bruce-Robertson, "Chromium deficiency, glucose
intolerance and neuropathy reversed by chromium supplementation in
a patient receiving long-term parenteral nutrition," Am. J. Clin.
Nutr., 30:531-538, 1977. [0650] Jeffreys, Royle, Wilson, Wong,
"Spontaneous mutation rates to new length alleles at
tandem-repetitive hypervariable loci in human DNA," Nature,
332:278-281, 1987. [0651] Jensen "Linkage analysis of
schizophrenia: The D.sub.1 dopamine receptor gene and several
flanking DNA markers," Human Heredity, 43:58-62, 1993. [0652]
Johnson, Jr. and Fedio, "P300 activity in patients following
unilateral temporal lobectomy: a preliminary report. In: Cerebral
Psychophysiology: Studies in Event-Related Potentials, W. C.
McMcCallum, R. Zappoli, F. Denoth (Eds.), EEG Suppl. 38, Elsevier,
Amsterdam, 552-557, 1986. [0653] Johnson, Muhleman, MacMurray,
Gade, Verde, Ask, Kelley, Comings, "Association between the
cannabinoid receptor gene (CNR1), and the P300 wave of
event-related potentials, and drug dependence," Mol. Psychiatry,
2:169-171, 1997. [0654] Jonidas et al., Nature, 369:623-625, 1993.
[0655] Jonsson et al., "Dopamine-related genes and their
relationship to monoamine metabolites in CSF," Biol. Psychiatry,
40:1032-1043, 1996. [0656] Jurinke, van den Boom, Collazo, Jacob,
Koster, "Recovery of nucleic acids from immobilized
biotin-strepavidin complexes using ammonium hydroxide and
application in MALDI-TOF mass spectrometry," Anal. Chem.,
69:904-910, 1997. [0657] Kaats et al., 1990. [0658] Kaats, Fisher,
Blum, "The effects of chromium picolinate supplementation on body
composition in different age groups," Abstract, American Aging
Association 21st annual meeting, Denver, Colo., October, 1991.
[0659] Kaats et al., "The short-term therapy efficacy of treating
obesity with a plan of improved nutrition and moderate caloric
restriction" Curr. Ther. Res. 51:261-274, 1992. [0660] Kaats, Blum,
Fisher, Adelman, "Effects of chromium picolinate supplementation on
body composition: a randomized dobule-masked placebo-controlled
study," Current Therap. Res., 10:747-756, 1996. [0661] Kannel and
McGee, "Diabetes and cardiovascular risk factors," The Framingham
Study. Circulation, 59:8-13, 1979. [0662] Kauck, Poustka, Benner,
Speiler, Lesch, Poustka, Association of the serotonin transporter
(5-HTT) promoter long variant with autism, Am. J. Hum. Genet.,
61:A280, 1997. [0663] Kaye, Ebert, Gwirtsman, et al., "Differences
in brain serotonergic metabolism between non-bulimic and bulimic
patients with anorexia nervosa," Am. J. Psychiatry, 141:1598-1601,
1984. [0664] Kennedy, German, Rutter, "The minisatellite in the
diabetes susceptibility locus IDDM2 regulates insulin
transcription," Nature Genet., 9:293-298, 1995. [0665] Khan and
Dekirmenjian, "Urinary excretion of catecholamine metabolites in
hyperkenetic child syndrome," Am. J. Psychiatry, 138:108-112, 1981.
[0666] Kimberg et al., 1997. [0667] Kitchalong, Fernandez, Bunting
et al., "Chromium picolinate supplementation in lamb rations.
Effects on performance, nitrogen balance, endocrine and metabolic
parameters," J. Animal Sci., 71(Suppl 1):291, 1993. [0668]
Klinteberg and Magnusson, "Aggressiveness and hyperactive behavior
as related to adrenaline excretion. Special Issue: Personality and
aggression," Eur. J. Personality, 3:81-93, 1989. [0669] Knell and
Comings, Tourette syndrome and attention deficit hyperactivity
disorder: Evidence for a genetic relationship, J. Clin. Psychiat.,
54:331-337, 1993. [0670] Kochersperger, Parker, Sicillano,
Darlington, Denney, "Assignment of genes for human monamine oxidase
A and B to the X chromosome," J. Neurosci. Res., 18:601-619, 1986.
[0671] Kokkevi and Stefanis, "Drug abuse and psychiatric
comorbidity," Com. Psychiatr., 36:329-337, 1995. [0672] Koob and
Bloom, "Cellular and molecular mechanisms of drug dependence,"
Science, 242:715-723, 1988. [0673] Kozikowski, Miller, Yamada, et
al., "Delineating the pharmacophoric elements of Huperzine A:
importance of the unsaturated three-carbon bridge to its AChE
inhibitory activity, "J. Med. Chem., 34:3399-3402, 1991. [0674]
Kreuz and Rose, Assessment of aggressive behavior and plasma
testosterone in a young criminal population, Psychosomatic
Medicine, 34:321-332, 1972. [0675] Krontiris, Devlin, Karp, Robert,
Risch, "An association between the risk of cancer and mutations in
the Hras 1 minisatellite locus," New Eng. J. Med., 329:517-523,
1993. [0676] Krontiris, DiMartino, Colb, Parkinson, "Unique allelic
restriction fragments of the human Ha-ras locus in leukocyte and
tumor DNAs of cancer patients," Nature, 313:369-374, 1985. [0677]
Kuperman et al., "Enzyme activity and behavior in hyperactive
children grown up,
" Biol. Psychiatry, 24:375-383, 1988. [0678] La Spada, Wilson,
Lubahn, Harding, Fischbeck, Clark, Kelly, Smith, Fairweather,
Brown, Johnston, Haites, Androgen receptor gene mutations in
X-linked spinal and bulbar muscular atrophy prenatal diagnosis for
dystrophia myotonica using the polymerase chain reaction, Nature,
11:467-470, 1991. [0679] Laganiere, Corey, Tang, Wulfert, Hanin,
"Acute and chronic studies with the anticholinesterase Huperzine A:
effect on central nervous system cholinergic parameters,"
Neuropharmacology, 30(7):763-768, 1991. [0680] Lahey, Schaughency,
Frame, Strauss, "Teacher ratings of attention problems in children
experimentally classified as exhibiting attention deficit disorder
with and without hyperactivity," J. Am. Acad. Child Psychiatry,
24(5):613-616, 1985. [0681] Lahey, Schaughency, Strauss, Frame,
"Are Attention Deficit Disorders With And Without Hyperactivity
Similar Or Dissimilar Disorders?" J. Am. Acad. Child Psychiatry,
23:302-309, 1984. [0682] Lahoste, Swanson, Wigal, Glabe, Wigal,
King, Kennedy, "Dopamine D4 receptor gene polymorphism is
associated with attention deficit hyperactivity disorder," Mol.
Psychiatry, 1:121-124, 1996. [0683] Lallement, Veyret, Masqueliez,
et al., "Efficacy of hyperine in preventing soman-induced seizures,
neuropathological changes and lethality," Fundam. Clin. Pharmacol.,
11:387-397, 1997. [0684] Lan, Heinzmann, Gal, Klisak, Orth, Lai,
Grimsley, Sparkes, Mohandas, Shih, "Human monamine oxidase A and B
genes map to Xp11.23 and are deleted in a patient with Norrie
disease," Genomics, 4:552-559, 1989 [0685] Lapin, Maker, Sershen,
Lajtha, "Action of nicotine on accumbens dopamine and attenutation
with repeated administration," Eur. J. Pharmacology, 160:53-59,
1989. [0686] Lario, Calls, Cases, Orila, Torras, Rivera, "Msp I
identifies a biallelic polymorphism in the promoter region of the
alpha 2A-adrenergic receptor gene," Clin. Genetics, 51:129-130,
1997. [0687] Lawford, Young, Rowell, Qualichefski, et al.,
"Bromocriptine in the treatment of alcoholics with D2 dopamine
receptor A1 allele," Nature Med., 1:337-341, 1995. [0688] Lazarova
et. al., Methods & Findings in Experimental & Clinical
Pharmacology, 8(9):547-552, 1986. [0689] LeDoux, "Emotional memory
systems in the brain," Behavior Brain Research, 20:69-79, 1993.
[0690] Lee and Reasner, "Beneficial effect of chromium
supplementation on serum triglyceride levels in NIDDM," Diabetes
Care, 17:1449-1452, 1994. [0691] Leibowitz and Hor, "Endorphinergic
and noradrenergic systems in the paraventricular nucleus: Effects
on eating behavior," Peptides, 3:421-428, 1982. [0692] Leibowitz,
"Brain neurotransmitters and appetite regulation,"
Psychopharmacological Bull., 21:412-418, 1985. [0693] Leiner et
al., "Reappraising the cerebellum: what does the hindbrain
contribute to the forebrain?" Behav. Neurosci., 103:998-1008, 1989.
[0694] LeMoal and Simon, "Mesocorticolimbic dopaminergic network:
functional and regulatory roles," Physiol. Rev., 71:155-234, 1991.
[0695] Lemoal et al., "Radiofrequency lesions of the ventral
mesencephalic tegmentum: Neurological and behavioral
considerations," Exp. Neurol., 50:521-535, 1976. [0696] Leppert,
Anderson, Quattlebaum, Stauffer, O'Connell, Nakamura, Laouel,
White, "Benign familial neonatal convulsions linked to genetic
markers on chromosome 20," Nature, 337:647-648, 1989. [0697] Lesch,
Bengel, Heils, Sabol, Greenberg, Petri, Benjamin, Muller, Hamer,
Murphy, Association of anxiety-related traits with a polymorphism
in the serotonin transporter gene regulatory region, Science,
274:1527-1531, 1996. [0698] Levin et al., "Cholinergic-dopaminergic
interactions in cognitive performance," Behavioal Neural. Biology,
54:271-299, 1990. [0699] Levin and Rose, "Acute and chronic
nicotinic interactions with dopamine systems and working memory
performance," Annals. NY Acad. Sci., 757:245-252, 1995. [0700]
Levin, Conners, Sparrow, Hinton, Erhardt, Meck, Rose, Marck,
"Nicotine effects on adults with attention-deficit/hyperactivity
disorder," Psychopharmacology (Berlin), 123:55-63, 1996. [0701]
Levine, Streeten, Doisy, "Effects of oral chromium supplementation
on the glucose tolerance of elderly human subjects," Metabolism,
17:114-125, 1968. [0702] Levine and Manley, "Transcriptional
repression of eukaryotic promoters," Cell, 59:405-408, 1989. [0703]
Li and Chung, "Isolation and Structure of an Untriakontapeptide
with Opiate Activity from Camel Pituitary Glands," Proc. Nat. Acad.
Sci. USA; 73:1145-1148, 1976. [0704] Li, Li, Sharp, Nucifora,
Schilling, Lanahen, Worley, Snyder, Ross, "A huntingtin-associated
protein enriched in brain with implications for pathology of
Huntington's disease," Nature, 378:398, 1995. [0705] Li, Tang,
Little, Koster, Hunter, McIver Jr., "High-resolution MALDI fourier
transform mass spectrometry of oligonuclotides," Anal. Chem.,
68:2090-2096, 1996. [0706] Liam, Chen, Chen, Wu, "The effects of
various levels of chromium picolinate on growth and serum traits of
pigs," J. Chin. Soc. Anim. Aci., 22(4):349-357, 1993. [0707]
Lichter, Barr, Kennedy, Van Tol, Kidd, Livak, "A hypervariable
segment in the human dopemine receptor (DRD4) gene," Hum. Mol.
Genet., 2:767-773, 1993. [0708] Lieberman et al., J. Psych. Res.,
17:135, 1983. [0709] Lin, Powell, Murray, Gill, "Monoamine oxidase
A gene and bipolar affective disorder," Am. J. Hum. Genet.,
54:1122-1124, 1994. [0710] Lindberg, Asberg, Sundqvist-Stensman,
5-hydroxyindole acetic acid levels in attempted suicides who have
killed their children, Lancet., 2:928, 1984. [0711] Lindemann,
Wood, Harper, Kornegay, "Chromium picolinate additions to diets of
growing-finishing pigs," J. Animal Sci., 71 (Suppl 1):167, 1993.
[0712] Little, Cornish, O'Donnell, Braun, Cotter, Koster, "MALDI on
a chip: Analysis of arrays of low-femtomole to subfemtomole
quantities of synthetic oligonucletides and DNA diagnostic products
dispensed by a piezoelectric pipet," Anal. Biochem., 69:4540-4546,
1997. [0713] Liu and Liu, "Intelligence promoting Chinese materia
medica," Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 15:59-61 (article
in Chinese), 1995a. [0714] Liu, Sobell, Heston, Sommer, "Screening
the dopamine D.sub.1 receptor gene in 131 schizophrenics and eight
alcoholics: identification of polymorphisms but lack of
functionally significant sequence changes," Am. J. Med. Gen.
(Neuropsych. Genet.), 60:165-171, 1995b. [0715] Lou, "Dopamine
precursors and brain function in phenylalanine hydroxylase
deficiency," Acta. Paediatrica., (Suppl) 407:86-88, 1994. [0716]
Lovinger and Grant, "Alcohol neurotoxicity: effects and
mechanisms," Handbook of Neurotoxicology, Marcel Dekker,
Publishers, New York, 1995. [0717] Lu, Shou, Tang, "Improving
effect of Huperzine A on discrimination performance in aged rats
and adult rats with experimental cognitive impairment," Chung Kuo
Yao Li Hsuch Pao, 9:11-15 (article in Chinese), 1988. [0718] Lyoo
et al., "The corpus callosum and lateral ventricles in children
with Attention-Deficit Hyperactivity Disorder: A brain magnetic
resonance imaging study," Biol. Psychiatry, 40:1060-1063, 1996.
[0719] Mackintosh, "A theory of attention: Variations in the
associability of stimuli with reinforcement," Psychology Review,
82:276-298, 1975. [0720] MacLusky and Naftolin, Sexual
differentiation of the central nervous system, Science,
211:1294-1303, 1981. [0721] MacMurray, Saucier, Muhleman, Gade,
Chiu, Wu, Blake, Ferry, Johnson, Comings, "Polygenic prediction of
parity: GABA.sub.A-b3 and dopamine DRD.sub.4 gene markers,"
Psychiat. Genet., 6:161, 1996. [0722] Mahaer and Wurtman,
"L-threonine administration increases glycine concentrations in the
rat central nervous system," Life Science, 26(26):1283-1286, 1980.
[0723] Maison et al., ".sup.123b-Cit Spect imaging of straital
dopamine transporter binding Tourette's disorder," Am. J.
Psychiatry, 152:1359-1361, 1995. [0724] Malafosse, Leboyer, Dulac,
Navalet, Plouin, Beck, Laklou, Mouchnino, Grandscene, Vallee,
Guilloud-Bataille, Samolyk, Baldy-Moulinier, Feingold Mallet,
"Confirmation of linkage of benign familial neonatal convulsion to
D20S19 and D20S20," Hum. Genet., 89:54-58, 1992. [0725] Malhotra et
al., "The association between the dopamine D.sub.4 16 amino acid
repeat polymorphisms and novelty seeking," Mol. Psychiatry,
1:388-389, 1996. [0726] Mann and Stanley, "Postmortem monoamine
oxidase enzyme kinetics in the frontal cortex of suicide victims
and controls," Acta Psychiatr. Scand., 69:135-139, 1984. [0727]
Marina et. al., "Izvestia Sib," Dep. of the Academy of Science of
the USSR, Ser. Biol. Sciences, 3:85-89, 1973. [0728] Mattsson,
Schalling, Olweus, Low, Svensson, Plasma testosterone, aggessive
behavior, and personality dimensions in young male delinquents, J.
Am. Acad. Child. Adolesc. Psychiatry, 19:476-480, 1980. [0729]
Maurer et al., "Topographic mapping of EEG and auditory evoked
P3000 in neuropsychopharmacology (topographic pharmacor-EEG and
pharmaco-AEp 300)," Pharmacopsychiatry, 21:338-342, 1988. [0730]
McCarty, "Homologous physiological effects of phenformin and
chromium picolinate," Med. Hypoth., 41:316-324, 1993. [0731]
McConville, Sanberg, Fogelson et. al., "The effect of nicotine plus
haloperidol compared to nicotine only and placebo only in reducing
tic severity and frequency in Tourette's disorder," Biol.
Psychiatry, 31:832-840, 1992. [0732] McGee, Williams, Moffitt,
Anderson, "A comparison of 13-year-old boys with attention deficit
and/or reading disorder on neuropsychological measures," J. Abnorm.
Child Psychol., 17:37-53, 1989. [0733] McKinney, Miller, Yamada, et
al., "Potencies and stereoselectivities of enantiomers of Huperzine
A for inhibtion of rat cortical acetylcholinesterase," Eur. J.
Pharmacol., 203:303-305, 1991. [0734] Mechelini, Urbanek, Dean,
Goldman, "Polymorphism and genetic mapping of the human oxytocin
receptor gene on chromosome 3," Am. J. Med. Genet, 60:183-187,
1995. [0735] Mefford, and Potter, "A neuroanatomical and
biochemical basis for attention deficit disorder with hyperactivity
in children: A defect in tonic adrenaline mediated inhibition of
locus coeruleus stimulation," Med. Hypotheses., 29:33-42, 1989.
[0736] Meltzer and Arora, "Platelet markers of suicidality," Ann.
N.Y. Acad. Sci., 487:271-280, 1986. [0737] Mertz, Nutr.,
123:626-633, 1992. [0738] Migeon, Brown, Axelman, Migeon, Studies
of the locus for androgen receptor: localization on the human X and
evidence for momology with the Tfm locus in the mouse, Proc. Natl.
Acad. Sci. USA, 78:6339-6343, 1981. [0739] Mikines, Sonne, Farrell,
Tronier, Gablo, "Effect of training on the dose-response
relationship for insulin action in men," J. Appl. Physiol.,
66:695-703, 1989. [0740] Miller et al., "Overload: ADHD and the
Additive Brain," Andrew McMeal, Kansas City, Mo., 1996. [0741]
Miller, "Neuropsychological perspectives on delinquency," Behav.
Sci. Law, 6:409-428, 1988. [0742] Misra, et al.,; "Stereospecific
potentiation of opiate analgesia by cocaine: Predominant role of
noradrenaline," Pain., 28:129-138, 1987. [0743] Moffitt and Silva,
"IQ and delinquency: A direct test of the differential detection
hypothesis," J. Abnormal Psychology, 97:330-333, 1988. [0744]
Moffitt, "Juvenile delinquency and attention deficit disorder:
Boys' developmental trajectories from age 3 to age 15," Child Dev.,
61:893-910, 1990. [0745] Moffitt, Adolescence-limited and
life-course-persistent antisocial behavior: A developmental
taxonomy," Psychological Rev., 10:674-701, 1993a. [0746] Moffitt,
"The neuropsychology of conduct disorder," Dev. Psychopathology,
5:135-151, 1993b. [0747] Moir and Eccleston, "The effects of
precursos loding in the cerebral metabolism of 5-hydroxyindoles,"
J. Neurochem., 15:1093-1108, 1968. [0748] Mooney and Cromwell
"Effect of chromium picolinate on performance, carcass composition
and tissue accretion in growing-finishing pigs," J. Animal Sci.,
71(Suppl 1): 167, 1993. [0749] Morrison et al., "A family study of
the hyperactive child syndrome," Bio. Psychiatry, 3:189-195, 1971.
[0750] Morrow et al., "Delay in P300 latency in patients with
organic solvent exposure," Arch. Neurol., 49:315-320, 1992. [0751]
Mullis, Faloona, Scharf, Saiki, Horn, Erlich, "Specific enzymatic
amplification of DNA in vitro: the polymerase chain reaction," Cold
Spring Harbor Syrup Quant. Biol., 51:263-272, 1986. [0752] Nadel,
Weisman-Shomer, Fry, "The fragile X syndrome single strand d(CGG)n
nucleotide repeats readily fold back to form unimolecular hairpin
structures," J. Biol. Chem., 270:28970-28977, 1995. [0753] Nauta,
Limbic innervation of the striatum. In Friedhoff and Chase (Eds.),
Gilles de la Tourette Syndrome (pp. 41-47). New York: Raven Press,
1982. [0754] Naylor and Clark, "d(TG)n.d(CA).sub.n sequences
upstream of the rat prolactin gene form Z-DNA and inhibit gene
transcription," Nucl. Acids Res., 18:1595-1601, 1990. [0755]
Neiswagner, Hill, Kaplan, "Association between alcoholism and the
TaqI A RFLP of the dopamine D.sub.2 receptor gene in the absence of
linkage," Psychiatr. Genet., 3:130 (abstract), 1995. [0756]
Neiswanger et al., "Association between alcoholism and the TaqI A
RFLP of the dopamine D.sub.2 receptor gene in absence of linkage"
Am. J. Med. Genet. (Neuropsychiatr. Genet.), 60:267-271, 1995.
[0757] Nelson, Demas, Huang, Fishman, Dawson, Dawson, Snyder,
"Behavioral abnormalities in male mice lacking neuronal nitric
oxide synthase," Nature, 378:383-386, 1995. [0758] Neshinge et al.,
"Event-related brain potentials as indicators of visual recognition
and detection of criminals by their use," Forensic Sci. Int.,
51:95-103, 1991. [0759] Newcom, Halperin, Healey, O'Brien,
Pascualvaca, Wolf, Morganstein, Sharma, Young, "Are ADDH and AD-HD
the Same or Different?," J. Am. Acad. Child Adoles. Psychiatry,
28(5):734-738, 1989. [0760] Noble, Blum, Ritchie, Montogomery,
Sheridan, "Allelic association of the D.sub.2 dopamine receptor
gene with receptor-binding characteristics in alcoholism," Arch.
Gen. Psychiatry, 48:648-654, 1991. [0761] Noble, Blum, Khalsa,
Ritchie, Montgomery, Wood, Fitch, Ozkaragoz, Sheridan, Anglin,
Parades, Treiman, Sparkes, "Allelic association of the D.sub.2
dopamine receptor gene with cocaine dependence," Drug Alc. Dep.,
33:271-285, 1993. [0762] Noble et al, "Prolonged P300 latency in
children with the D.sub.2 dopamine receptor A.sub.1 allele," Am. J.
Hum. Genet., 54:658-668, 1994. [0763] Nobel et al., "D.sub.2
dopamine receptor polymorphism and brain regional glucose
metabolism," Am. J. Med. Gen., 74:1-5, 1997. [0764] Nobel, "The
DRD.sub.2 Gene, Smoking, and Lung Cancer," J. Natl. Cancer Inst.,
90:343-363, 1998. [0765] Noldy et al., "Quantitative EEG and P300
in Cocaine withdrawal," Brain Topography, 3:262-263, 1990. [0766]
Nordheim, Tesser, Azorin, Kwon, Moler, Rich, "Isolation of
Drosophilia proteins that bind selectively to left-handed
Z-DNA,
" Proc. Natl. Acad. Sci. USA, 79:7729-7733, 1982. [0767] Nordheim
and Rich, "Negatively supercoiled simian virus 40 DNA containing
Z-DNA segments within transcriptional enhancer sequences," Nature,
303:674-679, 1983. [0768] Nordheim and Rich, "The sequence
(dC-dA)n.(dG-dT)n forms left-handed Z-DNA in negatively supercoiled
plasmids," Proc. Natl. Acad. Sci. USA, 80:1821-1825, 1983. [0769]
Nothen, Eggerman, Albus, Borrmann, Rietschel, Korner, Maier,
Minges, Lichtermann, Franzek, Weigelt, Knapp, Propping,
"Association analysis of the monamine oxidase A gene in bipolar
affective disorder by using family-based internal controls," Am. J.
Hum. Genet., 57:975-977, 1995. [0770] Nunes et al., "Treating
anxiety in patients with alcoholism" J. Clin. Psychiatry, 56(Supp
2):3-9, 1995. [0771] O'Donnell, Tang, Koster, Smith, Cantor,
High-density, covalent attachment of DNA to silicon wafers for
analysis by MALDI-TOF mass spectrometry," Anal. Chem.,
69:2438-2443, 1997. [0772] Oades, "Attention deficit disorder with
hyperactivity (ADHD): The contribution of catecholaminergic
activity," Prog. Neurobiol., 29:365-391, 1987. [0773] Offenbacher
and Pi-Sunyer, "Chromium in human nutrition," Ann. Rev. Nutr.,
8:543-563, 1988. [0774] Ogawa, Lubahn, Korach, Pfaff, Aggressive
behaviors of transgenic estrogen-receptor knockout male mice, Ann.
NY Acad. Sci., 794:384-385, 1996. [0775] Ogilvie, Battersby, Bubb,
Fink, Hamaar, Goodwin, Smith, "Polymorphism in serotonin
transporter gene associated with susceptibility to major
depression," Lancet, 347:731-733, 1996. [0776] Ohshima, Kang,
Larson, Wells, "Cloning, characterization and properties of seven
triplet repeat DNA sequences," J. Biol. Chem., 271:16773-16783,
1996. [0777] Olds, "Pleasure centers in the brain," Scientific
American, 195:5-116, 1956. [0778] Oltmans, "Norepinephrine and
dopamine levels in hypothalmic nuclei of the genetically obese
mouse (ob/ob)," Brain Res., 273:369-373, 1983. [0779] Olweus,
Stability of aggressive reaction panems in males: A review,
Psychological Bull., 86:852-875, 1988. [0780] Olweus, Mattsson,
Schalling, Low, Circulating testosteone levels and aggression in
adolescent males: A casual analysis, Psychosomatic Medicine,
50:261-272, 1988. [0781] Ostareck-Lederer, Ostareck, Standart,
Thiele, "Translation of 15-lipoxygenase mRNA is inhibited by a
protein that binds to a repeated sequence in the 3' untranslated
region," EMBO J., 13:1476-1481, 1994. [0782] Ostrovsky, Substance
Alc., Actions/Misuse, 5:247-253, 1984. [0783] Owen and McGuffin,
"Association and linkage: complementary strategies for complex
disorders," J. Med. Genet., 30:638-639, 1993. [0784] Ozelius, Hus,
Bruns, Powell, Chen, Weyler, Utterback, et al., "Human monamine
oxidase gene (MAOA): chromosome position (Xp21-p11) and DNA
polymorphism," Genomics, 3:53-58, 1988. [0785] Page, Ward,
Southern, "Effect of chromium picolinate on growth and carcass
characteristics of growing-finishing pigs," J. Am. Sci., 69(Suppl
1):403, 1991. [0786] Page, Southern, Ward, et al., "Effect of
chromium on growth serum and carcass traits, and organ weights of
growing-finishing pigs from different ancestral sources," J. Animal
Sci., 70(Suppl 1):235, 1992. [0787] Page, Southern, Ward, Thompson,
"Effect of chromium picolinate on growth and serum carcass traits
of growing finishing pigs," J. Animal Sci., 71:656-662, 1993.
[0788] Pandey, Dorus, Shaughnessy, Gaviria, Val, Davis, "Reduced
platelet MAO activity and vulnerability to psychiatric disorders,"
Psychiatry Res., 2:315-321, 1980. [0789] Pandey, Sharma, Janicak,
Davis, "Monamine oxidase and cortisol response in depression and
schizophrenia," Psychiatry Res., 44:1-8, 1992. [0790] Pang and
Kozikowski, "Prediction of the binding site of
1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl) methyl] piperidine in
acetylcholinesterase by docking studies with the SYSDOC program,"
J. Comput. Aided Mol. Des., 8:683-693, 1994a. [0791] Pang and
Kozikowski, "Prediction of the binding sites of Huperzine A in
acetylcholinesterase by docking studies," J. Comput. Aided Mol
Des., 8:669-681, 1994b. [0792] Pardo, Fox, Raichle, "Localization
of a human system for sustained attention by positron emission
tomography," Nature, 349:61-64, 1991. [0793] Pauls et al.,
"Demonstration of vertical transmission of attention deficit
disorder" Ann. Neurol., 14:363, 1983. [0794] Peck and Wang,
"Transcriptional block caused by negative super-coiling induced
structural change in an alternating CG sequence," Cell, 40:129-137,
1985. [0795] Pennington, Groisser, Welsh, "Contrasting cognitive
deficits in attention deficit hyperactivity disorder versus reading
disability," Dev. Psychol., 29:511-523, 1993. [0796] Persico et
al., "Polymorphisms of the D.sub.2 dopamine receptor gene with
receptor-binding characteristics in alcoholism," Arch. Gen. Psych.,
48:648-654, 1991. [0797] Persico and Uhl, "Polymorphisms of the
D.sub.2 dopamine receptor gene in polysubstance abusers," Chapter
20, (Eds. Blum and Noble), CRC Press, Boca Raton, 353-366, 1997.
[0798] Peterson, Leekman, Scalaill, Naftolin, Keefe, Charest,
Cohen, Steroid hormones and CNS sexual dimorphisms modulate symptom
expression in Tourtte's syndrome, Psychoneuroendocrinology,
17:553-563, 1992. [0799] Petkov and associates, Acta Physiologica
et Pharmacolgica Bulgarcia, 12(1):3-16, 1986. [0800] Phillips and
Mulley, "SSCP variants within the a4 subunit of the neuronal
nicotinic acetylcholine receptor gene," Clin. Genetics, 51:135-136,
1997. [0801] Picton and Stuss, "The component structure of the
human event-related potentials. In Motivation, Motor and Sensory
Processes of the Brain: Electrical Potentials, Behavior and
Clinical Use, H. H. Kornhuber and L. Keecke (Eds.), Progress in
Research, New York: Elsevier, 54:17-49, 1980. [0802] Pieretti,
Zhang, Fu, Warren, Oostra, Caskey, Nelson, "Absence of expression
of the FMR-1 gene in fragile X syndrome," Cell, 66:817-822, 1991.
[0803] Pliszka, Maas, Rogeness, Baker, "Urinary catecholamines in
attention-deficit hyperactivity disorder with and without comorbid
anxiety," J. Am. Acad. Child. Adolesc. Psychiatry., 33:1165-1173,
1994. [0804] Pliszka, Mccracken, Maas, "Catecholamines in
attention-deficit hyperactivity disorder: Current perspectives," J.
Am. Acad. Child Adolesc. Pschiatry, 35:264-272, 1996. [0805]
Plomin, McClearn, Smith, Vignetti, Chorney, Chorney, Venditti,
Kasarda, Thompson, Detterman, et. al, "DNA markers associated with
high versus low IQ: The IQ Quantitative Trait Loci (QTL) project,"
Behav. Genet., 24:107-118, 1994. [0806] Pohjalainen et al.,
"Genetic determinant of human D.sub.2 dopamine receptor binding
characteristics in vivo," Am. J. Human Gen., 59:2255, 1996. [0807]
Pollock and Schmidt, (eds.), In: Heart Disease and Rehabilitation,
3rd Ed., New York, N.Y., John Wiley and Sons, Inc., 1995. [0808]
Poloni et al., Experientia, 30:640, 1974. [0809] Polozhy et. al.,
"Biology of Siberian Plants Requiring Protection," Novisibirisk,
85-114; 1985. [0810] Polymeropoulos, Xiao, Rath, Merril,
Tetranucleotide repeat polymorphism at the human aromatase
cytochrome P-450 gene (CYP19), Nucleic Acids Res., 19:195, 1991.
[0811] Pontieri, Tanda, Orzi, DiChiara, "Effects of nicotine on the
nucleus accumbens and similarity to those of addictive drugs,"
Nature, 382:255-257, 1996. [0812] Pontius, "Dysfunction patterns
analogous to frontal lobe system and caudate nucleus syndrome in
some groups of minimal brain dysfunction," J. Am. Med. Women's
Assn., 26:285-292, 1973. [0813] Porjesz et al., "N2 component of
the event-related brain potential in abstinent alcoholics,"
Electroencephalogr. Clin. Neurophysiol., 66:121-131, 1987. [0814]
Posner and Peterson, "The attention system of the human brain,"
Annu. Rev. Neurosci., 13:25-42, 1990. [0815] Posner, Cohen, and
Rafal, "Neural systems control of spatial orienting," Philosophical
Transactions of the Royal Society of London, 298:187-198, 1982.
[0816] Posner, Early, Reiman, Pardo, Dhawan, "Asymmetrics in
hemispheric control of attention in schizophrenia," Archives of
General Psychiatry, 45, 814-821, 1988. [0817] Press, Geller, Evans,
"The effect of chromium picolinate on serum cholesterol and
apolipoprotein fractions in human subjects," West J. Med.,
152:41-45, 1990. [0818] Pricheps, Sutton, Hakerem, "Evoked
potentials in hyperkinetic and normal children under certainty and
uncertainty: a placebo and methylphenidate study,"
Psychophysiology, 13:419-428, 1976. [0819] Propping, Rey, Friedl,
Beckmann, "Platelet monamine oxidase in healthy subjects: the
`biochemical high-risk paradigm` revisited," Arch. Psychiatr.
Nervenkr., 230:209-219, 1981. [0820] Pugliese, Zeller, Fewrnandez,
Zalcberg, Bartlett, Ricordi, Pietropaolo, Eisenbarth, Bennett,
Patel, "The insulin gene is transcribed in the human thymus and
transcription levels correlate with allelic variation at the INV
VNTR-IDDM2 susceptibility locus for type 1 diabetes," Nature
Genet., 15:293-297, 1997. [0821] Qian, Wang, Zhou, Chen, Zhou,
Chen, "Pharmacokinetics of tablet huperzine A in six volunteers,"
Chung Kuo Yao Li Hsuch Pao, 16(5):396-398 (in chinese), 1995.
[0822] Rapoport, Donnelly, Zametkin, Carrougher, "Situational
Hyperactivity in a U.S. Clinical Setting," J. Child Psychol.
Psychiatry, 27(5):639-646, 1986. [0823] Rapoport, Mickkelsen,
Ebert, Brown, Weise, Kopin, "Urinary catecholamine and amphetamine
excretion in hyperactive and normal boys, J. Nerv. Ment. Dis.,
66:731-735, 1978. [0824] Raves Harel, Pang, Silman, Kozikowski,
Sussman, "Structure of acetylcholinesterase complexed with the
nootropic alkaloid, (-)-huperzine A," Nat. Struct. Biol.,
4(1):57-63, 1997. [0825] Regiawi, Subs. Alc., Actions/Misuse
1:151-158, 1980. [0826] Reith et al., "Sodium-Independent Binding
of .sup.3H Cocaine in Mouse Striatum is Serotonin Related," Brain
Research, 342(1):145-148, 1985. [0827] Riales, "Chromium in
Nutrition and Metabolism," New York, N.Y., Elsevier/North-Holland
Biomedical Press, 1979. [0828] Rich, Nordheim, Wang, The chemistry
and biology of left-handed Z-DNA, Annu. Rev. Biochem., 53:791-856,
1984. [0829] Richards, Samuels, Turnure, Ysseldyke, "Sustained and
selective attention in children with learning disabilities," J.
Learn. Disabil., 23:129-136, 1990. [0830] Riess, Weber, Hayden,
"(CA)n-dinucleotide repeat polymorphism at the locus for the
alpha2C adrenergic receptor (ADRA2C) on 4q16," Hum. Molec. Genet.,
1:452, 1992. [0831] Ringholz, "Inconsistent attention in chronic
survivors of severe closed head injury, "Doctoral Dissertation,
University of Houston, 1989. [0832] Risch and Botstein, "A manic
depressive history," Nature Genet., 12:351-353, 1996a. [0833] Risch
and Merikangas, "The future of genetic studies of complex human
diseases," Science, 273:1516-1517, 1996b. [0834] Risch and Zhang,
"Mapping quantitative trait loci with extreme discordant sib pairs:
Sample size considerations," Am. J. Hum. Genet., 58:836-843, 1996.
[0835] Riviere and Bueno, "Origin of the stimulation of food intake
by oral administration of enkephalinase inhibitors in sheep," Life
Sci., 41:333-339, 1987. [0836] Robins, Deviant Children Grown Up,
Baltimore: Williams and Wilkins, 1966. [0837] Robins, Helzer,
Croughan, Ratclif, "National Institute of Health diagnostic
interview schedule," Arch. Gen. Psychiatry., 38:381-389, 1981.
[0838] Roeback, Hla, Chambless, Fletcher, "Effects of chromium
supplementation on serum high-density lipoprotein cholesterol
levels in men taking beta blockers," Ann. Int. Med., 115:917-924,
1991. [0839] Rogan, Staubli, LeDoux, Fear conditioning induces
associated long-term potentiation in the amygdala, Nature,
390:604-607, 1997. [0840] Rogeness et. al., "Biochemical
differences in children with conduct disorder socialized and
undersocialized" Am. J. Psychiatry, 139:307-311, 1982. [0841]
Rogeness, Hernandez, Macedo, Mitchell, Amrung, Harris, "Clinical
characteristics of emotionally disturbed boys with very low
activities of dopamine b-hydroxylase," J. Am. Acad. Child. Adolesc.
Psychiatry., 23:203-208, 1984. [0842] Rogeness et al., "Plasma
dopamine-beta-hydroxylase and preschool behavior in children with
conduct disorder" Child Psychiatry Human Devel., 20:149-156, 1989a.
[0843] Rogeness, Maas, Javors, Macedo, Fischer, Harris, "Attention
deficit disorder symptoms and urine catecholamines," Psychiatry
Res., 27:241-251, 1989b. [0844] Roleda, Kaneko, Ehlers, "The
effects of acute cocaine administration on auditory event-related
potentials in rats," Neuroscience Letters, 160:4-8, 1993. [0845]
Rosvold, Mirsky, Sarason, Bransome, Beck, "A continuous performance
test of brain damage," Journal of Consulting Psychology,
20:343-352, 1956. [0846] Rourke, Bakker, Fisk, Strang, "Child
neuropsychology: an introduction to theory, research, and clinical
practice," NY, The Guilford Press, 389 pages, 1983. [0847] Rourke,
"Neuropsychology of Learning Disabilities: Essentials of Subtype
Analysis," NY, The Guilford Press, 351 pages, 1985. [0848] Rourke,
Fisk, Strang, "Neuropsychological assessment of children: a
treatment-oriented approach," NY, The Guilford Press, 286 pages,
1986. [0849] Rourke, "Nonverbal Learning Disabilities: The Syndrome
and the Model," NY, The Guilford Press, 253 pages, 1989. [0850]
Russchen, Bakst, Amaral, Price, The amydgalostriatial projections
in the monkey. An anterograde tracing study, Brain Res.,
329:241-257, 1985. [0851] Salzmann, Vidyasagar, Creutzfeldt,
"Functional comparison of neuronal properties in the primate
posterior hippocampus and parahippocampus (area TF/TH) during
different behavioural paradigms involving memory and selective
attention," Behavior Brain Research, 26:133-149, 1993. [0852]
Sanberg, Fogelson, Manderscheid, Parker, Norman, McConville,
"Nicotine gum and haloperidol in Tourette's syndrome [letter],"
Lancet., 1:5921, 1988. [0853] Sanberg, Silver, ShyIle, Philipp,
Cahill, Fogelson, McConville, "Nicotine for the treatment of
Tourette's syndrome," Pharmac. Ther., 74:21-25, 1997. [0854] Sara
et al., "Locus coerulues-evoked responses in behaving rats: a clue
to the role of noradrenaline in memory" Brain Research Bulletin,
35(5-6):457-465, 1994. [0855] Saratikav et. al., Pharmazine Bd.,
23:S203-305, 1968. [0856] Saratikov, Chem. Pharm. Mag., 4:56-59,
1977. [0857] Saratikov and Krasnov, "Rhodiola rosea is a valuable
medicinal plant," Tomsk, p. 252, 1987. [0858] Saratikov, "Golden
Root (Rhodiola rosea)," Tomsk, p. 155, 1974. [0859] Saratikov et.
al., "Izvestia Sib. Dep. Of the Academy of Science of the USSR,"
Ser. Biolmed. Sciences, 5(1):108-115, 1968. [0860] Sarkar,
Kapelner, Grandy, Marchionni, Civelli, Sobell, Heston, Sommer,
"Direct sequencing of the dopemine D2 receptor (DRD2) in
schizophrenics reveals three polymorphisms but no structural change
in the receptor," Genomics., 11:8-14, 1991. [0861] Satterfield, and
Schell, A prospective study of hyperactive boys with conduct
problems and normal boys: Adolescent and adult criminality,
J. Am. Acad. Child Adolesc. Psychiatry, 36:1726-1735, 1997. [0862]
Saxena, Qian, Kovach, Kozikowski, Pang, Vellom, Radic, Quinn,
Taylor, Doctor, "Identification of amino acid residues involved in
the binding of Huperzine A to cholinesterases," Protein Sci.,
3(10):1770-1778, 1994. [0863] Scatton, Rauquier, Javoid-Agid, Agid,
"Dopamine deficiency in the cerebral cortex in Parkinson's
disease," Neurology, 32:1039-1040, 1982. [0864] Schaal, Tremblay,
Soussignan, Susman, Male testosterone linked to high social
dominance but low physical aggression inearly adolescence, J. Am.
Acad. Child Adolesc. Psychiatry, 34:1322-1330, 1998. [0865]
Schachar, Sandberg, Rutter, "Agreement between teacher ratings and
observations of hyperactivity, inattentiveness, and defiance," J.
Abnorm. Child Psychology, 14(2):331-345, 1986. [0866] Schiavi,
Theilgaard, Owne, White, Sex chromosome anomalies, hormones, and
aggressivity, Arch. Gen. Psychiatry, 41:93-99, 1984. [0867]
Schneider and Shiffrin, "Controlled and automatic human information
processing. I. Detection, search, and attention," Psychology
Review, 84:1-66, 1977. [0868] Schoepfer, Whiting, Esch, Blacher,
Shimasaki, Lindstrom, "cDNA clones coding for the structural
subunit of a chicken brain nicotinic acetylcholine receptor,"
Neuron, 1:241-248, 1988. [0869] Schooler, Zahn, Murphy, Buchsbaum,
"Psychological correlates of monoamine oxidase activity in
normals," J. Nerv. Ment. Dis., 166:177-186, 1978. [0870] Schroth,
Chou, Ho, Mapping Z-DNA in the human genome, J. Biol. Chem.,
267:11846-11855, 1992. [0871] Schwartz and Mertz, "Chromium (III)
and the glucose tolerance factor," Arch. Biochem. Biophys.,
85:292-295, 1959. [0872] Schwartz et al., J. Pharm. Pharmol.
24:900-906, 1992. [0873] Schwartz, et al., Adv Biochem
Psychopharmacol., 22:219-235, 1980. [0874] Schwartz, et al., Fourth
World Congress on Biological Psychiatry, 418(600)2, 1985. [0875]
Schwartz, et al., "Modulation of Receptor Mechanisms in the
CNS:Hyper and Hyposensitivity to Catecholamines,"
Neuropharmacology; 17:665-685, 1978. [0876] Scourfield et al.,
"Substance abuse, comorbidity, and sensation seeking: gender
differences," Comp. Psychiatry, 37:384-392, 1996. [0877] See et
al., Nature, 258:577-580, 1975 [0878] Seiden and Sabol,
"Neurotoxicity of methamphetamine-related drugs and cocaine,"
Handbook of Neurotoxicology, Marcel Dekker, Publishers, New York,
1995. [0879] Self et al., "Opposite modulation of cocain seeking
behavior by D.sub.1 and D.sub.2-like dopamine receptor agonists,"
Science, 271:1586-1589, 1996. [0880] Shaikh, Brutus, Siegel,
Siegel, Regulation of feline aggresssion by the bed nucleus of
stria terminolis, Brain Res. Bull., 16:179-182, 1986. [0881]
Sharma, "Effects of nonpharmacological intervention on insulin
sensitivity," J. Cardiovasc. Pharmacol., 20 Suppl, 11:S27-34, 1992.
[0882] Shawitz et al., "Paradoxical response to amphetamine in
developing rats treated with 6-hydroxydopamine," Nature,
261:153-155, 1976. [0883] Shawitz et al., "Selective brain dopamine
depletion in developing rats: An experimental model of minimal
brain dysfunction," Science, 191:305-307, 1976. [0884] Shaywitz et
al., "CSF monamine metabolites in children with minimal brain
dysfuntion: Evidence for alteration of brain dopamine," J.
Pediatrics, 90:67-71, 1977. [0885] Shekim et al., "Urinary MHPG and
HVA excretion in boys with attention deficit hyperactivity disorder
and hyperactivity treated D-amphetamine," Biol. Psychiatry,
18:707-714, 1983. [0886] Shekim, Bylund, Frankel, Alexson, Jones,
Blue, Kirby, Corchoran, "Platelet MAO activity and personality
variations in normals," Psychiatry Res., 27:81-88, 1989. [0887]
Shekim, Dekirmenjian, Chapel, "Urinary MHPG excretion in minimal
brain dsyfunction and its modification by d-amphetamine," Am. J.
Psychiatry, 136:667-671, 1997. [0888] Shekim, Javaid, Davis,
Bylund, "Urinary MHPG and HVA excretion in boys with attention
deficit hyperactivity disorder and hyperactivity treated with
d-amphetamine," Biol. Psychiatry, 18:707-714, 1983. [0889] Sherif,
Marcusson, Oreland, "Brain gamma-aminobutyrate transaminase and
monoamine oxidase activities in suicide victims," Eur. Arch.
Psychiatry Clin. Neurosci., 241:139-144, 1991. [0890] Sherman,
Iacono, McGue, "Attention-deficit hyperactivity disorder
dimensions: A twin study of inattention and
impulsivity-hyperactivity," J. Am. Acad. Child. Adolesc.
Psychiatry., 36:745-753, 1997. [0891] Sherman, McGure, Iacono,
"Twin concordance for attention deficit hyperactivity disorder: A
comparison of teachers' and mothers' reports," Am. J. Psychiatry,
154:532-535, 1997. [0892] Sholl, Goy, Kim, Aromatase,
5-alpha-reductase, and androgen receptor levels in the fetal monkey
brain during fetal development, Endocrinology, 124:627-634, 1989.
[0893] Shulman, "Intelligence and delinquency," J. Criminal Law and
Criminol., 41:763-781, 1951. [0894] Sikich, and Todd, Are the
neuordevelopmental effects of gonadal hormones related to sex
differences in psychiatric illness, Psychiatr. Dev, 4:277-309,
1988. [0895] Silverstein, Smith, Johnston, "Effect of clonidine on
platelet alpha 2-adrenoreceptors and plasma norepinephrine of
children with Tourette syndrome," Dev. Med. Child Neurol.,
27:793-799, 1985. [0896] Simon, Vaughan, Ritter, "The scalp
topography of potentials in auditory and visual discrimination
tasks," Electroencephalography and Clinical. Neurophysiology,
42:528-535, 1977. [0897] Skekim, Davis, Bylund, Brunngraber, Fikes,
Lanham, "Platelet MAO in children with attention deficit disorder
and hyperactivity: a pilot study," Am. J. Psychiatry, 139:936-938,
1982. [0898] Skolnick, "Old Chinese herbal medicine used for fever
yields possible new Alzheimer disease therapy," JAMA, 277(10):776,
1997. [0899] Sleator and Ullmann, Clinical Pediatrics, 1981. [0900]
Sleddens, Oostra Brinkman, Trapman, Trinucleotide repeat
polymorphism in the androgen receptor (AR) gene, Nucleic Acids
Res., 20:1427, 1992. [0901] Sleddens, Oostra, Brinkman, Trapman,
Trinucleotide (GGN) repeat polymorphism in the human androgen
receptor (AR) gene, Hum. Molec. Genet., 2:493, 1993. [0902] Smith,
Stapleton, Moreno, Halgren, "The effects of anterior temporal
lobectomy on endogenous EPs recorded during verbal recognition
memory testing," Society for Neuroscience, Abs., 11:527, 1985.
[0903] Smith, O'Hara, Persico et al., "Genetic vulnerability to
drug abuse; the D.sub.2 dopamine receptor TaqI B.sub.1 restriction
fragment length polymorphism appears more frequently in
polysubstance abusers," Arch. Gen. Psych., 49(9):723-727, 1992.
[0904] Smythe et al., "The extrinsic modulation of hippocampal
synchrony (theta) depends on the coactivation of cholinergic and
Gaba-ergic medial septal inputs," Neurosci. BioBehav. Rev.,
16:289-308, 1992. [0905] Sobell, Heston, Sommer, "Delineation of
genetic predisposition to multifactorial disease: a general
approach on the threshold of feasibility," Genomics, 12:1-6, 1991.
[0906] Sostek, Buchsbaum, Rapoport, "Effects of amphetamine on
vigilance performance in normal and hyperactive children," Journal
of Abnormal Child Psychology, 8:491-500, 1980. [0907] Spandidos and
Holmes, "Transcriptional enhancer activity in the variable tandem
repeat DNA sequence downstream of the human Ha-ras-1 gene," FEBS
Lett., 218:41-46, 1987. [0908] Spielman et al., "Transmission test
for linkage disequilibrium: the insulin gene region and
insulin-dependent diabetus mellitus," Am. J. Hum. Genet.,
52:506-516, 1993. [0909] Stanzione, Fattapposta, Tagliati,
D'Alessio, Marciani, Foti, Amabile, "Dopamergic pharmacological
manipulations in normal humans confiirm the specificity of the
visual (PERG-VEP) and cognitive (P300) electrophysiological
alternations in Parkinson's Disease," Electroencephalography and
Clinical Neurophysiology, 44:447-448, 1990. [0910] Starke, Montel,
Gayk, Marker, "Comparison of the effects of clonidine on pre- and
postsynaptic adrenoceptors in the rabbit pulmonary artery,"
Naunyn-Schmiedeberg. Arch. Pharmacol., 285:133-150, 1974. [0911]
Stefanick, "Exercise and weight control," In: Exercise and Sport
Sciences Reviews, Volume 21, J. O. Holloszy, (ed)., Baltimore, Md.,
Williams and Wilkins, 1993. [0912] Steinlein, Anokhin, Mao, Schalt,
Vogel, "Localization of a gene for the human low voltage EEG on 20q
and genetic heterogenity," Genomics, 12:69-73, 1992. [0913]
Steinlein, Smigrodzki, Lindstrom, Anand, Kohler, Tocharentanaphol,
Vogel, "Refinement of the localization of the gene for neuronal
nicotinic acetylcholine receptor a4 subunit (CHRNA4) to human
chromosome 20q13.2-a13.3," Genomics, 22:493-495, 1994. [0914]
Steinlein, "Detection of a CfoI polymorphism within exon 5 of the
human neuronal nicotinic acetylcholine receptor alpha 4 subunit
gene (CHRNA4)," Hum. Genet., 96:130, 1995. [0915] Steinlein,
Mulley, Propping, Wallace, Phillips, Sutherland, Scheffer,
Berkovic, "A missense mutation in the neuronal nicotinic
acetylcholine receptor a4 subunit is associated with autosomal
dominant noctural frontal lobe epilepsy," Nature Genet.,
11:201-203, 1995. [0916] Steinlein, Weiland, Stoodt, Propping,
"Exon-intron structure of the human neuronal nicotinic
acetylcholine receptor a4 subunit (CHRNA4)," Genomics., 32:289-294,
1996. [0917] Steinlein, Deckert, Nothen, Franke, Maier, Beckman,
Propping, "Neuronal nicotinic acetylcholine receptor a4 subunit
(CHRNA4) and panic disorder: An association study," Am. J. Med.
Gen. (Neuropsych. Genet.), 74:199-201, 1997a. [0918] Steinlein,
Magnusson, Stoodt, Bertrand, Weiland, Berkovic, Nakken, Propping,
Bertrand, "An insertion mutation of the CHRNA4 gene in a family
with autosomal dominant noctural frontal lobe epilepsy," Hum.
Molec. Genet., 6:943-947, 1997b. [0919] Stevenson, Pennington,
Gilger, DeFries, Gillis, "Hyperactivity and spelling disability:
Testing for shared genetic etiology," J. Child. Psychol.
Psychiatry, 34:1137-1152, 1993. [0920] Stewart, Comings, Singer,
Deblois, The overlap between hyperactive and unsocialized
aggressive children, J. Child Psychol. Psychiatry, 22:35-45, 1981.
[0921] Stewart, Deblois, Comings, Psychiatric disorders in the
parents of hypemctive boys and those with conduct disorder, J.
Child Psychol. Psychiatry, 21:283-292, 1980. [0922] Strandburg et
al., "Continuous-processing-related event-related potentials in
children with Attention-Deficit Hyperactivity Disorder," Biol.
Psychiatry, 40:964-980, 1996. [0923] Struve and Straumanis,
"Separation of chronic marijuana (THC) users from nonusers: a
discriminate function analysis using quantitative
electroencephalographic variables," Biol. Psychiatry, 27:52A-53A,
1990. [0924] Suarez, Parsian, Hampe et al., "Linkage disequilibria
at the D.sub.2 dopamine receptor locus (DRD.sub.2) in alcoholics
and controls", Genomics, 19:12-20, 1994. [0925] Summar, The use of
linkage analysis and the Centre d'Etude Polymorphisme Humain (CEPH)
panel of DNA in the study of the arginine vasopressin, oxygtocin
and prodynorphin gene loci, Prog. Brain Res., 93:309-317, 1992.
[0926] Sutton, Braren, Zubin, John, "Evoked potential correlates of
stimulus uncertainty," Science, 150:1961-1969, 1965. [0927]
Tabakoff, Hoffman, Lee, Saito, Willard, Leon-Jones, "Differences in
platelet enzyme activity between alcoholics and nonalcoholics," New
Eng. J. Med., 318:134-139, 1988. [0928] Tajima, et al., Chem.
Pharm. Bull., 28:1935, 1980. [0929] Takagi, et al., Eur. J. Pharm.,
55:109, 1979. [0930] Tang, Han, Chen, et al., "Effects of Huperzine
A on learning and the retrieval process of discrimination
performance in rat," Chung Kuo Yao Li Hsuch Pao, 7:507-511 (article
in Chinese), 1986. [0931] Tang, De Sarno, Sugaya, et al., "Effect
of Huperzine A, a new cholinesterase inhibitor, on the central
cholinergic system of the rat," J. Neurosci. Res., 24:276-285,
1989. [0932] Tang, Kindel, Kozikowski, Hanin, "Comparison of the
effects of natural and synthetic huperzine-A on rat brain
cholinergic function in vitro and in vivo," J. Ethnopharmacol.,
44(3):147-155, 1994a. [0933] Tang, Xu, Feng, et al., "Effect of
cholinesterase inhibition in vitro by Huperzine analogs," Chung Kuo
Yao Li Hsuch, 15:107-110, 1994b. [0934] Tang, Fu, Kotter, Cotter,
Cantor, Koster, "Matrix-assisted laser desportion/ionization mass
spectrometry of immobilized duplex DNA probes," Nucleic Acids Res.,
23:3126-3131, 1995. [0935] Thawki, et al., J. Neurochem.,
41:611-617, 1983. [0936] Thelu, Zarski, Froissart, Rachail,
Seigneurin, "c-Ha-ras polymorphism in patients with hepatocellular
carcinoma," Gastroenterol. Clin. Biol., 17:903-907, 1993. [0937]
Tivol, Shalish, Schuback, Hus, Breakefield, "Mutational analysis of
the human MAOA gene," Am. J. Med. Gen. (Neuropsych. Genet.),
67:92-97, 1996. [0938] Tobiessen and Karowe, 1969. [0939]
Trachtenberg and Blum, "Improvement of cocaine-induced
neuromodulator deficits by neuronutrient tropamine," J.
Psychoactive Drugs, 20:315-331, 1988. [0940] Trepicchio and
Krontiris, "Members of the rel/NF-.kappa.B family of
transcriptional regulatory factors bind the HRAS 1 minisatellite
DNA sequence," Nucl. Acids Res., 21:977-985, 1992. [0941]
Trepicchio and Krontiris, "IGH minisatellite suppression of
USF-binding-site-and E.mu.-mediated transcriptional activation of
the adenovirus major late promoter," Nucl. Acids Res., 21:977-985,
1993. [0942] Ueda, et al., Biochem. Biophys. Res. Commun.,
137:897-902, 1986. [0943] Uhl et al., "Substance abuse
vulnerability at D.sub.2 receptor genes," Trends Neurosci.,
16:83-88, 1993. [0944] Unwin, "Nicotmic acetylcholine receptor
channel imaged in the open state," Nature, 373:37-43, 1993. [0945]
Uusitupa, Mykkanen, Sitonen, Laakso, Sarlund, Kolehmainen, Rasanen,
Kumpulainen, Pyorala, "Chromium supplementation in impaired glucose
tolerance of the elderly: effects on blood glucose, plasma insulin,
C-peptide and lipid levels," Br. J. Nutr., 68:209-216, 1992. [0946]
V. Petkov, 1981. [0947] Vafiadis, Bennett, Todd, Nadeau, Grabs,
Goodyer, Wickramasinghe, Colle, Polychronakos, "Insulin expression
in human thymus is modulated by INS VNTR alleles at the IDDM2
locus," Nature Genet., 15:289-292, 1997. [0948] Valzelli,
Psychobiology of Aggression and Violence, New York: Raven Press,
1981. [0949] van Praag, Serotonergic dysfunction and aggression
control, Psychol. Med., 21:15-19, 1991. [0950] Van Tol et al.,
"Multiple dopamine D.sub.4 receptor variants in human population,"
Nature 358:149-152, 1992. [0951] Vanyukov, Moss, Plail, Blackson,
Mezzich, Tarter, "Antisocial symptoms in preadolescent boys and in
their parents: associations with cortisol," Psychiatr. Res.,
46:9-17, 1993. [0952] Vasile, Duffy, McAnulty, Mooney,
Bloomingdale, Schildkaut, "Abnormal flash visual evoked responses
in melancholia: a replication study," Biological Psychiatry,
24:325-336 1992. [0953] Vaughan and Arezzo, "The neural basis of
event-related potentials. In T. W. Picton (Ed.),
Human Event-Related Potentials, EEG Handbook, 3:45-96, 1988. [0954]
Ved, Koenig, Dave, et al., "Huperzine-A, a potential therapeutic
agent for dementia, reduces neuronal cell death caused by
glutamate," Neuroreport, 8:963-968, 1997. [0955] Volkow et al.,
"Effects of methylphenedate on regional brain glucoes metabolism in
humans: relationship to dopamine D.sub.2 receptors," Am. J.
Psychiatry, 154:50-55, 1996. [0956] Volkow et al., "Is
methylphenidate like cocaine? Studies on their pharmacoketics and
distribution in human brain," Arch. Gen. Psychiatry, 52:456-463,
1995. [0957] Vonknorring, Hallmann, Vonknorring, Oreland, "Platelet
monoamine oxidase activity in type-1 and type-2 alcoholism,"
Alcohol Alcohol, 28:409-416, 1991. [0958] Vonknorring, Oreland,
Winblad, "Personality traits treated to monoamine oxidase activity
in platelets," Psychiatry Res., 12:11-26, 1984. [0959] Wada, Wada,
Boulter, Deneris, Heinemann, Patrick, Swanson, "Distribution of
alpha2, alpha3, alpha4, and beta2 neuronal nicotmic receptor
subunit mRNAs in the central nervous system: A hybridization
histochemical study in the rat," J. Comp. Neurol., 284:314-335,
1989. [0960] Wahis, Swenson, Moore, "Two hypervariable
minisatellite DNA binding proteins," Nucl. Acids Res.,
19:3269-3274, 1991. [0961] Waldmaqn, Rowe, Abramowitz, Kozel, Mohr,
Sherman, Cleveland, Sanders, Stevens, "Association of the dopamine
transporter gene (DAT 1) and attention deficit hyperactivity
disorder," Am. J. Hum. Genet., 59:A25, 1996. [0962]
Wallberg-Henriksson, "Exercise and diabetes mellitus," In: Exercise
and Sport Science Reviews, Volume 20, J. O. Holloszy, (ed).,
Baltimore, Md., Williams and Wilkins, 1992. [0963] Wang, Amirhaeri,
Kang, Wells, Griffith, "Preferential nucleosome assembly at DNA
triplet repeats from the myotonic dystrophy gene," Science,
265:669-671, 1994. [0964] Wang, Quigley, Kolpak, Crawford, van
Boom, van der Marcl, Rich, "Molecular structure of a left-handed
double helical DNA fragment at atomic resolution," Nature,
282:686-682, 1979. [0965] Wang, Yue, Tang, "Anti-cholinesterase
activity of Huperzine A," Chung Kuo Yao Li Hsuch Pao, 7:110-113
(article in Chinese), 1986. [0966] Wang, Feng, Lu, et al.,
"Pharmacokinetics of Huperzine A in rates and mice," Chung Kuo Yao
Li Hsuch Pao, 9:193-196 (article in Chinese), 1988. [0967]
Warburton, "Nicotine as a cognitive enhancer," Prog.
Neuropsychopharmacol. Biol. Psychiatry, 16:181-191, 1992. [0968]
Weeks and Lange, "The affected-pedigree-member method: power to
detect linkage," Am. J. Hum. Genet., 42:315-326, 1988. [0969] Weeks
and Lathrop, "Polygenic disease: methods for mapping complex
disease traits," Trends Genet., 11:513-519, 1995. [0970] Wei,
Ramchand, Hemmings, "Possible control of dopemine
.beta.-hydroxylase via a codominant mechanism associated with
polymorphic (GT)n repeat at this gene locus in healthy
individuals," Hum. Genet., 99:52-55, 1997. [0971] Weiland and
Steinlein, "Dincucleotide polymorphism in the first intron of the
human neuronal nicotinic acetylcholine receptor a4 subunit gene
(CHRNA4)," Clin. Genetics, 50:433-434, 1996. [0972] Weinberger et
al., "Mescocortical dopaminergic function and human cognition,"
Annals New York Acad. Sci., 537:330-338, 1988. [0973] Weiner et
al., "A controlled study of siblings of hyperactive children," J.
Nerv. Ment. Dis., 165:110-117, 1977. [0974] Weintramb et al., "Long
term weight control study (weeks 0 to 34)," Clin. Pharmacol. Ther.,
51:586-594, 1992. [0975] Wells, "Molecular basis of genetic
instability of triplet repeats," J. Biol. Chem., 271:2875-2878,
1996. [0976] Wesnes and Warburton, "Smoking, nicotine and human
performance," In: Nicotine and the Tobacco Smoking Habit, Sectin
114. The International Encyclopedia of Pharmacology and
Therapeutics, D. J. K. Balfour (Ed.), New York, Pergamon Press, pp.
133-152, 1984. [0977] West, "Epidemiology of Diabetes and it's
Vascular Lesions," New York, N.Y.: Elsevier, 1978. [0978] Weyler,
Hsu, Breakefield, "Biochemistry and genetics of monamine oxidase,"
J. Pharmacol. Ther., 47:391417, 1990. [0979] Whipple, Parker,
Noble, "An atypical neurocognitive profile in alcoholic fathers and
their sons," Journal of Studies on Alcohol, 49:240-244, 1988.
[0980] White, "A triple dissociation of memory systems:
hippocampus, amygdala, and dorsal striatum," Behavorial
Neuroscience, 107:3-22, 1993. [0981] Whiting and Lindstrom,
"Characterization of bovine and human nicotinic acetylcholine
receptors using monoclonal antibodies," J. Neurosci., 8:3395-3404,
1988. [0982] Whiting, Schoepfer, Conroy, Gore, Keyser, Shimasaki,
Esch, Lindstrom, "Expression of nicotinic acetylcholine receptor
subtypes in brain and retina," Mol. Brain Res., 10:61-70, 1991.
[0983] Wiberg, Gottfries, Oreland, "Low platelet monoamine oxidase
activity in human alcoholics," Med. Biol., 55:181-186, 1977. [0984]
Wilkins, Shallice, McCarthy, "Frontal lesions and sustained
attention," Neuropsychologia, 25:359-365, 1987. [0985] Williams et
al., Nature, 376:572-675, 1995. [0986] Williams, et al., "The
structured clinical interview for DSM-III-R(SCID). II. Multisite
Test-retest reliability," Arch. Gen. Psychiatry, 49:630-636, 1992.
[0987] Williams, "Alcoholism: The Nutritional Approach," Austin:
University of Texas Press, 1959. [0988] Wills, In: The Runaway
Brain, Basic Books, New York, N.Y., pp 1-358, 1993. [0989] Wilson
and Gondy, "Effects of chromium supplementation on fasting insulin
and lipid parameters in healthy, non-overweight young subjects,"
Diabetes Res. Clin. Prac., 28:179-184, 1995. [0990] Wise and
Bozarth, "Action of abused drugs on reward systems in the brain,
"In Blum and Manzo (Eds.), Neurotoxicology (pp. 111-133), New York:
Marcel Dekker, 1985. [0991] Wisler et al, 1981. [0992] Wittig,
Wolffl, Dorbic, Vahrson, Rich, "Transcription of human c-myc in
permeabilized nuclei is associated with formation of Z-DNA in three
discrete regions of the gene," EMBO J., 12:4653-4663, 1992. [0993]
Wolff, Plaetke, Jeffreys, White, "Unequal crossing over between
homologous chromosomes is not the maior mechanism involved in the
generation of new alleles at VNTR loci," Genomics, 5:382-384, 1989.
[0994] Wolff, Martinez, Rich, Majzoub, "Transcription of the human
corticotropin-releasing hormone gene in NPLC cells is correlated
with Z-DNA formation, "Proc. Natl. Acad. Sci. USA, 93:3664-3668,
1996. [0995] Wood, Allison, Goff, Williamson, Spencer, "On the
origin of P30-0 in man," In Kornhuber and Deecke (Eds.),
Motivation, Motor and Sensory Processes of the Brain: Electrical
Potentials, Behavior and Clinical Use. Progress in Brain Research.
(Vol. 54), New York: Elsevier, 1980. [0996] Wragg et al., The
Lancet, 347:509-512, 1996. [0997] Wright, "Mutation at VNTRs: are
minisatellites the evolutionary progeny of microsatellites,"
Genome, 37:345-346, 1994. [0998] Wu, Ikezono, Angus, Shelhamer,
"Characterization of the promoter for the human 85 kDA cytosolic
phospholipase A.sub.2 gene," Nucl. Acids Res., 22:5093-5098, 1994.
[0999] Wu, Muhleman, Comings, PCR amplification of the TaqI B1/B2
polymorphism at intron 5 of the dopamine b-hydroxylase gene,"
Psychiat. Genet., 7:39-40, 1997. [1000] Wurtman and Fernstrom,
"Control of brain neurotransmitter synthesis by precursor
availability and nutritional state," Biochemical Pharmacology, 25,
1691-1696 1976. [1001] Wurtman, Hefti, and Melamed, "Precursor
control of neurotransmitter synthesis," Pharmacological Review,
32:315-335, 1981. [1002] Wurtman, "Nutrients that modify brain
function," Sci. Am., 246:50-59, 1982. [1003] Wurtman, "Food
consumption, neurotransmitter synthesis, and human behavior,"
Experientia, 44:356-369, 1983. [1004] Wurtman and Ritter-Walker,
"Dietary Phenylalanine and Brain Function," Boston: Birkhauser,
1988. [1005] Wyatt, Potkin, Murphy, "Platelet monamine oxidase
activity in schizophrenia: a review of the data," Am. J.
Psychiatry, 136:377-385, 1979. [1006] Xiong and Tang, "Effect of
Huperzine A, a novel acetylcholinesterase inhibitor, on radial maze
performance in rates," Pharmacol. Biochem. Behav., 51:415-419,
1995. [1007] Xiong, Tang, Lin, et al., "Effects of isovaniHuperzine
A on cholinesterase and scioikanube-induced memory impairment,"
Chung Kuo Yao Li Hsuch Pao, 16:21-25 (in Chinese), 1995. [1008] Xu,
Gao, Weng, Du, Xu, Yang, Zhang, Tong, Fang, Chai et al., "Efficacy
of tablet huperzine-A on memory, cognition, and behavior in
Alzheimer's disease," Chung Kuo Yao Li Hsuch Pao, 16(5):391-395,
1995. [1009] Yamazaki, Nomoto, Mishima, Kominami, "A 35-kDA protein
binding to a cytosine-rich strand of hypervariable minisatellite
DNA," J. Biol. Chem., 267:12311-12316, 1992. [1010] Yan, Lu, Lou,
et al., "Effects of Huperzine A and B on skeletal muscle and the
electoenephalogram," Chung Kuo Yao Li Hsuch Pao, 8:117-123, 1987.
[1011] Yaspelkis, Patterson, Anderla, Ding, Ivy, "Carbohydrate
supplementation spares muscle glycogen during variable intensity
exercise", J. Appl. Physiol., 75:1477-1485, 1993. [1012] Yoshida et
al., "Molecular abnormality of an interactive aldehyde
dehydrogenase variant commonly found in Orientals," Proc. Natl.
Acad. Sci. USA, 81:258-261, 1984. [1013] Yu-cum and Yu-feng,
"Urinary 3-methoxy-4 hydroxyphenylglycol sulfate excretion in
seventy-three schoolchildren with minimal brain dysfunction
syndrome," Biol. Psychiatry, 19:861-868, 1984. [1014] Zametkin,
Karoum, Linnoila, Rapoport, Brown, Chuang, Wyatt, "Stimulants,
urinary catecholamines, and indoleamines in hyperactivity. A
comparison of methylphenidate and dextroamphetamine," Arch. Gen.
Psychiatry, 42:251-255, 1985. [1015] Zametkin et al., "Cerebral
glucose metabolism in adults with hyperactivity of childhood
onset," N. Engl. J. Med., 323:1361-1366, 1990a. [1016] Zametkin,
Nordahl, Gross, King, Sample, Rumsey, Hamburger, Cohen, "Cerebral
glucose metabolism in adults with hyperactivity of childhood
onset," N. Engl. J. Med., 323:1361-1366, 1990b. [1017] Zhang, Wang,
Zheng, et al., "Facilitation of cholinergic transmission by
Huperzine A in toad paravertebral ganglia in vitro," Chung Kuo Yao
Li Hsuch Pao, 15:158-161 (article in Chinese), 1994. [1018] Zhang,
Tang, Han, et al., "Drug evaluation of Huperzine A in the treatment
of senile memory disorders," Chung Kuo Yao Li Hsuch Pao, 12:250-252
(article in Chinese), 1991. [1019] Zhi, Yi, X I, "Huperzine A
ameliorates the spatial working memory impairments induced by
AF64A," Neuroreport, 6(16):2221-2224, 1995. [1020] Zhu and
Giacobini, "Second generation choliesterase inhibitors: effect of
(L)-Huperzine-A on cortical biogenic amines," J. Neurosci. Res.,
41:828-835, 1995. [1021] Zhu and Tang, "Facilitatory effects of
Huperzine A and B on learning and memory of spatial discrimination
in mice," Yao Hsueh Hsueh Pao, 22:812-817 (article in Chinese),
1987. [1022] Zhu and Tang, "Improvement of impaired memory in mice
by Huperzine A and Huperzine B," Chung Kuo Yao Li Hsuch Pao,
9:492-497 (article in Chinese), 1988. [1023] Zhu, "Development of
natural products as drugs acting on central nervous system," Mem.
Inst. Oswaldo Cruz, 86:173-175, 1991. [1024] Zola-Morgan, Squire,
Alvarez-Royo, Clower, "Independence of memory functions and
emotional behavior: separate contributions of the hippocampal
formation and the amygdala," Hippocampus, 1,207-220, 1991.
* * * * *