U.S. patent application number 11/910988 was filed with the patent office on 2008-08-28 for methods of and compositions for the prevention of anxiety, substance abuse, and dependence.
This patent application is currently assigned to Hythiam , Inc.. Invention is credited to Sanjay Sabnani.
Application Number | 20080207601 11/910988 |
Document ID | / |
Family ID | 37087555 |
Filed Date | 2008-08-28 |
United States Patent
Application |
20080207601 |
Kind Code |
A1 |
Sabnani; Sanjay |
August 28, 2008 |
Methods of and Compositions For the Prevention of Anxiety,
Substance Abuse, and Dependence
Abstract
Compositions for reducing dependency and addiction to substances
of abuse are provided. Chloride channels such as the GABA.sub.A
receptors are altered under conditions of dependency and withdrawal
such that the electrophysiological properties of the GABA.sub.A
receptor containing neurons are altered thereby providing a
pathophysiological condition resulting in symptoms of dependency
and withdrawal such as anxiety. Specifically, under conditions of
withdrawal the relative ratio of the a1 receptor subunit decreases
relative to the a4 receptor subunit. Endogenous neurosteroid
production is also associated with the molecular changes underlying
the alterations of GABA-gated chloride channels. Compositions of at
least two compounds including at least one inhibitor of
neurosteroid production are useful for treating the pathophysiology
of addiction, dependency and substance abuse withdrawal.
Inventors: |
Sabnani; Sanjay;
(Northridge, CA) |
Correspondence
Address: |
JOHN S. PRATT, ESQ;KILPATRICK STOCKTON, LLP
1100 PEACHTREE STREET
ATLANTA
GA
30309
US
|
Assignee: |
Hythiam , Inc.
Los Angeles
CA
|
Family ID: |
37087555 |
Appl. No.: |
11/910988 |
Filed: |
April 6, 2006 |
PCT Filed: |
April 6, 2006 |
PCT NO: |
PCT/US2006/013296 |
371 Date: |
October 9, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60669033 |
Apr 7, 2005 |
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60729013 |
Oct 21, 2005 |
|
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60728979 |
Oct 21, 2005 |
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Current U.S.
Class: |
514/221 ;
514/282; 514/284; 514/300; 514/321 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 1/14 20180101; A61K 31/5517 20130101; A61K 31/122 20130101;
A61P 25/18 20180101; A61K 31/58 20130101; A61P 25/30 20180101; A61P
25/36 20180101; A61P 43/00 20180101; A61P 25/00 20180101; A61K
31/137 20130101; A61P 25/34 20180101 |
Class at
Publication: |
514/221 ;
514/282; 514/284; 514/300; 514/321 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/439 20060101 A61K031/439; A61K 31/4353
20060101 A61K031/4353; A61K 31/437 20060101 A61K031/437; A61K
31/4525 20060101 A61K031/4525; A61K 31/55 20060101 A61K031/55 |
Claims
1-36. (canceled)
37. A composition comprising a pharmaceutical compound in
combination with an inhibitor of endogenous neurosteroid production
in a pharmaceutically acceptable carrier, wherein the
pharmaceutical compound is a stimulant, contraceptive,
tranquilizer, sedative, hypnotic, benzodiazepine, analgesic or
barbiturate.
38. The composition of claim 37, wherein the stimulant is
amphetamine, methylphenidate, dextroamphetamine, or a mixture
thereof.
39. The composition of claim 38, wherein the methylphenidate is
present in an amount between 5 mg and 20 mg.
40. The composition of claim 38, wherein the dextroamphetamine is
present in an amount between 5 mg and 60 mg.
41. The composition of claim 38, wherein the amphetamine and
dextroamphetamine are present in a mixture in an amount of between
2.5 mg and 60 mg.
42. The composition of claim 37, wherein the contraceptive is
ethinyl estradiol, mestranol, norethynodrel, norethindrone,
norethindrone acetate, norgestimate, desogestrel, ethynodiol
diacetate, norgestrel, levonorgestrel, medroxyprogesterone acetate,
or drospirenone or a combination thereof.
43. The composition of claim 42, wherein the medroxyprogesterone
acetate is present in an amount of 150 mg.
44. The composition of claim 37, wherein the tranquilizer, sedative
or hypnotic is chloral hydrate, chloral betaine, chlomethiazole,
diphenhydramine, ethchlorvynol, promethazine, zaleplon, zolpidem,
or zopiclone, or a combination thereof.
45. The composition of claim 37, wherein the inhibitor of
neurosteroid production is finasteride
46. The composition of claim 45, wherein the finasteride is present
in an amount between about 0.1 and 150 mg.
47. The composition of claim 45, wherein the finasteride is present
in an amount of about 5 mg.
48. A method of reducing substance abuse in a patient of a
pharmaceutical compound comprising administering to the patient a
composition comprising the pharmaceutical compound in combination
with an inhibitor of endogenous neurosteroid production in a
pharmaceutically acceptable carrier, wherein composition is
effective to reduce abuse of the pharmaceutical compound in the
patient, wherein the pharmaceutical compound is a stimulant,
contraceptive, tranquilizer, sedative, hypnotic, benzodiazepine,
analgesic or barbiturate.
49. The method of claim 48, wherein the stimulant is amphetamine,
methylphenidate, or dextroamphetamine, or a mixture thereof.
50. The method of claim 49, wherein the methylphenidate is present
in an amount between 5 mg and 20 mg.
51. The method of claim 49, wherein the dextroamphetamine is
present in an amount between 5 mg and 60 mg.
52. The method of claim 49, wherein the amphetamine and
dextroamphetamine are present in a mixture in an amount of between
2.5 mg and 60 mg.
53. The method of claim 48, wherein the contraceptive is ethinyl
estradiol, mestranol, norethynodrel, norethindrone, norethindrone
acetate, norgestimate, desogestrel, ethynodiol diacetate,
norgestrel, levonorgestrel, medroxyprogesterone acetate,
drospirenone or combinations thereof.
54. The method of claim 53, wherein the medroxyprogesterone acetate
is present in an amount of 150 mg.
55. The method of claim 48, wherein the tranquilizer, sedative or
hypnotic is chloral hydrate, chloral betaine, chlomethiazole,
diphenhydramine, ethchlorvynol, promethazine, zaleplon, zolpidem,
or zopiclone, or a combination thereof.
56. The method of claim 48, wherein the inhibitor of neurosteroid
production is finasteride.
57. The method of claim 56, wherein the finasteride is present in
an amount between about 0.1 and 150 mg.
58. The method of claim 56, wherein the finasteride is present in
an amount of about 5 mg.
59. The method of claim 48, further comprising administering a
composition comprising a compound that modulates expression of
GABA.sub.A subunits in a pharmaceutically acceptable carrier.
60. The method of claim 59, wherein the compound that modulates
expression of GABA.sub.A subunits is flumazenil.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention relies on, for priority, U.S.
Provisional Patent Application No. 60/669,033, entitled "Improved
Method for the Treatment of Substance Abuse", filed on Apr. 7,
2005, U.S. Provisional Patent Application No. 60/728,979 entitled
"Methods for the Treatment of Substance Abuse and Dependence",
filed on Oct. 21, 2005, and U.S. Provisional Patent Application No.
60/729,013 entitled "Methods for Treating Anxiety-Related
Diseases", filed on Oct. 21, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to improved methods of, and
compositions for, preventing psychological addiction to and
physiological dependence upon exogenous and endogenous substances.
More specifically, the present invention relates to methods of, and
compositions for, administering a pharmaceutical compound in
combination with an inhibitor of neurosteroid production to prevent
endogenous neurosteroid production. The present invention also
relates to administering a pharmaceutical compound in combination
with an inhibitor of neurosteroid production to avoid
cross-tolerance effects of both the endogenous and exogenous
substance.
[0003] The present invention also relates to methods of, and
compositions for, directly or indirectly, preventing the modulation
of GABA.sub.A by the progesterone metabolite allopregnanolone. More
specifically, the present invention relates to combining the
therapeutic activity of conventional pharmaceutical compounds with
the therapeutic activity of inhibitors of neurosteroid production
that inhibit the production of allopregnanolone.
[0004] The present invention also relates to methods for using
pharmaceutical compositions from a class of compounds that directly
or indirectly modulates GABA.sub.A by modulating the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit.
BACKGROUND OF THE INVENTION
[0005] Addiction is an uncontrollable compulsion to repeat a
behavior regardless of its negative consequences. Many drugs or
behaviors can lead to a pattern of actions recognized as addiction,
which include a craving for more of the drug or behavior, increased
physiological tolerance to exposure, and withdrawal symptoms in the
absence of the stimulus. Although a distinction is often made
between psychological addiction and physical dependence, the terms
are used interchangeably throughout this specification.
[0006] While addiction is generally thought to apply to illegal
narcotics, legal substances, such as prescription and
over-the-counter medications, may also cause addiction. While there
are many useful, legal prescription and over-the-counter
medications that have a positive therapeutic effect, they are
limited in use in that there is a tendency of addiction in patients
who use these medications.
[0007] Substance addiction and abuse is a multi-factorial
neurological disease. Over time, repeated exposure to various
substances, both endogenous and exogenous, causes modification of
the neurotransmission circuits and adaptations in post-receptor
signaling cascades. There are several effects of this neuronal
modification. Among them, there is a reduction in the ability of
natural rewards to activate the reward pathways leading to
depressed motivation and mood and an increased compulsion to
compensate for the physiological change.
[0008] While the common perception underlying addiction is that of
a "reward circuit", pleasure may not necessarily be a strong enough
impetus to drive people towards their addictions. Rather, addictive
behavior arises from an intense desire to manage and/or avoid the
anxiety that arises when someone is experiencing withdrawal.
Similarly, anxiety-related diseases are caused by behavior that
arises from an intense desire to manage and/or avoid the anxiety
experienced during endogenous neurosteroid withdrawal.
[0009] Traditional treatments for substance dependency, such as
benzodiazepine abuse, have been based upon cognitive-behavioral
therapy or drug therapy, or a combination thereof. Conventional
methods of treatment fail, however, in that they do not address the
physiochemical changes that occur with addiction and dependence. In
addition, conventional methods for treating substance abuse require
waiting until a patient is addicted to a substance and experiences
withdrawal symptoms.
[0010] What is therefore needed are improved methods of and
compositions for preventing psychological addiction to, and
physiological dependence upon, prescription or over the counter
medicines.
[0011] What is also needed is a method for making known
prescription or over the counter medicines less addictive and
habit-forming.
SUMMARY OF THE INVENTION
[0012] The present invention is directed towards improved methods
of, and compositions for, preventing psychological addiction to and
physiological dependence upon exogenous and endogenous substances.
More specifically, the present invention relates to methods of, and
compositions for, administering a pharmaceutical compound in
combination with an inhibitor of neurosteroid production to prevent
endogenous neurosteroid production. The present invention also
relates to administering a pharmaceutical compound in combination
with an inhibitor of neurosteroid production to avoid
cross-tolerance and compounded withdrawal effects of both the
endogenous and exogenous substance.
[0013] The present invention is also directed towards methods of,
and compositions for, directly or indirectly preventing the
modulation of GABA.sub.A by progesterone.
[0014] The present invention is also directed towards methods of,
and compositions for, directly or indirectly preventing the
modulation of GABA.sub.A by progesterone metabolite
allopregnanolone. More specifically, the present invention is
directed towards combining the therapeutic activity of conventional
pharmaceutical compounds with the therapeutic activity of
inhibitors of neurosteroid production that inhibit the production
of allopregnanolone.
[0015] Compositions are also provided that include a substance with
addictive properties in combination with an inhibitor of
neurosteroid production. Methods of administration of these
compounds are also provided herein. Such substances with addictive
properties may include stimulants, contraceptives, tranquilizers,
sedatives, hypnotics, benzodiazepines, analgesics and barbiturates.
These compositions may optionally include a modulator of receptor
subunit expression.
[0016] In one embodiment, the present invention is directed towards
compositions of a therapeutically effective dose of a
pharmaceutical compound in combination with a therapeutically
effective dose of an inhibitor of endogenous neurosteroid
production to prevent addiction to, or dependence on, a substance
of abuse.
[0017] In another embodiment, the present invention is directed
towards methods of administering a pharmaceutical compound, without
habit-forming or addictive side effects to prevent addiction or
reduce dependence, comprising administering a therapeutically
effective dose of a pharmaceutical compound in combination with a
therapeutically effective dose of an inhibitor of endogenous
neurosteroid production to prevent addiction or reduce dependence
on the pharmaceutical compound.
[0018] It is therefore an object of the invention to provide
compositions and methods for reducing dependence on or addiction to
substances of abuse.
[0019] It is another object of the invention to provide methods and
compositions for inhibiting the formation of neurosteroids.
[0020] It is another object of the invention to provide
compositions and methods for modulating the expression of GABA
receptor subunits.
[0021] Another object of the invention is to provide for the use of
a neurosteroid production inhibitor in the preparation of a
medicament to prevent addition or dependence on a substance of
abuse.
[0022] Another object of the invention is to provide for the use of
a neurosteroid production inhibitor and a pharmaceutical compound
in the preparation of a medicament to prevent addition or
dependence on a substance of abuse.
[0023] These and other objects, features and advantages of the
present invention will become apparent after a review of the
following detailed description of the disclosed embodiments and
claims and the drawings provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The Detailed Description should be considered in light of
the drawings, as briefly described below:
[0025] FIG. 1 illustrates the spectrum between inhibition and
substantially or completely reduced inhibition via the direct
and/or indirect allosteric modulation of GABA.sub.A.
[0026] FIG. 2 illustrates the internal thought filtering mechanism
in a person's brain.
[0027] FIG. 3a is a first schematic presentation of a plurality of
GABA.sub.A receptor subunits.
[0028] FIG. 3b is a second schematic presentation of a plurality of
GABA.sub.A receptor subunits.
[0029] FIG. 3c is an illustration of the insensitivity of the
modulated GABA.sub.A receptor to benzodiazepines. Note the .alpha.1
subunit: .alpha.1.beta.2.gamma.2-containing GABA.sub.A receptors
are the most common GABA receptors in the brain.
[0030] FIG. 4 is a chemical diagram of the blockade of the
conversion of progesterone to allopregnanolone via inhibitors of
neurosteroid production.
DETAILED DESCRIPTION OF THE INVENTION
I. Introduction
[0031] The present invention may be understood more readily by
reference to the following detailed description of specific
embodiments included herein. Although the present invention has
been described with reference to specific details of certain
embodiments, thereof, it is not intended that such details should
be regarded as limitations upon the scope of the invention.
[0032] The present invention is directed towards improved methods
of, and compositions for, preventing psychological addiction to and
physiological dependence upon exogenous and endogenous substances.
As used herein the term "substance of abuse" refers to addiction
forming substances such as but not limited to opioids,
benzodiazepines, cannabis, caffeine, nicotine, and other drugs that
stimulate neural reward pathways and promote addiction. More
specifically, the present invention relates to methods of, and
compositions for, administering a pharmaceutical compound in
combination with an inhibitor of neurosteroid production to prevent
endogenous neurosteroid production. The present invention also
relates to administering a pharmaceutical compound in combination
with an inhibitor of neurosteroid production to avoid
cross-tolerance and compounded withdrawal effects of both the
endogenous and exogenous substance.
[0033] The present invention is also directed towards methods of,
and compositions for, directly or indirectly preventing the
modulation of GABA.sub.A by progesterone.
[0034] The present invention is also directed towards methods of,
and compositions for, directly or indirectly preventing the
modulation of GABA.sub.A by progesterone metabolite
allopregnanolone. More specifically, the present invention is
directed towards combining the therapeutic activity of conventional
pharmaceutical compounds with the therapeutic activity of
inhibitors of neurosteroid production that inhibit the production
of allopregnanolone.
[0035] In one embodiment, effective prevention of endogenous
neurosteroid production and cross-tolerance between endogenous and
exogenous substances, requires addressing the underlying
pathophysiology that occurs prior to addiction resulting from
various substances, namely the conversion of progesterone and
deoxycorticosterone (DOC) and their metabolites allopregnanolone
and tetrahydrodeoxycorticosterone, which, upon chronic exposure to
and withdrawal, result in the increased expression of the
GABA.sub.A receptor .alpha..sub.4 subunit relative to the
.alpha..sub.1 subunit.
[0036] In one embodiment, an effective composition is one which
combines the therapeutic activity of a conventional pharmaceutical
compound with the therapeutic activity of an inhibitor of
neurosteroid production.
[0037] In one embodiment, an effective composition is one which
prevents psychological addiction to, and physiological dependence
upon, prescription or over the counter medicines.
[0038] In one embodiment, the present invention is directed towards
an effective composition that makes known prescription or over the
counter medicines less addictive and habit-forming.
[0039] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise opioids and their
derivatives.
[0040] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise tetrahydrocannibol and
its derivatives.
[0041] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise benzodiazepines.
[0042] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise tranquilizers, sedatives,
hypnotics, and barbiturates.
[0043] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise contraceptives.
[0044] In one embodiment, the pharmaceutical compound is selected
from the class of compounds that comprise stimulants and their
derivatives.
[0045] In one embodiment, the inhibitor of neurosteroid production
is a 5-alpha-reductase inhibitor. In one embodiment, the
5-alpha-reductase inhibitor is finasteride. In one embodiment, the
5-alpha-reductase inhibitor is dutasteride. In one embodiment, the
5-alpha-reductase inhibitor is an organic medicinal, such as, but
not limited to saw palmetto and spironolactone.
[0046] In one embodiment, the inhibitor of neurosteroid production
is a 3-alpha-hydroxysteroid oxidoreductase inhibitor. In one
embodiment, the 3-alpha-hydroxysteroid oxidoreductase inhibitor is
indomethacin.
[0047] In one embodiment, dependence upon, tolerance to, and
cross-tolerance between endogenous and exogenous substances can
further be prevented by optionally administering a pharmaceutical
composition from a class of compounds that directly or indirectly
modulates GABA.sub.A by modulating the expression of the GABA.sub.A
receptor .alpha..sub.4 subunit. More specifically, the compound is
one that serves as an agonist at the GABA.sub.A receptor, and more
specifically, at either the .alpha..sub.4 subunit or .alpha..sub.6
subunit, and is capable of positively potentiating GABA
current.
[0048] In one embodiment, the compound from the class of compounds
that directly or indirectly modulates GABA.sub.A by modulating the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit is
flumazenil. In one embodiment, flumazenil is administered in a
controlled-release formulation. In one embodiment, flumazenil is
administered via a subcutaneous implant. In another embodiment,
flumazenil is administered via a transdermal patch.
[0049] As used in this description, the term "substance abuse" is
used to refer to the various physical and psychological states that
manifest an individual's impaired control over substance use,
continued substance use despite adverse consequences, compulsive
substance use, and/or drug cravings. The term is intended to
include psychological dependence, physical dependence, tolerance, a
maladaptive pattern of substance use, preoccupation with substance
use, and/or the presence of withdrawal symptoms upon cessation of
use. Notwithstanding the above, the terms "addiction" and
"dependency" are used interchangeably throughout this text.
[0050] Reference will now be made in detail to specific embodiments
of the invention. While the invention will be described in
conjunction with specific embodiments, it is not intended to limit
the invention to one embodiment.
II. The GABAergic System
[0051] a. Gamma-Aminobutyric Acid (GABA)
[0052] GABA is a neurotransmitter that acts at inhibitory synapses
in the brain and spinal cord. The GABA system is found, among other
places, in the hippocampus, an area of the brain associated with
memory formation. Glutamic acid, or glutamate, is important in
brain function, as an excitatory neurotransmitter and as a
precursor for the synthesis of GABA in GABAergic neurons. Glutamate
activates both ionotropic and metabotropic glutamate receptors,
described in further detail below. GABA signals interfere with
registration and consolidation stages of memory formation.
[0053] b. GABA Receptor Types
[0054] The GABA receptors are a group of receptors with GABA as
their endogenous ligand. Several classes of GABA receptors are
known, including ionotropic receptors, which are ion channels
themselves, and metabotropic receptors, which are G-protein coupled
receptors that open ion channels via intermediaries. Glutamate and
GABA mediate their actions by the activation of their
receptors.
[0055] The ionotropic GABA receptors (GABA.sub.A receptors) are
based on the presence of eight subunit families consisting of 21
subunits (.alpha..sub.1-6, .beta..sub.1-4, .gamma..sub.1-4,
.delta., .epsilon., .pi., .theta., .rho..sub.1-3) and display an
extraordinarily structural heterogeneity. GABA.sub.A receptors are
composed of five circularly arranged, homologous subunits and are
important sites of drug action. Most often, the GABA.sub.A receptor
isomers comprise two .alpha. subunits, two .beta. subunits and one
.gamma. subunit. The metabotropic GABA receptors (GABA.sub.B
receptors) consist of two subunits: GABA.sub.B1 and GABA.sub.B2.
Physiological responses following activation of GABA.sub.B
receptors require the co-assembly of GABA.sub.B1 and GABA.sub.B2.
GABA.sub.C receptors also exist natively.
[0056] c. GABA.sub.A Receptor Subunits
[0057] The GABA.sub.A receptor system is implicated in a number of
central nervous system disorders, making GABA.sub.A receptor
ligands potential therapeutic agents. GABA.sub.A receptors are
ligand-gated ion channels that belong to the same super family of
receptors as glycine, nicotinic cholinergic, and serotonin
5HT.sub.3 receptors. Enhanced function of several GABA.sub.A
receptors accounts for the major actions of benzodiazepines,
described in greater detail below. In addition, a number of
compounds have exhibited functional selectivity for GABA.sub.A
receptors.
[0058] The GABA.sub.A receptor complex is a pentameric receptor
protein structure formed by co-assembly of subunits from seven
different classes. Five subunits are situated in a circular array
surrounding a central chloride-permeable pore. It has been
suggested that the mechanism for ligand-induced channel opening in
nicotinic acetylcholine receptors involves rotations of the
subunits in the ligand binding domain. Assuming that GABA.sub.A
receptors utilize a similar mechanism for channel opening, since
GABA.sub.A receptors belong to the same super family as the
nicotinic acetylcholine receptors, large substituents may interfere
with the channel opening (steric hindrance) resulting in
antagonistic effects of certain compounds. In addition, the
activation of GABA receptors will influence several other systems,
ultimately resulting in a general acute modification of the overall
function of the central nervous system.
[0059] The particular combination of subunits yields receptors with
different pharmacological and physiological properties, however,
the GABA.sub.A receptor composition is not immutable. Withdrawal
from anxiolytic benzodiazepines, which produce their effects by
facilitating GABA.sub.A receptor mediated inhibition, yields an
increase in the steady state mRNA levels of .alpha..sub.4 and
.beta..sub.1 subunit mRNA in both the cortex and hippocampus. It
should be noted that the .delta. subunit is often associated with
GABA.sub.A receptor subtypes containing the .alpha..sub.4
subunit.
[0060] GABA and GABA.sub.A receptors are involved in disease states
such as seizures, depression, anxiety and sleep disorders. GABA and
some of the other indirectly or directly acting GABA.sub.A receptor
agonists (GABA-mimetics), including allopregnanolone and
tetrahydrodeoxycorticosterone respectively, bind specifically to a
recognition site located at the interface between an .alpha. and a
.beta. subunit. The classical benzodiazepines, however, such as
diazepam and flunitrazepam, bind to an allosteric site located at
the interface between an .alpha. and a .gamma. subunit.
[0061] More specifically, GABA binds to the cleft between .alpha.
and .beta. subunits, an action which gates open the chloride
channel to allow for the influx of chloride ions into the cell.
This typically hyperpolarizes the cell, having an inhibitory action
on neuronal activity, by making the membrane potential of the cell
more negative, and consequentially, increases the depolarization
threshold to generate an action potential.
[0062] Most depressant and sedative drugs such as the
benzodiazepine tranquilizers, barbiturates, anesthetics and alcohol
are believed to have a modulatory effect on the GABA.sub.A receptor
at unique sites where they can enhance the actions of GABA in
accumulating negatively charged chloride ions into the cell,
inducing sedative or anesthetic effects.
[0063] The conformational restriction of various parts of the
molecule of GABA and biosteric replacements of the functional
groups of the amino acid leads to a broad spectrum of specific
GABA.sub.A agonists. Some of these molecules have played a key role
in the understanding of the pharmacology of the GABA.sub.A receptor
family.
[0064] The absence or presence of a particular .alpha. subunit
isoform in the GABA.sub.A receptors confers selectivity for certain
drugs. Different .alpha. subunits also mediate distinct
pharmacological actions of benzodiazepines, including
sedative-hypnotic and anxiolytic effects. Long-term administration
of benzodiazepines results in the development of tolerance to some
of the effects of these drugs, thus reducing their clinical
efficacy. While the molecular basis for these dependencies remains
unclear, tolerance and dependence appear to be related to the
pharmacodynamics of benzodiazepines.
[0065] Long-term administration of benzodiazepines modifies the
expression of genes that encode various GABA.sub.A subunits. These
changes in gene expression alter the sensitivity of GABA.sub.A
receptors to their pharmacological modulators and thereby underlie
the development of tolerance to or dependence on these drugs. The
subunit composition of GABA.sub.A receptor determines their
affinity for benzodiazepine receptor ligands as well as the
efficacy of these ligands. For example, classical benzodiazepine
agonists (e.g. diazepam), imidazopyridines, imidazoquinolones and
pyrazolopyrimidines show no affinity for or efficacy at GABA.sub.A
receptors that contain .alpha..sub.4 or .alpha..sub.6 subunits.
[0066] The subunit composition of native GABA.sub.A receptors plays
an important role in defining their physiological and
pharmacological function. It is possible to characterize the
physiological, pharmacological, and pathological roles of
GABA.sub.A receptors by understanding the mechanisms by which the
subunit composition of GABA.sub.A receptors is regulated. Thus, the
expression of specific GABA.sub.A receptor subunit genes may be
affected by various physiological and pharmacological modulators,
including but not limited to, pharmacological agents, endogenous
neurosteroids, and food.
[0067] For example, long-term exposure to and subsequent withdrawal
of benzodiazepines, zaleplon, zolpidem, or neurosteroids result in
selective changes in the expression of specific GABA.sub.A receptor
mRNA, including an increase of the .alpha..sub.4 subunit mRNA, and
polypeptide subunits and in GABA.sub.A receptor function in
cultured cells. Withdrawal from diazepam or imidazenil was
associated with both a reduced ability of diazepam to potentiate
GABA action and the ability of flumazenil to potentiate GABA
action. Chronic benzodiazepine treatment and subsequent withdrawal
lead to a change in the receptor subunit composition, and these new
synthesized receptors are less responsive to benzodiazepines. The
up-regulation of the .alpha..sub.4 subunit, however, may be
necessarily coupled with the down-regulation of other subunits for
the development of benzodiazepine dependence.
[0068] Withdrawal of zaleplon or zolpidem, like that of diazepam,
induced a marked increase in the amount of .alpha..sub.4 subunit
mRNA. These effects of zaleplon and zolpidem on GABA.sub.A receptor
gene expression are consistent with the reduced tolerance liability
of these drugs, compared with that of diazepam, as well as with
their ability to induce both physical dependence and withdrawal
syndrome.
[0069] Ethanol withdrawal-induced increases in the amounts of
.alpha..sub.4 subunit mRNA and protein are associated with reduced
sensitivity of GABA.sub.A receptors to GABA and benzodiazepines.
The effects of alcohol are similar to those of drugs that enhance
the function of GABA.sub.A receptors, which gate the Cl-currents
that mediate most inhibitory neurotransmission in the brain, as
described above. Acutely high doses of alcohol potentiate
GABA-gated currents at both native and recombinant GABA.sub.A
receptors, and chronically alter GABA.sub.A receptor expression.
Ethanol elicits its central effects through modulation of
neurotransmission mediated by various receptors, especially that
mediated by GABA.sub.A receptors. It has been shown that long-term
ethanol administration also affects the subunit composition and,
consequently, the functional properties of native GABA.sub.A
receptors. The pharmacological profile of ethanol is similar to
that of benzodiazepine and also results in the development of
cross-tolerance and dependence.
[0070] Exposure to diazepam at the time of ethanol withdrawal
antagonizes the withdrawal-induced increase in the abundance of the
.alpha..sub.4 subunit mRNA. The replacement of ethanol with
diazepam also blocked the ethanol withdrawal-induced impairment in
cellular metabolism. Cells exposed to GHB at the time of ethanol
withdrawal results in an inhibition in the increase in the
abundance of the .alpha..sub.4 subunit mRNA.
[0071] The modulatory action of flumazenil in cells that are
exposed to ethanol is similar to that measured in cells not exposed
to ethanol. In contrast, however, in ethanol withdrawn cells, 3
.mu.M flumazenil potentiates the GABA evoked Cl-current consistent
with the ethanol withdrawal-induced up-regulation of the
.alpha..sub.4 subunit in these cells. The substitution of 10 .mu.M
diazepam or 100 mM GHB for ethanol negated the positive modulation
of 3 .mu.M flumazenil induced by ethanol withdrawal.
[0072] The presence of the .alpha..sub.4 subunit in recombinant
GABA.sub.A receptors is associated with a reduced sensitivity to
classical benzodiazepine agonists and to zolpidem as well as with a
distinct pattern of regulation (positive rather than no allosteric
modulation) by flumazenil.
[0073] In general, chronic treatment with agonists that act at
different sites of the GABA.sub.A receptor results in changes in
the biochemical and functional properties of the receptor that are
accompanied by changes in the abundance of specific receptor
subunit mRNAs. In addition, chronic treatment with substances that
modulate GABA.sub.A function via a neurosteroid pathway results in
changes in the biochemical and functional properties of the
receptor that are accompanied by changes in the abundance of
specific receptor subunit mRNAs. The observation that the ethanol
withdrawal-induced increase in the expression of the .alpha..sub.4
subunit gene in cultured cerebellar granule cells is prevented by
diazepam is consistent with the fact that benzodiazepine treatments
are effective in treating alcohol withdrawal symptoms in humans.
Thus, a rapid and marked increase in the abundance of the
.alpha..sub.4 subunit induced by ethanol withdrawal might therefore
contribute to the development of diazepam-sensitive withdrawal
symptoms in humans.
III. GABA and Neurosteroids
[0074] Characterizations of the role of GABA.sub.A receptors
require an understanding of the mechanisms by which subunit
composition is regulated. The long-term administration of
sedative-hypnotic, anxiolytic, or anticonvulsant drugs can affect
expression of GABA.sub.A receptor subunit genes as well as the drug
sensitivity and function of these receptors, suggesting that the
mechanisms responsible for such changes might also underlie the
physiological modulation of GABA.sub.A receptors by endogenous
compounds such as neurosteroids.
[0075] The neuroactive steroids
3.alpha.-hydroxy-5.alpha.-pregnan-20-one (allopregnanolone) and
3.alpha.,21-dihydroxy-5.alpha.-pregnan-20-one
(tetradihydrodeoxycorticosterone, or THDOC) induce anxiolytic,
sedative, hypnotic, and anticonvulsant effects similar to
benzodiazepines and other anxiolytic drugs. The concentrations of
these neurosteroids are increased in the brain of humans both in
response to treatment with anxiogenic, antidepressant or
antipsychotic drugs as well as physiological or pathological
conditions (such as depression, stress, the luteal phase of the
menstrual cycle, and pregnancy) that affect mood and emotional
state. Additional studies implicate endogenous allopregnanolone as
a physiological regulator of both basal and stress-induced dopamine
release in the rat brain.
[0076] Steroid metabolites react with the GABA receptor complex to
alter brain excitability. Several of these steroids accumulate in
the brain after local synthesis or after metabolism of adrenal
steroids. Neurosteroids are synthesized in the peripheral and
central nervous system, from cholesterol or steroidal precursors
imported from peripheral sources. Both progesterone and estrogen
alter excitability of neurons of the central nervous system. For
example, estrogen reduces inhibition at the GABA.sub.A receptor,
enhances excitation at the glutamate receptor, and increases the
number of excitatory neuronal synapses. In contrast, progesterone
enhances GABA-mediated inhibition, increases GABA synthesis, and
increases the number of GABA.sub.A receptors. In particular,
progesterone and its metabolites have been demonstrated to have
profound effects on brain excitability. The levels of progesterone
and its metabolites vary with the phases of the menstrual cycle,
decreasing prior to the onset of menses. Progesterone is readily
converted to allopregnanolone (3.alpha.-OH-5.alpha.-pregnan-20-one
or 3.alpha.,5.alpha.-THP) in human brains.
[0077] Neurosteroids rapidly alter neuronal excitability thorough
interaction with neurotransmitter-gated ion channels.
Allopregnanolone is a positive potent modulator of the GABA.sub.A
receptor and enhances the action which gates open the chloride
channel to allow influx of chloride ions into the cell. This
typically hyperpolarizes the cell, having an inhibitory action on
neuronal activity, and thus allopregnanolone acts as a sedative or
anxiolytic agent and decreases anxiety.
[0078] GABA.sub.A-modulatory allopregnanolone, as described above,
is also responsible for producing anxiogenic withdrawal symptoms.
The withdrawal profile shown therein is similar to that reported
for other GABA.sub.A-modulatory drugs such as the benzodiazepines,
barbiturates, and ethanol. Thus, the actions of neuroactive
steroids on traditional transmitter receptor in the brain lead to
alterations in the GABA.sub.A receptor subunit composition that
result in changes in the intrinsic channel properties of the
receptor and behavioral excitability. Changes are also associated
with significant increases in both the mRNA and protein for the
.alpha..sub.4 subunit of the GABA.sub.A receptor in the
hippocampus.
[0079] Thus, the endogenous neurosteroid allopregnanolone exhibits
withdrawal properties, similar to GABA-modulators, as described
above, increasing anxiety susceptibility following abrupt
discontinuation after chronic administration. The increase in
neuronal excitability has been attributed to upregulation of the
GABA.sub.A .alpha..sub.4 subunit. Thus, the
.alpha..sub.4.beta..sub.2.gamma. is preferentially expressed
following hormone withdrawal. Blockade of the .alpha..sub.4 gene
transcript prevents withdrawal properties.
[0080] The increase in expression of the GABA.sub.A receptor
.alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit can be attributed to many factors. These
include, but are not limited to 1) compositions, both endogenous
and exogenous, which, upon withdrawal, increase the GABA.sub.A
receptor .alpha..sub.4 subunit relative to the GABA.sub.A receptor
.alpha..sub.1 subunit; and 2) compositions, both exogenous or
endogenous that result in the increase of expression of the
GABA.sub.A receptor .alpha..sub.4 subunit or the decrease of
expression of the GABA.sub.A receptor .alpha..sub.1 subunit.
[0081] Chronic administration of hormones or contraceptive
compounds, and in particular, those containing progesterone, result
in the up-regulation of the GABA.sub.A-receptor .alpha..sub.4
subunit. As endogenous neurosteroid levels fluctuate, a person's
tolerance liability to certain exogenous substances also
fluctuates. For example, but not limited to such example, in a
patient with low endogenous hormone levels, the administration of a
particular dosage of progesterone that the patient is regularly
taking may still result in withdrawal symptomatology, since the
patient has developed tolerance to higher levels of progesterone,
compounded by both endogenous and exogenous sources. Thus, even
with a tolerance to a consistent amount of an endogenous substance,
cross-tolerance effects may also be seen due to fluctuating
endogenous neurosteroid levels.
[0082] Certain substances, both endogenous and exogenous, can cause
modifications in the allostatic control of GABA.sub.A, directly or
indirectly, via an endogenous neurosteroid pathway. Most substances
that cross the blood-brain barrier in sufficient quantity can
stimulate a neuroprotective, neurosteroid response. In general, the
more neuroexcitatory the substance, the more neurosteroid response
is achieved. With the increase of neurosteroids, GABA.sub.A
receptor activity is enhanced, causing a constant state of
activation which, over time, may cause neurosteroid tolerance.
Therefore, once the neuroexcitatory substance is no longer present,
the brain's neurosteroid levels will decrease to natural levels,
causing the individual to go through a state of "withdrawal" from
the neurosteroid.
[0083] In the course of this "withdrawal", certain GABA.sub.A
receptor subunits may be expressed, or suppressed, in a manner that
causes the person's brain to be susceptible to greater feelings of
anxiety. In particular, his brain's GABA.sub.A receptor
.alpha..sub.1 subunits decrease in relative amounts to GABA.sub.A
receptor .alpha..sub.4 subunits. As a result of neurosteroid
"withdrawal" and the subsequent up-regulation of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits, the GABA receptor is
no longer effectively modulated by GABA, and, therefore, results in
the person experiencing a greater sense of anxiety.
[0084] In one embodiment, an individual's lowered degree of
inhibitory control over his thoughts is caused by the modification
of the receptivity of the synaptic GABA.sub.A receptors to the
neurotransmitter GABA in the individual's brain. For example,
substance abuse diminishes GABA receptivity; thus, the exogenous
substance or "drug" modulates the GABA.sub.A receptor. When the
user ceases consumption of the exogenous substance, due to changes
in the GABA.sub.A receptor composition upon withdrawal (i.e.
increased relative amount of GABA.sub.A receptor .alpha..sub.4
subunits compared to GABA.sub.A receptor .alpha..sub.1 subunits),
the receptor is not effectively modulated by GABA, thus causing
anxiety.
[0085] FIG. 1 illustrates the spectrum between inhibition and
disinhibition via the direct and/or indirect allosteric modulation
of GABA.sub.A. Spectrum 100 further depicts the range between
inhibition 105 and disinhibition 110. An increase in an exogenous
or endogenous substance that directly or indirectly enhances the
function of GABA or the GABA.sub.A receptor 115 can result in an
increase in GABA agonism and thus an increase in inhibition,
anxiolysis, amnesia, and sedation, and even a comatose state.
[0086] However, as mentioned in greater detail above, stress, drug
use, and even behavior activates these adaptive responses and
disrupts homeostasis--the brain's internal balance. Upon withdrawal
of both endogenous and exogenous substances, there is a marked
increase in the .alpha..sub.4 subunit 120 of relative to the
.alpha..sub.1 subunit 125 of the GABA.sub.A receptor 115, as shown
in spectrum 150. The increase of the .alpha..sub.4 subunit 120 of
the GABA.sub.A receptor 115 causes the receptor to become
insensitive to benzodiazepines and other compositions that act upon
and/or enhance the function of GABA and the GABA.sub.A receptor.
Therefore, when the systems involved in allostasis do not
self-regulate (i.e. do not shut off when not needed or do not
activate when needed), the brain experiences a compensatory drive
to address this inactive or constantly active state, often
exhibited in the form of anxiety or cravings.
[0087] Anxiety may be defined in a plurality of ways, including a
vague unpleasant emotion that is experienced in anticipation of
some, often ill-defined misfortune, a complex combination of the
feeling of fear, apprehension and worry often accompanied by
physical sensations such as palpitations, chest pain and/or
shortness of breath, a feeling of apprehension, fear, nervousness,
or dread accompanied by restlessness or tension, and/or a
debilitating condition of fear, which interferes with normal life
functions.
[0088] In one embodiment, anxiety comprises a physiological state
in which an individual has a lowered degree of inhibitory control
over his thoughts, as described above with respect to FIG. 1. Such
lowered degree of inhibitory control may be caused by the turning
off, inhibition, or otherwise down-modulation of an internal
thought filtering mechanism in the person's brain. Referring to
FIG. 2, the internal thought filtering mechanism 200 comprises
certain centers within a person's prefrontal cortex 205, including
the orbitofrontal cortex 210, which is considered responsible for
exerting control, and the anterior cingulate 215, which is
considered responsible for motivation and drive impulses. These
brain centers are substantially affected by certain physiological
inputs, such as a reward circuit that comprises the nucleus
accumbens 220 and ventral tegmental 225 areas of the brain.
[0089] When normally regulated, the orbitofrontal cortex 210 can
exert control over a person's thoughts and avoid having an
individual feel "overwhelmed" by vague, unpleasant emotions and
feelings of fear, apprehension and worry. If GABA.sub.A receptor
functionality is somehow impaired, however, GABA dysregulation
occurs and can result in an impaired ability of the orbitofrontal
cortex 210 to exert control over a person's thoughts and,
therefore, a lowered degree of inhibitory control.
[0090] Consequently, the individual becomes compulsively driven to
"address" this anxiety by making sure he obtains whatever
substance, or engage in whatever activity, his brain believes it
needs in order to eliminate the feelings of anxiety, e.g. regain
inhibitory control over his thoughts. Therefore, it is the
physiological drive to address feelings of anxiety that causes an
individual to consciously engage in behavior which could be
classified as self-destructive, such as substance abuse.
[0091] Exogenous substances, such as opioids, benzodiazepines,
cannabis, caffeine, nicotine, and other drugs, directly or
indirectly affect GABA.sub.A receptor functionality and, when those
exogenous substances are withheld from an individual, cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit
(hereinafter generally referred to as the .alpha..sub.4 subunit) to
increase relative to the expression of the .alpha..sub.1
subunit.
[0092] Endogenous substances may also have similar effects.
Specifically, GABA-modulatory steroids, such as progesterone and
deoxycorticosterone (DOC) and their metabolites allopregnanolone
and tetrahydrodeoxycorticosterone respectively, affect GABA.sub.A
receptor functionality and thus, when progesterone or DOC is
decreased or "withdrawn" in an individual, cause the expression of
the GABA.sub.A receptor .alpha..sub.4 subunit to increase relative
to the expression of the .alpha..sub.1 subunit.
[0093] In particular, such substances may directly or indirectly
stimulate GABA.sub.A via a neurosteroid mediated pathway. When
those substances are later withheld, the amount of .alpha..sub.4
subunits relative to .alpha..sub.1 subunits increases. This ratio
change is often temporary and is subject to reversal. However, a
distinct pathophysiology emerges when it becomes non-reversing,
namely when .alpha..sub.4 subunits no longer down-regulate relative
to .alpha..sub.1 subunits. As described above, when such
pathophysiology gets established, the GABA.sub.A receptor therefore
becomes less sensitive to benzodiazepines and effectively,
modulation by the neurotransmitter GABA, and is less capable of
exerting inhibitory control over an individual's thoughts and
behavior.
[0094] In one embodiment, it is possible to calculate a GABA-active
steroid score ("GS Score") for nearly all substances. For every
substance that crosses the blood brain barrier, or is active on the
central nervous system, there is a minimum threshold level needed
of that particular substance to effectively raise levels of
GABA-active steroids. Thus, the GS Score correlates direct agonism
of GABA.sub.A and the indirect modulation of GABA.sub.A via a
neurosteroid mediated pathway, such as, but not limited to
allopregnanolone. For example, but not limited to such example,
cocaine has a lower GS Score than aspartame, since cocaine is more
potent and it takes a lower threshold dose of cocaine to raise
levels of GABA-active steroids. The GS Score is a methodology for
measuring and assigning a numeric value to the relative addictive
properties of substances.
[0095] Referring to FIG. 3a, a benzodiazepine sensitive GABA.sub.A
receptor 300a is shown. The GABA.sub.A receptor comprises a
plurality of subunits, including two .beta..sub.2 subunits 305a, a
.gamma..sub.2 subunit 310a, and two .alpha..sub.1 subunits 315a. By
affecting the functionality and expression of receptor subunit
mRNAs, certain endogenous and exogenous substances cause the
expression of the GABA.sub.A receptor .alpha..sub.4 subunit to
increase relative to the expression of the .alpha..sub.1 subunit.
Referring to FIG. 3b, the modified GABA.sub.A receptor 300b
comprises a plurality of subunits, including two .beta..sub.2
subunits 305b, a .gamma..sub.2 subunit 310b, and two .alpha..sub.4
subunits 315b. As shown in FIG. 3c, the GABA.sub.A receptor
therefore becomes less sensitive to benzodiazepines and
effectively, modulation by the neurotransmitter GABA, and is less
capable of exerting inhibitory control over an individual's
thoughts and behavior.
IV. Conventional Compositions for Use in the Present Invention
[0096] Reference will now be made to specific compositions and
classes of pharmaceutical compounds for use in the present
invention. It should be understood to those of ordinary skill in
the art that any number of pharmaceutical compounds that possess
addictive properties can be used in the present invention and that
the list is not exhaustive. Published dosing and administration
literature, available, for example, from the FDA or the Physician
Desk Reference (PDR), are incorporated herein by reference.
[0097] Compositions for use in the present invention include
alcohol, nicotine, caffeine, tea, coffee, tobacco,
1-(1-Phenylcyclohexyl)pyrrolidine,
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine,
1-[1-(2-Thienyl)cyclohexyl]piperidine,
1-[1-(2-Thienyl)cyclohexyl]pyrrolidine, 13
Beta-ethyl-17beta-hydroxygon-4-en-3-one,
17Alpha-methyl-3alpha,17beta-dihydroxy-5alpha-androstane,
17Alpha-methyl-3beta, 17beta-dihydroxy-5alpha-androstane,
17Alpha-methyl-3beta,17beta-dihydroxyandrost-4-ene,
17Alpha-methyl-4-hydroxynandrolone
(17alpha-methyl-4-hydroxy-17beta-hydroxyestr-4-en-3-one),17Alpha-methyl-d-
elta1-dihydrotestosterone
(17beta-hydroxy-17alpha-methyl-5alpha-androst-1-en-3-one),
19-Nor-4-androstenediol (3beta, 17beta-dihydroxyestr-4-ene;
3alpha,17beta-dihydroxyestr-4-ene), 19-Nor-4-androstenedione
(estr-4-en-3,17-dione), 19-Nor-5-androstenediol
(3beta,17beta-dihydroxyestr-5-ene;
3alpha,17beta-dihydroxyestr-5-ene), 19-Nor-5-androstenedione
(estr-5-en-3,17-dione), 1-Androstenediol
(3beta,17beta-dihydroxy-5alpha-androst-1-ene;
3alpha,17beta-dihydroxy-5alpha-androst-1-ene), 1-Androstenedione
(5alpha-androst-1-en-3,17-dione),
1-Methyl-4-phenyl-4-propionoxypiperidine, 1-Phenylcyclohexylamine,
1-Piperidinocyclohexanecarbonitrile,
2,5-Dimethoxy-4-(n)-propylthiophenethylamine,
2,5-Dimethoxy-4-ethylamphetamine, 2,5-Dimethoxyamphetamine,
3,4,5-Trimethoxyamphetamine, 3,4-Methylenedioxyamphetamine,
3,4-Methylenedioxymethamphetamine,
3,4-Methylenedioxy-N-ethylamphetamine,
3Alpha,17beta-dihydroxy-5alpha-androstane,
3Beta,17beta-dihydroxy-5alpha-androstane, 3-Methylfentanyl,
3-Methylthiofentanyl, 4-Androstenediol
(3beta,17beta-dihydroxy-androst-4-ene), 4-Androstenedione
(androst-4-en-3,17-dione), 4-Bromo-2,5-dimethoxyamphetamine,
4-Bromo-2,5-dimethoxyphenethylamine, 4-Dihydrotestosterone
(17beta-hydroxyandrostan-3-one), 4-Hydroxy-19-nortestosterone
(4,17beta-dihydroxyestr-4-en-3-one), 4-Hydroxytestosterone
(4,17beta-dihydroxyandrost-4-en-3-one), 4-Methoxyamphetamine,
4-Methyl-2,5-dimethoxyamphetamine, 4-Methylaminorex (cis isomer),
5-Androstenediol (3beta,17beta-dihydroxy-androst-5-ene),
5-Androstenedione (androst-5-en-3,17-dione),
5-Methoxy-3,4-methylenedioxyamphetamine,
5-Methoxy-N,N-diisopropyltryptamine, Acetorphine,
Acetyl-alpha-methylfentanyl, Acetyldihydrocodeine, Acetylmethadol,
Alfentanil, Allylprodine, Alphacetylmethadol,
levo-alphacetylmethadol, Alpha-ethyltryptamine, Alphameprodine,
Alphamethadol, Alpha-methylfentanyl, Alpha-methylthiofentanyl,
Alpha-methyltryptamine, Alphaprodine, Alprazolam, Aminorex,
Amobarbital, Amobarbital suppository dosage form, Amphetamine,
Anabolic steroids, Androstanedione (5alpha-androstan-3,17-dione),
Anileridine, Aprobarbital, Barbital, Barbituric acid derivative,
Benzethidine, Benzoylecgonine, Benzphetamine, Benzylmorphine,
Betacetylmethadol, Beta-hydroxy-3-methylfentanyl,
Beta-hydroxyfentanyl, Betameprodine, Betamethadol, Betaprodine,
Bezitramide, Bolasterone
(7alpha,17alpha-dimethyl-17beta-hydroxyandrost-4-en-3-one),
Boldenone (17beta-hydroxyandrost-1,4-diene-3-one), Bromazepam,
Bufotenine, Buprenorphine, Butabarbital (secbutabarbital),
Butalbital, Butobarbital (butethal), Butorphanol, Calusterone
(7beta, 17alpha-dimethyl-17beta-hydroxyandrost-4-en-3-one),
Camazepam, Carfentanil, Cathine, Cathinone, Chloral betaine,
Chloral hydrate, Chlordiazepoxide, Chlorhexadol, Chlorphentermine,
Clobazam, Clonazepam, Clonitazene, Clorazepate, Clortermine,
Clostebol (4-chloro-17beta-hydroxyandrost-4-en-3-one), Clotiazepam,
Cloxazolam, Coca Leaves, Cocaine, Codeine, Codeine, Codeine
methylbromide Codeine-N-oxide, Cyprenorphine,
Dehydrochloromethyltestosterone
(4-chloro-17beta-hydroxy-17alpha-methylandrost-1,4-dien-3-one),
Delorazepam, Deltal-dihydrotestosterone
(17beta-hydroxy-5alpha-androst-1-en-3-one), Desomorphine,
Dexfenfluramine, Dextromoramide, Diampromide, Diazepam,
Dichloralphenazone, Diethylpropion, Diethylthiambutene,
Diethyltryptamine, Difenoxin, Dihydrocodeine, Dihydroetorphine,
Dihydromorphine, Dimenoxadol, Dimepheptanol, Dimethylthiambutene,
Dimethyltryptamine, Dioxaphetyl butyrate, Diphenoxylate,
Dipipanone, Diprenorphine, Drostanolone
(17beta-hydroxy-2alpha-methyl-5alpha-androstan-3-one), Drotebanol,
Ecgonine, Estazolam, Ethchlorvynol, Ethinamate, Ethyl loflazepate,
Ethylestrenol (17alpha-ethyl-17beta-hydroxyestr-4-ene),
Ethylmethylthiambutene, Ethylmorphine, Etonitazene, Etorphin,
Etoxeridine, Fencamfamin, Fenethylline, Fenfluramine, Fenproporex,
Fentanyl, Fludiazepam, Flunitrazepam, Fluoxymesterone
(9-fluoro-17alpha-methyl-11beta,17beta-dihydroxyandrost-4-en-3-one),
Flurazepam, Formebolone
(2-formyl-17alpha-methyl-11alpha,17beta-dihydroxyandrost-1,4-dien-3-one),
Furazabol (17alpha-methyl-17beta-hydroxyandrostano[2,3-c]-furazan),
Furethidine, Gamma Hydroxybutyric Acid, Glutethimide, Halazepam,
Haloxazolam, Heroin, Hydrocodone, Hydromorphinol, Hydromorphone,
Hydroxypethidine, Ibogaine, Isomethadone, Ketamine, Ketazolam,
Ketobemidone, Levo-alphacetylmethadol, Levomethorphan,
Levomoramide, Levophenacylmorphan, Levorphanol, Loprazolam,
Lorazepam, Lormetazepam, Lysergic acid, Marihuana, Mazindol,
Mebutamate, Mecloqualone, Medazepam, Mefenorex, Meperidine,
Meprobamate, Mescaline, Mestanolone
(17alpha-methyl-17beta-hydroxy-5alpha-androstan-3-one), Mesterolone
(1 alpha-methyl-17beta-hydroxy-5alpha-androstan-3-one), Metazocine,
Methadone, Methamphetamine, Methandienone
(17alpha-methyl-17beta-hydroxyandrost-1,4-diene-3-one), Methandriol
(17alpha-methyl-3beta,17beta-dihydroxyandrost-5-ene), Methaqualone,
Methcathinone, Methenolone
(1-methyl-17beta-hydroxy-5alpha-androst-1-en-3-one), Methohexital,
Methyldesorphine, Methyldienolone
(17alpha-methyl-17beta-hydroxyestr-4,9(10)-dien-3-one),
Methyldihydromorphine, Methylphenidate, Methylphenobarbital
(mephobarbital), Methyltestosterone
(17alpha-methyl-17beta-hydroxyandrost-4-en-3-one), Methyltrienolone
(17alpha-methyl-17beta-hydroxyestr-4,9,11-trien-3-one),
Methyprylon, Metopon, Mibolerone
(7alpha,17alpha-dimethyl-17beta-hydroxyestr-4-en-3-one), Midazolam,
Modafinil, Moramide-intermediate, Morpheridine, Morphine,
Myrophine, N,N-Dimethylamphetamine, Nabilone, Nalorphine,
Nandrolone (17beta-hydroxyestr-4-en-3-one), N-Benzylpiperazine,
N-Ethyl-1-phenylcyclohexylamine, N-Ethyl-3-piperidyl benzilate,
N-Ethylamphetamine, N-Hydroxy-3,4-methylenedioxyamphetamine,
Nicocodeine, Nicomorphine, Nimetazepam, Nitrazepam,
N-Methyl-3-piperidyl benzilate, Noracymethadol, Norbolethone
(13beta,17alpha-diethyl-17beta-hydroxygon-4-en-3-one), Norclostebol
(4-chloro-17beta-hydroxyestr-4-en-3-one, Nordiazepam,
Norethandrolone (17alpha-ethyl-17beta-hydroxyestr-4-en-3-one),
Norlevorphanol, Normethadone, Normethandrolone
(17alpha-methyl-17beta-hydroxyestr-4-en-3-one), Normolphine,
Norpipanone, Opium extracts, Opium fluid extract, Opium poppy,
Opium tincture, Oxandrolone
(17alpha-methyl-17beta-hydroxy-2-oxa-5alpha-androstan-3-one),
Oxazepam, Oxazolam, Oxycodone, Oxymesterone
(17alpha-methyl-4,17beta-dihydroxyandrost-4-en-3-one), Oxymetholone
(17alpha-methyl-2-hydroxymethylene-17beta-hydroxy-5alpha-androstan-3-one)-
, Oxymorphone, Para-Fluorofentanyl, Parahexyl, Paraldehyde,
Pemoline, Pentazocine, Pentobarbital, Petrichloral, Peyote,
Phenadoxone, Phenampromide, Phenazocine, Phencyclidine,
Phendimetrazine, Phenmetrazine, Phenobarbital, Phenomorphan,
Phenoperidine, Phentermine, Phenylacetone, Pholcodine, Piminodine,
Pinazepam, Pipradrol, Piritramide, Poppy Straw, Prazepam,
Proheptazine, Properidine, Propiram, Psilocybin, Psilocyn,
Pyrovalerone, Quazepam, Racemethorphan, Racemoramide, Racemorphan,
Remifentanil, Secobarbital, Sibutramine, Stanozolol
(17alpha-methyl-17beta-hydroxy-5alpha-androst-1-eno[3,2-c]-pyrazole),
Stenbolone (17beta-hydroxy-2-methyl-5alpha-androst-1-en-3-one),
Sufentanil, Sulfondiethylmethane, Sulfonethylmethane,
Sulfonmethane, Talbutal, Temazepam, Testolactone
(13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid lactone),
Testosterone (17beta-hydroxyandrost-4-en-3-one),
Tetrahydrocannabinols, Tetrahydrogestrinone
(13beta,17alpha-diethyl-17beta-hydroxygon-4,9,11-trien-3-one),
Tetrazepam, Thebacon, Thebaine, Thiamylal, Thiofentanyl,
Thiopental, Tiletamine, Zolazepam, Tilidine, Trenbolone
(17beta-hydroxyestr-4,9,11-trien-3-one), Triazolam, Trimeperidine,
Vinbarbital, Zaleplon, Zolpidem, Zopiclone, Vicodin, Hydrocodone,
Codan, Hycodan, Hydromet, Hydropane, Mycodone, Tussigon
Hydrocodone, Percocet, Oxycodone, Xanax, Alprazolam, OxyContin,
Lortab, Tramadol, Lexapro, Escitalopram, Neurontin, Gabapentin,
Valium, Diazepam, Lisinopril, Lipitor, Atorvastatin, Amoxicillin,
Zoloft Sertraline, Naproxen, Lyrica, Pregabalin, Morphine,
Clonazepam, Alprazolam, Adderall, Darvocet, Klonopin, Clonazepam,
Seroquel Quetiapine, Methadone, Trazodone, Flexeril
Cyclobenzaprine, Cyclobenzaprine, Prednisone, Cymbalta Duloxetine,
Lorazepam, Cephalexin, Atenolol, Phentermine, Soma, Carisoprodol,
Levaquin, Levofloxacin, Propoxyphene, Norvasc, Amlodipine,
Metformin, Amitriptyline, Ativan Lorazepain, Gabapentin, Ambien,
Zolpidem, Diazepam, Ultram, Tramadol, Protonix, Pantoprazole,
Mobic, Meloxicam, Zocor, Simvastatin, Doxycycline, Skelaxin,
Metaxalone, Sitrex, Guaifenesin, Phenylephrine, Paxil, Paroxetine,
Toprol, Metoprolol, Acetaminophen, Promethazine, Topamax
Topiramate, Plavix Clopidogrel, Risperdal, Risperidone, Prozac,
Fluoxetine, Clindamycin, Wellbutrin, Bupropion, Nexium,
Esomeprazole, Clonidine, Effexor, Venlafaxine, Synthroid
Levothyroxine, Furosemide, Carisoprodol, Keflex, Cephalexin,
Provigil, Modafinil, Lamictal, Lamotrigine, Vytorin, Zyrtec,
Viagra, Sildenafil, Abilify, Aripiprazole, Diclofenac,
Methocarbamol, Concerta, Methylphenidate, Diovan, Valsartan,
Hydroxyzine, Metronidazole, Biaxin, Clarithromycin, Celebrex,
Celecoxib, Methadose, Lasix, Furosemide, Prevacid, Lansoprazole,
Ritalin, Methylphenidate, Zetia, Ezetimibe, Nabumetone, Zithromax,
Azithromycin, Ibuprofen, Flagyl, Celexa, Citalopram, Temazepam,
Altace, Ramipril, Singulair, Montelukast, Levothyroxine, Actos,
Pioglitazone, Etodolac, Lunesta, Eszopiclone, Omnicef, Cefdinir,
Robaxin, Methocarbamol, Roxicet, Zyprexa, Olanzapine, Elavil,
Amitriptyline, BuSpar, Buspirone, Voltaren, Benicar, Olmesartan,
Avelox, Moxifloxacin, Coreg Carvedilol, Citalopram, Phenergan,
Promethazine, Adipex, Phentermine, Coumadin, Warfarin, Ranitidine,
Advair, Ketek, Telithromycin, TriCor, Fenofibrate, Lithium,
Relafen, Nabumetone, Suboxone, Buprenorphine, DuraDex, Fioricet,
Omeprazole, Reglan, Metoclopramide, Roxicodone, Naprosyn, Naproxen,
Demerol, Meperidine, Lovastatin, Prolex, Baclofen, Percodan,
Strattera, Atomoxetine, Allegra, Fexofenadine, Flomax, Tamsulosin,
Meclizine, Avandia, Rosiglitazone, Paroxetine, Pediatex,
Carbinoxamine, Rozerem, Ramelteon, Zanaflex, Tizanidine, Verapamil,
Zantac, Ranitidine, Bupropion, Avapro, Irbesartan, Diltiazem,
Enalapril, Enalaprilat, Tizanidine, Aciphex, Rabeprazole, Lactinex,
Clalis, Tadalafil, Prilosec, Omeprazole, Dextroproxyp,
Dextromethorphan, Ethchlorvynol, Fentanyl, Gamma-hydroxybutyrate,
Glutethimide, Hydromorphone, Ketamine, Levo-alpha-acetylmethadol,
Meperidine, Meprobamate, Methamphetamine, Methaqualone, Methadone,
Methcathinone, Morphine, Nicotine, Opium, Paraldehyde,
Phencyclidine, Flunitrazepam, Paracetamol, NSAIDs, Opiates,
Tetrahydrocannabinol, Aspirin, Celecoxib, Diclofenac, Diflunisal,
flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, Meloxicam,
Naproxen, Piroxicam, Rofecoxib, Valdecoxib, Alfentanil,
Buprenorphine, Carfentanil, Codeine, Codeinone, Dextropropoxyphene,
Diamorphine, Dihydrocodeine, Fentanyl, Hydromorphone, Nalbuphine,
Oxymorphone, Pentazocine, Pethidine (Meperidine), Propoxyphene,
Remifentanil, Sufentanil, Tramadol, Amobarbital, Aprobarbital,
Butabarbital, Butalbital, Hexobarbital, Methylphenobarbital,
Pentobarbital, Phenobarbital, Secobarbital, Sodium thiopental,
Talbutal, Thiobarbital, Allobarbital, Barbexaclone, Barbital,
Butobarbital, Cyclobarbital, Ethallobarbital, Heptabarbital,
Mephobarbital, Metharbital, Methohexital, Primidone, Proxibarbal,
Reposal, Secobarbital, Thiopental, Vinbarbital, Vinylbital,
Adinazolam, Alprazolam, Bromazepam, Brotizolam, Camazepam,
Chlordiazepoxide, Cinolazepam, Clobazam, Clonazepam, Clorazepate,
Clotiazepam, Cloxazolam, Diazepam, Doxefazepam, Estazolam, Ethyl
loflazepate, Etizolam, Fludiazepam, Flunitrazepam, Flurazepam,
Gidazepam, Halazepam, Ketazolam, Loprazolam, Lorazepam,
Lormetazepam, Medazepam, Midazolam, Nimetazepam, Nitrazepam,
Nordazepam, Oxazepam, Pinazepam, Orthotricyclen, Watson 240-0.5,
Tri-sprintec tab, Sezonel, Alene, Miciona, Triguilar, Apre, Metr,
Mivelle, Prazepam, Quazepam, Temazepam, Tofisopam, Triazolam,
Valerian, and St. John's Wort (collectively referred to as
"Conventional Compositions").
[0098] Specific classes of Conventional Compositions are discussed
below. Exemplary compositions that fall within the classes of
compositions listed below are provided in Table 1. It should be
noted that the list contains exemplary compounds for use with the
present invention and is not exhaustive.
[0099] a. Contraceptive Compounds
[0100] A woman's progesterone is actively modulated by the
administration of prescription hormones, such as, but not limited
to, contraception with progesterone, that keeps the woman on a
constant progesterone cycle.
[0101] Contraceptive medications contain hormones (estrogen and
progesterone, or progesterone alone). The medications are available
in various forms, such as pills, injection (into a muscle), topical
(skin) patches, and slow-release systems (vaginal rings, skin
implants, and contraceptive infused intrauterine devices. The rate
of absorption of progesterone is highly dependent upon the
administration route.
[0102] In particular, the altered tolerance liability of a person
to exogenous sources of progesterone and other hormones may be due
to the cross-tolerance effects between administered and endogenous
progesterone. As mentioned above, endogenous levels of progesterone
and its metabolites such as allopregnanolone, fluctuate, thus
resulting in the altered tolerance liability of a patient to
administered progesterone.
[0103] b. Stimulants
[0104] Stimulants can be used as recreational drugs or therapeutic
drugs to increase alertness. They are also used to boost endurance
and productivity as well as to suppress appetite. The class of
compounds that comprises stimulants includes, but is not limited to
caffeine, amphetamines, ecstasy, and cocaine.
[0105] Stimulants increase the amount of norepinephrine and
dopamine in the brain, which increases blood pressure and heart
rate, constricts blood vessels, increases blood glucose, and
increases breathing. Effects can feel like an increase alertness,
attention, and energy along with a sense of euphoria.
[0106] Stimulants can be addictive in that individuals begin to use
them compulsively. Taking high doses of some stimulants repeatedly
over a short time can lead to feelings of hostility or paranoia.
Additionally, high doses of a stimulant may result in dangerously
high body temperatures and an irregular heartbeat.
[0107] i. Caffeine
[0108] Caffeine, also known as trimethylxanthine, is a naturally
occurring cardiac stimulant and mild diuretic. Caffeine induces
nervousness and insomnia in normal individuals, and it increases
the level of anxiety in patients prone to anxiety and panic
attacks. As an anxiogenic, caffeine changes brain and body
functions and results in a rapid release of adrenaline, thereby
causing a rapid heartbeat, increased blood pressure, and rapid,
shallow breathing.
[0109] Caffeine may directly or indirectly act on the GABA receptor
GABA.sub.A, the activation of which dampens higher neuronal
activity. In addition, it has been suggested that neuroactive
steroids modulate the stimulant and anxiogenic effects of caffeine.
More specifically, Concas et al. demonstrated that IP
administration of caffeine resulted in dose-dependent increases in
the plasma and brain concentrations of allopregnanolone as well as
in those of its precursors pregnenolone and progesterone. Thus, the
effects of caffeine on the plasma and brain concentrations of
neuroactive steroids was shown to be similar to those of anxiogenic
drugs, including those of direct and indirect inhibitors of the
GABA.sub.A receptor complex that induce experimental anxiety in
humans. It was also demonstrated that these effects are antagonized
by systemic administration of anxiolytic drugs, further
demonstrating that both pharmacologic treatments and experimental
conditions that induce anxiety-like or conflict behavior also
induces increases in the plasma and brain concentrations of
neuroactive steroids.
[0110] In addition, it is suggested that because caffeine induces
both neurotransmitter release and anxiety-like behavior associated
with increases in the plasma and brain concentrations of
neuroactive steroids that the HPA axis might mediate such actions
of caffeine. The transient increase in the brain concentration of
allopregnanolone triggered by caffeine may reflect a physiological
mechanism for reducing the activation of the neuroendocrine and
neurochemical pathways associated with the state of arousal and for
limiting the extent of neuronal excitability; consistent with the
fact that neuroactive steroids function to counteract
overexcitation of the CNS.
[0111] Caffeine can induce physical dependence and is addictive,
thus long-term use can be problematic due to the development of
tolerance and dependency. An abrupt discontinuation of substance
use may result in anxiety and confusion.
[0112] ii. Prescription Stimulants
[0113] Attention Deficit Disorder is often treated using stimulant
medications, the most popular of which includes methylphenidate,
which is more commonly known by its trade name, Ritalin;
amphetamine, which may be sold as a mixture with dextroamphetamine
and commonly known by its trade name Adderall; and
dextroamphetamine, which is more commonly known by its trade name
Dexedrine. These drugs are known to enhance brain activity and were
used historically to treat asthma, obesity, neurological disorders,
and a variety of other ailments, before their potential for abuse
and addiction became apparent.
[0114] c. Analgesics
[0115] An analgesic, more commonly referred to as painkillers is
any member of the group of drugs used to relieve pain and to
achieve analgesia. They include paracetemol, the non-steroidal
anti-inflammatory drugs such as aspirin, and the opioids, such as
morphine.
[0116] i. Opioids
[0117] "Opioid" is a term used for the class of drugs with
opium-like and/or morphine-like pharmacological action. An opioid
is any agent that binds to opioid receptors, which are mainly found
in the central nervous system and gastrointestinal tract. There are
many types of opioids, including endogenous opioids produced in the
body (endorphins, dynorphins, enkephalins); opium alkaloids found
in the opium plant (morphine, codeine, thebaine); semi-synthetic
opioid derivatives (heroin, oxycodone, hydrocodone, dihydrocodeine,
hydromorphine, oxymorphone, nicomorphine); and wholly synthetic
opioid derivatives (phenylheptylamines, phenylpiperidines,
diphenylpropylamine derivatives, benzomorphan derivatives,
oripavine derivatives, morphinan derivatives, loperimide,
diphenoxylate). As used herein, the term "opiates" shall refer to
any compound that binds to opioid receptors, including natural
opium alkaloids, semi-synthetic opioids derived therefrom, and
synthetic opioids that have a similar physiochemistry to natural
opiates and generally metabolize to morphine.
[0118] In a clinical setting, opioids are used as analgesics and
for relieving chronic and/or severe pain and other disease
symptoms. Some opioids, however, are abused or used illegally for
their euphoria-inducing properties when administered intravenously
or when smoked.
[0119] ii. Tetrahydrocannibol
[0120] Cannabis, or marijuana, is a plant containing THC
(delta-9-tetrahydrocannabinol), a psychoactive chemical. When
smoked, THC readily diffuses into an individual's lungs and,
consequently, into his bloodstream. THC changes brain and body
functions and initially results in a feeling of haziness and
light-headedness and deleterious effect on short-term memory,
coordination, learning, and problem-solving.
[0121] Long-term use can be problematic due to the development of
tolerance and dependency. THC may directly or indirectly act on the
GABA receptor GABA.sub.A, the activation of which dampens higher
neuronal activity. THC use can result in a variety of side effects,
including, but not limited to learning and memory problems,
distorted perception, anxiety, paranoia, and panic attacks. In
addition, THC induces physical dependence and is addictive. Typical
treatments for THC abuse have been based on cognitive-behavioral
therapy and weaning a patient off of the drug. These methods,
however, fail in that they do not address the physiochemical
changes that occur with addiction.
[0122] Although considered illegal in the United States, in some
areas, cannabis is prescribed under strict supervision for
medicinal purposes. Medically, cannabis is most often used as an
appetite stimulant and pain reliever for certain terminal
illnesses. It is also used to relieve glaucoma and certain
neurological illnesses, such as epilepsy, migraine and bipolar
disorder.
[0123] d. Barbiturates
[0124] Barbiturates are drugs that act as central nervous system
(CNS) depressant, producing a wide range of effects--from mild
sedation to anesthesia. Today, barbiturates are infrequently used
as anticonvulsants and for the induction of anesthesia. Sometimes,
two or more barbiturates are combined in a single tablet or
capsule.
[0125] Barbiturates enhance the functioning of GABA and are general
depressants to nerve and muscle tissue. Mild to moderate
barbiturate toxicity mimics alcohol intoxication. Severe acute
barbiturate toxicity results in CNS problems, including lethargy
and coma.
[0126] e. Benzodiazepines
[0127] The term benzodiazepine refers to a class of drugs with
hypnotic, anxiolytic, anticonvulsant, amnestic and muscle relaxant
properties. Benzodiazepines are divided into three
groups--short-acting (less than six hours); intermediate-acting
(six to ten hours); and long-acting (strong sedative effects that
persist).
[0128] Benzodiazepines are often used for short-term relief of
severe, disabling anxiety or insomnia. Long-term use can be
problematic due to the development of tolerance and dependency. As
described in detail above, they act on the GABA receptor
GABA.sub.A, the activation of which dampens higher neuronal
activity. Benzodiazepine use can result in a variety of side
effects, including, but not limited to drowsiness, ataxia,
confusion, vertigo, and impaired judgment. In addition,
benzodiazepines induce physical dependence and are potentially
addictive. An abrupt discontinuation of substance use may result in
convulsions, confusion, psychosis, or effects similar to delirium
tremens. Onset of withdrawal syndrome may be delayed and is
characterized by insomnia, anxiety, tremor, perspiration, loss of
appetite, and delusions. Typical treatments for benzodiazepine
abuse have been based on cognitive-behavioral therapy, weaning a
patient off of the drug, and, in some cases, administering a
benzodiazepine antagonist to counteract the drug's effects. These
methods, however, fail in that they do not address the
physiochemical changes that occur with addiction.
[0129] f. Non-Benzodiazepine Anxiolytics, Sedatives, Hypnotics, and
Tranquilizers
[0130] Non-benzodiazepine hypnotics are used for the short term
treatment of insomnia (or difficulty in getting to sleep or staying
asleep). Some, like chlormethiazole, can be used to help with
agitation and restlessness, and to help with alcohol withdrawal
symptoms.
[0131] Due to the effects that these drugs have on the brain, as
described above, they can sometimes produce a type of dependence
(or addiction) in some people if taken regularly every night for
more than about four to six weeks.
[0132] g. Anti-Depression Drugs
[0133] Clinical depression is a health condition with both mental
and physical components. Physiological symptoms of depression may
be due to changes or imbalances of chemicals which transmit
information in the brain, called neurotransmitters. Many modern
anti-depressant drugs attempt to increase levels of certain
neurotransmitters, like serotonin. Further, it has been shown that
progesterone and its effects on GABA have been implicated in
depression and anti-depressant dependence.
[0134] Cessation of a CNS drug, such as selective serotonin
reuptake inhibitors, tricyclic antidepressants, and monoamine
oxides inhibitors, may cause withdrawal, an increased total
GABA.sub.A receptor .alpha..sub.4 subunits relative to GABA.sub.A
receptor .alpha..sub.1 subunits, which in turn, causes anxiety.
[0135] i. Selective Serotonin Reuptake Inhibitors (SSRIs)
[0136] Selective serotonin reuptake inhibitors relieve depression
by increasing the availability of one of the body's natural
mood-enhancing chemicals, the neurotransmitter serotonin. Recent
research indicates that SSRIs trigger chemical activity along more
than one track at a time. Fluoxetine (Prozac.RTM.), paroextine
(Paxil.RTM.), and sertraline (Zoloft.RTM.) all show a dramatic,
positive effect (10 to 30-fold) on the levels of allopregnanolone,
a steroid made in the brain, which modulates mood and plays a role
in heightened anxiety and depression found in severe premenstrual
disorders and other conditions.
[0137] In this GABA-pathway, allopregnanolone boosts mood-enhancing
neurotransmitter receptors by increasing how many and how long
certain openings in the ion channels remain open. Recent clinical
studies suggest that fluoxetine and fluvoxamine increase the brain
and cerebrospinal fluid content of allopregnanolone.
V. Compounds that Inhibit Neurosteroid Binding on the GABA.sub.A
Receptor.
[0138] In one embodiment, the present invention is directed towards
a method of using a compound from a class of compounds that
competitively bind to the GABA.sub.A receptor neurosteroid binding
site. In one embodiment, the compound is one that inhibits
allopregnanolone from binding to the GABA.sub.A receptor. In
another embodiment, the compound is one that, upon withdrawal, does
not result in the increase of the .alpha..sub.4 subunit relative to
the .alpha..sub.1 subunit.
[0139] For example, but not limited to such example, Maitra et al.
(1998) demonstrated that the 3beta-pregnane isomers epipregnanolone
and isopregnanolone both inhibited the ability of allopregnanolone
and alphaxalone to potentiate GABA.sub.A receptor function.
VI. Compounds that Inhibit Neurosteroid Production
[0140] In one embodiment, the present invention is directed towards
a method of using a compound from a class of compounds that inhibit
neurosteroid production ("Inhibitors of Neurosteroid Production").
In one embodiment, the compound is one that inhibits the conversion
of progesterone to its metabolite allopregnanolone. In another
embodiment, the compound is one that inhibits the conversion of
progesterone metabolite 5.alpha.-dihydroprogesterone into
allopregnanolone.
[0141] As shown in FIG. 4, progesterone is first converted to
5.alpha.-dihydroprogesterone via an enzyme called
5.alpha.-reductase. 5.alpha.-dihydroprogesterone is then converted
to 5.alpha.,3.alpha.-pregnenolone (allopregnanolone) via the
3.alpha.-hydroxysteroid oxidoreductase enzyme.
[0142] Reference will now be made to specific classes of inhibitors
of neurosteroid production for use in the present invention. While
the classes and inhibitors of neurosteroid production are described
generally herein, it should be understood to those of ordinary
skill in the art that any number of inhibitors of neurosteroid
production that prevent the conversion of progesterone into its
metabolite allopregnanolone can be used in the present invention
and that the list is not exhaustive.
[0143] In one embodiment, an individual is administered a
therapeutically effective amount of a 5-alpha-reductase inhibitor
which blocks the conversion of progesterone into allopregnanolone.
One exemplary 5-alpha-reductase inhibitor is finasteride or analogs
or derivatives thereof. Preferably, the 5.alpha.-reductase
inhibitor is capable of acting as a Type I inhibitor, a Type II
inhibitor, or a combination thereof, and inhibits the
5.alpha.-reductase enzyme from converting progesterone to
5.alpha.-dihydroprogesterone and thus from creating progesterone
metabolite allopregnanolone.
[0144] There are currently accepted dosing regimens for
5-alpha-reductase inhibitors. In one embodiment, an individual is
administered a therapeutically effective amount of a
3-alpha-hyrodxysteroid oxidoreductase inhibitor which blocks the
conversion of progesterone metabolite 5.alpha.-dihydroprogesterone
into allopregnanolone. One exemplary 3-alpha-hyrodxysteroid
oxidoreductase is indomethacin or analogs or derivatives thereof.
There are currently accepted dosing regimens for
3-alpha-hyrodxysteroid oxidoreductase inhibitors. The present
invention contemplates operating in a dosing range of established
safety and efficacy in order to maximally decrease the production
of progesterone and make the individual most receptive to
treatment.
[0145] Bitran et al (1995) have demonstrated that treatment with a
5-alpha-reductase inhibitor prevents the conversion of progesterone
to allopregnanolone and eliminates the anxiolytic activity of
progesterone. In addition, it has been suggested that the
anxiogenic withdrawal properties of allopregnanolone can be
prevented by previous administration of a 3.alpha.-hydroxysteroid
oxidoreductase blocker such as indomethacin.
[0146] a. 5.alpha.-Reductase Inhibitors
[0147] The 5.alpha.-reductase inhibitors are a group of drugs with
anti-androgenic activity that effectively decrease the amount of
the 5.alpha.-reductase enzyme and thus inhibit neurosteroid
production.
[0148] i. Finasteride
[0149] Finasteride is a synthetic 4-azasteroid compound, and is a
5alpha-reductase inhibitor. Finasteride is
4-azaandrost-1-ene-17-carboxamide,N-(1,1-dimethylethyl)-3-oxo-,(5.alpha.,
17.beta.)-. The empirical formula of finasteride is
C.sub.23H.sub.36N.sub.2O.sub.2 and its molecular weight is
372.55.
[0150] Finasteride is a competitive and specific 5.alpha.-reductase
inhibitor. Finasteride has no affinity for the androgen receptor
and has no androgenic, antiandrogenic, estrogenic, antiestrogenic,
or progestational effects.
[0151] Progesterone is metabolically converted to the GABA.sub.A
receptor-potentiating neuroactive steroid allopregnanolone by
5.alpha.-reductase isoenzymes followed by 3.alpha.-hydroxysteroid
oxidoreduction. Finasteride acts as a competitive
5.alpha.-reductase inhibitor and thus blocks the production of
allopregnanolone from progesterone.
[0152] In one embodiment, finasteride is delivered using at least
one oral tablet with a total daily dose of less than 10 mg,
preferably less than 5 mg. It should be appreciated that, to the
extent approved by regulatory authorities, finasteride can also be
delivered in gel capsules or via injection or infusion. Finasteride
should not be used by women of childbearing age. Finasteride's side
effects include breast enlargement and tenderness, skin rash,
swelling of lips, abdominal pain, back pain, decreased libido,
decreased volume of ejaculate, diarrhea, dizziness, headache,
impotence, and testicular pain.
[0153] ii. Dutasteride
[0154] Dutasteride is a synthetic 4-azasteroid compound that is a
selective inhibitor of both the Type I and Type II isoforms of the
steroid 5.alpha.-reductase, an intracellular enzyme. Dutasteride is
chemically designated as (5.alpha.,17.beta.)-N-{2,5
bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide.
The empirical formula of dutasteride is
C.sub.27H.sub.30F.sub.6N.sub.2O.sub.2, representing a molecular
weight of 528.5.
[0155] As a competitive Type I and Type II 5.alpha.-reductase
inhibitor, dutasteride inhibits the conversion of progesterone to
allopregnanolone. Dutasteride does not bind to the human androgen
receptor.
[0156] In one embodiment, dutasteride is delivered using at least
one capsule with a total daily dose of less than 10 mg, preferably
less than 0.5 mg. It should be appreciated that, to the extent
approved by regulatory authorities, dutasteride can also be
delivered in tablets or via injection or infusion. Dutasteride
should not be used by women of childbearing age. Dutasteride's side
effects include cough, difficulty swallowing, dizziness, fast
heartbeat, hives or welts, itching skin, puffiness or swelling of
the eyelids or around the eyes, face, lips, or tongue, redness of
skin, shortness of breath, skin rash, swelling of face, fingers,
feet, and/or lower legs, tightness in chest, unusual tiredness or
weakness, wheezing, abnormal ejaculation, decreased interest in
sexual intercourse, decreased sexual performance or desire,
impotence, inability to have or keep an erection, loss in sexual
ability, desire, drive, or performance, or swelling of the breasts
or breast soreness.
[0157] iii. Other 5.alpha.-Reductase Inhibitors
[0158] The present invention also encompasses the use of other
5-alpha reductase inhibitors, including a) 4-aza-4-methyl-5
alpha-pregnane-3,20-dione (AMPD), which inhibits pituitary
progesterone 5-alpha reduction, b) cyproterone acetate, and c)
spironolactone, which is a diuretic that blocks two pathways to the
production of androgens, or male hormones, one of which is the
inhibition of 5.alpha.-reductase.
[0159] The present invention also encompasses the use of organic
sources of 5-alpha reductase inhibition, including organic sources
such as saw palmetto. Saw palmetto (Serenoa repens) is a natural
source of a 5.alpha.-reductase inhibitor. Some studies suggest that
it may be comparable to finasteride if taken for six months. Saw
Palmetto is advantageous because it is 1) substantially free of
side effects and 2) cost effective.
[0160] b. Other Inhibitors of Neurosteroid Production
[0161] The present invention further includes the use of
3.alpha.-hydroxysteroid oxidoreductase blockers. Gallo and Smith
(1993) suggest that the anxiogenic withdrawal property of
progesterone could be prevented by previous administration of a
3.alpha.-hydroxysteroid oxidoreductase blocker. In one embodiment,
indomethacin is used. Indomethacin is a non-steroidal
anti-inflammatory drug (NSAID) that reduces fever, pain and
inflammation. It is similar to ibuprofen and naproxen. Indomethacin
is effective in reducing the production of prostaglandins.
[0162] It should be appreciated that any composition that can be
used to inhibit neurosteroid production can be used in the present
invention. In one embodiment, compounds are preferably screened to
determine whether they can be used in the treatment methodologies
of the present invention.
[0163] Specifically, an appropriate cellular model is used to model
the inhibition of neurosteroid production. The efficacy of the
composition is measured by measuring the relative levels of
progesterone and allopregnanolone in a model prior to the
administration of the composition and after the administration of
the composition. In cases where the relative levels of progesterone
and allopregnanolone decrease after administration, the composition
may be suitable as an inhibitor to neurosteroid production.
VII. Compounds that Modulate the Expression of Certain GABA.sub.A
Receptor Subunits
[0164] The level of efficacy of a partial agonist/antagonist
depends upon the disease or dependence in question. Thus, by
measuring the level of efficacy or activity of a partial
agonist/antagonist at a receptor site, it is possible to determine
what the disease state is and determine what conformational changes
have occurred in the GABA.sub.A receptor subunits. Based upon this
information, certain compositions can be classified according to
the changes they cause in GABA.sub.A subunits. In addition, since
the GABA binding site in the GABA.sub.A receptor is located at the
interface between .alpha. and .beta. subunits, the GABA.sub.A
antagonists can bind to and stabilize a distinct inactive receptor
conformation.
[0165] In one embodiment, the present invention is directed towards
using a compound from a class of compounds that modulates the
expression of certain GABA.sub.A receptor subunits. More
specifically, the compound is one that serves as an agonist at the
GABA.sub.A receptor, and more specifically, at either the
.alpha..sub.4 subunit or .alpha..sub.6 subunit, and is capable of
positively potentiating GABA current.
[0166] Thus, the compound of choice is one that effectuates an
increase in the expression of the GABA.sub.A receptor .alpha..sub.1
subunit relative to the expression of the .alpha..sub.4 subunit.
This increase in expression of the .alpha..sub.1 subunit may be
effectuated by one or more of the following: a) upregulating the
expression of .alpha..sub.1 subunits; b) downregulating the
expression of .alpha..sub.4 subunits; c) masking .alpha..sub.4
subunits; or d) preventing the upregulation of the .alpha..sub.4
subunit.
[0167] The focus is thus on using a compound from the class of
compounds that modulates the expression of certain GABA.sub.A
receptor subunits, and more specifically, moves the relative
balance of the .alpha..sub.4 subunit to the .alpha..sub.1 subunit
closer to a normal state from an abnormal, allostatic state.
[0168] a. Flumazenil
[0169] In one embodiment, the present invention relates to the use
of a therapeutically effective quantity of a drug, and more
specifically, one that modulates the expression of GABA.sub.A
subunits, such as, but not limited to, flumazenil, in a methodology
for treatment of substance abuse. In one embodiment, the compound
may comprise certain imidazobenzodiazepines and derivatives of
ethyl
8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-
-3-carboxylate, including various substitutions of the carboxylate
functional group, such as carboxylic acids, esters, acyl chlorides,
acid anhydrides, amides, nitriles, alkyls, alkanes, cycloalkanes,
alkenes, alcohols, aldehydes, ketones, benzenes, phenyls, and salts
thereof. In another embodiment, the compound comprises flumazenil
or carboxylic acids, esters, acyl chlorides, acid anhydrides,
amides, nitriles, alkyls, alkanes, cycloalkanes, alkenes, alcohols,
aldehydes, ketones, benzenes, phenyls, and salts thereof.
[0170] Flumazenil acts a partial agonist of GABA.sub.A, inhibits
the upregulation of the .alpha..sub.4 subunit and/or increases the
amount of the .alpha..sub.1 subunit relative to the amount of the
.alpha..sub.4 subunit, and does not cause the upregulation of the
.alpha..sub.4 subunit and/or does not cause the amount of the
.alpha..sub.4 subunit to increase relative to the amount of the
.alpha..sub.1 subunit once the compound is no longer present in the
patient's system.
[0171] In one embodiment, a method is provided for the treatment of
substance abuse that includes the administration to a patient in
need of said treatment of a therapeutically effective quantity of
flumazenil, usually between 0.5 mg/day and 20 mg/day, between 0.5
mg/day and 15 mg/day, specifically between 1.0 and 3.0 mg/day, and
more specifically between 1.5 and 2.5 mg/day, of flumazenil, broken
down into multiple doses of flumazenil between 0.1 and 0.3 mg and
intended for administration during predetermined time periods or
intervals, until said therapeutically effective quantity of
flumazenil has been reached. In one embodiment, the predetermined
time period is in the range of 1 and 15 minutes and the "per dose"
quantity of flumazenil is between 0.1 and 0.3 mg.
[0172] One of ordinary skill in the art would appreciate that the
individual doses can range in amount, and the time interval between
the individual doses can range in amount, provided that the total
dose delivered is in the range of 0.5 mg/day and 20 mg/day, between
0.5 mg/day and 15 mg/day, between 1.0 and 3.0 mg/day, and or
between 1.5 and 2.5 mg/day. In one embodiment, the dose is in the
range of 1.0 mg/day and 3.0 mg/day. The individual doses are
delivered at relatively consistent time intervals. Therefore, the
time period intervals can range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or minutes
or fractions thereof. Doses delivered at each time period,
separated by the time intervals, can be between 0.1 and 0.3 mg, or
fractions thereof, keeping in mind the total drug delivered is
preferably less than 3.0 mg/day. The present invention therefore
provides for the delivery of multiple, sequential doses, delivered
at substantially consistent time intervals.
[0173] Conventional uses of flumazenil comprise either singular
doses or much larger doses over shorter periods of time and are
directed toward reversing sedative effects of anesthesia, conscious
sedation, or benzodiazepine overdose. Further, ROMAZICON.RTM., a
brand name for flumazenil marketed by Roche, is expressly indicated
to complicate the management of withdrawal syndromes for alcohol,
barbiturates and cross-tolerant sedatives and was shown to have an
adverse effect on the nervous system, causing increased agitation
and anxiety. For a single dose to address anesthesia and conscious
sedation, it is conventionally recommended to use a dose of 0.2 mg
to 1 mg of ROMAZICON.RTM. with a subsequent dose in no less than 20
minutes. For repeat treatment, 1 mg doses may be delivered over
five minutes up to 3 mg doses over 15 minutes. A larger dose may be
administered over short periods of time, such as 3 mg doses
administered within 6 minutes.
VIII. Novel Compositions that Combine Conventional Compositions
with Inhibitors of Neurosteroid Production
[0174] As described herein, reference will be made to specific
pharmacological compounds for use in the present invention. While
the invention will be described in conjunction with specific
embodiments, it is not intended to limit the invention to one
embodiment. It should be understood by one of ordinary skill in the
art that a plurality of drug combinations are possible. The present
invention contemplates operating in a dosing range of established
safety and efficacy in order to maximally decrease the production
of allopregnanolone while administering a pharmacological
compound.
[0175] Prior to prescribing any medication, the physician in charge
should make a determination, prior to treatment, if a patient
diagnosed with any symptom or disorder, other than substance
dependence, should receive medication for this disorder. For
example, a patient diagnosed with arterial hypertension should be
prescribed with the appropriate medication or continue with any
existing medication if they are not contraindicated for use with
the compositions used in the treatment methodology of the present
invention.
[0176] The present invention is broadly directed toward the
combination of any Conventional Composition, in any dosage form or
amount, with any Inhibitor of Neurosteroid Production, in the same
dosage form and in any amount. For purposes of illustration,
specific novel compositions will be described below. It should be
appreciated that the actual dosage and administration route of the
Conventional Compositions vary greatly and depend upon the status
of an individual patient. It should also be appreciated that,
accordingly, the actual dosage and administration route of the
Inhibitor of Neurosteroid Production will vary as well. However, a
person of ordinary skill in the medical art would be able to
appropriately select a dosage amount for the Conventional
Composition and the Inhibitor of Neurosteroid Production should be
provided in the same dosage form and in a sufficient amount to be
therapeutically effective at blocking neurosteroid production.
[0177] As used herein, a "therapeutically effective amount" of a
composition of the present invention refers to a sufficient amount
to reduce or prevent neurosteroid production. The therapeutically
effective amount is also an amount effective to reduce, alleviate
or ameliorate symptoms of dependency such as for example, anxiety.
A reduction or amelioration of the symptoms may be determined using
standard clinical tests where a reduction or amelioration of the
symptoms indicates a therapeutically effective amount has been
administered. Examples of such clinical tests are the Hamilton
Anxiety Rating Scale and the Beck Anxiety Inventory for anxiety
where an improvement in an individual's test score indicates a
therapeutically effective amount has been administered.
Therapeutically effective amounts for use in humans can be
determined from animal models. For example, a dose for humans can
be formulated to achieve circulating concentration that has been
found to be effective in animals. Useful animal models of anxiety
are well known in the art.
[0178] a. Formulations
[0179] The compounds useful in the present invention, or
pharmaceutically acceptable salts thereof, can be delivered to a
patient using a wide variety of routes or modes of administration.
Suitable routes of administration include, but are not limited to,
inhalation, transdermal, oral, rectal, transmucosal, intestinal and
parenteral administration, including intramuscular, subcutaneous
and intravenous injections. These methods also include the use of
the aforementioned compounds in the manufacture of compositions,
drugs or medicaments useful for reducing the production of
neurosteroids. The claimed methods also include the use of the
aforementioned compounds in the manufacture of compositions, drugs
or medicaments useful for treating, reducing or ameliorating
addictive properties of certain substances.
[0180] The term "pharmaceutically acceptable salt" means those
salts which retain the biological effectiveness and properties of
the compounds used in the present invention, and which are not
biologically or otherwise undesirable. Such salts may be prepared
from inorganic and organic bases. Salts derived from inorganic
bases include, but are not limited to, the sodium, potassium,
lithium, ammonium, calcium, and magnesium salts. Salts derived from
organic bases include, but are not limited to, salts of primary,
secondary and tertiary amines, substituted amines including
naturally-occurring substituted amines, and cyclic amines,
including isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, ethanolamine,
2-dimethylaminoethanol, tromethanine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine,
piperidine, and N-ethylpiperidine. It should also be understood
that other carboxylic acid derivatives would be useful in the
practice of this invention, for example carboxylic acid amides,
including carboxamides, lower alkyl carboxamides, di(lower alkyl)
carboxamides, and the like.
[0181] The compounds, or pharmaceutically acceptable salts thereof,
may be administered singly, in combination with other compounds,
and/or in cocktails combined with other therapeutic agents. Of
course, the choice of therapeutic agents that can be
co-administered with the compounds of the invention will depend, in
part, on the condition being treated.
[0182] The active compounds (or pharmaceutically acceptable salts
thereof) may be administered per se or in the form of a
pharmaceutical composition wherein the active compound(s) is in
admixture or mixture with one or more pharmaceutically acceptable
carriers, excipients or diluents. Pharmaceutical compositions for
use in accordance with the present invention may be formulated in
conventional manner using one or more physiologically acceptable
carriers comprising excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen.
[0183] For injection, the compounds may be formulated in aqueous
solutions, preferably in physiologically compatible buffers such as
Hanks's solution, Ringer's solution, or physiological saline
buffer. For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0184] For oral administration, the compounds can be formulated
readily by combining the active compound(s) with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained as a solid
excipient, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain tablets or dragee cores. Suitable excipients
are, in particular, fillers such as sugars, including lactose,
sucrose, mannitol, or sorbitol; cellulose preparations such as, for
example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinylpyrrolidone (PVP). If desired, disintegrating
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0185] Dragee cores can be provided with suitable coatings. For
this purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0186] For administration orally, the compounds may be formulated
as a sustained release preparation. Numerous techniques for
formulating sustained release preparations are described in the
following references--U.S. Pat. Nos. 4,891,223; 6,004,582;
5,397,574; 5,419,917; 5,458,005; 5,458,887; 5,458,888; 5,472,708;
6,106,862; 6,103,263; 6,099,862; 6,099,859; 6,096,340; 6,077,541;
5,916,595; 5,837,379; 5,834,023; 5,885,616; 5,456,921; 5,603,956;
5,512,297; 5,399,362; 5,399,359; 5,399,358; 5,725,883; 5,773,025;
6,110,498; 5,952,004; 5,912,013; 5,897,876; 5,824,638; 5,464,633;
5,422,123; and 4,839,177; and WO 98/47491.
[0187] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0188] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in a conventional
manner.
[0189] For administration by inhalation, the active compound(s) may
be conveniently delivered in the form of an aerosol spray
presentation from pressurized packs or a nebulizer, with the use of
a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of e.g. gelatin for use in
an inhaler or insufflator may be formulated containing a powder mix
of the compound and a suitable powder base such as lactose or
starch.
[0190] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0191] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions.
[0192] Alternatively, the active compound(s) may be in powder form
for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use.
[0193] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0194] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation or
transcutaneous delivery (for example subcutaneously or
intramuscularly), intramuscular injection or a transdermal patch.
Thus, for example, the compounds may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0195] A further embodiment of the present invention is related to
a nanoparticle. The compounds of the present invention may be
incorporated into the nanoparticle. The nanoparticle within the
scope of the invention is meant to include particles at the single
molecule level as well as those aggregates of particles that
exhibit microscopic properties. Methods of using and making the
above-mentioned nanoparticle can be found in the art (U.S. Pat.
Nos. 6,395,253, 6,387,329, 6,383,500, 6,361,944, 6,350,515,
6,333,051, 6,323,989, 6,316,029, 6,312,731, 6,306,610, 6,288,040,
6,272,262, 6,268,222, 6,265,546, 6,262,129, 6,262,032, 6,248,724,
6,217,912, 6,217,901, 6,217,864, 6,214,560, 6,187,559, 6,180,415,
6,159,445, 6,149,868, 6,121,005, 6,086,881, 6,007,845, 6,002,817,
5,985,353, 5,981,467, 5,962,566, 5,925,564, 5,904,936, 5,856,435,
5,792,751, 5,789,375, 5,770,580, 5,756,264, 5,705,585, 5,702,727,
and 5,686,113).
[0196] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0197] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredient is
contained in a therapeutically or prophylactically effective
amount, i.e., in an amount effective to achieve therapeutic or
prophylactic benefit, as previously discussed. Of course, the
actual amount effective for a particular application will depend on
the condition being treated and the route of administration.
Determination of an effective amount is well within the purview of
those skilled in the art, especially in light of the disclosure
herein.
[0198] b. Methods of Use
[0199] The methods of the present invention include the use of the
aforementioned compounds in the manufacture of compositions, drugs
or medicaments useful for reducing the addictive and habit-forming
properties of certain compounds in the classes described above.
These methods also include the use of the aforementioned compounds
in the manufacture of compositions, drugs or medicaments useful for
reducing the production of neurosteroids. The claimed methods also
include the use of the aforementioned compounds in the manufacture
of compositions, drugs or medicaments useful for reducing the
tolerance of certain compounds in the classes described above.
[0200] c. Exemplary Compositions
[0201] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are intended neither to limit nor define
the invention in any manner. The following examples will serve to
further illustrate the present invention without, at the same time,
however, constituting any limitation thereof. On the contrary, it
is to be clearly understood that resort may be had to various
embodiments, modifications and equivalents thereof which, after
reading the description herein, may suggest themselves to those
skilled in the art without departing from the spirit of the
invention.
EXAMPLE 1
[0202] An orally administered tablet comprises between 100 mg and
1000 mg, preferably 300, 325, 400, 500, 650, or 750 mg, of
VICODIN.RTM. and 0.1 to 150 mg, preferably 5 mg, of
finasteride.
EXAMPLE 2
[0203] An orally administered tablet comprises between 100 mg and
1000 mg, preferably 325, 500, or 650 mg, of PERCOCET.RTM. and 0.1
to 150 mg, preferably 5 mg, of finasteride.
EXAMPLE 3
[0204] An orally administered tablet comprises between 0.1 and 5
mg, preferably 0.25, 0.5, 1, 2, or 3 mg, of XANAX.RTM. and 0.1 to
150 mg, preferably 5 mg, of finasteride.
EXAMPLE 4
[0205] An orally administered tablet comprises between 1 mg and 200
mg, preferably 10, 20, 40, or 90 mg, of PROXAC.RTM. and 0.1 to 150
mg, preferably 5 mg, of finasteride.
EXAMPLE 5
[0206] An orally administered tablet comprises between 1 mg and 50
mg, preferably 2, 5, or mg, of VALIUM.RTM. and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
EXAMPLE 6
[0207] An orally administered tablet comprises between 1 mg and 200
mg, preferably 5, 10, 20, 30, 40, 80, 100, or 160 mg, of
OXYCONTIN.RTM. and 0.1 to 150 mg, preferably 5 mg, of
finasteride.
EXAMPLE 7
[0208] An orally administered tablet comprises between 10 mg and
1000 mg, preferably 100, 325, 500, and 650 mg, of DARVOCET.RTM. and
0.1 to 150 mg, preferably 5 mg, of finasteride.
EXAMPLE 8
[0209] An orally administered tablet comprises between 1 mg and 50
mg, preferably 5, 6.25, or 10 mg, of zolpidem and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
EXAMPLE 9
[0210] An orally administered tablet comprises between 1 mg and 200
mg, preferably 10, 12.5, 20, 30, or 40 mg, of PAXIL.RTM. and 0.1 to
150 mg, preferably 5 mg, of finasteride.
EXAMPLE 10
[0211] An orally administered tablet comprises between 0.5 mg and
100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of diazepam and 0.1 to
150 mg, preferably 5 mg, of finasteride.
EXAMPLE 11
[0212] An orally administered tablet comprises between 0.5 mg and
100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of methadone and 0.1
to 150 mg, preferably 5 mg, of finasteride.
EXAMPLE 12
[0213] An orally administered tablet comprises between 0.01 mg and
1000 mg of any of the aforementioned conventional compositions and
0.1 to 150 mg, preferably 5 mg, of finasteride.
EXAMPLE 13
[0214] An orally administered tablet comprises between 0.01 mg and
1000 mg of any of the aforementioned conventional compositions and
0.1 to 1000 mg of any of the inhibitors of neurosteroid
production.
EXAMPLE 14
[0215] An orally administered capsule comprises between 150 mg and
750 mg, preferably 500 mg, of VICODIN.RTM. and 0.1 to 100 mg,
preferably 0.5 mg, of dutasteride.
EXAMPLE 15
[0216] An orally administered capsule comprises between 100 mg and
1000 mg, preferably 500 mg, of PERCOCET.RTM. and 0.1 to 100 mg,
preferably 0.5 mg, of dutasteride.
EXAMPLE 16
[0217] An orally administered capsule comprises between 1 mg and
250 mg, preferably 10, 20, or 40 mg, of PROZAC.RTM. and 0.1 to 100
mg, preferably 0.5 mg, of dutasteride.
EXAMPLE 17
[0218] An orally administered capsule comprises between 1 mg and 50
mg, preferably 10, 15, 2.5, 20, or 5 mg, of VALIUM.RTM. and 0.1 to
100 mg, preferably 0.5 mg, of dutasteride.
EXAMPLE 18
[0219] An orally administered capsule comprises between 1 mg and
200 mg, preferably 5 mg, of OXYCONTIN.RTM. and 0.1 to 100 mg,
preferably 0.5 mg, of dutasteride.
EXAMPLE 19
[0220] An orally administered capsule comprises between 0.5 mg and
100 mg, preferably 2.5, 5, 10, 15, or 20 mg, of diazepam and 0.1 to
100 mg, preferably 0.5 mg, of dutasteride.
EXAMPLE 20
[0221] An orally administered capsule comprises between 1 mg and
500 mg, preferably 10, 15, 30, 20, 100, 120 mg, of morphine and 0.1
to 100 mg, preferably 0.5 mg, of dutasteride.
EXAMPLE 21
[0222] An orally administered capsule comprises between 10 mg to
1000 mg, preferably 100, 200 or 400 mg, of CELEBREX.RTM. and 0.1 to
5 mg, preferably 0.5 mg, of dutasteride.
EXAMPLE 22
[0223] An orally administered tablet comprises between 1 mg and 100
mg, preferably 15, 30, or 60 mg, of codeine and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
EXAMPLE 23
[0224] An orally administered tablet comprises between 1 mg to 500
mg, preferably 25, 50, or 100 mg, of ZOLOFT.RTM. and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
EXAMPLE 24
[0225] A nicotine patch having between 0.1 to 150 mg, preferably 5
mg, of finasteride therein.
[0226] While the examples are presented in terms of pharmaceutical
compositions in the form of tablets and capsules, it should be
appreciated that they could take a solution or injectable dosage
form. Moreover, it should be appreciated that for those substances
without defined dosage regimens, such as alcohol, caffeine, and
nicotine, an inhibitor of neurosteroid production can be added as
required to achieve a reduction in dependence.
EXAMPLE 25
[0227] A solution comprising any amount of wine, beer, or other
alcoholic beverage, such as 6 ounces, 12 ounces, 1 pint, or 1
quart, and 0.1 to 150 mg, preferably 5 mg, of finasteride dissolved
therein.
EXAMPLE 26
[0228] An orally administered tablet comprises 0.25 mg
norgestimate, 0.035 mg ethinyl estradiol, and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
EXAMPLE 27
[0229] An orally administered tablet comprises between 0.5 mg and 1
mg of norethindrone, 0.035 mg ethinyl estradiol, and 0.1 to 150 mg,
preferably 5 mg, of finasteride.
[0230] The above examples are merely illustrative of the many
applications of the system of present invention. Although only a
few embodiments of the present invention have been described
herein, it should be understood that the present invention might be
embodied in many other specific forms without departing from the
spirit or scope of the invention. Therefore, the present examples
and embodiments are to be considered as illustrative and not
restrictive, and the invention is not to be limited to the details
given herein, but may be modified within the scope of the appended
claims. All patents, publications and abstracts cited above are
incorporated herein by reference in their entirety.
TABLE-US-00001 TABLE 1 EXEMPLARY LISTING OF PHARMACOLOGICAL
COMPOUNDS AND SUGGESTED DOSAGES FOR USE WITH THE PRESENT INVENTION
DRUG CLASS SECONDARY DRUG CLASS EXEMPLARY DRUG LISTING DOSAGE
ANALGESICS OPIATES (PAINKILLERS) ALFENTANIL FOR USE DURING GENERAL
ANESTHESIA ALFENTA (alfentanil SPONTANEOUSLY BREATHING/ASSISTED
VENTILATION: hydrochloride) Induction of Analgesia: 8-20 mcg/kg;
Maintenance of Analgesia: 3-5 mcg/kg q 5-20 min or 0.5 to 1
mcg/kg/min; Total dose: 8-40 mcg/kg ASSISTED OR CONTROLLED
VENTILATION: Incremental Injection (to attenuate response to
laryngoscopy and intubation): Induction of Analgesia: 20-50 mcg/kg;
Maintenance of Analgesia: 5-15 mcg/kg q 5-20 min; Total dose: Up to
75 mcg/kg. Continuous Infusion: (To provide attenuation of response
to intubation and incision): Infusion rates are variable and should
be treated to the desired clinical effect. Induction of Analgesia:
50-75 mcg/kg; Maintenance of Analgesia: 0.5 to 3 mcg/kg/min
(Average rate 1 to 1.5 mg/kg/min); Total dose: Dependent on
duration of procedure. Anesthetic Induction: Induction of
Analgesia: 130-245 mcg/kg; Maintenance of Analgesia: 0.5 to 1.5
mcg/kg/min or general anesthetic; Total dose: Dependent on duration
of procedure. At these doses, truncal rigidity should be expected
and a muscle relaxant should be utilized; Administer slowly (over 3
minutes); Concentration of inhalation agents reduced by 30-50% for
initial hour. MONITORED ANESTHESIA CARE (MAC) (For sedated and
responsive, spontaneously breathing patients): Induction of M.C.
3-8 mcg/kg; Maintenance of M.C. 3-5 mcg/kg q 5-20 min or 0.25 to 1
mcg/kg/min; Total dose: 3-40 mcg/kg BUPRENORPHINE Administered
sublingually as a single daily dose in the range of 12 to 16
mg/day. Buprenorphine is also delivered transdermally in 25, 50,
and 75 mcg/hour. BUTORPHANOL This formulation of butorphanol is
administered every 3-4 hours either as a nasal spray or injected
into the buttock or hip muscle or into a vein. The FDA does not
regulate Stadol .RTM. in most states. CODEINE (also METHYL
MORPHINE) Codeine and codeine-combo preparations are usually taken
every 4-6 hours. Adults: 15 to 60 mg every 4 to 6 hours (usual
adult dose, 30 mg). Children: 1 Year of Age and Older - 0.5 mg/kg
of b.d. weight or 15 mg/m2 of b.d. surface every 4 to 6 hours. 200
mg (oral) of codeine is about equal to 30 mg (oral) of morphine.
CODEINON See Hydrocodone for details. PROPOXYPHENE Acetaminophen
(Tylenol) and propoxyphene. (DARVOCET) It is formulated as a tablet
taken every 4 hours by mouth. DEXTROPROPOXYPHENE Oral analgesic
potency is one-half to one-third that of codeine, with 65 mg
approximately equivalent to about 600 mg of aspirin.
Dextropropoxyphene is prescribed for relief of mild to moderate
pain. HEROIN ILLICIT SUBSTANCE/NO APPROVED DOSING
(DIACETYLMORPHINE) DIHYDROCODEINE Dihydrocodeine is approximately
twice as potent as codeine; this is taken into consideration while
dosing dihydrocodeine. Codeine Dosage: For the treatment of mild
pain to moderate pain: Adults: 15-60 mg PO (oral) every 4-6 hours.
For the treatment of non- productive cough: Adults: 10-20 mg PO
(oral) every 4-6 hours. For the treatment of diarrhoea: Adults: 30
mg PO (oral) FENTANYL Route of administration: patch, injected,
oral transmucosal. The patch is usually changed every 72 hours or
as directed by physician. Fentanyl (DURAGESIC .RTM.) should ONLY be
used in patients who are already receiving opioid therapy, who have
demonstrated opioid tolerance, and who require a total daily dose
at least equivalent to DURAGESIC .RTM. 25 mcg/h. Patients who are
considered opioid- tolerant are those who have been taking, for a
week or longer, at least 60 mg of morphine daily, or at least 30 mg
of oral oxycodone daily, or at least 8 mg oral hydromorphone daily,
or an equianalgesic dose of another opioid. HYDROCODONE
DIHYDROCODEINONE Five mg of hydrocodone is equivalent to 30 mg of
codeine when administered orally. Also, a dose of 15 mg (1/4 gr) of
hydrocodone is equivalent to 10 mg (1/6 gr) of morphine. The
typical therapeutic dose of 5 to 10 mg is pharmacologically
equivalent to 30 to 60 mg of oral codeine. HYDROMORPHONE Dilaudid
.RTM. is formulated as oral tablets and liquid, rectal suppository,
intra-muscular (buttock or hip muscle) injection, and intravenous
(I.V.) solution. Dosing is every 4-6 hours for the oral forms and
every 6-8 hours for the suppository. An I.V. drip allows for
continuous administration and around-the-clock pain relief. It can
be given intravenously, intramuscularly, rectally, or orally. LAAM
The initial dose street addicts should be 20 to 40 mg. Each
Levomethadyl Acetate subsequent dose, administered at 48- or
72-hour intervals, may be Hydrochloride, also known as adjusted in
increments of 5 to 10 mg until a pharmacokinetic and
Levo-alpha-acetylmethadol or pharmacodynamic steady-state is
reached. Patients dependent on Levacetylmethadol (LAM) methadone
may require higher initial doses. METHADONE It comes as tablets,
dispersible tablets, liquid, and liquid concentrate. Patients take
it every 3-4 hours for severe pain and every 6-8 hours for chronic
pain. MORPHINE and NO APPROVED DOSING FOR PURE MORPHINE. SEE
MORPHINONE SALTS. MORPHINE SULFATE MS Contin .RTM. comes in the
form of tablets, capsules, liquid, and rectal suppository, which
are taken every 4 hours. Long-acting tablets and capsules can be
taken every 8-12 hours or 1-2 per day, respectively. OPIUM
(NATURAL) ILLEGAL - NO FDA RECOMMENDED USAGE OXYCODONE OxyContin
.RTM. comes in liquid and tablet forms taken every 6 hours.
Long-acting tablets are available to take every 12 hours.
OXYMORPHONE Injection: Subcutaneous or intramuscular
administration: initially 1 mg to 1.5 mg, repeated every 4 to 6
hours as needed. Intravenous: 0.5 mg initially. For analgesia
during labor 0.5 mg to 1 mg intramuscularly is recommended. Rectal
Suppositories: One suppository, 5 mg, every 4 to 6 hours. PETHIDINE
(MEPERIDINE) Adults: The usual dosage is 50 mg to 150 mg
intramuscularly, subcutaneously, or orally, every 3 or 4 hours as
necessary. Children: The usual dosage is 0.5 mg/lb to 0.8 mg/lb
intramuscularly, subcutaneously, or orally up to the adult dose,
every 3 or 4 hours as necessary. REMIFENTANIL During Induction of
Anesthesia: ULTIVA should be administered at an infusion rate of
0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the
induction of anesthesia. If endotracheal intubation is to occur
less than 8 minutes after the start of the infusion of ULTIVA, then
an initial dose of 1 mcg/kg may be administered over 30 to 60
seconds. For exact dosing for induction, maintenance and
continuation of general anesthesia, including special cases, please
refer to FDA Documents. SUFENTANIL Not more than 3 total doses.
Each dose must be at least one hour apart. THEBAINE Thebaine is not
used therapeutically, but is converted into a variety of compounds
including codeine, hydrocodone, hydromorphone, oxycodone,
oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and
etorphine. It is controlled in Schedule II of the Controlled
Substances Act as well as under international law. TRAMADOL
Tramadol is approximately 10% as potent as morphine, when given by
the IV/IM route. Oral doses range from 50-400 mg daily, with up to
600 mg daily when given IV/IM. TETRAHYRDOCANNIBINOL/THC MARINOL
Marinol: widely available through prescription. It comes in the THC
form of a pill and is also being studied by researchers for
suitability and some via other delivery methods, such as an inhaler
or patch. The active other ingredient of Marinol is synthetic THC,
which has been found to cannibinoids, have relieve the nausea and
vomiting associated with chemotherapy and analgesic the loss of
appetite associated with various other disease states. properties.
THC - Herbal and Synthetic ILLICIT SUBSTANCE - NO FDA-APPROVED
DOSAGE KETAMINE Intravenous Route: The initial dose of ketamine
administered intravenously may range from 1 mg/kg to 4.5 mg/kg (0.5
to 2 mg/lb). The average amount required to produce five to ten
minutes of surgical anesthesia has been 2 mg/kg (1 mg/lb).
Intramuscular Route: The initial dose of ketamine administered
intramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A
dose of 10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of
surgical anesthesia. BARBITURATES ALLOBARBITAL MRTD (Maximum
Recommended Therapeutic Dose) - 3.33000 mg/kg- body weight (bw)/day
based upon an average adult weighing 60 kg. AMOBARBITAL Defined
Daily Dose - 0.1 g, No data available from FDA. APROBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) - 2.67000 mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg. For trouble in
sleeping: Adults-40 to 160 milligrams (mg) at bedtime. For daytime
sedation: Adults-40 mg three times a day. BARBEXACLONE 100 mg of
barbexaclone is equivalent to 60 mg of phenobarbital. BARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- (VERONAL) body
weight (bw)/day based upon an average adult weighing 60 kg -
10.00000 BUTABARBITAL Butabarbital Oral is used to treat the
following: Severe Anxiety, Additional Agent to Induce General
Anesthesia, Abnormal Trouble Sleeping MRTD (Maximum Recommended
Therapeutic Dose) in mg/kg- body weight (bw)/day based upon an
average adult weighing 60 kg - 2.000 BUTALBITAL MRTD (Maximum
Recommended Therapeutic Dose) in mg/kg- Butalbital, 5-allyl-5- body
weight (bw)/day based upon an average adult weighing
isobutylbarbituric acid. 60 kg - 5.000 COMMON COMBINATIONS INCLUDE:
Butalbital and acetaminophen butalbital, acetaminophen, and
caffeine butalbital and aspirin butalbital, aspirin, and caffeine
BUTOBARBITAL 50 mg of Butobarbital is equivalent to 10 mg of
Diazepam; Acc. to (SONERYL) Nordic Statistics on Medicines, the
Defined Daily Dose of Butobarbital is 150 mg. No data available
from FDA. CYCLOBARBITAL MRTD (Maximum Recommended Therapeutic Dose)
in mg/kg- body weight (bw)/day based upon an average adult weighing
60 kg - 6.67000 ETHALLOBARBITAL N.A. HEPTABARBITAL Defined Daily
Dose - 0.2 g, No data available from FDA. HEXOBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 8.33000
MEPHOBARBITAL Epilepsy: Average dose for adults: 400 mg to 600 mg
daily; children (METHYLPHENOBARBITAL) under 5 years: 16 mg to 32 mg
three or four times daily; children over 5 years: 32 mg to 64 mg
three or four times daily. Sedation: Adults: 32 mg to 100 mg
optimum dose, 50 mg three to four times daily. Children: 16 mg to
32 mg three to four times daily. METHARBITAL METHOHEXITAL For
induction of anesthesia, a 1% solution is administered at a rate of
about 1 mL/5 seconds. The dose required for induction may range
from 50 to 120 mg or more but averages about 70 mg. The usual
dosage in adults ranges from 1 to 1.5 mg/kg. Maintenance of
anesthesia may be accomplished by intermittent injections of the 1%
solution or, more easily, by continuous intravenous drip of a 0.2%
solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL
of a 1% solution) may be given as required, usually every 4 to 7
minutes. For continuous drip, the average rate of administration is
about 3 mL of a 0.2% solution/minute (1 drop/second). PENTOBARBITAL
The usual adult dosage of NEMBUTAL Sodium Solution is 150 to 200 mg
as a single IM injection; the recommended pediatric dosage ranges
from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg.
The rate of IV injection should not exceed 50 mg/min for
pentobarbital sodium. PHENOBARBITAL Pediatric Oral Dosage (as
recommended by the American Academy of Pediatrics): Preoperative: 1
to 3 mg/kg. Adult Oral Dosage: Daytime sedative: 30 to 120 mg daily
in 2 to 3 divided doses. Bedtime hypnotic: 100 to 320 mg.
Anticonvulsant: 50 to 100 mg 2 to 3 times daily.
PRIMIDONE Adult Dosage: Patients 8 years of age and older who have
received no previous treatment may be started on primidone
according to the following regimen using Primidone 250 mg tablets.
Days 1-3: 100 to 125 mg at bedtime; Days 4-6: 100 to 125 mg b.i.d.;
Days 7-9: 100 to 125 mg t.i.d.; Day 10-maintenance; 250 mg t.i.d.
For most adults and children 8 years of age and over, the usual
maintenance dosage is three to four 250 mg primidone tablets daily
in divided doses (250 mg t.i.d. or q.i.d.). If required, an
increase to five or six 250 mg tablets daily may be made but daily
doses should not exceed 500 mg q.i.d. Pediatric Dosage: For
children under 8 years of age, the following regimen may be used:
Days 1-3: 50 mg at bedtime; Days 4-6: 50 mg b.i.d.; Days 7-9: 100
mg b.i.d.; Day 10-maintenance: 125. mg t.i.d. to 250 mg t.i.d. For
children under 8 years of age, the usual maintenance dosage is 125
to 250 mg three times daily, or 10-25 mg/kg/day in divided doses.
SECOBARBITAL For oral dosage form (capsules): For trouble in
sleeping: Adults-100 milligrams (mg) at bedtime. Children-Dose must
be determined by your doctor. For daytime sedation: Adults-30 to 50
mg three or four times a day. Children-Dose is based on body weight
or size and must be determined by your doctor. The usual dose is 2
mg per kilogram (kg) (0.9 mg per pound) of body weight three times
a day. For sedation before surgery: Adults-200 to 300 mg one or two
hours before surgery. Children-Dose is based on body weight and
must be determined by your doctor. The usual dose is 2 to 6 mg per
kg (0.9 to 2.7 mg per pound) of body weight one or two hours before
surgery. However, the dose is usually not more than 100 mg. For
injection dosage form: For trouble in sleeping: Adults-100 to 200
mg injected into a muscle, or 50 to 250 mg injected into a vein.
Children-Dose is based on body weight or size and must be
determined by your doctor. The usual dose is 3 to 5 mg per kg (1.4
to 2.3 mg per pound) of body weight, injected into a muscle.
However, the dose is usually not more than 100 mg. For sedation
before dental procedures: Adults-Dose is based on body weight and
must be determined by your doctor. The usual dose is 1.1 to 2.2 mg
per kg (0.5 to 1 mg per pound) of body weight, injected into a
muscle ten to fifteen minutes before the procedure. Children-Dose
must be determined by your dentist. For sedation before a nerve
block: Adults-100 to 150 mg, injected into a vein. For sedation
before surgery: Children-Dose is based on body weight and must be
determined by your doctor. The usual dose is 4 to 5 mg per kg (1.8
to 2.3 mg per pound) of body weight, injected into a muscle.
TALBUTAL MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
(Lotusate .RTM.), also called 5-allyl- body weight (bw)/day based
upon an average adult weighing 5-sec-butylbarbituric acid. 60 kg -
3.30000 THIOBARBITAL N.A. THIOPENTAL Use in Anesthesia: Moderately
slow induction can usually be Pentothal (Thiopental Sodium
accomplished in the "average" adult by injection of 50 to 75 mg for
Injection, USP). (2 to 3 mL of a 2.5% solution) at intervals of 20
to 40 seconds, depending on the reaction of the patient. Once
anesthesia is established, additional injections of 25 to 50 mg can
be given whenever the patient moves. Use in Convulsive States: For
the control of convulsive states following anesthesia (inhalation
or local) or other causes, 75 to 125 mg (3 to 5 mL of a 2.5%
solution) should be given as soon as possible after the convulsion
begins. Convulsions following the use of a local anesthetic may
require 125 to 250 mg of Pentothal given over a ten minute period.
Use in Psychiatric Disorders: For narcoanalysis and narcosynthesis
in psychiatric disorders, premedication with an anticholinergic
agent may precede administration of Pentothal. After a test dose,
Pentothal (Thiopental Sodium for Injection, USP) is injected at a
slow rate of 100 mg/mm (4 mL/min of a 2.5% solution) with the
patient counting backwards from 100. Shortly after counting becomes
confused but before actual sleep is produced, the injection is
discontinued. Allow the patient to return to a semidrowsy state
where conversation is coherent. Alternatively, Pentothal may be
administered by rapid I.V. drip using a 0.2% concentration in 5%
dextrose and water. At this concentration, the rate of
administration should not exceed 50 mL/min. VINBARBITAL MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- Vinbarbital
(5-Ethyl-5-(1- body weight (bw)/day based upon an average adult
weighing methyl-1-butenyl)barbituric 60 kg - 3.33000 acid).
VINYLBITAL Defined Daily Dose - 0.15 g, No data available from FDA.
Butylvinyl BENZODIAZEPINES ALPRAZOLAM Dosage Depends on Disorder:
Oral (For anxiety or nervous tension): Start: 0.25 mg to 0.5 mg 3
times daily. Maximum: 4 mg in 24 hours. Oral (For panic disorder):
Start: 0.5 mg 3 times daily. Increases: 1 mg daily in 3 to 4 day
intervals. Maximum: 10 mg in 24 hours. BROMAZEPAM Not commercially
available in the U.S. BROTIZOLAM Brotizolam is not approved for
sale in the United States or Canada. CAMAZEPAM Defined Daily Dose -
30 mg, No data available from FDA. CHLORDIAZEPOXIDE For relief of
mild and moderate anxiety disorders and symptoms of anxiety: 5 mg
or 10 mg, 3 or 4 times daily. For relief of server anxiety
disorders and symptoms of anxiety: 20 mg or 25 mg, 3 or 4 times
daily. Geriatric patients or in the presence of debilitating
disease: 5 mg, 2 to 4 times daily. CLONAZEPAM Seizure Disorders:
Adults: The initial dose for adults with seizure disorders should
not exceed 1.5 mg/day divided into three doses. Dosage may be
increased in increments of 0.5 to 1 mg every 3 days until seizures
are adequately controlled or until side effects preclude any
further increase. Maintenance dosage must be individualized for
each patient depending upon response. Maximum recommended daily
dose is 20 mg. Pediatric Patients: Klonopin is administered orally.
In order to minimize drowsiness, the initial dose for infants and
children (up to 10 years of age or 30 kg of body weight) should be
between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day
given in two or three divided doses. Dosage should be increased by
no more than 0.25 to 0.5 mg every third day until a daily
maintenance dose of 0.1 to 0.2 mg/kg of body weight has been
reached, unless seizures are controlled or side effects preclude
further increase. Whenever possible, the daily dose should be
divided into three equal doses. If doses are not equally divided,
the largest dose should be given before retiring. Panic Disorder:
Adults: The initial dose for adults with panic disorder is 0.25 mg
bid. An increase to the target dose for most patients of 1 mg/day
may be made after 3 days. The recommended dose of 1 mg/day is based
on the results from a fixed dose study in which the optimal effect
was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that
study were less effective than the 1 mg/day dose and were
associated with more adverse effects. Nevertheless, it is possible
that some individual patients may benefit from doses of up to a
maximum dose of 4 mg/day, and in those instances, the dose may be
increased in increments of 0.125 to 0.25 mg bid every 3 days until
panic disorder is controlled or until side effects make further
increases undesired. To reduce the inconvenience of somnolence,
administration of one dose at bedtime may be desirable. Treatment
should be discontinued gradually, with a decrease of 0.125 mg bid
every 3 days, until the drug is completely withdrawn. CLOTIAZEPAM
Clotiazepam is not approved for sale in the United States or Canada
CLORAZEPATE ORAL: START: 15 mg/daily INCREASES: As needed. MAXIMUM:
60 mg in 24 hours CLOXAZOLAM Cloxazolam is not approved for sale in
the United States or Canada. DELORAZEPAM Defined Daily Dose - 3 mg,
No data available from FDA. DIAZEPAM Management of Anxiety
Disorders and Relief of Symptoms of Anxiety: Depending upon
severity of symptoms - 2 mg to 10 mg, 2 to 4 times daily.
Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 times
during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as
needed. Adjunctively for Relief of Skeletal Muscle Spasm: 2 mg to
10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2
mg to 10 mg, 2 to 4 times daily. Geriatric Patients, or in the
presence of debilitating disease: 2 mg to 2.5 mg, 1 or 2 times
daily initially; increase gradually as needed and tolerated.
Pediatric patients: Because of varied responses to CNS-acting
drugs, initiate therapy with lowest dose and increase as required.
Not for use in pediatric patients under 6 months. 1 mg to 2.5 mg, 3
or 4 times daily initially; increase gradually as needed and
tolerated. ESTAZOLAM The recommended initial dose for adults is 1
mg at bedtime; however, some patients may need a 2 mg dose. In
healthy elderly patients, 1 mg is also the appropriate starting
dose, but increases should be initiated with particular care. In
small or debilitated older patients, a starting dose of 0.5 mg,
while only marginally effective in the overall elderly population,
should be considered. ETIZOLAM Etizolam is not approved for sale in
the United States or Canada. FLUDIAZEPAM Defined Daily Dose - 0.75
mg, No data available from FDA. FLUNITRAZEPAM Flunitrazepam has not
been approved by the Food and Drug Administration for medical use
in the United States. It is available only by private prescription
in the United Kingdom FLURAZEPAM Dosage should be individualized
for maximal beneficial effects. The usual adult dosage is 30 mg
before retiring. In some patients, 15 mg may suffice. In elderly
and/or debilitated patients, 15 mg is usually sufficient for a
therapeutic response HALAZEPAM For oral dosage form (tablets): For
anxiety: Adults-20 to 40 milligrams (mg) three or four times a day.
Children younger than 18 years of age-Use and dose must be
determined by your doctor. Older adults-20 mg one or two times a
day. HALOXAZOLAM Defined Daily Dose - 7.50 mg, No data available
from FDA. LOPRAZOLAM It is available in 1 mg tablets. The usual
adult dose is 1-2 mg at bedtime, the higher dose being recommended
for patients who have previously been treated with benzodiazepines
for severe persistent insomnia. An initial dose of 0.5 mg-1.0 mg is
recommended in elderly and debilitated patients. LOREZEPAM The
usual range is 2 to 6 mg/day given in divided doses, the largest
dose being taken before bedtime, but the daily dosage may vary from
1 to 10 mg/day. For anxiety, most patients require an initial dose
of 2 to 3 mg/day given b.i.d. or t.i.d. For insomnia due to anxiety
or transient situational stress, a single daily dose of 2 to 4 mg
may be given, usually at bedtime. For elderly or debilitated
patients, an initial dosage of 1 to 2 mg/day in divided doses is
recommended, to be adjusted as needed and tolerated. MEDAZEPAM
Defined daily dose as used in the Nordic Statistics on Medicines -
20 mg; No data available from FDA. MIDAZOLAM For preoperative
sedation/anxiolysis/amnesia. Intramuscular - The recommended
premedication dose of VERSED for good risk (ASA Physical Status I
& II) adult patients below the age of 60 years is 0.07 to 0.08
mg/kg IM (approximately 5 mg IM) administered up to 1 hour before
surgery. The dose must be individualized and reduced when IM VERSED
is administered to patients with chronic obstructive pulmonary
disease, other higher risk surgical patients, patients 60 or more
years of age, and patients who have received concomitant narcotics
or other CNS depressants. In a study of patients 60 years or older,
who did not receive concomitant administration of narcotics, 2 to 3
mg (0.02 to 0.05 mg/kg) of VERSED produced adequate sedation during
the preoperative period. The dose of 1 mg IM VERSED may suffice for
some older patients if the anticipated intensity and duration of
sedation is less critical. Intravenous - VERSED 1 mg/mL formulation
is recommended for sedation/anxiolysis/amnesia for procedures to
facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL
formulations may be diluted with 0.9% sodium chloride or 5%
dextrose in water. 1. Healthy Adults Below the Age of 60: Titrate
slowly to the desired effect (eg, the initiation of slurred
speech). Some patients may respond to as little as 1 mg. No more
than 2.5 mg should be given over a period of at least 2 minutes. A
total dose greater than 5 mg is not usually necessary to reach the
desired endpoint. If narcotic premedication or other CNS
depressants are used, patients will require approximately 30% less
VERSED than unpremedicated patients. 2. Patients Age 60 or Older,
and Debilitated or Chronically Ill Patients: Titrate slowly to the
desired effect (eg, the initiation of slurred speech). Some
patients may respond to as little as 1 mg. No more than 1.5 mg
should be given over a period of no less than 2 minutes. If
additional titration is necessary, it should be given at a rate of
no more than 1 mg over a period of 2 minutes, waiting an additional
2 or more minutes each time to fully evaluate the sedative effect.
Total doses greater than 3.5 mg are not usually necessary.
Epileptic fit: 10 mg intranasally or as buccal. NIMETAZEPAN MRTD
(Maximum Recommended Therapeutic Dose) in mg/kg- body weight
(bw)/day based upon an average adult weighing 60 kg - 0.08330
NITRAZEPAM Nitrazepam shortens the time required to fall asleep and
lengthens
the duration of this sleep. Typically, it may work within an hour
and allow the individual to maintain sleep for 4 to 6 hours. It is
no longer available in the United States. NORDAZEPAM Defined Daily
Dose - 15 mg, No data available from FDA. OXAZEPAM Mild to moderate
anxiety, with associated tension, irritability, agitation or
related symptoms of functional origin or secondary to organic
disease: 10 to 15 mg, 3 or 4 times daily. Severe anxiety syndromes,
agitation, or anxiety associated with depression: 15 to 30 mg, 3 or
4 times daily. Older patients with anxiety, tension, irritability,
and agitation: Initial dosage - 10 mg, 3 times daily. if necessary,
increase cautiously to 15 mg, 3 or 4 times daily. Alcoholics with
acute inebriation, tremulousness, or anxiety on withdrawal: 15 to
30 mg, 3 or 4 times daily. OXAZOLAM 20 mg is equivalent to 10 mg of
Diazepam. MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-
body weight (bw)/day based upon an average adult weighing 60 kg -
1.0000 PINAZEPAM MRTD (Maximum Recommended Therapeutic Dose) in
mg/kg- body weight (bw)/day based upon an average adult weighing 60
kg - 0.33300 PRAZEPAM MRTD (Maximum Recommended Therapeutic Dose)
in mg/kg- body weight (bw)/day based upon an average adult weighing
60 kg - 1.00000 QUAZEPAM The recommended initial dose is 15
milligrams daily. Your doctor may later reduce this dosage to 7.5
milligrams. TEMAZEPAM While the recommended usual adult dose is 15
mg before retiring, 7.5 mg may be sufficient for some patients, and
others may need 30 mg. In transient insomnia, a 7.5 mg dose may be
sufficient to improve sleep latency. In elderly and/or debilitated
patients it is recommended that therapy be initiated with 7.5 mg
until individual responses are determined. TETRAZEPAM Defined Daily
Dose - 100 mg, No data available from FDA. TOFISOPAM Tofisopam is
not approved for sale in the US or Canada. However, Vela
Pharmaceuticals of New Jersey is developing the D- enantiomer
(dextofisopam) as a treatment for IBS. TRIAZOLAM The recommended
dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg
may be found to be sufficient for some patients (e.g., low body
weight). A dose of 0.5 mg should be used only for exceptional
patients who do not respond adequately to a trial of a lower dose
since the risk of several adverse reactions increases with the size
of the dose administered. A dose of 0.5 mg should not be exceeded.
In geriatric and/or debilitated patients the recommended dosage
range is 0.125 mg to 0.25 mg. Therapy should be initiated at 0.125
mg in this group and the 0.25 mg dose should be used only for
exceptional patients who do not respond to a trial of the lower
dose. A dose of 0.25 mg should not be exceeded in these patients.
HORMONES/CONTRACEPTIVES ESTROGENS See other columns.
Hormone-Containing Contraceptives General Dosing Information:
include: ethinyl Combination contraceptives are those containing
both estrogen and estradiol and progesterone. mestranol. Several
types of combination birth control pills exist, including
PROGESTERONES monophasic pills, biphasic pills, triphasic pils, and
91-day cycle include: pills. Norethynodrel, USE: Starting at the
beginning of the pill pack, take one each day at norethindrone,
approximately the same time every day to increase efficacy.
norethindrone WHEN TO BEGIN: The following regimens may be used
when acetate, first starting on birth control pills: norgestimate,
Taking one pill each day, starting on the fifth day after the
desogestrel, onset of menses and continuing for 21 or 28 days.
ethyndiol Beginning pills on the first day of the menstrual period.
diacetate, Beginning on the first Sunday after the menstrual period
norgestrel, starts. levonorgestrel, 21-DAY PILL CONTAINER: Take one
pill daily for 21 days, stop drospirenone. for 7 days, then resume
taking the pills with a new container of pills. 28-DAY PILL
CONTAINER: Start with the first pill in the container and swallow
one daily for 28 days. Do not stop taking the pills. The last 7 ae
usually placebos. 91-DAY PILL CONTAINER: One pill is taken daily
for 12 weeks, followed by one week of inactive pills. A menstrual
period occurs during the week of inactive pills, so women on this
regimen have a period only once every three months. Monophasic
Pills: Alesse, Brevicon, Demulen, Desogen, Levlen, Levlite,
Loestrin, Microgestin, Modicon, Necon, Nelova, Nordette, Norinyl,
Ortho-Cept, Ortho-Cyclen, Ortho-Novum, Ovcon, Ovral, Yasmin, Zovia.
Monophasic pills have a constant dose of estrogen and progestin in
each of the hormonally active pills through the entire cycle (21
days of ingesting active pills). Several of the brands listed above
may be available in several strengths of estrogen or progesterone,
from which doctors choose according to a woman's individual needs.
Biphasic Pills: Jenest, Mircette, Necon 10/11, Nelova 10/11, and
Ortho-Novum 10/11 Biphasic Pills typically contain two different
progesterone doses. The progesterone dose is increased about
halfway through the cycle. Triphasic Pills: Cyclessa, Estrostep,
Ortho-Novum 7/7/7, Ortho Tri- Cyclen, Ortho Tri-Cyclen LO,
Tri-Levlen, Tri-Norinyl, Triphasil, Trivora Triphasic pills
gradually increase the dose of estrogen during the cycle (some
pills also increase the progesterone dose). Three different
increasing pill doses are contained in each cycle. Ninety-One Day
BCP: Levonorgestrel/ethynl estradiol (Seasonale) These pills are
monophasic birth control pills that have been approved for use on a
daily basis for 84 days without interruption. Users have fewer
schedules menstrual cycles (only 1 period every 3 months). Topical
Contraceptive Patch: Norelgestromin/ethinyl estradiol (Ortho Evra)
A new patch is applied on the same day of the week, each week for
three weeks in a row. The first patch is applied on either the
first day of the menstrual period or on the Sunday following
menses. On the fourth week, no patch is applied. Another 4-week
cycle is started by applying a new patch following the 7-day patch
free period. Long-Acting, Injectable, Progesterone-Only
Contraceptives: Medroxyprogesterone acetate (Depo-Provera) The
first injection is given within five days following the onset of
menstruation. After that, an injection is needed every 11-13 weeks.
Unlike pills, the injection works right away. Progesterone-Only
Pills: Norethindrone (Nor-QD) Progesterone-only pills, also known
as mini-pills, are not used widely in the US. POPs are ingested
once daily, every day. They may be started on any day, and there
are no pill-free days or different colored pills to track. Since
progesterone is the only hormonal ingredient, estrogen-related side
effects are avoided. Vaginal Ring: Etonogestrel/ethinyl estradiol
(NuvaRing) The ring is self-inserted into the vagina. Exact
positioning is not required for it to be effective. The vaginal
ring must be inserted within 5 days of the onset of the menstrual
period, even if bleeding is still occurring. During the first
cycle, an additional method of contraception is recommended. The
ring remains in place continuously for three weeks. It is removed
for one week. The next ring is then inserted one week after the
last ring was removed. NON-BENZODIAZEPINE CHLORAL HYDRATE The usual
hypnotic dose is 500 mg to 1 g, taken 15 to 30 minutes ANXIOLYTICS
SEDATIVES before bedtime or 1/2 hour before surgery. The usual
sedative dose is HYPNOTICS TRANQUILIZERS 250 mg three times daily
after meals. Generally, single doses or daily dosage should not
exceed 2 g. CHLORAL BETAINE Chloral betaine 707 mg (chloral hydrate
414 mg) Dose: 1-2 tablets with water or milk at bedtime, max. 5
tablets (2 g chloral hydrate) daily CLOMETHIAZOLE (or MRTD (Maximum
Recommended Therapeutic Dose) in mg/kg- CHLOMETHIAZOLE) body weight
(bw)/day based upon an average adult weighing 60 kg - 6.40000
DIPHENHYDRAMINE Adults: 25 to 50 mg three or four times daily.
Children (over 20 lb): 12.5 to 25 mg three to four times daily.
Maximum daily dosage not to exceed 300 mg. ETHCHLORVYNOL Due to the
problems it can cause, it is unusual for ethchlorvynol to be
prescribed for periods exceeding seven days. PROMETHIAZINE.
Administration of 12.5 to 25 mg Phenergan by the oral route or by
rectal suppository at bedtime will provide sedation in children.
Adults usually require 25 to 50 mg for nighttime, presurgical, or
obstetrical sedation. ZALPELON The recommended dose of Sonata for
most nonelderly adults is 10 mg. (imidazopyridine) For certain low
weight individuals, 5 mg may be a sufficient dose. Although the
risk of certain adverse events associated with the use of Sonata
appears to be dose dependent, the 20 mg dose has been shown to be
adequately tolerated and may be considered for the occasional
patient who does not benefit from a trial of a lower dose. ZOLPIDEM
The recommended dose for adults is 10 mg immediately before
(pyrazolopyrimidine) bedtime, indicated for the short-term
treatment of insomnia. ZOPICLONE The usual dose is 7.5 mg at
bedtime. This dose should not be exceeded. Depending on clinical
response and tolerance, the dose may be lowered to 3.75 mg.
Geriatrics: In the elderly and/or debilitated patient an initial
dose of 3.75 mg at bedtime is recommended. The dose may be
increased to 7.5 mg if the starting dose does not offer adequate
therapeutic effect. STIMULANTS CAFFEINE Caffeine Oral is used to
treat the following: Absence of Breathing in the Newborn Caffeine
Oral may also be used to treat: Drowsiness, Low Energy Caffeine
citrate is indicated for the short term treatment of apnea of
prematurity in infants between 28 and <33 weeks gestational age.
Caffeine Citrate: Loading Dose - 20 mg/kg Maintenance Dose - 5
mg/kg NICOTINE NICOTROL Inhaler is indicated as an aid to smoking
cessation for the relief of nicotine withdrawal symptoms. NICOTROL
Inhaler therapy is recommended for use as proof of a comprehensive
behavioral smoking cessation program. It it supplied as 42
cartridges each containing 10 mg (4 mg is delivered) nicotine.
Initial Treatment: Up to 12 Weeks: 6-16 cartridges/day Gradual
Reduction (if needed) - 6-12 Weeks: No tapering strategy has been
shown to be superior to any other in clinical studies. OTC
MEDICATIONS DEXTROMETHORPHAN Now prescription only in the United
States. MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- body
weight (bw)/day based upon an average adult weighing 60 kg -
2.00000 MISCELLANEOUS GHB It has been used as a general anesthetic,
and a hypnotic in the Gamma-hydroxybutyrate treatment of insomnia.
GHB has also been used to treat clinical depression, and improve
athletic performance. In the US, the FDA permits the use of GHB to
reduce the number of cataplexy attacks in patients with narcolepsy.
In Italy, GHB is used for the treatment of alcoholism (50 to 100 mg
per kg per day, in 3 or more divided doses), both for acute alcohol
withdrawal and medium to long term detoxification. LD50 of GHB is
estimated to be between 1100 mg/kg and 2000 mg/kg in rodents and is
almost certainly lower in humans. MEPROBROMATE Meprobromate is
available in 200 mg and 400 mg tablets for oral administration.
Symptoms of meprobromate overdose include coma, drowsiness, loss of
muscle control, severly impaired breathing, shock, sluggishness,
and unresponsiveness. Death has been reported with ingestion of as
little as 12 g of meprobromate and survival with as much as 40 g.
METHQUALONE In the United States, the marketing of methaqualone
pharmaceutical products stopped in 1984, and methaqualone was
transferred to Schedule I of the CSA. NITROUS OXIDE Nitrous Oxide
is a weak general anesthetic, and is generally not used alone. It
has a very low short-term toxicity and is an excellent analgesic.
In general anesthesia it is often used in a 2:1 ratio with oxygen
in addition to more powerful general anesthetic agents. Possession
of nitrous oxide is illegal in most localities in the United States
for the purposes of inhaling or ingesting if not under the care of
a physician or dentist. PCP Not available for medicinal use.
Phencyclidine HERBAL VALERIAN ROOT Dosing not regulated/approved by
FDA. MEDICINALS (Valeriana officinalis, Large doses are known to
cause withdrawal symptoms when Valerianaceae) stopped, as it is
mildly addictive. Those with liver disease are advised not to use
valerian. Valerian is the source of valeric acid. SALVINORIN A N.A.
Salvinorin A is the main active Salvinorin A is a dissociative
hallucinogenic compound that is psychotropic constituent of the
active at the extremely low doses of 0.2-0.5 mg, second only to
plant Salvia divinorum LSD in quantitative potency, making it the
most potent naturally (diviner's sage, Mexican mint). occurring
drug known to date. A dose of 200 to 500 micrograms produces
profound hallucinations when smoked. Its' effects in the open field
test in mice and loco motor activity tests in rats are similar to
mescaline. ST. JOHN'S WORT The dosage of St John's wort
preparations vary greatly between Refers to the species Hypericum
formulations, due to variability in the plant source and
preparation perforatum. processes. The doses of St. John's wort
extract used in clinical trials generally range from 350 to 1800 mg
daily (equivalent to 0.4 to 2.7 mg hypericin depending on the
preparation). The recommended dosage for various forms of St John's
wort as recommended by the British Herbal Medicine Association
Scientific Committee (1983) are as follows: dried herb: 2-4 g or by
infusion three times daily liquid extract 2-4 mL (1:1 in 25%
alcohol) three times daily tincture 2-4 mL (1:10 in 45% alcohol)
three times daily ANTI-DEPRESSION DRUGS CITALOPRAM HBR Celexa
(citalopram HBr) is indicated for the treatment of (CELEXA)
depression. Celexa (citalopram HBr) should be administered at an
initial dose of 20 mg once daily, generally with an increase to a
dose of 40 mg/ day. Dose increases should usually occur in
increments of 20 mg at intervals of no less than one week
ESCITALOPRAM OXALATE LEXAPRO (escitalopram) is indicated for the
treatment of major LEXAPRO .TM. depressive disorder and Generalized
Anxiety Disorder (GAD). The recommended dose of LEXAPRO is 10 mg
once daily. FLUOXETINE Prozac is indicated for the treatment of:
Major Depressive Disorder: HYDROCHLORIDE a dose of 20 mg/day,
administered in the morning, is recommended as the initial dose.
The maximum fluoxetine dose should not exceed 80 mg/day. Obsessive
Compulsive Disorder: a dose of 20 mg/day, administered in the
morning, is recommended as the initial dose. The maximum fluoxetine
dose should not exceed 80 mg/day. Bulimia Nervosa: the recommended
dose is 60 mg/day, administered in the morning. Panic Disorder:
Treatment should be initiated with a dose of 10 mg/day. After 1
week, the dose should be increased to 20 mg/day. PAROXETINE Major
Depressive Disorder: The recommended initial dose is HYDROCHLORIDE
20 mg/day. Some patients not responding to a 20-mg dose may benefit
from dose increases, in 10-mg/day increments, up to a maximum of 50
mg/day. Obsessive Compulsive Disorder: The recommended dose of
PAXIL in the treatment of OCD is 40 mg daily. Patients should be
started on 20 mg/day and the dose can be increased in 10-mg/day
increments. The maximum dosage should not exceed 60 mg/day. Panic
Disorder: The target dose of PAXIL in the treatment of panic
disorder is 40 mg/day. The maximum dosage should not exceed 60
mg/day. Social Anxiety Disorder: The recommended and initial dosage
is 20 mg/day. Generalized Anxiety Disorder: The recommended
starting dosage and the established effective dosage is 20 mg/day.
Posttraumatic Stress Disorder: The recommended starting dosage and
the established effective dosage is 20 mg/day. FLUVOXAMINE MALEATE
Fluvoxamine is indicated in the treatment of depression and for
(LUVOX). Obsessive Compulsive Disorder (OCD). The recommended
starting dose for LUVOX Tablets in adult patients is 50 mg,
administered as a single daily dose at bed time. The maximum
therapeutic dose should not to exceed 300 mg per day. SERTRALINE
Major Depressive Disorder and Obsessive-Compulsive Disorder:
HYDROCHLORIDE ZOLOFT treatment should be administered at a dose of
50 mg once daily. Panic Disorder, Posttraumatic Stress Disorder and
Social Anxiety Disorder: ZOLOFT treatment should be initiated with
a dose of 25 mg once daily. After one week, the dose should be
increased to 50 mg once daily. Premenstrual Dysphoric Disorder:
ZOLOFT treatment should be initiated with a dose of 50 mg/day,
either daily throughout the menstrual cycle or limited to the
luteal phase of the menstrual cycle, depending on physician
assessment. AMITRIPTYLINE For the relief of symptoms of depression.
Endogenous depression is more likely to be alleviated than are
other depressive states. Oral Dosage: 75 mg of amitriptyline HCl a
day in divided doses. If necessary, this may be increased to a
total of 150 mg per day. Intramuscular Dosage: Initially, 20 to 30
mg (2 to 3 ml) four times a day. DESIPRAMINE Desipramine
hydrochloride is indicated for relief of symptoms in HYDROCHLORIDE
various depressive syndromes, especially endogenous depression. The
usual adult dose is 100 to 200 mg per day. Dosages above 300 mg/day
are not recommended. Not recommended for use in children.
NORTRIPTYLINE Nortriptyline HCl is indicated for the relief of
symptoms of depression. Endogenous depressions are more likely to
be alleviated than are other depressive states. It is not
recommended for children. Usual Adult Dose - 25 mg three or four
times daily. Doses above 150 mg/day are not recommended. Elderly
and Adolescent Patients - 30 to 50 mg/day, in divided doses, or the
total daily dosage may be given once a day. DULOXETINE Cymbalta is
indicated for the treatment of major depressive disorder
HYDROCHLORIDE (MDD) and pain associated with diabetic peripheral
neuropathy. Major Depressive Disorder: Cymbalta should be
administered at a total dose of 40 mg/day Diabetic Peripheral
Neuropathic Pain: Cymbalta should be administered at a total dose
of 60 mg/day given once a day VENLAFAXINE Effexor (venlafaxine
hydrochloride) is indicated for the treatment of Effexor major
depressive disorder. The recommended starting dose for Effexor is
75 mg/day, up to a maximum of 375 mg/day, generally in three
divided doses PHENELZINE SULFATE The usual starting dose of Nardil
is one tablet (15 mg) three times a day. Maintenance dose may be as
low as one tablet, 15 mg, a day or every other day, and should be
continued for as long as is required. TRANYLCYPROMINE For the
treatment of Major Depressive Episode Without (Parnate)
Melancholia. The usual effective dosage is 30 mg per day, usually
given in divided doses; may be extended to a maximum of 60 mg per
day. When tranylcypromine is withdrawn, monoamine oxidase activity
is recovered in 3 to 5 days, although the drug is excreted in 24
hours. MIRTAZEPINE Indicated for the treatment of major depressive
disorder. The recommended starting dose for REMERON .RTM.
(mirtazapine) Tablets is 15 mg/day, up to a maximum of 45 mg/day.
NEFAZODONE SERZONE (nefazodone hydrochloride) is indicated for the
HYDROCHLORIDE treatment of depression. When deciding among the
alternative SERZONE .RTM. treatments available for this condition,
the prescriber should consider the risk of hepatic failure
associated with SERZONE treatment. The recommended starting dose
for SERZONE (nefazodone hydrochloride) is 200 mg/day TRAZODONE
DESYREL is indicated for the treatment of depression. HYDROCHLORIDE
An initial dose of 150 mg/day in divided doses is suggested, up to
DESYREL but not in excess of 600 mg/day in divided doses. BUPROPION
WELLBUTRIN is indicated for the treatment of depression.
HYDROCHLORIDE The usual adult dose is 300 mg/day, given 3 times
daily. WELLBUTRIN (bupropion WELLBUTRIN should be discontinued in
patients who do not hydrochloride) demonstrate an adequate response
after an appropriate period of treatment at 450 mg/day. When
Wellbutrin is used in combination with an SSRI to offset sexual
side effects, the usual dose is 75 mg per day. Isocarboxazid The
maximum daily dose of isocarboxazid is 60 mg. Moclobemide
Depression: The initial dose is 300 mg daily in 2 or 3 divided
doses. Social Phobia: The recommended dose is 600 mg daily in 2 or
3 divided doses. A single 300 mg dose of moclobemide inhibits 80%
of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B
(MAO-B), blocking the decomposition of norepinephrine, serotonin
and, to a lesser extent, dopamine. No reuptake inhibition on any of
the neurotransmitters occurs. Selegiline 10 mg per day administered
as divided doses of 5 mg each. NEUROSTEROID 5-ALPHA- INHIBITORS
REDUCTASE INHIBITORS FINASTERIDE The recommended dosage is 1 mg
orally once per day. It may be administered with or without meals.
An alternate dosage of 5 mg orally once per day is also included.
It may be administered with or without meals. In general, daily use
for three months or more is necessary before benefit is observed.
Continued use is recommended to sustain benefit, which should be
re-evaluated periodically. Withdrawal of treatment leads to
reversal of effect within 12 months. In clinical studies, single
doses of finasteride up to 400 mg and multiple doses of finasteride
up to 80 mg/day for three months did not result in adverse
reactions. DUTASTERIDE The recommended therapeutic dose of
dutasteride is 0.5 mg taken orally once per day. Dutasteride
pharmacokinetics has not been investigated in subjects less than 18
years of age. No dose adjustment is necessary in the elderly. In
volunteer studies, single doses of dutasteride up to 40 mg (80
times the therapeutic dose) for 7 days have been administered
without significant safety concerns. In a clinical study, daily
doses of 5 mg (10 times the therapeutic dose) were administered to
60 subjects for 6 months with no additional adverse effects to
those seen at therapeutic does of 0.5 mg. SAW PALMETTO
Tablets/Capsules. A dose of 160 mg twice daily or 320 milligrams
daily (containing 80% to 90% liposterolic content) for up to 11
months has been taken by mouth. Higher doses may be used under
medical supervision. Berries. A dose of one to two grams of ground,
dried, or whole berries daily has been taken by mouth. Tincture. A
dose of two to four milliliters (1:4) three times daily has been
taken by mouth. Fluid Extract of Berry Pulp. A dose of one to two
milliliters (1:1) three times daily has been taken by mouth. Rectal
Suppositories. A dose of 640 milligrams once daily has been used.
Rectal use of saw palmetto is no better than taking saw palmetto by
mouth. Tea. Tea made from berries may not be effective because the
proposed active ingredient does not dissolve in water.
SPIRONOLACTONE Treatment protocols may involve continuous
spironolactone use at 50 mg to 200 mg per day or cyclic use; for
example, 50 mg or 100 mg twice daily from the 4.sup.th to the
22.sup.nd day of the menstrual cycle. Numerous treatment protocols
involving spironolactone have been used in different studies, but
no particular treatment approach has been shown to be significantly
superior. 3-ALPHA REDUCTASE INHIBITORS INDOMETHACIN Indomethacin
can be administered in the form of capsules (25 mg and 50 mg);
sustained-release capsules (75 mg); a suspension (25 mg/ml); or a
suppository (50 mg). The recommended dose for adults is 50-200 mg
per day split into 2-3 doses. CLASS OF COMPOUNDS THAT FLUMAZENIL
ROMAZICON is indicated for the complete or partial reversal of
SELECTIVELY MODULATES (Romazicon) the sedative effects of
benzodiazepines in cases where general GABA.sub.A RECEPTORS
anesthesia has been induced and/or maintained with benzodiazepines,
where sedation has been produced with benzodiazepines for
diagnostic and therapeutic procedures, and for the management of
benzodiazepine overdose. Reversal of Conscious Sedation: The
recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a second dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Reversal of General Anesthesia in Adult Patients: The recommended
initial dose of ROMAZICON is 0.2 mg (2 mL) administered
intravenously over 15 seconds. If the desired level of
consciousness is not obtained after waiting an additional 45
seconds, a further dose of 0.2 mg (2 mL) can be injected and
repeated at 60-second intervals where necessary (up to a maximum of
4 additional times) to a maximum total dose of 1 mg (10 mL).
Management of Suspected Benzodiazepine Overdose in Adult Patients:
the recommended initial dose of ROMAZICON is 0.2 mg (2 mL)
administered intravenously over 30 seconds. if the desired level of
consciousness is not obtained after waiting 30 seconds, a further
dose of 0.3 mg (3 mL) can be administered over another 30 seconds.
Further doses of 0.5 mg (5 mL) can be administered over
30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.
MILTIRONE The below doses are based on scientific research,
publications, traditional use, or expert opinion. Many herbs and
supplements have not been thoroughly tested, and safety and
effectiveness may not be proven. You should read product labels,
and discuss doses with a qualified healthcare provider before
starting therapy. Standardization: There is no widely accepted
standardization or well-studied dosing of miltirone, and many
different doses are used traditionally. Adults (18 years and
older): By mouth. Oral dosing has not been studied in
well-conducted trials in humans, and therefore no specific dose can
be recommended. By injection: In research from the 1970s, an 8
milliliter injection of miltirone (16 grams of the herb) was given
intravenously (diluted in 500 milliliters of a 10% glucose
solution) for up to four weeks for ischemic stroke. Safety and
effectiveness have not been established for this route of
administration and it cannot not recommended at his time. Children
(younger than 18 years): There is not enough scientific evidence to
recommend the safe use of danshen in children, and it should be
avoided due to potentially serious side effects. FLAVONOIDS They
have been classified N.A. according to their chemical structure,
and are usually subdivided into 6 subgroups: Flavonols, including
Quercetin, Kaempferol, Myricetin, Isorhamnetin Flavones, including
Luteolin, Apigenin Flavanones, including Hesperetin, Naringenin,
Eriodictyol Flavan-3-ols, including (+)- Catechin,
(+)-Gallocatechin, (-)- Epicatechin, (-)- *Epigallocatechin, (-)-
Epicatechin 3-gallate, (-)- Epigallocatechin 3-gallate, Theaflavin,
Theaflavin 3- gallate, Theaflavin 3'-gallate, Theaflavin 3,3'
digallate, Thearubigins Isoflavones, including Genistein, Daidzein,
Glycitein Anthocyanidins, including Cyanidin, Delphinidin,
Malvidin, Pelargonidin, Peonidin, Petunidin DOPAMINE ERGOT The dose
of bromocriptine will be different for different patients. AGONISTS
ALKALOIDS Follow your doctor's orders or the directions on the
label. The following information includes only the average doses of
bromocriptine. If your dose is different, do not change it unless
your doctor tells you to do so. The number of capsules or tablets
that you take depends on the strength of the medicine. Also, the
number of doses you take each day, the time allowed between doses,
and the length of time you take the medicine depend on the medical
problem for which you are taking bromocriptine. For oral dosage
forms (capsules and tablets): For infertility, male hormone problem
(male hypogonadism), starting the menstrual cycle (amenorrhea), or
stopping abnormal milk secretion from nipples (galactorrhea):
Adults and teenagers 15 years of age or older-At first, 1.25 to 2.5
milligrams (mg) once a day taken at bedtime with a snack. Then your
doctor may change your dose by 2.5 mg every three to seven days as
needed. Doses greater than 5 mg a day are taken in divided doses
with meals or at bedtime with a snack. Teenagers less than 15 years
of age and children-Use and dose must be determined by your doctor.
For lowering growth hormone (acromegaly): Adults and teenagers 15
years of age or older-At first, 1.25 to 2.5 milligrams (mg) once a
day taken at bedtime with a snack for three days. Then your doctor
may change your dose by 1.25 or 2.5 mg every three to seven days as
needed. Doses greater than 5 mg are divided into smaller doses and
taken with meals or at bedtime with a snack. Teenagers less than 15
years of age and children-Use and dose must be determined by your
doctor. For Parkinson's disease: Adults and teenagers 15 years of
age or older-At first, 1.25 milligrams (mg) one or two times a day
taken with meals or at bedtime with a snack. Then your doctor may
change your dose over several weeks as needed. Teenagers less than
15 years of age and children-Use and dose must be determined by
your doctor. For pituitary tumors: Adults and teenagers 15 years of
age or older-At first, 1.25 milligrams (mg) two or three times a
day taken with meals. Then your doctor may change your dose over
several weeks as needed. Teenagers less than 15 years of age and
children-Use and dose must be determined by your doctor.
PRESCRIPTION METHYLPHENIDATE Methylphendiate comes in 5 mg, 10 mg
and 20 mg tablets. STIMULANTS ADULTS Tablets: Administer in divided
doses, 2 or 3 times daily, preferably 30 to 45 minutes before
meals. Average dosage is 20 to 30 mg daily. Some patient may
require 40 to 60 mg daily. In others, 10 to 15 mg daily will be
adequate. FOR CHILDREN, DOSAGES SHOULD BE INITIATED IN INCREMENTS
Days 1-3: One 5 mg tablet per day Days 4-6: Two 5 mg tablets per
day Add one pill every fourth day until a dosage of 20 mg per day
is achieved. Daily dosage above 60 mg is not recommended. ADDERALL.
Attention Deficit Disorder with Hyperactivity: Not recommended for
children under 3 years of age. In children from 3 to 5 years of
age, start with 2.5 mg daily; daily dosage may be raised in
increments of 2.5 mg at weekly intervals until optimal response is
obtained. In children 6 years of age and older, start with 5 mg
once or twice daily; daily dosage may be raised in increments of 5
mg at weekly intervals until optimal response is obtained. Only in
rare cases will it be necessary to exceed a total of 40 mg per day.
Give first dose on awakening; additional doses (1 or 2) at
intervals of 4 to 6 hours. Where possible, drug administration
should be interrupted occasionally to determine if there is a
recurrence of behavioral symptoms sufficient to require continued
therapy. Narcolepsy: Usual dose 5 mg to 60 mg per day in divided
doses, depending on the individual patient response. Narcolepsy
seldom occurs in children under 12 years of age; however, when it
does, dextroamphetamine sulfate may be used. The suggested initial
dose for patients aged 6-12 is 5 mg daily; daily dose may be raised
in increments of 5 mg at weekly intervals until optimal response is
obtained. In patients 12 years of age and older, start with 10 mg
daily; daily dosage may be raised in increments of 10 mg at weekly
intervals until optimal response is obtained. If bothersome adverse
reactions appear (e.g., insomnia or anorexia), dosage should be
reduced. Give first dose on awakening; additional doses (1 or 2) at
intervals of 4 to 6 hours. DEXEDRINE Narcolepsy. Usual dose 5 to 60
mg per day in divided doses, depending on the individual patient
response. Narcolepsy seldom occurs in children under 12 years of
age; however, when it does Dexedrine (dextroamphetamine sulfate)
may be used. The suggested initial dose for patients aged 6 to 12
is 5 mg daily; daily dose may be raised in increments of 5 mg at
weekly intervals until optimal response is obtained. In patients 12
years of age and older, start with 10 mg daily; daily dosage may be
raised in increments of 10 mg at weekly intervals until optimal
response is obtained. If bothersome adverse reactions appear (e.g.
insomnia or anorexia), dosage should be reduced. Spansule capsules
may be used for once-a-day dosage wherever appropriate. With
tablets give first dose on awakening, additional doses (1 or 2) at
intervals of 4 to 6 hours. Attention Deficit Disorder with
Hyperactivity. Not recommended for pediatric patients under 3 years
of age. In pediatric patients from 3 to 5 years of age, start with
2.5 mg daily, by tablet daily dosage may be raised in increments of
2.5 mg at weekly intervals until optimal response is obtained. In
pediatric patients 6 years of age and older, start with 5 mg once
or twice daily, daily dosage may be raised in increments of 5 mg at
weekly intervals until optimal response is obtained. Only in rare
cases will it be necessary to exceed a total of 40 mg per day.
Spansule capsules may be used for once-a-day dosage wherever
appropriate. With tablets, give first dose on awakening additional
doses (1 or 2) at intervals of 4 to 6 hours.
* * * * *