U.S. patent application number 13/606271 was filed with the patent office on 2013-04-18 for molecular genetic approach to treatment and diagnosis of alcohol and drug dependence.
The applicant listed for this patent is Bankole A. Johnson. Invention is credited to Bankole A. Johnson.
Application Number | 20130096173 13/606271 |
Document ID | / |
Family ID | 47832574 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130096173 |
Kind Code |
A1 |
Johnson; Bankole A. |
April 18, 2013 |
MOLECULAR GENETIC APPROACH TO TREATMENT AND DIAGNOSIS OF ALCOHOL
AND DRUG DEPENDENCE
Abstract
The present invention provides compositions and methods useful
for diagnosing, treating, and monitoring alcohol dependence and
disorders and susceptibility to alcohol dependence disorders, as
well as drug related dependence and disorders.
Inventors: |
Johnson; Bankole A.;
(Charlottesville, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson; Bankole A. |
Charlottesville |
VA |
US |
|
|
Family ID: |
47832574 |
Appl. No.: |
13/606271 |
Filed: |
September 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61532781 |
Sep 9, 2011 |
|
|
|
Current U.S.
Class: |
514/397 ;
435/6.11; 506/9 |
Current CPC
Class: |
A61P 25/30 20180101;
C12Q 2600/106 20130101; C12Q 1/6883 20130101; C12Q 2600/156
20130101; A61K 31/4178 20130101 |
Class at
Publication: |
514/397 ;
435/6.11; 506/9 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; C12Q 1/68 20060101 C12Q001/68 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0001] This invention was made with government support under Grant
Nos. AA010522-12, AA0032903, AA001016 and AA012964 awarded by the
National Institutes of Health. The government has certain rights in
the invention.
CROSS REFERENCE TO RELATED APPLICATIONS
[0002] This application is entitled to priority pursuant to 35
U.S.C. .sctn.119(e) to U.S. provisional patent application No.
61/532,781, filed on Sep. 9, 2011. The entire disclosure of the
afore-mentioned provisional patent application is incorporated
herein by reference.
Claims
1. A method of treating an addictive disease or disorder,
comprising: administering to a patient in need thereof a
therapeutically effective amount of an antagonist of the serotonin
receptor 5-HT.sub.3, wherein the patient's serotonin transporter
gene SLC6A4 is known to have a genotype selected from sets (a)-(q):
(a.) the AA genotype of rs1176719 and the AG genotype of rs1150226;
(b.) the AA genotype of rs1176719 and the AG genotype of rs1150226
and the AC genotype of rs17614942; (c.) the AA genotype of
rs1176719 and the AG genotype of rs1150226 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (d.) the AA genotype of
rs1176719 and the AG genotype of rs1150226 and the AC genotype of
rs17614942 and the LL genotype of 5-HTTLPR, and the TT genotype of
rs1042173; (e.) the AA genotype of rs1176719 and the AG genotype of
rs1150226 and the GG genotype of rs1176713 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (f.) the AA genotype of
rs1176719 and the AG genotype of rs1150226 and the AC genotype of
rs17614942 and the GG genotype of rs1176713 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (g.) the AA genotype of
rs1176719 and the GG genotype of rs1176713; (h.) the AA genotype of
rs1176719 and the GG genotype of rs1176713 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (i.) the AA genotype of
rs1176719 and the GG genotype of rs1176713 and the AC genotype of
rs17614942 and the LL genotype of 5-HTTLPR, and the TT genotype of
rs1042173; (j.) the GG genotype of rs1176713 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (k.) the GG genotype of
rs1176713 and the AG genotype of rs1150226 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (l.) the GG genotype of
rs1176713 and the AC genotype of rs17614942 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; (m.) the GG genotype of
rs1176713 and the AG genotype of rs1150226 and the AC genotype of
rs17614942 and the LL genotype of 5-HTTLPR, and the TT genotype of
rs1042173; (n.) the AG genotype of rs1150226 and the AA genotype of
rs1176719 and the AC genotype of rs17614942 and the GG genotype of
rs1176713; (o.) the AG genotype of rs1150226 and the AA genotype of
rs1176719 and the GG genotype of rs1176713; (p.) the AG genotype of
rs1150226 and the AC genotype of rs17614942 and the GG genotype of
rs1176713; and, (q.) the AA genotype of rs1176719 and the AC
genotype of rs17614942 and the GG genotype of rs1176713.
2. The method of claim 1, wherein the patient is known to have
genotype set (a).
3. The method of claim 1, wherein the patient is known to have
genotype set (b).
4. The method of claim 1, wherein the patient is known to have
genotype set (c).
5. The method of claim 1, wherein the patient is known to have
genotype set (d).
6. The method of claim 1, wherein the patient is known to have
genotype set (e).
7. The method of claim 1, wherein the patient is known to have
genotype set (f).
8. The method of claim 1, wherein the patient is known to have
genotype set (g).
9. The method of claim 1, wherein the patient is known to have
genotype set (h).
10. The method of claim 1, wherein the patient is known to have
genotype set (i).
11. The method of claim 1, wherein the patient is known to have
genotype set (j).
12. The method of claim 1, wherein the patient is known to have
genotype set (k).
13. The method of claim 1, wherein the patient is known to have
genotype set (l).
14. The method of claim 1, wherein the patient is known to have
genotype set (m).
15. The method of claim 1, wherein the patient is known to have
genotype set (n).
16. The method of claim 1, wherein the patient is known to have
genotype set (O).
17. The method of claim 1, wherein the patient is known to have
genotype set (p).
18. The method of claim 1, wherein the patient is known to have
genotype set (q).
19. The method of claim 1, wherein the antagonist of the serotonin
receptor 5-HT.sub.3 is administered at a dosage ranging from 0.1
.mu.g/kg to 1000 .mu.g/kg per application.
20. The method of claim 19, wherein the antagonist of the serotonin
receptor 5-HT.sub.3 is ondansetron.
21. The method of claim 20, wherein the ondanesetron is
administered at a dosage of 3.0 .mu.g/kg per application.
22. The method of claim 20, wherein the ondanesetron is
administered at a dosage of 4.0 .mu.g/kg per application.
23. The method of claim 1, wherein the addictive disease or
disorder is selected from the group consisting of alcohol-related
diseases and disorders, obesity-related diseases and disorders,
eating disorders, impulse control disorders, nicotine-related
disorders, amphetamine-related disorders, methamphetamine-related
disorders, cannabis-related disorders, cocaine-related disorders,
hallucinogen use disorders, inhalant-related disorders,
benzodiazepine abuse or dependence related disorders,
opioid-related disorders, gambling, sexual disorders, computer use
related disorders, and electronic use related disorders.
24. The method of claim 23, wherein the addictive disease or
disorder is an alcohol-related disease or disorder.
25. The method of claim 24, wherein the alcohol-related disease or
disorder is selected from the group consisting of early onset
alcoholism, late onset alcoholism, alcohol-induced psychotic
disorder with delusions, alcohol abuse, heavy drinking, excessive
drinking, alcohol intoxication, alcohol withdrawal, alcohol
intoxication delirium, alcohol withdrawal delirium, alcohol-induced
persisting dementia, alcohol-induced persisting amnestic disorder,
alcohol dependence, alcohol-induced psychotic disorder with
hallucinations, alcohol-induced mood disorder, alcohol-induced or
associated bipolar disorder, alcohol-induced or associated post
traumatic stress disorder, alcohol-induced anxiety disorder,
alcohol-induced sexual dysfunction, alcohol-induced sleep disorder,
alcohol-induced or associated gambling disorder, alcohol-induced or
associated sexual disorder, alcohol-related disorder not otherwise
specified, alcohol intoxication, and alcohol withdrawal.
26. The method of claim 1, wherein a response from the treatment,
comprises: a reduction in drinking.
27. A method of selecting patients with an addictive disease or
disorder who will be responsive to treatment with an antagonist of
the serotonin receptor 5-HT.sub.3, comprising: determining whether
the patient's serotonin transporter gene SLC6A4 has a genotype set
selected from sets (a)-(q): (a.) the AA genotype of rs1176719 and
the AG genotype of rs1150226; (b.) the AA genotype of rs1176719 and
the AG genotype of rs1150226 and the AC genotype of rs17614942;
(c.) the AA genotype of rs1176719 and the AG genotype of rs1150226
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(d.) the AA genotype of rs1176719 and the AG genotype of rs1150226
and the AC genotype of rs17614942 and the LL genotype of 5-HTTLPR,
and the TT genotype of rs1042173; (e.) the AA genotype of rs1176719
and the AG genotype of rs1150226 and the GG genotype of rs1176713
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(f.) the AA genotype of rs1176719 and the AG genotype of rs1150226
and the AC genotype of rs17614942 and the GG genotype of rs1176713
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(g.) the AA genotype of rs1176719 and the GG genotype of rs1176713;
(h.) the AA genotype of rs1176719 and the GG genotype of rs1176713
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(i.) the AA genotype of rs1176719 and the GG genotype of rs1176713
and the AC genotype of rs17614942 and the LL genotype of 5-HTTLPR,
and the TT genotype of rs1042173; (j.) the GG genotype of rs1176713
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(k.) the GG genotype of rs1176713 and the AG genotype of rs1150226
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(l.) the GG genotype of rs1176713 and the AC genotype of rs17614942
and the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
(m.) the GG genotype of rs1176713 and the AG genotype of rs1150226
and the AC genotype of rs17614942 and the LL genotype of 5-HTTLPR,
and the TT genotype of rs1042173; (n.) the AG genotype of rs1150226
and the AA genotype of rs1176719 and the AC genotype of rs17614942
and the GG genotype of rs1176713; (o.) the AG genotype of rs1150226
and the AA genotype of rs1176719 and the GG genotype of rs1176713;
(p.) the AG genotype of rs1150226 and the AC genotype of rs17614942
and the GG genotype of rs1176713; and, (q.) the AA genotype of
rs1176719 and the AC genotype of rs17614942 and the GG genotype of
rs1176713.
28. The method of claim 17, further comprising: administering an
antagonist of the serotonin receptor 5-HT.sub.3 to the patient, if
the patient has a genotype of set (a)-(q).
Description
BACKGROUND
[0003] Alcohol abuse and dependence are widespread and it is
estimated that 14 million American adults abused alcohol or were
dependent on it in 1992 and that approximately 10% of Americans
will be affected by alcohol dependence sometime during their lives.
Alcohol dependence, characterized by the preoccupation with alcohol
use, tolerance, and withdrawal, is a chronic disorder with genetic,
psychosocial, and environmental factors influencing its development
and manifestations. Studies have demonstrated the significance of
opioids (i.e., beta-endorphin), dopamine (DA), serotonin (5-HT),
.gamma.-amino-butyric acid (GABA) and glutamate for the development
and maintenance of alcohol dependence.
[0004] Despite the number of studies performed in this area, few
drugs for alcohol dependence are approved in the U.S. The approved
drugs are disulfuram, naltrexone, Vivitrex.RTM./Vivitrol.RTM. (a
long-acting depot formulation of naltrexone), and acamprosate.
Disulfuram is an irreversible inhibitor of aldehyde dehydrogenase
leading to increased levels of acetaldehyde, a toxic intermediate
in alcohol metabolism. Patients who take disulfuram and drink
alcohol experience an increased dilation of arterial and capillary
tone producing hypotension, nausea, vomiting, flushing, headache
and possibly in some, worse symptoms. Therefore, the concept behind
the use of disulfuram is that the alcohol-dependent individual
associates drinking with unpleasant adverse events and, as a
result, avoids further alcohol consumption. Nevertheless, recent
research shows that disulfuram has limited utility because
compliance is low unless it is administered by a partner or
spouse.
[0005] There is a long felt need in the art for compositions and
methods useful for diagnosing, treating, and monitoring alcohol
disorders and susceptibility to alcohol disorders.
SUMMARY OF THE INVENTION
[0006] The present invention relates to molecular genetics
techniques to predict which alcohol or drug dependent subjects are
amenable to specific treatments and to predict those subjects for
which such treatment might produce an adverse event.
[0007] The present invention also relates to methods and assays
useful for determining whether a subject has a predisposition to
developing an addictive disease or disorder, determining whether a
subject will be responsive to particular treatments, and
compositions and methods useful for treating a subject in need of
treatment.
[0008] The present invention also relates to compositions and
methods useful for treating subjects having an addictive disease or
disorder (or who are predisposed thereto) based on identification
of genetic markers indicative of a subject being predisposed to
such disease or disorder or being predisposed to responding to
treatment thereof.
[0009] The present invention also relates to molecular genetics
techniques and/or other ways to subtype groups by biological or
psychological measures or variables to determine which subjects
will respond best to treatment for an addictive disease or
disorder.
[0010] These and other aspects that will become apparent are based
on the discovery that molecular genetics techniques can be used to
predict which alcohol or drug dependent subjects are amenable to
specific treatments and to predict those subjects for which such
treatment might produce an adverse event. Various aspects of the
invention are described in further detail below.
DETAILED DESCRIPTION
Abbreviations, Generic Names, and Acronyms
[0011] 5-HT.sub.3--a subtype of serotonin receptor, the serotonin-3
receptor
[0012] 5-HTOL--5-hydroxytryptophol
[0013] 5-HTT--serotonin transporter (also referred to as SERT,
5HTT, HTT, and OCD1)
[0014] 5-HTTLPR--serotonin transporter-linked polymorphic
region
[0015] ADE--alcohol deprivation effect
[0016] ADI--adolescence diagnostic interview
[0017] ASPD--antisocial personality disorder
[0018] AUD--alcohol use disorder
[0019] BBCET--Brief Behavioral Compliance Enhancement Treatment
[0020] BED--binge eating disorder
[0021] b.i.d.--twice a day
[0022] B.sub.max--maximum specific paroxetine binding density
[0023] BRENDA--Biopsychosocial, Report, Empathy, Needs, Direct
advice, and Assessment
[0024] CBI--combined behavioral intervention
[0025] CBT--Cognitive Behavioral Coping Skills Therapy, also
referred to as cognitive behavioral therapy
[0026] CDT--carbohydrate-deficient transferrin
[0027] ChIPS--children's interview for psychiatric syndrome
[0028] CMDA--cortico-mesolimbic dopamine
[0029] DA--dopamine
[0030] DDD--drinks/drinking day
[0031] DSM--Diagnostic and Statistical Manual of Mental
Disorders
[0032] EOA--early-onset alcoholic(s)
[0033] GABA--.gamma.-amino-butyric acid (also referred to as
.gamma.-amino butyric acid and .gamma.-aminobutyric acid)
[0034] GGT--.gamma.-glutamyl transferase
[0035] ICD--impulse control disorder
[0036] IP--intraperitoneal
[0037] K.sub.d--affinity constant
[0038] K.sub.m--equilibrium constant
[0039] L--long
[0040] LOA--late-onset alcoholic(s)
[0041] MET--Motivational Enhancement Therapy
[0042] miRNA--micro RNA
[0043] MM--Medical Management
[0044] NAc--nucleus accumbens
[0045] Naltrexone--a .mu. opioid receptor antagonist
[0046] ncRNA--non-coding RNA
[0047] NMDA--N-methyl-D-aspartate
[0048] NOS--not otherwise specified
[0049] Ondansetron (Zofran.RTM.)--a serotonin receptor
antagonist
[0050] P--alcohol-preferring rats
[0051] S--short
[0052] SERT--serotonin transporter (also referred to as 5-HTT)
[0053] SLC6A4--human 5-HT transporter gene.
[0054] SNP--single nucleotide polymorphism
[0055] SSRI--selective serotonin re-uptake inhibitor
[0056] Topiramate (Topamax.RTM.)--an anticonvulsant
[0057] TSF--Twelve-Step Facilitation Therapy (e.g., Alcoholics
Anonymous)
[0058] V.sub.max--maximum serotonin uptake velocity
[0059] VTA--ventral tegmental area
DEFINITIONS
[0060] In describing and claiming the invention, the following
terminology will be used in accordance with the definitions set
forth below. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which this invention belongs.
Any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention. As used herein, each of the following terms has the
meaning associated with it in this section. Specific values listed
below for radicals, substituents, and ranges are for illustration
only; they do not exclude other defined values or other values
within defined ranges for the radicals and substituents.
[0061] As used herein, the articles "a" and "an" refer to one or to
more than one, i.e., to at least one, of the grammatical object of
the article. By way of example, "an element" means one element or
more than one element.
[0062] The term "about," as used herein, means approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
20%.
[0063] One of ordinary skill in the art will appreciate that
addictive disorders such as those related to alcohol or drugs, does
mean that a subject is dependent unless specifically defined as
such.
[0064] The term "additional therapeutically active compound," in
the context of the present invention, refers to the use or
administration of a compound for an additional therapeutic use
other than just the particular disorder being treated. Such a
compound, for example, could include one being used to treat an
unrelated disease or disorder, or a disease or disorder which may
not be responsive to the primary treatment for the addictive
disease or disorder being treated. Disease and disorders being
treated by the additional therapeutically active agent include, for
example, hypertension and diabetes.
[0065] As used herein, the term "aerosol" refers to suspension in
the air. In particular, aerosol refers to the particlization or
atomization of a formulation of the invention and its suspension in
the air.
[0066] Cells or tissue are "affected" by a disease or disorder if
the cells or tissue have an altered phenotype relative to the same
cells or tissue in a subject not afflicted with a disease,
condition, or disorder.
[0067] As used herein, an "agonist" is a composition of matter
that, when administered to a mammal, such as a human, enhances or
extends a biological activity of interest. Such effect may be
direct or indirect.
[0068] The term "alcohol abuser," as used herein, refers to a
subject who meets DSM IV criteria for alcohol abuse (i.e.,
"repeated use despite recurrent adverse consequences") but is not
dependent on alcohol.
[0069] As used herein, an "analog" of a chemical compound is a
compound that, by way of example, resembles another in structure
but is not necessarily an isomer (e.g., 5-fluorouracil is an analog
of thymine).
[0070] An "antagonist" is a composition of matter that when
administered to a mammal, such as a human, inhibits or impedes a
biological activity attributable to the level or presence of an
endogenous compound in the mammal. Such effect may be direct or
indirect.
[0071] As used herein, the term "anti-alcohol agent" refers to any
active drug, formulation, or method that exhibits activity to treat
or prevent one or more symptom(s) of alcohol addiction, alcohol
abuse, alcohol intoxication, and/or alcohol withdrawal, including
drugs, formulations and methods that significantly reduce, limit,
or prevent alcohol consumption in mammalian subjects.
[0072] The term "appetite suppression," as used herein, is a
reduction, a decrease or, in cases of excessive food consumption,
an amelioration in appetite. This suppression reduces the desire or
craving for food. Appetite suppression can result in weight loss or
weight control as desired.
[0073] The term "average drinking," as used herein, refers to the
mean number of drinks consumed during a one week period. The term
"average drinking" is used interchangeably herein with the term
"average level of drinking."
[0074] A "biomarker" is a specific biochemical in the body which
has a particular molecular feature that makes it useful for
measuring the progress of disease or the effects of treatment, or
for measuring a process of interest.
[0075] A "compound," as used herein, refers to any type of
substance or agent that is commonly considered a drug, or a
candidate for use as a drug, as well as combinations and mixtures
of the above.
[0076] A "control" subject is a subject having the same
characteristics as a test subject, such as a similar type of
dependence, etc. The control subject may, for example, be examined
at precisely or nearly the same time the test subject is being
treated or examined. The control subject may also, for example, be
examined at a time distant from the time at which the test subject
is examined, and the results of the examination of the control
subject may be recorded so that the recorded results may be
compared with results obtained by examination of a test
subject.
[0077] A "test" subject is a subject being treated.
[0078] As used herein, a "derivative" of a compound refers to a
chemical compound that may be produced from another compound of
similar structure in one or more steps, as in replacement of H by
an alkyl, acyl, or amino group.
[0079] As used herein, the term "diagnosis" refers to detecting a
risk or propensity to an addictive related disease or disorder. In
any method of diagnosis exist false positives and false negatives.
Any one method of diagnosis does not provide 100% accuracy.
[0080] A "disease" is a state of health of a subject wherein the
subject cannot maintain homeostasis, and wherein if the disease is
not ameliorated then the subject's health continues to deteriorate.
In contrast, a "disorder" in a subject is a state of health in
which the subject is able to maintain homeostasis, but in which the
subject's state of health is less favorable than it would be in the
absence of the disorder. However, the definitions of "disease" and
"disorder" as described above are not meant to supersede the
definitions or common usage related to specific addictive diseases
or disorders.
[0081] A disease, condition, or disorder is "alleviated" if the
severity of a symptom of the disease or disorder, the frequency
with which such a symptom is experienced by a patient, or both, are
reduced.
[0082] As used herein, an "effective amount" means an amount
sufficient to produce a selected effect, such as alleviating
symptoms of a disease or disorder. In the context of administering
two or more compounds, the amount of each compound, when
administered in combination with another compound(s), may be
different from when that compound is administered alone. The term
"more effective" means that the selected effect is alleviated to a
greater extent by one treatment relative to the second treatment to
which it is being compared.
[0083] The term "elixir," as used herein, refers in general to a
clear, sweetened, alcohol-containing, usually hydroalcoholic liquid
containing flavoring substances and sometimes active medicinal
agents.
[0084] The term "excessive drinker," as used herein, refers to men
who drink more than 21 alcohol units per week and women who consume
more than 14 alcohol units per week. One standard drink is 0.5 oz
of absolute alcohol, equivalent to 10 oz of beer, 4 oz of wine, or
1 oz of 100-proof liquor. These individuals are not dependent on
alcohol but may or may not meet DSM IV criteria for alcohol
abuse.
[0085] As used herein, a "functional" molecule is a molecule in a
form in which it exhibits a property or activity by which it is
characterized. A functional enzyme, for example, is one that
exhibits the characteristic catalytic activity by which the enzyme
is characterized.
[0086] The term "heavy drinker," as used herein, refers to men who
drink more than 14 alcohol units per week and women who consume
more than 7 alcohol units per week. One standard drink is 0.5 oz of
absolute alcohol, equivalent to 10 oz of beer, 4 oz of wine, or 1
oz of 100-proof liquor. These individuals are not dependent on
alcohol but may or may not meet DSM IV criteria for alcohol
abuse.
[0087] The term "heavy drinking", as used with respect to the
alcohol-dependent population of Example 1, refers to drinking at
least about 21 standard drinks/week for women and at least 30
drinks/week for men during the 90 days prior to enrollment in the
study and is more fully described therein.
[0088] A "heavy drinking day," as used herein, refers to the
consumption by a man or woman of more than about five or four
standard drinks per drinking day, respectively.
[0089] The term "heavy drug use," as used herein, refers to the use
of any drug of abuse, including, but not limited to, cocaine,
methamphetamine, other stimulants, phencyclidine, other
hallucinogens, marijuana, sedatives, tranquilizers, hypnotics,
opiates at intervals or in quantities greater than the norm. The
intervals of use include intervals such as at least once a month,
at least once a week, and at least once a day. "Heavy drug use" is
defined as testing "positive" for the use of that drug on at least
2 occasions in any given week with at least 2 days between testing
occasions.
[0090] As used herein, the term "inhaler" refers both to devices
for nasal and pulmonary administration of a drug, e.g., in
solution, powder and the like. For example, the term "inhaler" is
intended to encompass a propellant driven inhaler, such as is used
to administer antihistamine for acute asthma attacks, and plastic
spray bottles, such as are used to administer decongestants.
[0091] The term "inhibit a complex," as used herein, refers to
inhibiting the formation of a complex or interaction of two or more
proteins, as well as inhibiting the function or activity of the
complex. The term also encompasses disrupting a formed complex.
However, the term does not imply that each and every one of these
functions must be inhibited at the same time.
[0092] As used herein, an "instructional material" includes a
publication, a recording, a diagram, or any other medium of
expression which can be used to communicate the usefulness of a
compound of the invention in the kit for effecting alleviation of
the various diseases or disorders recited herein. Optionally, or
alternately, the instructional material may describe one or more
methods of alleviating the diseases or disorders in a subject. The
instructional material of the kit of the invention may, for
example, be affixed to a container which contains the identified
compound invention or be shipped together with a container which
contains the identified compound. Alternatively, the instructional
material may be shipped separately from the container with the
intention that the instructional material and the compound be used
cooperatively by the recipient.
[0093] "Intensity of drinking" refers to the number of drinks,
which can be equated with values such as drinks/day,
drinks/drinking day, etc. Therefore, greater intensity of drinking
means more drinks/day, or drinks/drinking day, etc.
[0094] As used herein, a "ligand" is a compound that specifically
binds to a target compound or molecule. A ligand "specifically
binds to" or "is specifically reactive with" a compound when the
ligand functions in a binding reaction which is determinative of
the presence of the compound in a sample of heterogeneous
compounds.
[0095] A "receptor" is a compound or molecule that specifically
binds to a ligand.
[0096] The term "measuring the level of expression" or "determining
the level of expression" as used herein refers to any measure or
assay which can be used to correlate the results of the assay with
the level of expression of a gene or protein of interest. Such
assays include measuring the level of mRNA, protein levels, etc.
and can be performed by assays such as northern and western blot
analyses, binding assays, immunoblots, etc. The level of expression
can include rates of expression and can be measured in terms of the
actual amount of an mRNA or protein present.
[0097] The term "nasal administration" in all its grammatical forms
refers to administration of at least one compound of the invention
through the nasal mucous membrane to the bloodstream for systemic
delivery of at least one compound of the invention. The advantages
of nasal administration for delivery are that it does not require
injection using a syringe and needle, it avoids necrosis that can
accompany intramuscular administration of drugs, and trans-mucosal
administration of a drug is highly amenable to self
administration.
[0098] "Obesity" is commonly referred to as a condition of
increased body weight due to excessive fat. Drugs to treat obesity
are generally divided into three groups: (1) those that decrease
food intake, such as drugs that interfere with monoamine receptors,
such as noradrenergic receptors, serotonin receptors, dopamine
receptors, and histamine receptors; (2) those that increase
metabolism; and (3) those that increase thermogenesis or decrease
fat absorption by inhibiting pancreatic lipase (Bray, 2000,
Nutrition, 16:953-960 and Leonhardt et al., 1999, Eur. J. Nutr.,
38:1-13). Obesity has been defined in terms of body mass index
(BMI). BMI is calculated as weight (kg)/[height (m)].sup.2,
according to the guidelines of the U.S. Centers for Disease Control
and Prevention (CDC), and the World Health Organization (WHO).
Physical status: The use and interpretation of anthropometry.
Geneva, Switzerland: World Health Organization 1995. WHO Technical
Report Series), for adults over 20 years old, BMI falls into one of
these categories: below 18.5 is considered underweight, 18.5-24.9
is considered normal, 25.0-29.9 is considered overweight, and 30.0
and above is considered obese.
[0099] The term "per application" as used herein refers to
administration of a drug or compound to a subject.
[0100] As used herein, the term "pharmaceutically acceptable
carrier" includes any of the standard pharmaceutical carriers, such
as a phosphate buffered saline solution, water, emulsions such as
an oil/water or water/oil emulsion, and various types of wetting
agents. The term also encompasses any of the agents approved by a
regulatory agency of the US Federal government or listed in the US
Pharmacopeia for use in animals, including humans.
[0101] As used herein, the term "physiologically acceptable" ester
or salt means an ester or salt form of the active ingredient which
is compatible with any other ingredients of the pharmaceutical
composition, and which is not deleterious to the subject to which
the composition is to be administered.
[0102] A "predisposition" to an addictive disease or disorder
refers to situations in which a subject has an increased chance of
abusing a substance such as alcohol or a drug or becoming addicted
to alcohol or a drug or other addictive diseases or disorders.
[0103] The term "prevent," as used herein, means to stop something
from happening, or taking advance measures against something
possible or probable from happening. In the context of medicine,
"prevention" generally refers to action taken to decrease the
chance of getting a disease or condition.
[0104] The term "problem drinker," as used herein, encompasses
individuals who drink excessively and who report that their alcohol
consumption is causing them problems. Such problems include, for
example, driving while intoxicated, problems at work caused by
excessive drinking, and relationship problems caused by excessive
drinking by the subject.
[0105] The term "psychosocial management program," as used herein,
relates to the use of various types of counseling and management
techniques used to supplement the combination pharmacotherapy
treatment of addictive and alcohol-related diseases and
disorders.
[0106] "Reduce"--see "inhibit".
[0107] The term "reduction in drinking", as used herein, refers to
a decrease in drinking according to one or more of the measurements
of drinking such as heavy drinking, number of drinks/day, number of
drinks/drinking day, etc.
[0108] The term "regulate" refers to either stimulating or
inhibiting a function or activity of interest.
[0109] A "sample," as used herein, refers to a biological sample
from a subject, including, but not limited to, normal tissue
samples, diseased tissue samples, biopsies, blood, saliva, feces,
semen, tears, and urine. A sample can also be any other source of
material obtained from a subject which contains cells, tissues, or
fluid of interest as interpreted in the context of the claim and
the type of assay to be performed using that sample.
[0110] By "small interfering RNAs (siRNAs)" is meant, inter alia,
an isolated dsRNA molecule comprising both a sense and an
anti-sense strand. In one aspect, it is greater than 10 nucleotides
in length. siRNA also refers to a single transcript that has both
the sense and complementary antisense sequences from the target
gene, e.g., a hairpin. siRNA further includes any form of dsRNA
(proteolytically cleaved products of larger dsRNA, partially
purified RNA, essentially pure RNA, synthetic RNA, recombinantly
produced RNA) as well as altered RNA that differs from naturally
occurring RNA by the addition, deletion, substitution, and/or
alteration of one or more nucleotides.
[0111] By the term "specifically binds," as used herein, is meant a
molecule which recognizes and binds a specific molecule, but does
not substantially recognize or bind other molecules in a sample, or
it means binding between two or more molecules as in part of a
cellular regulatory process, where the molecules do not
substantially recognize or bind other molecules in a sample.
[0112] The term "standard," as used herein, refers to something
used for comparison. For example, it can be a known standard agent
or compound which is administered or added and used for comparing
results when adding a test compound, or it can be a standard
parameter or function which is measured to obtain a control value
when measuring an effect of an agent or compound on a parameter or
function. Standard can also refer to an "internal standard," such
as an agent or compound which is added at known amounts to a sample
and is useful in determining such things as purification or
recovery rates when a sample is processed or subjected to
purification or extraction procedures before a marker of interest
is measured. Internal standards are often a purified marker of
interest which has been labeled, such as with a radioactive
isotope, allowing it to be distinguished from an endogenous
marker.
[0113] The term "one standard drink," as used herein, is 0.5 oz of
absolute alcohol, equivalent to 10 oz of beer, 4 oz of wine, or 1
oz of 100-proof liquor.
[0114] A "subject" of diagnosis or treatment is a mammal, including
a human.
[0115] The term "subject comprises a predisposition to the early
onset of alcoholism," as used herein, refers to a subject who has,
or is characterized by, a predisposition to the early onset of
alcoholism.
[0116] The term "symptom," as used herein, refers to any morbid
phenomenon or departure from the normal in structure, function, or
sensation, experienced by the patient and indicative of disease. In
contrast, a sign is objective evidence of disease. For example, a
bloody nose is a sign. It is evident to the patient, doctor, nurse
and other observers.
[0117] As used herein, the term "treating" may include prophylaxis
of the specific disease, disorder, or condition, or alleviation of
the symptoms associated with a specific disease, disorder or
condition and/or preventing or eliminating the symptoms. A
"prophylactic" treatment is a treatment administered to a subject
who does not exhibit signs of a disease or exhibits only early
signs of the disease for the purpose of decreasing the risk of
developing pathology associated with the disease. "Treating" is
used interchangeably with "treatment" herein.
[0118] A "therapeutic" treatment is a treatment administered to a
subject who exhibits signs of pathology for the purpose of
diminishing or eliminating those signs.
[0119] A "therapeutically effective amount" of a compound is that
amount of compound which is sufficient to provide a beneficial
effect to the subject to which the compound is administered.
[0120] The term "pharmaceutically-acceptable salt" refers to salts
which retain the biological effectiveness and properties of the
compounds of the present invention and which are not biologically
or otherwise undesirable. In many cases, the compounds of the
present invention are capable of forming acid and/or base salts by
virtue of the presence of amino and/or carboxyl groups or groups
similar thereto.
Embodiments
[0121] The polymorphisms identified herein also include their
related miRNA, mRNA, ncRNA, or protein expression, levels, or
states of function, or other biochemical products or chemical
associations, which may serve as biomarkers.
[0122] In an aspect, a method of treating an addictive disease or
disorder is provided, comprising: administering to a patient in
need thereof a therapeutically effective amount of an antagonist of
the serotonin receptor 5-HT3, wherein the patient's serotonin
transporter gene SLC6A4 is known to have at least one, including
two, three, four, five or more, of rs1176719 (including the AA
genotype), rs1150226 (including the AG genotype), rs17614942
(including the AC genotype), rs1042173 (including the TT genotype),
rs1176713 (including the GG genotype), LL genotype of 5-HTTLPR, or
any combination thereof. For example, the patient's serotonin
transporter gene SLC6A4 is known to have rs1176719 and rs1150226;
rs1176719, rs1150226 and rs17614942; rs1176719, rs1150226,
5-HTTLPR, and rs1042173; rs1176719, rs1150226, rs17614942,
5-HTTLPR, and rs1042173; rs1176719, rs1150226, rs1176713, 5-HTTLPR,
and rs1042173; rs1176719, rs1150226, rs17614942, 5-HTTLPR,
rs1042173; rs1176719 and rs1176713; rs1176719, rs1176713, 5-HTTLPR,
and rs1042173; rs1176719, rs1176713, rs17614942, 5-HTTLPR, and
rs1042173; rs1176713, 5-HTTLPR, and rs1042173; rs1176713,
rs1150226, 5-HTTLPR, rs1042173; rs1176713, rs17614942, 5-HTTLPR,
and rs1042173; rs1176713, rs1150226, rs17614942, 5-HTTLPR, and
rs1042173; rs1150226, rs1176719, rs17614942 and rs1176713;
rs1150226, rs1176719 and rs1176713; rs1150226, rs17614942 and
rs1176713; and rs1176719, rs17614942 and rs1176713. At any of the
above, the genotype can be AA, AT, AC, AG, TT, TA, TG, TC, CC, CA,
CG, CT, GG, GC, GT, GA or LL, LS or SS.
[0123] In an aspect, a method of treating an addictive disease or
disorder is provided, comprising: administering to a patient in
need thereof a therapeutically effective amount of an antagonist of
the serotonin receptor 5-HT.sub.3, wherein the patient's serotonin
transporter gene SLC6A4 is known to have a genotype selected from
sets (a)-(q): [0124] (a.) the AA genotype of rs1176719 and the AG
genotype of rs1150226; [0125] (b.) the AA genotype of rs1176719 and
the AG genotype of rs1150226 and the AC genotype of rs17614942;
[0126] (c.) the AA genotype of rs1176719 and the AG genotype of
rs1150226 and the LL genotype of 5-HTTLPR, and the TT genotype of
rs1042173; [0127] (d.) the AA genotype of rs1176719 and the AG
genotype of rs1150226 and the AC genotype of rs17614942 and the LL
genotype of 5-HTTLPR, and the TT genotype of rs1042173; [0128] (e.)
the AA genotype of rs1176719 and the AG genotype of rs1150226 and
the GG genotype of rs1176713 and the LL genotype of 5-HTTLPR, and
the TT genotype of rs1042173; [0129] (f.) the AA genotype of
rs1176719 and the AG genotype of rs1150226 and the AC genotype of
rs17614942 and the GG genotype of rs1176713 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; [0130] (g.) the AA
genotype of rs1176719 and the GG genotype of rs1176713; [0131] (h.)
the AA genotype of rs1176719 and the GG genotype of rs1176713 and
the LL genotype of 5-HTTLPR, and the TT genotype of rs1042173;
[0132] (i.) the AA genotype of rs1176719 and the GG genotype of
rs1176713 and the AC genotype of rs17614942 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; [0133] (j.) the GG
genotype of rs1176713 and the LL genotype of 5-HTTLPR, and the TT
genotype of rs1042173; [0134] (k.) the GG genotype of rs1176713 and
the AG genotype of rs1150226 and the LL genotype of 5-HTTLPR, and
the TT genotype of rs1042173; [0135] (l.) the GG genotype of
rs1176713 and the AC genotype of rs17614942 and the LL genotype of
5-HTTLPR, and the TT genotype of rs1042173; [0136] (m.) the GG
genotype of rs1176713 and the AG genotype of rs1150226 and the AC
genotype of rs17614942 and the LL genotype of 5-HTTLPR, and the TT
genotype of rs1042173; [0137] (n.) the AG genotype of rs1150226 and
the AA genotype of rs1176719 and the AC genotype of rs17614942 and
the GG genotype of rs1176713; [0138] (o.) the AG genotype of
rs1150226 and the AA genotype of rs1176719 and the GG genotype of
rs1176713; [0139] (p.) the AG genotype of rs1150226 and the AC
genotype of rs17614942 and the GG genotype of rs1176713; and,
[0140] (q.) the AA genotype of rs1176719 and the AC genotype of
rs17614942 and the GG genotype of rs1176713.
[0141] In another aspect, the patient is known to have a genotype
of set (a).
[0142] In another aspect, the patient is known to have a genotype
of set (b).
[0143] In another aspect, the patient is known to have a genotype
of set (c).
[0144] In another aspect, the patient is known to have a genotype
of set (d).
[0145] In another aspect, the patient is known to have a genotype
of set (e).
[0146] In another aspect, the patient is known to have a genotype
of set (f).
[0147] In another aspect, the patient is known to have a genotype
of set (g).
[0148] In another aspect, the patient is known to have a genotype
of set (h).
[0149] In another aspect, the patient is known to have a genotype
of set (i).
[0150] In another aspect, the patient is known to have a genotype
of set (j).
[0151] In another aspect, the patient is known to have a genotype
of set (k).
[0152] In another aspect, the patient is known to have a genotype
of set (l).
[0153] In another aspect, the patient is known to have a genotype
of set (m).
[0154] In another aspect, the patient is known to have a genotype
of set (n).
[0155] In another aspect, the patient is known to have a genotype
of set (O).
[0156] In another aspect, the patient is known to have a genotype
of set (p).
[0157] In another aspect, the patient is known to have a genotype
of set (q).
[0158] In another aspect, a method of treating an addictive disease
or disorder is provided, comprising: administering to a patient in
need thereof a therapeutically effective amount of an antagonist of
the serotonin receptor 5-HT.sub.3, wherein the patient's serotonin
transporter gene SLC6A4 is known to have the AA or AG genotype of
rs1150226.
[0159] In another aspect, a method of treating an addictive disease
or disorder is provided, comprising: administering to a patient in
need thereof a therapeutically effective amount of an antagonist of
the serotonin receptor 5-HT.sub.3, wherein the patient's serotonin
transporter gene SLC6A4 is known to have the GG genotype of
rs1150226 and the AA or GG genotype of rs1176719.
[0160] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
comprising: testing the biological sample of the patient for at
least one of genotype sets (a)-(e):
[0161] (a) the AA genotype of rs1176719;
[0162] (b) the AG genotype of rs1150226;
[0163] (c) the AC genotype of rs17614942;
[0164] (d) the GG genotype of rs1176713; and,
[0165] (e) the LL genotype of 5-HTTLPR and the TT genotype of
rs1042173.
[0166] In another aspect, the biological sample is (a) tested for
at least two of genotype sets (a)-(e).
[0167] In another aspect, the biological sample is tested for at
least three of genotype sets (a)-(e).
[0168] In another aspect, the biological sample is tested for at
least four of genotype sets (a)-(e).
[0169] In another aspect, the biological sample is tested for all
five of genotype sets (a)-(e).
[0170] In another aspect, the biological sample is tested for a
combination of genotypes selected from one of groups
(I)-(XXVI):
[0171] (I.) (a)+(b)
[0172] (II.) (a)+(c)
[0173] (III.) (a)+(d)
[0174] (IV.) (a)+(e)
[0175] (V.) (b)+(c)
[0176] (VI.) (b)+(d)
[0177] (VII.) (b)+(e)
[0178] (VIII.) (c)+(d)
[0179] (IX.) (c)+(e)
[0180] (X.) (d)+(e)
[0181] (XI.) (a)+(b)+(c)
[0182] (XII.) (a)+(b)+(d)
[0183] (XIII.) (a)+(b)+(e)
[0184] (XIV.) (a)+(c)+(d)
[0185] (XV.) (a)+(c)+(e)
[0186] (XVI.) (a)+(d)+(e)
[0187] (XVII.) (b)+(c)+(d)
[0188] (XVIII.) (b)+(c)+(e)
[0189] (XIX.) (b)+(d)+(e)
[0190] (XX.) (c)+(d)+(e)
[0191] (XXI.) (a)+(b)+(c)+(d)
[0192] (XXIII.) (a)+(b)+(c)+(e)
[0193] (XXIII.) (a)+(b)+(d)+(e)
[0194] (XXIV.) (a)+(c)+(d)+(e)
[0195] (XXV.) (b)+(c)+(d)+(e)
[0196] (XXVI.) (a)+(b)+(c)+(d)+(e)
[0197] In another aspect, method of genotype testing further
comprises: publishing the results of the testing.
[0198] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
consisting essentially of: testing the biological sample of the
patient for at least one of genotype sets (a)-(e).
[0199] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
consisting of: testing the biological sample of the patient for at
least one of genotype sets (a)-(e).
[0200] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
comprising: testing the biological sample of the patient for at
least one of genotype sets (b)-(e):
[0201] (b) the AG genotype of rs1150226;
[0202] (c) the AC genotype of rs17614942;
[0203] (d) the GG genotype of rs1176713; and,
[0204] (e) the LL genotype of 5-HTTLPR and the TT genotype of
rs1042173.
[0205] In another aspect, the biological sample is tested for at
least two of genotype sets (b)-(e).
[0206] In another aspect, the biological sample is tested for at
least three of genotype sets (b)-(e).
[0207] In another aspect, the biological sample is tested for all
four of genotype sets (b)-(e).
[0208] In another aspect, the biological sample is tested for a
combination of genotypes selected from one of groups (i)-(xi):
[0209] i. (b)+(c)
[0210] ii. (b)+(d)
[0211] iii. (b)+(e)
[0212] iv. (c)+(d)
[0213] v. (c)+(e)
[0214] vi. (d)+(e)
[0215] vii. (b)+(c)+(d)
[0216] viii. (b)+(c)+(e)
[0217] ix. (b)+(d)+(e)
[0218] x. (c)+(d)+(e)
[0219] xi. (b)+(c)+(d)+(e)
[0220] In another aspect, method of genotype testing, further
comprises: publishing the results of the testing.
[0221] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
consisting essentially of: testing the biological sample of the
patient for at least one of genotype sets (b)-(e).
[0222] In another aspect, the present invention provides a method
for determining the genotypes of a biological sample of a patient,
consisting of: testing the biological sample of the patient for at
least one of genotype sets (b)-(e).
[0223] Publishing can include printing the results on a readable
medium (e.g., paper) or communicating the results electronically
(e.g., an electronic message made available via an e-mail, text
message, phone message, or to a computing device).
[0224] The biological sample is any sample from a patient that
contains genetic information capable of being tested for at least
one of the listed genotypes. Examples include saliva (e.g., a
buccal swab), semen, and blood.
[0225] The genotype testing can be performed according to known
methods, which include, dynamic allele-specific hybridization
(DASH), molecular beacons, high-density oligonucleotide SNP arrays,
restriction fragment length polymorphism (RFLP), PCR-based methods
(e.g., tetra primer ARMS-PCR), flap endonuclease methodology,
primer extension methodology (e.g., Illumina's Infinium
technology), 5'-nuclease methodology (e.g., Taq DNA polymerase's
5'-nuclease (e.g., Applied Biosystems Taqman.RTM. allelic
discrimination assay)), oligonucleotide ligase assay, single strand
conformation polymorphism, temperature gradient gel
electrophoresis, denaturing high performance liquid chromatography,
and capillary electrophoresis (e.g., Applied Bio systems
SNPlex.RTM. technology).
[0226] Examples of the antagonist of the serotonin receptor
5-HT.sub.3 include ondansetron, tropisetron, granisetron,
palonosetron, dolasetron, and metocclopromide.
[0227] In another aspect, the antagonist of the serotonin receptor
5-HT.sub.3 is ondansetron.
[0228] Examples of the dosage of the antagonist of the serotonin
receptor 5-HT.sub.3 (e.g., ondansetron) include: (a) about 0.1-1000
.mu.g/kg per application; (b) about 1 .mu.g/kg; (c) about 2
.mu.g/kg; (d) about 3 .mu.g/kg; (e) about 4 .mu.g/kg; (f) about 5
.mu.g/kg; (g) about 6 .mu.g/kg; (h) about 7 .mu.g/kg; (i) about 8
.mu.g/kg; (j) about 9 .mu.g/kg; (k) about 10, about 11, about 12,
about 13, about 14, about 15, about 16, about 17, about 18, about
19, about 20, about 21, about 22, about 23, about 24, about 25,
about 26, about 27, about 28, about 29, about 30, about 35, about
40, about 45, about 50, about 55, about 60, about 65, about 70,
about 75, about 80, about 90, to about 100 .mu.g/kg; and, (l) about
100, about 200, about 300, about 400, about 500, about 600, about
700, about 800, about 900, to about 1000 .mu.g/kg.
[0229] Examples of the timing of administration include
administering: (a) once a day, (b) twice a day, (c) once a week,
(d) twice a week, (e) once a month, (f) twice a month, (g) once
every 3 months, and (h) once every 6 months.
[0230] In another aspect, the addictive disease or disorder is
selected from the group consisting of alcohol-related diseases and
disorders, obesity-related diseases and disorders, eating
disorders, impulse control disorders, nicotine-related disorders,
amphetamine-related disorders, methamphetamine-related disorders,
cannabis-related disorders, cocaine-related disorders, hallucinogen
use disorders, inhalant-related disorders, benzodiazepine abuse or
dependence related disorders, opioid-related disorders, gambling,
sexual disorders, computer use related disorders, and electronic
use related disorders.
[0231] In another aspect, the addictive disease or disorder is an
alcohol-related disease or disorder.
[0232] In another aspect, the alcohol-related disease or disorder
is selected from the group consisting of early onset alcoholism,
late onset alcoholism, alcohol-induced psychotic disorder with
delusions, alcohol abuse, heavy drinking, excessive drinking,
problem drinking, alcohol intoxication, alcohol withdrawal, alcohol
intoxication delirium, alcohol withdrawal delirium, alcohol-induced
persisting dementia, alcohol-induced persisting amnestic disorder,
alcohol dependence, alcohol-induced psychotic disorder with
hallucinations, alcohol-induced mood disorder, alcohol-induced or
associated bipolar disorder, alcohol-induced or associated post
traumatic stress disorder, alcohol-induced anxiety disorder,
alcohol-induced sexual dysfunction, alcohol-induced sleep disorder,
alcohol-induced or associated gambling disorder, alcohol-induced or
associated sexual disorder, alcohol-related disorder not otherwise
specified, alcohol intoxication, and alcohol withdrawal.
[0233] In another aspect, the alcohol-related disease or disorder
is early onset alcoholism. In another aspect, the alcohol-related
disease or disorder is late onset alcoholism.
[0234] In another aspect, the response from the treatment,
comprises: a reduction in drinking. Examples of reduction in
drinking include, but are not limited to reduction of (a) heavy
drinking, (b) excessive drinking, (c) drinks/day, (d) percentage of
subjects not drinking heavily, and (e) drinks/drinking day.
Examples of reduction in drinking also include, but are not limited
to, effective treatment of (A) alcohol abuse (as defined in
DSM-IV), (B) alcohol dependence (as defined in DSM-IV), and (C)
alcohol use disorder (as defined in DSM-V). Examples of reduction
in drinking also include, but are not limited to increasing the (I)
percentage of subjects with no heavy drinking, (II) percentage of
subjects who are abstinent, and (III) days abstinent. Examples of
reduction in drinking also include, but are not limited to
maintaining (i) reduced drinking, (ii) reduced heavy drink, (iii)
reduced binge drinking, and (iv) abstinence.
[0235] In another aspect, the method reduces the quantity of
alcohol consumed compared with the amount of alcohol consumed
before said treatment or compared with a control subject not
receiving said treatment. In another aspect, the alcohol
consumption comprises heavy drinking or excessive drinking.
[0236] In another aspect, the method improves the physical or
psychological sequelae associated with alcohol consumption compared
with a control subject not receiving said treatment.
[0237] In another aspect, the method increases the abstinence rate
of said subject compared with a control subject not receiving said
treatment.
[0238] In another aspect, the method reduces the average level of
alcohol consumption compared with the level before said treatment
or compared with a control subject not receiving said
treatment.
[0239] In another aspect, the method reduces alcohol consumption
and increases abstinence compared with the alcohol consumption and
abstinence before said treatment or compared with a control subject
not receiving said treatment.
[0240] In another aspect, the subject is submitted to a
psychosocial management program.
[0241] In another aspect, the psychosocial management program is
selected from the group consisting of Brief Behavioral Compliance
Enhancement Treatment; Cognitive Behavioral Coping Skills Therapy;
Motivational Enhancement Therapy; Twelve-Step Facilitation Therapy;
Combined Behavioral Intervention; Medical Management;
psychoanalysis; psychodynamic treatment; Biopsychosocial, Report,
Empathy, Needs, Direct Advice and Assessment; and,
computer-delivered education or treatment.
[0242] In another aspect, the subject is further subjected to
hypnosis or acupuncture.
[0243] In another aspect, effective amounts of at least two
antagonists are administered.
[0244] In another aspect, effective amounts of at least three
antagonists are administered.
[0245] In another aspect, the present invention provides a method
of selecting patients with an addictive disease or disorder who
will be responsive to treatment with an antagonist of the serotonin
receptor 5-HT.sub.3, comprising: determining whether the patient's
serotonin transporter gene SLC6A4 has a genotype selected from sets
(a)-(q).
[0246] In another aspect, the method of selecting, further
comprises: administering an antagonist of the serotonin receptor
5-HT.sub.3 to the patient, if the patient satisfies one of sets
(a)-(q).
[0247] In another aspect, the present invention provides a method
of treating a patient with an addictive disease or disorder,
comprising: [0248] (a.) determining whether the patient, in the
patient's serotonin transporter gene SLC6A4, has one of genotype
sets (a)-(q); and, [0249] (b.) administering an antagonist of the
serotonin receptor 5-HT.sub.3 to the patient, if the patient
satisfies one of (a)-(q).
[0250] In another aspect, the present invention provides a method
of predicting a response to treatment for an addictive disease or
disorder in a subject comprising: determining whether the patient,
in the patient's serotonin transporter gene SLC6A4, has one of
genotypes (a)-(q).
[0251] In another aspect, the present invention further comprises:
administering to a patient in need thereof a therapeutically
effective amount of a second therapeutic agent (e.g., topiramate
and/or naltrexone).
[0252] The present invention further encompasses the use of
adjunctive treatments and therapy such as psychosocial management
regimes, hypnosis, and acupuncture.
[0253] One of ordinary skill in the art will appreciate that in
some instances a patient being treated for an addictive disorder is
not necessarily dependent. Such patients include, for example,
patients who abuse alcohol, drink heavily, drink excessively, are
problem drinkers, or are heavy drug users. The present invention
provides compositions and methods for treating or preventing these
behaviors in non-dependent patients.
[0254] In another aspect, the present invention provides
compositions and methods for improving the physical or
psychological sequelae associated with alcohol consumption compared
with a control subject not receiving the treatment.
[0255] In another aspect, the present invention provides
compositions and methods for increasing the abstinence rate of a
subject compared with a control subject not receiving the
treatment.
[0256] In another aspect, the present invention provides
compositions and methods for reducing the average level of alcohol
consumption in a subject compared with the level of alcohol
consumption before the treatment or compared with the level of
alcohol consumption by a control subject not receiving the
treatment.
[0257] In another aspect, the present invention provides
compositions and methods for reducing alcohol consumption and for
increasing abstinence compared with the alcohol consumption by the
subject before treatment or with a control subject not receiving
the treatment.
[0258] In another aspect, the present invention provides
compositions and methods for treating a subject with a
predisposition to early-onset alcoholism.
[0259] In another aspect, the present invention provides
compositions and methods for treating a subject with a
predisposition to late-onset alcoholism.
[0260] One of ordinary skill in the art will appreciate that there
are multiple parameters or characteristics of alcohol consumption
which may characterize a subject afflicted with an alcohol-related
disease or disorder. It will also be appreciated that combination
therapies may be effective in treating more than one parameter, and
that there are multiple ways to analyze the effectiveness of
treatment. The parameters analyzed when measuring alcohol
consumption or frequency of alcohol consumption include, but are
not limited to, heavy drinking days, number of heavy drinking days,
average drinking days, number of drinks per day, days of
abstinence, number of individuals not drinking heavily or abstinent
over a given time period, and craving. Both subjective and
objective measures can be used to analyze the effectiveness of
treatment. For example, a subject can self-report according to
guidelines and procedures established for such reporting. The
procedures can be performed at various times before, during, and
after treatment. Additionally, assays are available for measuring
alcohol consumption. These assays include breath alcohol meter
readings, measuring serum CDT and GGT levels, and measuring 5-HTOL
urine levels.
[0261] When combination therapy is used, the timing of
administration of the combination can vary. First example, the
first compound and a second compound can be administered nearly
simultaneously. Other examples include (a) the first compound being
administered prior to the second compound, (b) the first compound
being administered subsequent to the second compound, and (c) if
three or more compounds are administered, one of ordinary skill in
the art will appreciate that the three or more compounds can be
administered simultaneously or in varying order.
[0262] In another aspect, the present invention provides a method
of treating, comprising administering at least two compounds
selected from the group consisting of topiramate, ondansetron, and
naltrexone. In one aspect, topiramate and ondansetron are used.
[0263] Because the serotonin system has intimate connections and is
modulated in the brain by other neurotransmitters, particularly
dopamine, GABA, glutamate, opioids, and cannabinoid, the present
invention also encompasses the use of medications and drugs that
affect the structure and function of these other neurotransmitters
when combined with any serotonergic agent (including ondansetron).
In one aspect, the combination is efficacious for individuals with
the polymorphisms described herein. In another aspect, the present
invention provides compositions, compounds and methods that are
associated with these co-modulating neurotransmitters (i.e.,
dopamine, GABA, glutamate, opioids, and cannabinoid), including,
but not limited to, topiramate, baclofen, gabapentin, naltrexone,
nalmefene, and rimonabant-in combination with any serotonergic
agent (including but not limited to ondansetron, selective
serotonin re-uptake blockers, and other agonists or antagonists of
other serotonin receptors or moieties) can produce a therapeutic
effect to improve the clinical outcomes for individuals who use,
abuse, misuse, or are dependent on alcohol. Because abused drugs
are predicted to work through similar mechanisms, the present
invention further provides combinations of these co-modulating
drugs with any other serotonergic agent to be used to treat
individuals with any substance use, abuse, misuse, dependence, or
habit-forming behavior with the polymorphisms described herein or
anywhere else in the serotonergic or co-modulating neurotransmitter
systems (i.e., dopamine, GABA, glutamate, opioids, and
cannabinoid), either alone or in combination.
[0264] In a further aspect, the combination pharmacotherapy
treatment is used in conjunction with behavioral modification or
therapy.
[0265] The dosage of the active compound(s) being administered will
depend on the condition being treated, the particular compound, and
other clinical factors such as age, sex, weight, and health of the
subject being treated, the route of administration of the
compound(s), and the type of composition being administered
(tablet, gel cap, capsule, solution, suspension, inhaler, aerosol,
elixir, lozenge, injection, patch, ointment, cream, etc.). It is to
be understood that the present invention has application for both
human and veterinary use.
[0266] The drugs can be administered in formulations that contain
all drugs being used, or the drugs can be administered separately.
In some cases, it is anticipated that multiple doses/times of
administration will be useful. The present invention further
provides for varying the length of time of treatment.
[0267] In another aspect, the present invention provides a
composition comprising: an antagonist of the serotonin receptor
5-HT.sub.3. In another aspect, the composition further comprises a
second therapeutic agent. In another aspect, the composition
further comprises a third therapeutic agent.
[0268] Topiramate (C.sub.12H.sub.21NO.sub.8S; IUPAC name:
2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate;
CAS Registry No. 97240-79-4) is disclosed herein as a drug useful
in combination drug therapy. Examples of topiramate dosages
include: (a) about 15, about 25, about 35, about 35, about 55,
about 65, about 75, about 85, about 95, about 100, about 200, about
300, about 400, about 500, about 600, about 700, about 800, about
900, about 1000, about 1100, about 1200, about 1300, about 1400,
about 1500, about 1600, about 1700, about 1800, about 1900, about
2000, about 2100, about 2200, about 2300, about 2400, to about 2500
mg/day, (b) about 25-1000 mg/day, (c) about 50, about 60, about 70,
about 80, about 90, about 100, about 200, about 300, about 400, to
about 500 mg/day, (f) about 275 mg/day, (g) about 1 mg/day, (h)
about 1 mg/kg, (i) about 10 mg/kg, (j) about 100 mg/kg, and
[0269] (k) about 0.1, about 0.2, about 0.3, about 0.4, about 0.5,
about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 2,
about 3, about 4, about 5, about 6, about 7, about 8, about 9,
about 10, about 20, about 30, about 40, about 50, about 60, about
70, about 80, about 90 to about 100 mg/kg/day.
[0270] An aspect of psychotropic drugs is to produce weight gain.
These increases in weight gain can induce a range of metabolic
problems including abnormal sugar, fat, and carbohydrate
metabolism. Because topiramate can cause weight loss and improve
endocrine function, it is proposed herein that topiramate may be
used to ameliorate weight gain caused by other psychotropic drugs
with which it is combined as well as alcohol and any other abused
drugs.
[0271] An adverse event of topiramate is cognitive impairment. In
the general population, this is reported by 2.4% of individuals who
take topiramate (Johnson & Johnson Pharmaceutical Research
& Development. Investigator's Brochure: Topiramate
(RWJ-17021-000), 10th ed.; December 2005). In the substance abuse
field, the occurrence rate of cognitive impairment is about 18.7%
(Johnson B A, Ait-Daoud N, Bowden C L et al. Oral topiramate for
treatment of alcohol dependence: a randomized controlled trial.
Lancet 2003, 361:1677-1685). Topiramate-associated cognitive
effects are due to its anti-glutaminergic properties. It is,
therefore, not obvious that ondansetron, a serotonin-3 receptor
antagonist, will alleviate these complaints of cognitive
impairment. Ondansetron appears to have cholinergic effects,
perhaps through interactions with the GABA system that seem to
ameliorate topiramate-associated cognitive impairment. Hence, the
rate of cognitive impairment reported by this triple combination
would be less than that for topiramate on its own.
[0272] Ondansetron (C.sub.18H.sub.19N.sub.3O; CAS Registry No.
99614-02-5; IUPAC name:
9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydrocarbazol-
-4-one) is disclosed herein as a drug useful alone or as part of
combination drug therapy. Ondansetron is a 5-HT.sub.3 receptor
antagonist and has functionally opposite effects to SSRIs and
blocks serotonin agonism at the 5-HT.sub.3 receptor. The dosage and
treatment regimen for administering ondansetron when it is being
used as one compound of a combination therapy can be varied based
on the other drug or drugs with which it is being administered, or
based on other criteria such as the age, sex, health, and weight of
the subject.
[0273] The present invention further provides for the use of other
drugs such as naltrexone (C.sub.20H.sub.23NO.sub.4;
17-(Cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6-one
hydrochloride; CAS Registry No. 16590-41-3) as part of the drug
combination therapy disclosed herein. Examples of naltrexone
dosages include: (a) 10 mg/day, (b) 50 mg/day, (c) 100 mg/day, (d)
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,
150, 200, 250, to 300 mg per application, (e) 10-50 mg per
application, and (f) 25 mg per application.
[0274] Naltrexone also has adverse events--nausea and
vomiting--that reduce compliance to it. Indeed, about 15% of
individuals in alcohol trials are unable to tolerate a naltrexone
dose of 50 mg/day. This has led to the development of depot
formulations that release naltrexone slowly to reduce the incidence
of nausea and vomiting. Nevertheless, these depot formulation(s)
appear to have similar compliance rates to the oral form of the
medication. Ondansetron reduces nausea and decreases vomiting by
slowing gut motility. Therefore, a combination that adds
ondansetron to naltrexone will diminish the nausea and vomiting
caused by naltrexone. This is a therapeutic advance because many
more people will be able to tolerate the treatment due to increased
compliance, and higher doses than the typically administered
naltrexone dose of 50 mg/day can be given to improve the
therapeutic response.
[0275] The present invention provides for multiple methods for
delivering the compounds of the invention. The compounds may be
provided, for example, as pharmaceutical compositions in multiple
formats as well, including, but not limited to, tablets, capsules,
pills, lozenges, syrups, ointments, creams, elixirs, suppositories,
suspensions, inhalants, injections (including depot preparations),
and liquids.
[0276] The invention further encompasses treating and preventing
obesity, i.e., for affecting weight loss and preventing weight
gain. Obesity is a disorder characterized by the accumulation of
excess fat in the body. Obesity has been recognized as one of the
leading causes of disease and is emerging as a global problem.
Increased instances of complications such as hypertension,
non-insulin-dependent diabetes mellitus, arteriosclerosis,
dyslipidemia, certain forms of cancer, sleep apnea, and
osteoarthritis have been related to increased instances of obesity
in the general population In one aspect, the invention encompasses
administering to a subject in need thereof a combination therapy to
induce weight loss. For example, subjects having a BMI of greater
than about 25 (25.0-29.9 is considered overweight) are identified
for treatment. In one aspect, the individuals have a BMI of greater
than 30 (30 and above is considered obese). In another aspect, a
subject may be targeted for treatment to prevent weight gain. In
one embodiment, an individual is instructed to take at least one
compound of the invention at least once daily and at least a second
compound of the invention at least once daily. The compound may be
in the form of, for example, a tablet, a lozenge, a liquid, etc. In
one aspect, a third compound is also taken daily. In one
embodiment, compounds may be taken more than once daily. In another
embodiment, compounds are taken less than once daily. The dosages
can be determined based on what is known in the art or what is
determined to be best for a subject of that age, sex, health,
weight, etc. Compounds useful for treating obesity according to the
methods of the invention, include, but are not limited to,
topiramate, naltrexone, and ondansetron. See Weber (U.S. Pat. Pub.
No. 20070275970) and McElroy (U.S. Pat. No. 6,323,236) for
additional information and techniques for administering drugs
useful for treating obesity, addictive disorders, and impulse
control disorders, and for determining dosage schemes.
[0277] Pharmaceutically-acceptable base addition salts can be
prepared from inorganic and organic bases. Salts derived from
inorganic bases, include by way of example only, 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, such as alkyl amines, dialkyl
amines, trialkyl amines, substituted alkyl amines, di(substituted
alkyl) amines, tri(substituted alkyl) amines, alkenyl amines,
dialkenyl amines, trialkenyl amines, substituted alkenyl amines,
di(substituted alkenyl) amines, tri(substituted alkenyl) amines,
cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amines,
trisubstituted cycloalkyl amines, cycloalkenyl amines,
di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted
cycloalkenyl amines, disubstituted cycloalkenyl amines,
trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,
triaryl amines, heteroaryl amines, diheteroaryl amines,
triheteroaryl amines, heterocyclic amines, diheterocyclic amines,
triheterocyclic amines, mixed di- and tri-amines where at least two
of the substituents on the amine are different and are selected
from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,
heterocyclic, and the like. Also included are amines where the two
or three substituents, together with the amino nitrogen, form a
heterocyclic or heteroaryl group. Examples of suitable amines
include, by way of example only, isopropylamine, trimethyl amine,
diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine,
arginine, histidine, caffeine, procaine, hydrabamine, choline,
betaine, ethylenediamine, glucosamine, N-alkylglucamines,
theobromine, purines, piperazine, piperidine, morpholine,
N-ethylpiperidine, and the like. 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, dialkyl carboxamides, and
the like.
[0278] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
Psychosocial Intervention and Management
[0279] The drug combination treatments of the present invention can
be further supplemented by providing to subjects a form of
psychosocial intervention and/or management, such as Brief
Behavioral Compliance Enhancement Treatment (BBCET). BBCET, a
standardized, manual-guided, brief (i.e., delivered in about 15
minutes), psycho social adherence enhancement procedure, emphasizes
that medication compliance is crucial to changing participants'
drinking behavior (Johnson et al., Brief Behavioral Compliance
Enhancement Treatment (BBCET) manual. In: Johnson B A, Ruiz P,
Galanter M, eds. Handbook of clinical alcoholism treatment.
Baltimore, Md.: Lippincott Williams & Wilkins; 2003, 282-301).
Brief interventions (Edwards et al., J. Stud. Alcohol. 1977,
38:1004-1031) such as BBCET, have been shown to benefit treatment
of alcohol dependence.
BBCET was modeled on the clinical management condition in the
National Institute of Mental Health collaborative depression trial,
which was used as an adjunct to the medication condition for that
study (Fawcett et al. Psychopharmacol Bull. 1987, 23:309-324).
BBCET has been used successfully as the psychosocial treatment
platform in the single-site and multi-site efficacy trials of
topiramate for treating alcohol dependence (Johnson et al., Lancet.
2003, 361:1677-1685; Johnson et al., JAMA, 2007, 298:1641-1651). It
is delivered by trained clinicians, including nurse practitioners
and other non-specialists. Uniformity and consistency of BBCET
delivery are ensured by ongoing training and supervision. BBCET is
copyrighted material (Johnson et al., Brief Behavioral Compliance
Enhancement Treatment (BBCET) manual. In: Johnson B A, Ruiz P,
Galanter M, eds. Handbook of clinical alcoholism treatment.
Baltimore, Md.: Lippincott Williams & Wilkins; 2003,
282-301).
[0280] The present invention further encompasses the use of
psychosocial management regimens other than BBCET, including, but
not limited to, Cognitive Behavioral Coping Skills Therapy (CBT)
(Project MATCH Research Group. Matching Alcoholism Treatments to
Client Heterogeneity: Project MATCH posttreatment drinking
outcomes. J Stud Alcohol. 1997; 58:7-29), Motivational Enhancement
Therapy (MET) (Project MATCH Research Group. Matching Alcoholism
Treatments to Client Heterogeneity: Project MATCH posttreatment
drinking outcomes. J. Stud. Alcohol. 1997, 58:7-29), Twelve-Step
Facilitation Therapy (TSF) (Project MATCH Research Group. Matching
Alcoholism Treatments to Client Heterogeneity: Project MATCH
posttreatment drinking outcomes. J. Stud. Alcohol. 1997, 58:7-29),
Combined Behavioral Intervention (CBI), (Anton et al., JAMA, 2006,
295:2003-2017) Medical Management (MM) (Anton et al., JAMA, 2006,
295:2003-2017), or the Biopsychosocial, Report, Empathy, Needs,
Direct advice, and Assessment (BRENDA) model (Garbutt et al., JAMA,
2005, 293:1617-1625). The present invention further encompasses the
use of alternative interventions such as hypnosis or acupuncture to
assist in treating an addictive disease or disorder.
[0281] The psychosocial management programs can be used before,
during, and after treating the subject with the combination drug
therapy of the invention.
[0282] One of ordinary skill in the art will recognize that
psychosocial management procedures, as well as alternative
interventions such as hypnosis or acupuncture, can also be used in
conjunction with combination drug therapy to treat addictive and
impulse-related disorders other than alcohol-related diseases and
disorders.
[0283] The present invention further encompasses the use of
combination pharmacotherapy and behavioral (psychosocial)
intervention or training to treat other addictive and/or impulse
control disorders.
[0284] For example, binge eating disorder (BED) is characterized by
discrete periods of binge eating during which large amounts of food
are consumed in a discrete period of time and a sense of control
over eating is absent. Persons with bulimia nervosa have been
reported to have electroencephalographic abnormalities and to
display reduced binge eating in response to the anti-epileptic drug
phenyloin. In addition, in controlled trials in patients with
epilepsy, topiramate was associated with suppression of appetite
and weight loss unrelated to binge eating. Ondansetron has been
shown to reduce binge eating.
[0285] BED is a subset of a larger classification of mental
disorders broadly defined as Impulse Control Disorders (ICDs)
characterized by harmful behaviors performed in response to
irresistible impulses. It has been suggested that ICDs may be
related to obsessive-compulsive disorder or similarly, maybe forms
of obsessive-compulsive disorders. It has also been hypothesized
that ICDs may be related to mood disorder or may be forms of
affective spectrum disorder, a hypothesized family of disorders
sharing at least one common physiologic abnormality with major
depression. In the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV), the essential feature of an ICD is the failure
to resist an impulse, drive, or temptation to perform an act that
is harmful to the person or to others. For most ICDs, the
individual feels an increasing sense of tension or arousal before
committing the act, and then experiences pleasure, gratification,
or release at the time of committing the act. After the act is
performed, there may or may not be regret or guilt. ICDs are listed
in a residual category, the ICDs Not Elsewhere Classified, which
includes intermittent explosive disorder (IED), kleptomania,
pathological gambling, pyromania, trichotillomania, and ICDs not
otherwise specified (NOS). Examples of ICDs NOS are compulsive
buying or shopping, repetitive self-mutilation, nonparaphilic
sexual addictions, severe nail biting, compulsive skin picking,
personality disorders with impulsive features, attention
deficit/hyperactivity disorder, eating disorders characterized by
binge eating, and substance use disorders.
[0286] Many drugs can cause physical and/or psychological
addiction. Those most well known drugs include opiates, such as
heroin, opium and morphine; sympathomimetics, including cocaine and
amphetamines; sedative-hypnotics, including alcohol,
benzodiazepines, and barbiturates; and nicotine, which has effects
similar to opioids and sympathomimetics. Drug addiction is
characterized by a craving or compulsion for taking the drug and an
inability to limit its intake. Additionally, drug dependence is
associated with drug tolerance, the loss of effect of the drug
following repeated administration, and withdrawal, the appearance
of physical and behavioral symptoms when the drug is not consumed.
Sensitization occurs if repeated administration of a drug leads to
an increased response to each dose. Tolerance, sensitization, and
withdrawal are phenomena evidencing a change in the central nervous
system resulting from continued use of the drug. This change
motivates the addicted individual to continue consuming the drug
despite serious social, legal, physical, and/or professional
consequences.
[0287] Attention-deficit disorders include, but are not limited to,
Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive
Type; Attention-Deficit/Hyperactivity Disorder, Predominately
Hyperactivity-Impulsive Type; Attention-Deficit/Hyperactivity
Disorder, Combined Type; Attention-Deficit/Hyperactivity Disorder
not otherwise specified (NOS); Conduct Disorder; Oppositional
Defiant Disorder; and Disruptive Behavior Disorder not otherwise
specified (NOS).
[0288] Depressive disorders include, but are not limited to, Major
Depressive Disorder, Recurrent; Dysthymic Disorder; Depressive
Disorder not otherwise specified (NOS); and Major Depressive
Disorder, Single Episode.
[0289] Parkinson's disease includes, but is not limited to,
neuroleptic-induced parkinsonism.
[0290] Addictive disorders include, but are not limited to, eating
disorders, impulse control disorders, alcohol-related disorders,
nicotine-related disorders, amphetamine-related disorders,
cannabis-related disorders, cocaine-related disorders, gambling,
sexual disorders, hallucinogen use disorders, inhalant-related
disorders, and opioid-related disorders, all of which are further
subclassified as listed below.
[0291] Eating disorders include, but are not limited to, Bulimia
Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; and Eating
Disorder not otherwise specified (NOS).
[0292] Impulse control disorders include, but are not limited to,
Intermittent Explosive Disorder, Kleptomania, Pyromania,
Pathological Gambling, Trichotillomania, and Impulse Control
Disorder not otherwise specified (NOS).
[0293] Nicotine-related disorders include, but are not limited to,
Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related
Disorder not otherwise specified (NOS).
[0294] Amphetamine-related disorders include, but are not limited
to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine
Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication
Delirium, Amphetamine-Induced Psychotic Disorder with delusions,
Amphetamine-Induced Psychotic Disorders with hallucinations,
Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety
Disorder, Amphetamine-Induced Sexual Dysfunction,
Amphetamine-Induced Sleep Disorder, Amphetamine Related Disorder
not otherwise specified (NOS), Amphetamine Intoxication, and
Amphetamine Withdrawal.
[0295] Cannabis-related disorders include, but are not limited to,
Cannabis Dependence; Cannabis Abuse; Cannabis Intoxication;
Cannabis Intoxication Delirium; Cannabis-Induced Psychotic
Disorder, with delusions; Cannabis-Induced Psychotic Disorder with
hallucinations; Cannabis-Induced Anxiety Disorder; Cannabis-Related
Disorder not otherwise specified (NOS); and Cannabis
Intoxication.
[0296] Cocaine-related disorders include, but are not limited to,
Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine
Withdrawal, Cocaine Intoxication Delirium, Cocaine-Induced
Psychotic Disorder with delusions, Cocaine-Induced Psychotic
Disorders with hallucinations, Cocaine-Induced Mood Disorder,
Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual
Dysfunction, Cocaine-Induced Sleep Disorder, Cocaine-Related
Disorder not otherwise specified (NOS), Cocaine Intoxication, and
Cocaine Withdrawal.
[0297] Hallucinogen-use disorders include, but are not limited to,
Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen
Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication
Delirium, Hallucinogen-Induced Psychotic Disorder with delusions,
Hallucinogen-Induced Psychotic Disorder with hallucinations,
Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety
Disorder, Hallucinogen-Induced Sexual Dysfunction,
Hallucinogen-Induced Sleep Disorder, Hallucinogen Related Disorder
not otherwise specified (NOS), Hallucinogen Intoxication, and
Hallucinogen Persisting Perception Disorder (Flashbacks).
[0298] Inhalant-related disorders include, but are not limited to,
Inhalant Dependence; Inhalant Abuse; Inhalant Intoxication;
Inhalant Intoxication Delirium; Inhalant-Induced Psychotic
Disorder, with delusions; Inhalant-Induced Psychotic Disorder with
hallucinations; Inhalant-Induced Anxiety Disorder; Inhalant-Related
Disorder not otherwise specified (NOS); and Inhalant
Intoxication.
[0299] Opioid-related disorders include, but are not limited to,
Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid
Intoxication Delirium, Opioid-Induced Psychotic Disorder, with
delusions, Opioid-Induced Psychotic Disorder with hallucinations,
Opioid-Induced Anxiety Disorder, Opioid-Related Disorder not
otherwise specified (NOS), Opioid Intoxication, and Opioid
Withdrawal.
[0300] Tic disorders include, but are not limited to, Tourette's
Disorder, Chronic Motor or Vocal Tic Disorder, Transient Tic
Disorder, Tic Disorder not otherwise specified (NOS), Stuttering,
Autistic Disorder, and Somatization Disorder.
[0301] The present invention further encompasses the treatment of
at least two addictive diseases or disorders or impulse control
disorders simultaneously. For example, the present invention
provides for the simultaneous treatment of alcohol related
disorders and weight control (see Examples).
[0302] The present invention also encompasses the use of the
compounds and combination therapies of the invention in
circumstances where mandatory treatment may be applicable. For
example, a court may require that a subject be treated or take part
in a treatment program using compounds or combination therapies of
the invention as part of a mandated therapy related to alcohol
abuse, excessive drinking, drug use, etc. More particularly, the
invention encompasses forensic uses where a court would require a
subject who has been convicted of driving under the influence to be
subjected to the methods of the invention as part of a condition of
bail, probation, treatment, etc.
[0303] The invention also encompasses the use of pharmaceutical
compositions comprising compounds of the invention to practice the
methods of the invention, the compositions comprising at least one
appropriate compound and a pharmaceutically-acceptable carrier.
[0304] The pharmaceutical compositions useful for practicing the
invention may be, for example, administered to deliver a dose of
between 1 ng/kg/day and 100 mg/kg/day.
[0305] Pharmaceutical compositions that are useful in the methods
of the invention may be administered, for example, systemically in
oral solid formulations, or as ophthalmic, suppository, aerosol,
topical or other similar formulations. In addition to the
appropriate compounds, such pharmaceutical compositions may contain
pharmaceutically-acceptable carriers and other ingredients known to
enhance and facilitate drug administration. Other possible
formulations, such as nanoparticles, liposomes, resealed
erythrocytes, and immunologically based systems may also be used to
administer an appropriate compound, or an analog, modification, or
derivative thereof according to the methods of the invention.
[0306] Compounds which are identified using any of the methods
described herein may be formulated and administered to a subject
for treatment of the diseases disclosed herein. One of ordinary
skill in the art will recognize that these methods will be useful
for other diseases, disorders, and conditions as well.
[0307] The invention encompasses the preparation and use of
pharmaceutical compositions comprising a compound useful for
treatment of the diseases disclosed herein as an active ingredient.
Such a pharmaceutical composition may consist of the active
ingredient alone, in a form suitable for administration to a
subject, or the pharmaceutical composition may comprise the active
ingredient and one or more pharmaceutically acceptable carriers,
one or more additional ingredients, or some combination of these.
The active ingredient may be present in the pharmaceutical
composition in the form of a physiologically acceptable ester or
salt, such as in combination with a physiologically acceptable
cation or anion, as is well known in the art.
[0308] The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter
developed in the art of pharmacology. In general, such preparatory
methods include the step of bringing the active ingredient into
association with a carrier or one or more other accessory
ingredients, and then, if desirable, shaping or packaging the
product into a desired single- or multi-dose unit.
[0309] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for ethical administration to
humans, it will be understood by the skilled artisan that such
compositions are generally suitable for administration to animals
of all sorts. Modification of pharmaceutical compositions suitable
for administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design and
perform such modification with merely ordinary, if any,
experimentation. Subjects to which administration of the
pharmaceutical compositions of the invention is contemplated
include, but are not limited to, humans and other primates, mammals
including commercially relevant mammals such as cattle, pigs,
horses, sheep, cats, and dogs, and birds including commercially
relevant birds such as chickens, ducks, geese, and turkeys.
[0310] One type of administration encompassed by the methods of the
invention is parenteral administration, which includes, but is not
limited to, administration of a pharmaceutical composition by
injection of the composition, by application of the composition
through a surgical incision, by application of the composition
through a tissue-penetrating non-surgical wound, and the like. In
particular, parenteral administration is contemplated to include,
but is not limited to, subcutaneous, intraperitoneal,
intramuscular, and intrasternal injection, and kidney dialytic
infusion techniques
[0311] Pharmaceutical compositions that are useful in the methods
of the invention may be prepared, packaged, or sold in formulations
suitable for oral, rectal, vaginal, parenteral, topical, pulmonary,
intranasal, inhalation, buccal, ophthalmic, intrathecal or another
route of administration. Other contemplated formulations include
projected nanoparticles, liposomal preparations, resealed
erythrocytes containing the active ingredient, and
immunologically-based formulations.
[0312] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in bulk, as a single unit dose, or as a
plurality of single unit doses. As used herein, a "unit dose" is a
discrete amount of the pharmaceutical composition comprising a
predetermined amount of the active ingredient. The amount of the
active ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject, or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0313] The relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and any additional ingredients
in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the subject
treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0314] In addition to the active ingredient, a pharmaceutical
composition of the invention may further comprise one or more
additional pharmaceutically active agents. Particularly
contemplated additional agents include anti-emetics and scavengers
such as cyanide and cyanate scavengers.
[0315] Controlled- or sustained-release formulations of a
pharmaceutical composition of the invention may be made using
conventional technology.
[0316] A formulation of a pharmaceutical composition of the
invention suitable for oral administration may be prepared,
packaged, or sold in the form of a discrete solid dose unit
including, but not limited to, a tablet, a hard or soft capsule, a
cachet, a troche, or a lozenge, each containing a predetermined
amount of the active ingredient. Other formulations suitable for
oral administration include, but are not limited to, a powdered or
granular formulation, an aqueous or oily suspension, an aqueous or
oily solution, or an emulsion.
[0317] As used herein, an "oily" liquid is one which comprises a
carbon-containing liquid molecule and which exhibits a less polar
character than water.
[0318] A tablet comprising the active ingredient may, for example,
be made by compressing or molding the active ingredient, optionally
with one or more additional ingredients. Compressed tablets may be
prepared by compressing, in a suitable device, the active
ingredient in a free-flowing form such as a powder or granular
preparation, optionally mixed with one or more of a binder, a
lubricant, an excipient, a surface active agent, and a dispersing
agent. Molded tablets may be made by molding, in a suitable device,
a mixture of the active ingredient, a pharmaceutically acceptable
carrier, and at least sufficient liquid to moisten the mixture.
Pharmaceutically acceptable excipients used in the manufacture of
tablets include, but are not limited to, inert diluents,
granulating and disintegrating agents, binding agents, and
lubricating agents. Known dispersing agents include, but are not
limited to, potato starch and sodium starch glycollate. Known
surface active agents include, but are not limited to, sodium
lauryl sulphate. Known diluents include, but are not limited to,
calcium carbonate, sodium carbonate, lactose, microcrystalline
cellulose, calcium phosphate, calcium hydrogen phosphate, and
sodium phosphate. Known granulating and disintegrating agents
include, but are not limited to, corn starch and alginic acid.
Known binding agents include, but are not limited to, gelatin,
acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and
hydroxypropyl methylcellulose. Known lubricating agents include,
but are not limited to, magnesium stearate, stearic acid, silica,
and talc.
[0319] Tablets may be non-coated or may be coated using known
methods to achieve delayed disintegration in the gastrointestinal
tract of a subject, thereby providing sustained release and
absorption of the active ingredient. By way of example, a material
such as glyceryl monostearate or glyceryl distearate may be used to
coat tablets. Further by way of example, tablets may be coated
using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and
4,265,874 to form osmotically-controlled release tablets. Tablets
may further comprise a sweetening agent, a flavoring agent, a
coloring agent, a preservative, or some combination of these in
order to provide pharmaceutically elegant and palatable
preparation.
[0320] Hard capsules comprising the active ingredient may be made
using a physiologically degradable composition, such as gelatin.
Such hard capsules comprise the active ingredient, and may further
comprise additional ingredients including, for example, an inert
solid diluent such as calcium carbonate, calcium phosphate, or
kaolin.
[0321] Soft gelatin capsules comprising the active ingredient may
be made using a physiologically degradable composition, such as
gelatin. Such soft capsules comprise the active ingredient, which
may be mixed with water or an oil medium such as peanut oil, liquid
paraffin, or olive oil.
[0322] Lactulose can also be used as a freely erodible filler and
is useful when the compounds of the invention are prepared in
capsule form.
[0323] Liquid formulations of a pharmaceutical composition of the
invention which are suitable for oral administration may be
prepared, packaged, and sold either in liquid form or in the form
of a dry product intended for reconstitution with water or another
suitable vehicle prior to use.
[0324] Liquid suspensions may be prepared using conventional
methods to achieve suspension of the active ingredient in an
aqueous or oily vehicle. Aqueous vehicles include, for example,
water and isotonic saline. Oily vehicles include, for example,
almond oil, oily esters, ethyl alcohol, vegetable oils such as
arachis, olive, sesame, or coconut oil, fractionated vegetable
oils, and mineral oils such as liquid paraffin. Liquid suspensions
may further comprise one or more additional ingredients including,
but not limited to, suspending agents, dispersing or wetting
agents, emulsifying agents, demulcents, preservatives, buffers,
salts, flavorings, coloring agents, and sweetening agents. Oily
suspensions may further comprise a thickening agent. Known
suspending agents include, but are not limited to, sorbitol syrup,
hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone,
gum tragacanth, gum acacia, and cellulose derivatives such as
sodium carboxymethylcellulose, methylcellulose, and
hydroxypropylmethylcellulose. Known dispersing or wetting agents
include, but are not limited to, naturally occurring phosphatides
such as lecithin, condensation products of an alkylene oxide with a
fatty acid, with a long chain aliphatic alcohol, with a partial
ester derived from a fatty acid and a hexitol, or with a partial
ester derived from a fatty acid and a hexitol anhydride (e.g.,
polyoxyethylene stearate, heptadecaethyleneoxycetanol,
polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan
monooleate, respectively). Known emulsifying agents include, but
are not limited to, lecithin and acacia. Known preservatives
include, but are not limited to, methyl, ethyl, or n-propyl para
hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening
agents include, for example, glycerol, propylene glycol, sorbitol,
sucrose, and saccharin. Known thickening agents for oily
suspensions include, for example, beeswax, hard paraffin, and cetyl
alcohol.
[0325] In one aspect, a preparation in the form of a syrup or
elixir or for administration in the form of drops may comprise
active ingredients together with a sweetener, which can be
calorie-free, and which may further include methylparaben or
propylparaben as antiseptics, a flavoring and a suitable color.
[0326] Liquid solutions of the active ingredient in aqueous or oily
solvents may be prepared in substantially the same manner as liquid
suspensions, the primary difference being that the active
ingredient is dissolved, rather than suspended in the solvent.
Liquid solutions of the pharmaceutical composition of the invention
may comprise each of the components described with regard to liquid
suspensions, it being understood that suspending agents will not
necessarily aid dissolution of the active ingredient in the
solvent. Aqueous solvents include, for example, water and isotonic
saline. Oily solvents include, for example, almond oil, oily
esters, ethyl alcohol, vegetable oils such as arachis, olive,
sesame, or coconut oil, fractionated vegetable oils, and mineral
oils such as liquid paraffin.
[0327] Powdered and granular formulations of a pharmaceutical
preparation of the invention may be prepared using known methods.
Such formulations may be administered directly to a subject, used,
for example, to form tablets, to fill capsules, or to prepare an
aqueous or oily suspension or solution by addition of an aqueous or
oily vehicle thereto. Each of these formulations may further
comprise one or more of a dispersing or wetting agent, a suspending
agent, and a preservative. Additional excipients, such as fillers
and sweetening, flavoring, or coloring agents, may also be included
in these formulations.
[0328] A pharmaceutical composition of the invention may also be
prepared, packaged, or sold in the form of oil in water emulsion or
a water-in-oil emulsion. The oily phase may be a vegetable oil such
as olive or arachis oil, a mineral oil such as liquid paraffin, or
a combination of these. Such compositions may further comprise one
or more emulsifying agents including naturally occurring gums such
as gum acacia or gum tragacanth, naturally occurring phosphatides
such as soybean or lecithin phosphatide, esters or partial esters
derived from combinations of fatty acids and hexitol anhydrides
such as sorbitan monooleate, and condensation products of such
partial esters with ethylene oxide such as polyoxyethylene sorbitan
monooleate. These emulsions may also contain additional ingredients
including, for example, sweetening or flavoring agents.
[0329] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for rectal
administration. Such a composition may be in the form of, for
example, a suppository, a retention enema preparation, and a
solution for rectal or colonic irrigation.
[0330] Suppository formulations may be made by combining the active
ingredient with a non irritating pharmaceutically acceptable
excipient which is solid at ordinary room temperature (i.e. about
20.degree. C.) and which is liquid at the rectal temperature of the
subject (i.e. about 37.degree. C. in a healthy human). Suitable
pharmaceutically acceptable excipients include, but are not limited
to, cocoa butter, polyethylene glycols, and various glycerides.
Suppository formulations may further comprise various additional
ingredients including, but not limited to, antioxidants and
preservatives.
[0331] Retention enema preparations or solutions for rectal or
colonic irrigation may be made by combining the active ingredient
with a pharmaceutically acceptable liquid carrier. As is well known
in the art, enema preparations may be administered using, and may
be packaged within, a delivery device adapted to the rectal anatomy
of the subject. Enema preparations may further comprise various
additional ingredients including, but not limited to, antioxidants
and preservatives.
[0332] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for vaginal
administration. Such a composition may be in the form of, for
example, a suppository, an impregnated or coated
vaginally-insertable material such as a tampon, a douche
preparation, or gel or cream or a solution for vaginal
irrigation.
[0333] Methods for impregnating or coating a material with a
chemical composition are known in the art, and include, but are not
limited to methods of depositing or binding a chemical composition
onto a surface, methods of incorporating a chemical composition
into the structure of a material during the synthesis of the
material (i.e. such as with a physiologically degradable material),
and methods of absorbing an aqueous or oily solution or suspension
into an absorbent material, with or without subsequent drying.
[0334] Douche preparations or solutions for vaginal irrigation may
be made by combining the active ingredient with a pharmaceutically
acceptable liquid carrier. As is well known in the art, douche
preparations may be administered using, and may be packaged within,
a delivery device adapted to the vaginal anatomy of the subject.
Douche preparations may further comprise various additional
ingredients including, but not limited to, antioxidants,
antibiotics, antifungal agents, and preservatives.
[0335] As used herein, "parenteral administration" of a
pharmaceutical composition includes any route of administration
characterized by physical breaching of a tissue of a subject and
administration of the pharmaceutical composition through the breach
in the tissue. Parenteral administration thus includes, but is not
limited to, administration of a pharmaceutical composition by
injection of the composition, by application of the composition
through a surgical incision, by application of the composition
through a tissue-penetrating non-surgical wound, and the like. In
particular, parenteral administration is contemplated to include,
but is not limited to, subcutaneous, intraperitoneal,
intramuscular, and intrasternal injection, and kidney dialytic
infusion techniques.
[0336] Formulations of a pharmaceutical composition suitable for
parenteral administration comprise the active ingredient combined
with a pharmaceutically acceptable carrier, such as sterile water
or sterile isotonic saline. Such formulations may be prepared,
packaged, or sold in a form suitable for bolus administration or
for continuous administration. Injectable formulations may be
prepared, packaged, or sold in unit dosage form, such as in ampules
or in multi-dose containers containing a preservative. Formulations
for parenteral administration include, but are not limited to,
suspensions, solutions, emulsions in oily or aqueous vehicles,
pastes, and implantable sustained-release or biodegradable
formulations. Such formulations may further comprise one or more
additional ingredients including, but not limited to, suspending,
stabilizing, or dispersing agents. In one embodiment of a
formulation for parenteral administration, the active ingredient is
provided in dry (i.e., powder or granular) form for reconstitution
with a suitable vehicle (e.g., sterile pyrogen free water) prior to
parenteral administration of the reconstituted composition.
[0337] The pharmaceutical compositions may be prepared, packaged,
or sold in the form of a sterile injectable aqueous or oily
suspension or solution. This suspension or solution may be
formulated according to the known art, and may comprise, in
addition to the active ingredient, additional ingredients such as
the dispersing agents, wetting agents, or suspending agents
described herein. Such sterile injectable formulations may be
prepared using a non-toxic parenterally acceptable diluent or
solvent, such as water or 1,3-butane diol, for example. Other
acceptable diluents and solvents include, but are not limited to,
Ringer's solution, isotonic sodium chloride solution, and fixed
oils such as synthetic mono- or di-glycerides. Other
parentally-administrable formulations which are useful include
those which comprise the active ingredient in microcrystalline
form, in a liposomal preparation, or as a component of a
biodegradable polymer systems. Compositions for sustained release
or implantation may comprise pharmaceutically acceptable polymeric
or hydrophobic materials such as an emulsion, an ion exchange
resin, a sparingly soluble polymer, or a sparingly soluble
salt.
[0338] Formulations suitable for topical administration include,
but are not limited to, liquid or semi-liquid preparations such as
liniments, lotions, oil in water or water in oil emulsions such as
creams, ointments or pastes, and solutions or suspensions.
Topically-administrable formulations may, for example, comprise
from about 1% to about 10% (w/w) active ingredient, although the
concentration of the active ingredient may be as high as the
solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0339] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for pulmonary
administration via the buccal cavity. Such a formulation may
comprise dry particles which comprise the active ingredient and
which have a diameter in the range from about 0.5 to about 7
nanometers, and from about 1 to about 6 nanometers. Such
compositions are conveniently in the form of dry powders for
administration using a device comprising a dry powder reservoir to
which a stream of propellant may be directed to disperse the powder
or using a self-propelling solvent/powder-dispensing container such
as a device comprising the active ingredient dissolved or suspended
in a low-boiling propellant in a sealed container. Such powders can
comprise particles wherein at least 98% of the particles by weight
have a diameter greater than 0.5 nanometers and at least 95% of the
particles by number have a diameter less than 7 nanometers. In one
embodiment, at least 95% of the particles by weight have a diameter
greater than 1 nanometer and at least 90% of the particles by
number have a diameter less than 6 nanometers. Dry powder
compositions can include include a solid fine powder diluent such
as sugar and are conveniently provided in a unit dose form.
[0340] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally, the propellant may constitute about 50% to
about 99.9% (w/w) of the composition, and the active ingredient may
constitute about 0.1% to about 20% (w/w) of the composition. The
propellant may further comprise additional ingredients such as a
liquid non-ionic or solid anionic surfactant or a solid diluent
(including those having a particle size of the same order as
particles comprising the active ingredient).
[0341] Pharmaceutical compositions of the invention formulated for
pulmonary delivery may also provide the active ingredient in the
form of droplets of a solution or suspension. Such formulations may
be prepared, packaged, or sold as aqueous or dilute alcoholic
solutions or suspensions, optionally sterile, comprising the active
ingredient, and may conveniently be administered using any
nebulization or atomization device. Such formulations may further
comprise one or more additional ingredients including, but not
limited to, a flavoring agent such as saccharin sodium, a volatile
oil, a buffering agent, a surface active agent, or a preservative
such as methylhydroxybenzoate. The droplets provided by this route
of administration may have have an average diameter in the range
from about 0.1 to about 200 nanometers.
[0342] The formulations described herein as being useful for
pulmonary delivery are also useful for intranasal delivery of a
pharmaceutical composition of the invention.
[0343] Another formulation suitable for intranasal administration
is a coarse powder comprising the active ingredient and having an
average particle from about 0.2 to about 500 micrometers. Such a
formulation is administered in the manner in which snuff is taken,
i.e., by rapid inhalation through the nasal passage from a
container of the powder held close to the nares.
[0344] Formulations suitable for nasal administration may, for
example, comprise from about as little as about 0.1% (w/w) and as
much as about 100% (w/w) of the active ingredient, and may further
comprise one or more of the additional ingredients described
herein.
[0345] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for buccal
administration. Such formulations may, for example, be in the form
of tablets or lozenges made using conventional methods, and may,
for example, comprise about 0.1% to about 20% (w/w) active
ingredient, the balance comprising an orally dissolvable or
degradable composition and, optionally, one or more of the
additional ingredients described herein. Alternately, formulations
suitable for buccal administration may comprise a powder or an
aerosolized or atomized solution or suspension comprising the
active ingredient. Such powdered, aerosolized, or atomized
formulations, when dispersed, can have an average particle or
droplet size in the range from about 0.1 to about 200 nanometers,
and may further comprise one or more of the additional ingredients
described herein.
[0346] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for
ophthalmic administration. Such formulations may, for example, be
in the form of eye drops including, for example, a 0.1% to 1.0%
(w/w) solution or suspension of the active ingredient in an aqueous
or oily liquid carrier. Such drops may further comprise buffering
agents, salts, or one or more other of the additional ingredients
described herein. Other opthalmically-administrable formulations
which are useful include those which comprise the active ingredient
in microcrystalline form or in a liposomal preparation.
[0347] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for
intramucosal administration. The present invention provides for
intramucosal administration of compounds to allow passage or
absorption of the compounds across mucosa. Such type of
administration is useful for absorption orally (gingival,
sublingual, buccal, etc.), rectally, vaginally, pulmonary, nasally,
etc.
[0348] In some aspects, sublingual administration has an advantage
for active ingredients which in some cases, when given orally, are
subject to a substantial first pass metabolism and enzymatic
degradation through the liver, resulting in rapid metabolization
and a loss of therapeutic activity related to the activity of the
liver enzymes that convert the molecule into inactive metabolites,
or the activity of which is decreased because of this
bioconversion.
[0349] In some cases, a sublingual route of administration is
capable of producing a rapid onset of action due to the
considerable permeability and vascularization of the buccal mucosa.
Moreover, sublingual administration can also allow the
administration of active ingredients which are not normally
absorbed at the level of the stomach mucosa or digestive mucosa
after oral administration, or alternatively which are partially or
completely degraded in acidic medium after ingestion of, for
example, a tablet.
[0350] Sublingual tablet preparation techniques known from the
prior art are usually prepared by direct compression of a mixture
of powders comprising the active ingredient and excipients for
compression, such as diluents, binders, disintegrating agents and
adjuvants. In an alternative method of preparation, the active
ingredient and the compression excipients can be dry- or
wet-granulated beforehand. In one aspect, the active ingredient is
distributed throughout the mass of the tablet. WO 00/16750
describes a tablet for sublingual use that disintegrates rapidly
and comprises an ordered mixture in which the active ingredient is
in the form of microparticles which adhere to the surface of
water-soluble particles that are substantially greater in size,
constituting a support for the active microparticles, the
composition also comprising a mucoadhesive agent. WO 00/57858
describes a tablet for sublingual use, comprising an active
ingredient combined with an effervescent system intended to promote
absorption, and also a pH-modifier.
[0351] The compounds of the invention can be prepared in a
formulation or pharmaceutical composition appropriate for
administration that allows or enhances absorption across mucosa.
Mucosal absorption enhancers include, but are not limited to, a
bile salt, fatty acid, surfactant, or alcohol. In specific
embodiments, the permeation enhancer can be sodium cholate, sodium
dodecyl sulphate, sodium deoxycholate, taurodeoxycholate, sodium
glycocholate, dimethylsulfoxide or ethanol. In a further
embodiment, a compound of the invention can be formulated with a
mucosal penetration enhancer to facilitate delivery of the
compound. The formulation can also be prepared with pH optimized
for solubility, drug stability, and absorption through mucosa such
as nasal mucosa, oral mucosa, vaginal mucosa, respiratory, and
intestinal mucosa.
[0352] To further enhance mucosal delivery of pharmaceutical agents
within the invention, formulations comprising the active agent may
also contain a hydrophilic low molecular weight compound as a base
or excipient. Such hydrophilic low molecular weight compounds
provide a passage medium through which a water-soluble active
agent, such as a physiologically active peptide or protein, may
diffuse through the base to the body surface where the active agent
is absorbed. The hydrophilic low molecular weight compound
optionally absorbs moisture from the mucosa or the administration
atmosphere and dissolves the water-soluble active peptide. The
molecular weight of the hydrophilic low molecular weight compound
is generally not more than 10000 and in one embodiment not more
than 3000. Exemplary hydrophilic low molecular weight compounds
include polyol compounds, such as oligo-, di- and monosaccharides
such as sucrose, mannitol, lactose, L-arabinose, D-erythrose,
D-ribose, D-xylose, D-mannose, D-galactose, lactulose, cellobiose,
gentibiose, glycerin, and polyethylene glycol. Other examples of
hydrophilic low molecular weight compounds useful as carriers
within the invention include N-methylpyrrolidone, and alcohols
(e.g., oligovinyl alcohol, ethanol, ethylene glycol, propylene
glycol, etc.). These hydrophilic low molecular weight compounds can
be used alone or in combination with one another or with other
active or inactive components of the intranasal formulation.
[0353] When a controlled-release pharmaceutical preparation of the
present invention further contains a hydrophilic base, many options
are available for inclusion. Hydrophilic polymers such as a
polyethylene glycol and polyvinyl pyrrolidone, sugar alcohols such
as D-sorbitol and xylitol, saccharides such as sucrose, maltose,
lactulose, D-fructose, dextran, and glucose, surfactants such as
polyoxyethylene-hydrogenated castor oil, polyoxyethylene
polyoxypropylene glycol, and polyoxyethylene sorbitan higher fatty
acid esters, salts such as sodium chloride and magnesium chloride,
organic acids such as citric acid and tartaric acid, amino acids
such as glycine, beta-alanine, and lysine hydrochloride, and
aminosaccharides such as meglumine are given as examples of the
hydrophilic base. In one embodiment, polyethylene glycol, sucrose,
polyvinyl pyrrolidone and polyethylene glycol can be used. One or a
combination of two or more hydrophilic bases can be used in the
present invention.
[0354] The present invention contemplates pulmonary, nasal, or oral
administration through an inhaler. In one embodiment, delivery from
an inhaler can be a metered dose.
[0355] An inhaler is a device for patient self-administration of at
least one compound of the invention comprising a spray inhaler
(e.g., a nasal, oral, or pulmonary spray inhaler) containing an
aerosol spray formulation of at least one compound of the invention
and a pharmaceutically acceptable dispersant. In one aspect, the
device is metered to disperse an amount of the aerosol formulation
by forming a spray that contains a dose of at least one compound of
the invention effective to treat a disease or disorder encompassed
by the invention. The dispersant may be a surfactant, such as, but
not limited to, polyoxyethylene fatty acid esters, polyoxyethylene
fatty acid alcohols, and polyoxyethylene sorbitan fatty acid
esters. Phospholipid-based surfactants also may be used.
[0356] In other embodiments, the aerosol formulation is provided as
a dry powder aerosol formulation in which a compound of the
invention is present as a finely divided powder. The dry powder
formulation can further comprise a bulking agent, such as, but not
limited to, lactose, sorbitol, sucrose, and mannitol.
[0357] In another specific embodiment, the aerosol formulation is a
liquid aerosol formulation further comprising a pharmaceutically
acceptable diluent, such as, but not limited to, sterile water,
saline, buffered saline and dextrose solution.
[0358] In further embodiments, the aerosol formulation further
comprises at least one additional compound of the invention in a
concentration such that the metered amount of the aerosol
formulation dispersed by the device contains a dose of the
additional compound in a metered amount that is effective to
ameliorate the symptoms of disease or disorder disclosed herein
when used in combination with at least a first or second compound
of the invention.
[0359] Thus, the invention provides a self administration method
for outpatient treatment of an addiction related disease or
disorder such as an alcohol-related disease or disorder. Such
administration may be used in a hospital, in a medical office, or
outside a hospital or medical office by non-medical personnel for
self administration.
[0360] Compounds of the invention will be prepared in a formulation
or pharmaceutical composition appropriate for nasal administration.
In a further embodiment, the compounds of the invention can be
formulated with a mucosal penetration enhancer to facilitate
delivery of the drug. The formulation can also be prepared with pH
optimized for solubility, drug stability, absorption through nasal
mucosa, and other considerations.
[0361] Capsules, blisters, and cartridges for use in an inhaler or
insufflator may be formulated to contain a powder mix of the
pharmaceutical compositions provided herein; a suitable powder
base, such as lactose or starch; and a performance modifier, such
as l-leucine, mannitol, or magnesium stearate. The lactose may be
anhydrous or in the form of the monohydrate. Other suitable
excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose, and trehalose. The pharmaceutical compositions
provided herein for inhaled/intranasal administration may further
comprise a suitable flavor, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium.
[0362] For administration by inhalation, the compounds for use
according to the methods of the invention are 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 drugs
and a suitable powder base such as lactose or starch.
[0363] As used herein, "additional ingredients" include, but are
not limited to, one or more of the following: excipients; surface
active agents; dispersing agents; inert diluents; granulating and
disintegrating agents; binding agents; lubricating agents;
sweetening agents; flavoring agents; coloring agents;
preservatives; physiologically degradable compositions such as
gelatin; aqueous vehicles and solvents; oily vehicles and solvents;
suspending agents; dispersing or wetting agents; emulsifying
agents, demulcents; buffers; salts; thickening agents; fillers;
emulsifying agents; antioxidants; antibiotics; antifungal agents;
stabilizing agents; and pharmaceutically acceptable polymeric or
hydrophobic materials. Other "additional ingredients" which may be
included in the pharmaceutical compositions of the invention are
known in the art and described, for example in Genaro, ed., 1985,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., which is incorporated herein by reference.
[0364] Typically, dosages of the compounds of the invention which
may be administered to an animal, including a human, range in
amount from about 1.0 .mu.g to about 100 g per kilogram of body
weight of the animal. The precise dosage administered will vary
depending upon any number of factors, including but not limited to,
the type of animal and type of disease state being treated, the age
of the animal and the route of administration. In one embodiment,
the dosage of the compound will vary from about 1 mg to about 10 g
per kilogram of body weight of the animal. In another embodiment,
the dosage will vary from about 10 mg to about 1 g per kilogram of
body weight of the animal.
[0365] The compounds may be administered to a subject as frequently
as several times daily, or it may be administered less frequently,
such as once a day, once a week, once every two weeks, once a
month, or even less frequently, such as once every several months
or even once a year or less. The frequency of the dose will be
readily apparent to the skilled artisan and will depend upon any
number of factors, such as, but not limited to, the type and
severity of the disease being treated, the type and age of the
animal, etc.
[0366] The invention also includes a kit comprising the compounds
of the invention and an instructional material that describes
administration of the compounds. In another embodiment, this kit
comprises a (e.g., sterile) solvent suitable for dissolving or
suspending the composition of the invention prior to administering
the compound to the mammal.
[0367] As used herein, an "instructional material" includes a
publication, a recording, a diagram, or any other medium of
expression that can be used to communicate the usefulness of the
compounds of the invention in the kit for effecting alleviation of
the various diseases or disorders recited herein. Optionally, or
alternately, the instructional material may describe one or more
methods of alleviating the diseases or disorders. The instructional
material of the kit of the invention may, for example, be affixed
to a container that contains a compound of the invention or be
shipped together with a container that contains the compounds.
Alternatively, the instructional material may be shipped separately
from the container with the intention that the instructional
material and the compound be used cooperatively by the
recipient.
[0368] Other methods and techniques useful for the practice of the
invention that are not described are known in the art, for example,
see International application no. PCT/US2008/064232.
[0369] Without further description, it is believed that one of
ordinary skill in the art can, using the preceding description and
the following illustrative examples, make and utilize the compounds
of the present invention and practice the claimed methods. The
following working examples, therefore, point out embodiments of the
present invention, and are not to be construed as limiting in any
way the remainder of the disclosure.
EXAMPLES
Example 1
Analysis of Gene Patterns Related to Response to Ondansetron
Treatment
[0370] Genotype data was collected from 281 patients participating
in a clinical trial wherein ondansetron was administered. Epistatic
analysis among SNPs from serotonin (SERT), 5HT-3A, and 5HT-3B
reveal that significant epistatic effect exists among the three
genes in affecting response to ondesetron treatment as measured by
drinks/drinking day (DDD), drinks/day (DD), percentage heavy
drinking days (PHDD), and percentage of days abstinent (PDA).
Combination of Either 5-HTT (LL+TT) or rs1150226 (AG) or rs1176713
(GG)
TABLE-US-00001 LL/TT or AG or GG Outcomes/Genotype combination
(90/283 = 32%) Comparison OND [40/133] vs. Placebo [50/139] Drinks
per Drinking Days -1.77 [-2.94, -0.59] (DDD) (0.003) Percentage of
Heavy Drinking Days -11.60% [-22.49, -0.71] (PHDD) (0.037)
Percentage Days of Abstinent 11.96% [1.11, 22.81] (PDA) (0.031)
Percentage of Subjects with No Heavy Odds Ratio Drinking Days
(PSNHDD) Comparison OND [8/23] vs. Placebo [3/27] Last 1 month: 0-1
HDD 2.24 [0.81, 6.19] (0.122)** DDD: (F = 8.9, p = 0.003); PHDD: (F
= 4.6, p = 0.032); PDA: (F = 3.78, p = 0.052); **p-value for
interaction between treatment and the genotype combination was
greater than 0.10
Combination of Either rs1150226 (AG) or rs17614942 (AC) or
rs1176719 (AA)
TABLE-US-00002 AG or AC or AA Outcomes/Genotype combination (70/283
= 25%) Comparison OND [34/134] vs. Placebo [36/138] Drinks per
Drinking Days -2.35 [-3.69, -1.01] (DDD) (0.0006) Percentage of
Heavy Drinking Days -18.14% [-30.30, -5.97] (PHDD) (0.004)
Percentage Days of Abstinent 12.16% [-0.07, 24.39] (PDA) (0.051)**
Percentage of Subjects with No Heavy Odds Ratio Drinking Days
(PSNHDD) Comparison OND [9/36] vs. Placebo [3/30] Last 1 month: 0-1
HDD 5.26 [1.24, 22.39] (0.025) DDD: (F = 12.2, p = 0.0005); PHDD:
(F = 8.7, p = 0.003); PDA: (F = 2.63, p = 0.105);
Results from Combined Genotypes
TABLE-US-00003 Estimated Lower Upper P- Drinks per drinking days
(DDD) Mean 95% CI 95% CI value rs1150226 (AG) in 5-HT3A: -1.81
-3.51 -0.12 0.036 OND (n = 20) vs. Placebo (n = 24) rs17614942 (AC)
in 5-HT3B: -2.73 -4.59 -0.87 0.004 OND (n = 17) vs. Placebo (n =
19) AG + AC: -2.42 -4.47 -0.36 0.021 OND (n = 14) vs. Placebo (n =
16) rs1176719 (AA) in 5-HT3A: -3.27 -5.75 -0.80 0.010 OND (n = 11)
vs. Placebo (n = 11) rs1176713 (GG) in 5-HT3A: -3.92 -7.00 -0.84
0.013 OND (n = 6) vs. Placebo (n = 9) AA + GG: -3.91 -6.99 -0.83
0.013 OND (n = 6) vs. Placebo (n = 9)
Results from Two or Three Genotypes
TABLE-US-00004 Estimated Lower Upper Drinks per drinking days (DDD)
Mean 95% CI 95% CI P-value LL/TT + AG: -3.92 -8.09 0.26 0.066 OND
(n = 5) vs. Placebo (n = 3) LL/TT + AC: -4.25 -7.87 -0.63 0.021 OND
(n = 6) vs. Placebo (n = 4) LL/TT + AG + AC: -4.05 -8.41 0.31 0.068
OND (n = 4) vs. Placebo (n = 3) LL/TT + AA: -8.50 -13.05 -3.96
0.0002 OND (n = 4) vs. Placebo (n = 3) LL/TT + GG: -7.65 -12.65
-2.64 0.003 OND (n = 3) vs. Placebo (n = 3) LL/TT + AA + GG: -7.66
-12.67 -2.65 0.003 OND (n = 3) vs. Placebo (n = 3)
[0371] Combination of LL/TT or AG or AC or AA or GG
TABLE-US-00005 LL/TT or AG or AC or AA or GG Outcomes/Genotype
combination (97/283 = 34.3%) Comparison OND [34/134] vs. Placebo
[36/138] Drinks per Drinking Days -1.66 [-2.79, -0.52] (DDD)
(0.004) Percentage of Heavy Drinking Days -11.25% [-21.66, -0.84]
(PHDD) (0.034) Percentage Days of Abstinent 8.08% [-2.40, 18.56]
(PDA) (0.131)** Percentage of Subjects with No Odds Ratio Heavy
Drinking Days (PSNHDD) Comparison OND [13/34] vs. Placebo [10/30]
Last 1 month: 0-1 HDD 2.32 [0.86, 6.25] (0.095)**
Example 2
CART Analysis of Gene Patterns Related to Response to Ondansetron
Treatment
[0372] A decision tree is a structure that can be used to divide up
a large collection of records into successively smaller sets of
records by applying a sequence of simple decision rules. One
advantage of decision tree is that the results can be easily
interpreted. CART is a popular decision tree algorithm first
published in Breiman et al 1984. CART starts by dividing data into
2 sub-groups (child nodes) that are homogeneous with respect to a
particular target variable, in our case the target variable is the
binary class label Z. By doing exhaustive search over all possible
cutoffs for all possible candidate covariates, sub-groups are
formed by identifying optimal split point for the optimal candidate
covariate. Repeat the process recursively at each child node until
one of the stopping criteria is met. In the end, CART prunes tree
to smaller optimal size using cross-validation. After the final
tree is determined, the class label (treatment) for "new subjects"
is given by running them down the tree and identifying which
terminal node they belong. The class label of the terminal node is
formed by majority vote of cases in this node, that is if the
proportion of class 1 in this node p>0.5, then the class label
is 1, otherwise is 0.
[0373] Let t denote the node, which is a region of the covariates
space. A Split denoted by s on a numeric variable Xj take the form
Xj<xji, where xji is a cut-off selected by trying all values of
Xj in the data set as candidate split points. s splits the node t
into left and right daughter nodes tL=I{Xj<xji}t and
tR=I{Xj.gtoreq.xji}t. The impurity function is used as a measure of
node homogeneity. To calculate the impact of a split, compute
increase in purity (or reduction in impurity) and choose a split
that gives maximal value over all possible splits as the best
splitter for node t. Gini criterion is the usual splitting criteria
chosen by CART for categorical target.
[0374] Decision tree keeps growing as long as a new split can be
found that improves the ability to separate the records of the
training set into more pure subsets. The full tree would not do the
best job when applied to new dataset.
[0375] The CART identifies candidate sub-trees through a process of
repeated pruning. CART relies on a concept called adjusted error
rate, AER.alpha.(T)=error rate(T)+.alpha. node count(T). This is a
measure that increases each tree(T)'s misclassification rate on the
training set by imposing a complexity penalty based on the number
of final nodes in the tree. One can form a sequence of sub-trees of
the full tree by varying the penalty value (cost complexity
parameter), .alpha. and determining the tree that minimizes the
adjusted error rate.
[0376] Data Analysis Result:
[0377] After deleting the subjects with missing data, 251 subjects
were included in the data analysis. Y=phd base90-mean(phdweek);
X=(phd base90,Onage,age,male,sert,rs1042173, . . . , rs1672717).
There are total 21 genotypes. T=1 (ondansetron) and T=0 (placebo).
The goal is to find a subgroup defined by X where the treatment
effect is significant. After transforming this problem to a
classification problem,
[0378] CART was used to find the best subgroup with decision tree
form.
[0379] The result is:
[0380] gen1=I (rs1150226=AA or AG): There are 42 subjects (17% of
251) in this subgroup. The sample mean difference of
gen1=E(Y|T=1)-E(Y|T=0)=50.9%-22.2%=28.7%.
[0381] gen2=I (rs1150226=GG)I(rs1176719=AA or AG)I(phd
base90.gtoreq.0.8663): There are 49 subjects (20% of 251) in this
subgroup. The sample mean difference of
gen2=E(Y|T=1)-E(Y|T=0)=37.6%-22.6%=15.0%.
[0382] gen=I(rs1150226=AA or AG)+I(rs1150226=GG)I(rs1176719=AA or
GG)I(phd base90.gtoreq.0.8663): There are 91 subjects (37% of 251)
in this subgroup. The sample mean difference of
gen=E(Y|T=1)-E(Y|T=0)=43.0%-22.4%=20.6%.
[0383] The overall sample mean
difference=E(Y|T=1)-E(Y|T=0)=32.1%-31.9%=0.2%
[0384] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
by reference herein in their entirety.
[0385] Headings are included herein for reference and to aid in
locating certain sections. These headings are not intended to limit
the scope of the concepts described therein under, and these
concepts may have applicability in other sections throughout the
entire specification.
[0386] While this invention has been disclosed with reference to
specific embodiments, it is apparent that other embodiments and
variations of this invention may be devised by others skilled in
the art without departing from the true spirit and scope of the
invention.
* * * * *