U.S. patent application number 11/013259 was filed with the patent office on 2005-05-12 for treatments for neurogenetic disorders, impulse control disorders, and wound healing.
This patent application is currently assigned to University of Florida. Invention is credited to Driscoll, Daniel John, Lessig, Mary Catherine, Shapira, Nathan Andrew.
Application Number | 20050101543 11/013259 |
Document ID | / |
Family ID | 22946345 |
Filed Date | 2005-05-12 |
United States Patent
Application |
20050101543 |
Kind Code |
A1 |
Shapira, Nathan Andrew ; et
al. |
May 12, 2005 |
Treatments for neurogenetic disorders, impulse control disorders,
and wound healing
Abstract
The subject invention provides methods and compositions for the
treatment of neurogenetic disorders, particularly DSM-IV impulse
control disorders such as intermittent explosive disorder,
kleptomania, pyromania, pathologic gambling, trichotillomania, and
other impulse control disorders such as compulsive buying and
problematic Internet use. In a preferred embodiment, the subject
invention provides methods for treating or controlling symptoms
associated with ADHD or PWS comprising the administration of
therapeutically effective amounts of compositions containing
compounds of the formulas I-V. In another embodiment, the subject
invention provides for methods of promoting wound healing
comprising the administration of a therapeutically effective amount
of a composition comprising the compounds of formulas I-V.
Compositions may administered to a wound site via a salve,
ointment, or as a component of a bandage or bioadhesive applied to
the site of injury. The invention also provides therapeutically
effective compositions comprising one or more of the compounds of
formulas I-V.
Inventors: |
Shapira, Nathan Andrew;
(Gainesville, FL) ; Lessig, Mary Catherine;
(Seattle, WA) ; Driscoll, Daniel John;
(Gainesville, FL) |
Correspondence
Address: |
Frank C. Eisenschenk, Ph.D.
Saliwanchik, Lloyd & Saliwanchik
A Professional Association
P.O. Box 142950
Gainesville
FL
32614-2950
US
|
Assignee: |
University of Florida
Gainesville
FL
|
Family ID: |
22946345 |
Appl. No.: |
11/013259 |
Filed: |
December 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11013259 |
Dec 15, 2004 |
|
|
|
09997447 |
Nov 30, 2001 |
|
|
|
60250113 |
Nov 30, 2000 |
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Current U.S.
Class: |
514/23 ; 514/459;
514/464; 514/517 |
Current CPC
Class: |
A61K 31/255 20130101;
A61K 31/00 20130101; A61K 31/7024 20130101; A61P 25/00 20180101;
A61K 31/18 20130101; A61K 31/357 20130101; A61K 31/351 20130101;
A61P 17/02 20180101; A61K 31/35 20130101 |
Class at
Publication: |
514/023 ;
514/464; 514/459; 514/517 |
International
Class: |
A61K 031/70; A61K
031/255; A61K 031/35; A61K 031/36 |
Claims
We claim:
1. A method of treating dermatological injury or tissue damage
comprising: a) providing an individual having a dermatological
injury or tissue damage; and b) administering, to said individual,
a therapeutically effective amount of a composition comprising a
carrier and an anticonvulsant agent of the formula: 8wherein
X.sub.1 is CH.sub.2 or oxygen; R.sub.1 is hydrogen or alkyl; and
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently hydrogen
or lower alkyl and, when X.sub.1 is CH.sub.2, R.sub.4 and R.sub.5
can combine to form a benzene ring and when X.sub.1 is oxygen,
R.sub.2 and R.sub.3 and/or R.sub.4 and R.sub.5 together may be a
methylenedioxy group of the following formula: 9wherein R.sub.6 and
R.sub.7 are the same or different and are hydrogen, lower alkyl or
are alkyl and are joined to form a cyclopentyl or cyclohexyl
ring.
2. The method according to claim 1, wherein said composition is
topically administered, orally administered, parenterally
administered or administered via injection.
3. The method according to claim 1, wherein said composition
comprises a salve, ointment, aerosol, cosmetic, liquid, tablet,
powder, capsule, or bioadhesive.
4. The method according to claim 1, wherein said composition is
administered as a component of a bandage, transdermal patch, wound
dressing, cosmetic, or bioadhesive.
5. The method according to claim 2, wherein said composition is
topically administered.
6. The method according to claim 2, wherein said composition is
orally administered.
7. The method according to claim 2, wherein said composition is
parenterally administered.
8. The method according to claim 2, wherein said composition is
administered via injection.
9. The method according to claim 1, wherein the anticonvulsant
agent of Formula I is topiramate
(2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fruc- topyranose
sulfamate).
10. The method according to claim 9, wherein the dosage of
topiramate is: a) 0.1 mg to about 400 mg; b) about 10 mg to about
200 mg; c) about 20 mg to about 100 mg; or d) about 25 mg.
11. A method of promoting wound healing comprising: a) providing an
individual having a wound; and b) administering, to said
individual, a therapeutically effective amount of a composition
comprising a carrier and an anticonvulsant agent of the formula:
10wherein X.sub.1 is CH.sub.2 or oxygen; R.sub.1 is hydrogen or
alkyl; and R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently
hydrogen or lower alkyl and, when X.sub.1 is CH.sub.2, R.sub.4 and
R.sub.5 can combine to form a benzene ring and when X.sub.1 is
oxygen, R.sub.2 and R.sub.3 and/or R.sub.4 and R.sub.5 together may
be a methylenedioxy group of the following formula: 11wherein
R.sub.6 and R.sub.7 are the same or different and are hydrogen,
lower alkyl or are alkyl and are joined to form a cyclopentyl or
cyclohexyl ring.
12. The method according to claim 11, wherein said composition is
topically administered, orally administered, parenterally
administered or administered via injection.
13. The method according to claim 11, wherein said composition
comprises a salve, ointment, aerosol, cosmetic, liquid, tablet,
powder, capsule, or bioadhesive.
14. The method according to claim 11, wherein said composition is
administered as a component of a bandage, transdermal patch, wound
dressing, cosmetic, or bioadhesive.
15. The method according to claim 12, wherein said composition is
topically administered.
16. The method according to claim 11, wherein the anticonvulsant
agent of Formula I is topiramate
(2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fruc- topyranose
sulfamate).
17. The method according to claim 16, wherein the dosage of
topiramate is: a) 0.1 mg to about 400 mg; b) about 10 mg to about
200 mg; c) about 20 mg to about 100 mg; or d) about 25 mg.
18. A method for treating or controlling neurogenetic disorders in
an individual comprising the administration of a therapeutically
effective amount of a composition comprising an anti-convulsant
agent and a pharmaceutically acceptable carrier; wherein said
neurogenetic disorders are selected from the group consisting of
hereditary ataxias and related disorders, Friedreich ataxia, ataxia
telangiectasia, olivopontine cerebellar degeneration, Ramsay Hunt
syndrome, abetalipoproteinemia, Machado-Joseph disease, familial
spastic paraparesis, movement disorders, juvenile Huntington
disease, dystonias, blepharospasm, spasmodic torticolis, tremor,
myoclonus, Hallervorden-Spatz disease, phakomatoses, neurocutaneous
syndromes, neurofibromatosis, tuberous sclerosis, Sturge-Weber, Von
Hippel-Landau disease, mitochondrial encephalomyopathies, MELAS
syndrome, Keams-Sayre, Leigh disease, hereditary disorders of nerve
and muscle, infantile spinal muscular atrophy, Charcot-Marie-Tooth
disease, hereditary sensory and autonomic neuropathies, genetic
myasthenic syndromes, metabolic myopathies, muscular dystrophies,
myotonias, Laurence-Moon-Bardet-Biedl syndrome, Aicardi,
Sjogren-Larsson syndrome, Prader-Willi syndrome, Angelman syndrome,
gouging, oppositional behavior, and obsessive ruminations.
19. The method according to claim 18, wherein said neurogenetic
disorder is obsessive ruminations.
20. The method according to claim 18, wherein said anticonvulsant
agent has the formula: 12wherein X.sub.1 is CH.sub.2 or oxygen;
R.sub.1 is hydrogen or alkyl; and R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 are independently hydrogen or lower alkyl and, when X.sub.1
is CH.sub.2, R.sub.4 and R.sub.5 can combine to form a benzene ring
and when X.sub.1 is oxygen, R.sub.2 and R.sub.3 and/or R.sub.4 and
R.sub.5 together may be a methylenedioxy group of the following
formula: 13wherein R.sub.6 and R.sub.7 are the same or different
and are hydrogen, lower alkyl or are alkyl and are joined to form a
cyclopentyl or cyclohexyl ring.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/997,447, filed Nov. 30, 2001,which claims
the benefit of U.S. Provisional Application No. 60/250,113, filed
Nov. 30, 2000, both of which are hereby incorporated by reference
herein in their entireties, including any figures, tables, or
drawings.
BACKGROUND OF THE INVENTION
[0002] As many as one-third of the approximate 3,000 known genetic
disorders are believed to have important neurological involvement.
Individually, most genetic disorders are of low incidence in the
general population; however, collectively they represent an
enormous burden on affected individuals, their families, and
society. Many neurogenetic disorders manifest themselves early in
life leading to either a premature death or to lifelong disability
with significant attendant psychological and economic
hardships.
[0003] Examples of these types of disorders include: (1) Hereditary
ataxias and related disorders such as Friedreich ataxia, ataxia
telangiectasia, olivopontine cerebellar degeneration, Ramsay Hunt
syndrome, abetalipoproteinemia, Machado-Joseph disease, and
familial spastic paraparesis; (2) Movement disorders such as
Juvenile Huntington disease, the dystonias including blepharospasm
and spasmodic torticolis, tremor, myoclonus, and Hallervorden-Spatz
disease; (3) Phakomatoses, or neurocutaneous syndromes such as
neurofibromatosis, tuberous sclerosis, Sturge-Weber, and Von
Hippel-Landau disease; (4) Mitochondrial encephalomyopathies such
as the MELAS syndrome, Keams-Sayre, and Leigh disease; (5)
Hereditary disorders of nerve and muscle such as infantile spinal
muscular atrophy, Charcot-Marie-Tooth disease, hereditary sensory
and autonomic neuropathies, genetic myasthenic syndromes, metabolic
myopathies, muscular dystrophies, and myotonias.
[0004] There are numerous other neurological disorders that are
also believed to result from genetic abnormalities such as the
Laurence-Moon-Bardet-Biedl, Aicardi, Sjogren-Larsson, Prader-Willi
and Angelman syndromes.
[0005] In addition to those diseases that have a recognizable
pattern of inheritance, there are many other neurological disorders
that seem to have, in some cases, a familial basis. These may well
represent neurogenetic disorders with multifactorial etiology. Such
diseases can be as diverse as disorders of defective cellular
migration (such as lissencephaly, heterotopias), neural tube
defects, congenital hydrocephalus, myoclonic epilepsy, attention
deficit hyperactivity disorder (ADHD), and narcolepsy.
[0006] It is estimated that ADHD affects about 4% to 6% of the U.S.
population. ADHD is not limited to children and is a chronic
lifetime disease. Approximately one-half to two-thirds of children
with ADHD will continue to have significant problems in adulthood
and experience difficulties which impact employment, familial, and
social relationships.
[0007] According to the DSM-IV (the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition) some common symptoms of
ADHD include: (1) often fails to give close attention to details or
makes careless mistakes; (2) often has difficulty sustaining
attention to tasks; (3) often does not seem to listen when spoken
to directly; (4) often fails to follow instructions carefully and
completely; (5) losing or forgetting important things; (6) feeling
restless, often fidgeting with hands or feet, or squirming; (7)
running or climbing excessively; (8) often talks excessively; (9)
often blurts out answers before hearing the whole question; and
(10) often has difficulty awaiting turn. It should be kept in mind
that the exact nature and severity of ADHD symptoms varies from
person to person however. Approximately one-third of people with
ADHD do not have the hyperactive or overactive behavior
component.
[0008] To meet diagnostic criteria, these behaviors must be
excessive, long-term, and pervasive. The behaviors must appear
before age 7, and continue for at least 6 months. A crucial element
requires that the behaviors must create a real handicap in at least
two areas of a person's life, such as school, home, work, or social
settings. These criteria set ADHD apart from the "normal"
distractibility and impulsive behavior of childhood, or the effects
of the hectic and overstressed lifestyle prevalent in our
society.
[0009] There are no reports in the literature of topiramate
specifically used to treat deficits in attention and concentration.
Carbamazepine (Tegretol) has been reported to be useful for the
treatment of patients experiencing sudden confusion and depression.
Within weeks of initiating treatment, the patients experienced
fewer incidences of sudden confusion and depression, and an
increase in attention and focus. Persinger, M. A., "Subjective
improvement following treatment with carbamazepine (Tegretol) for a
subpopulation of patients with traumatic brain injuries", Percept
Mot Skills 90:37-40 (2000). Carbamazepine has also been shown to be
effective in treating children with features of ADHD. Silva, R. R.;
Munoz, D. M.; Alpert, M., "Carbamazepine use in children and
adolescents with features of attention-deficit hyperactivity
disorder: a meta-analysis", J Am Acad Child Adolesc Psychiatry
35:352-358 (1996). In some patients, with or without intellectual
disability, being treated for refractory partial epilepsy,
gabapentin is an equally effective add-on medication. Mikati, M.
A.; Choueri, R.; Khurana, D. S.; et al., "Gabapentin in the
treatment of refractory partial epilepsy in children with
intellectual disability", J Intellect Disabil Res 42:57-62 (suppl.
1, 1998). Three dementia patients are noted in the literature to
have received topiramate in a retrospective chart review of 58
consecutive psychiatric patients receiving topiramate. Marcotte,
D., "Use of topiramate, a new anti-epileptic as a mood stabilizer",
J Affect Disorder 50:245-251 (1998). "Improvement" was rated by a
Likert scale from `worse,` to `no change,` to `minimally improved,`
to `moderately improved,` to `markedly improved.` The three
patients with dementia are described to have `moderate` or `marked`
improvement when on topiramate. The author of this chart review
hypothesized that topiramate may have some anti-psychotic
effect.
[0010] While there have been no reported efforts to use topiramate
for the treatment of impulsivity, there have been a limited number
of publications reporting the effects of anti-convulsant treatment
on impulsivity (or measures of impulsivity). These references tend
to show no change or worsening of impulsivity with anti-convulsant
treatment. For example, one large study showed no overall effect on
measures of impulsivity of anti-convulsant medication in epileptic
children (Mitchell, W. G.; Zhou, Y.; Chavez, J. M.; Guzman, B. L.,
"Reaction time, attention, and impulsivity in epilepsy", Pediatr
Neurol 8:19-24 (1992)) and another large study showed, at higher
total serum levels of anti-convulsant medication in children with
epilepsy, more impulsive errors on complex reaction time testing
(Mitchell, W. G.; Zhou. Y.; Chavez, J. M.; Guzman, B. L., "Effects
of anti-epileptic drugs on reaction time, attention, and
impulsivity in children", Pediatrics 91:101-105 (1993)). It is
notable that both of these studies focused on children with
epilepsy.
[0011] A case report from 1987 described carbamazepine being useful
for intermittent explosive disorder in a patient with Prader-Willi
Syndrome (Gupta, B. K.; Fish, D. N.; Yerevanian, B. I.,
"Carbamazepine for intermittent explosive disorder in a
Prader-Willi syndrome patient", J Clin Psychiatry 48:423 (1987)).
Carbamazepine has also been reported useful in the treatment of
pathological gambling (Haller, R.; Hinterhuber, H., "Treatment of
pathological gambling with carbamazepine", Pharmacopsychiatry
27:129 (1994)). There are also reports in the literature of
divalproex being effective for explosive mood and mood lability
(Donovan, S. J.; Stewart, J. W.; Nunes, E. V.; Quitkin, F. M.;
Parides, M.; Daniel, W.; Susser, Klein D. F., "Divalproex treatment
for youth with explosive temper and mood lability: a double-blind,
placebo-controlled crossover design", Am J Psychiatry 157:818-820
(2000)) and for a patient with kleptomania and mixed mania (Kmetz,
G. F.; McElroy, S. L.; Collin, D. J., "Response of kleptomania and
mixed mania to valproate", Am J Psychiatry 154:580-581 (1997)).
[0012] Prader-Willi Syndrome (PWS) is a neurogenetic multisystem
disorder characterized by infantile hypotonia, mental retardation,
short stature, hypogonadism, dysmorphic features, and hyperphagia
with a high risk of obesity. Also very common in PWS are behavioral
and psychiatric manifestations. These include self-injury (e.g.
gouging, nail biting, and skin picking), explosive outbursts,
oppositional behavior, obsessive ruminations, and compulsive
behaviors including hoarding, counting, and arranging. PWS is
typically a sporadic condition, which usually results from a
deletion in chromosome 15q11-q13 or maternal uniparental disomy of
chromosome 15. Glenn, C. G.; Driscoll, D. J.; Thomas, P. Y.;
Nicholls, R. D., "Genomic imprinting: potential function and
mechanisms revealed by the Prader-Willi and Angelman syndromes",
Mol Hum Reprod 3:321-332 (1997).
[0013] PWS is also a relatively common genetic condition with an
estimated prevalence of approximately 1/10,000 to 1/25,000. Glenn,
C. G.; Driscoll, D. J.; Thomas, P. Y.; Nicholls, R. D., "Genomic
imprinting: potential function and mechanisms revealed by the
Prader-Willi and Angelman syndromes", Mol Hum Reprod 3:321-332
(1997). It was first described in 1956 (Prader, A.; Labhart, A.;
Willi, H., "Ein Syndrome von adipositas, Kleinwuchs, Kryptorchismus
und Oligophrenic nach myoteniertigem zusland in neugeborenanalter",
Schwiez Med Wschr 86:1260-1 (1956)), and the physical problems
(such as the obesity related cardiovascular diseases, diabetes
mellitus, etc.) and behavioral problems result in the major causes
of morbidity and mortality. Martin, A.; Matthew, S.; Koenig, K.; et
al., "Prader-Willi syndrome", Am J Psychiatry 155:1265-1273
(1998).
[0014] Treatment for the physical, behavioral, and psychological
problems associated with PWS is complex. The mainstay of treatment
for behavioral problems including hyperphagia is behavioral
modification including strategies such as token economies or star
systems. Dykens, E. M.; Hodapp, R. M., "Treatment issues in genetic
mental retardation syndromes", Professional Psychology: Research
and Practice 28:263-270 (1997). Additionally, medication management
of individuals with PWS has been demonstrated to have benefit.
Growth hormone therapy in children with PWS can increase muscle
tone and enhance growth. Carrel, A. L.; Myers, S. C.; Whitman, B.
Y.; et al., "Growth hormone improves body composition, fat
utilization, physical strength and agility, and growth in
Prader-Willi syndrome: A controlled study", J Pediatr 134:215-221
(1999); Lindgren, A. C.; Hagenas, L.; Muller, J.; et al., "Effects
of growth hormone treatment on growth and body composition in
Prader-Willi syndrome: a preliminary report", The Swedish National
Growth Hormone Advisory Group. Acta Paediatr Suppl 423:60-62
(1997). Therefore, growth hormone can help to normalize body
habitus. Martin, A.; Matthew, S.; Koenig, K.; et al., "Prader-Willi
syndrome", Am J Psychiatry 155:1265-1273 (1998); Carrel, A. L.;
Myers, S. C.; Whitman, B. Y.; et al., "Growth hormone improves body
composition, fat utilization, physical strength and agility, and
growth in Prader-Willi syndrome: A controlled study", J Pediatr
134:215-221 (1999); Lindgren, A. C.; Hagenas, L.; Muller, J.; et
al., "Effects of growth hormone treatment on growth and body
composition in Prader-Willi syndrome: a preliminary report", The
Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl
423:60-62 (1997). In terms of obesity, the anorectic fenfluramine
was shown to be helpful for weight loss and aggressive behavior in
PWS utilizing a double-blind placebo-controlled trial. Selikowitz,
M.; Sunman, J.; Pendergast, A.; et al., "Fenfluramine in
Prader-Willi syndrome: a double-blind, placebo controlled trial",
Arch Dis Childhood 65:112-114 (1990). Unfortunately due to
cardiovascular consequences, fenfluramine is not now currently
available. There are few studies of anorectic agents in PWS and
anecdotal reports have been discouraging in terms of their
benefits. Martin, A.; Matthew, S.; Koenig, K.; et al.,
"Prader-Willi syndrome", Am J Psychiatry 155:1265-1273 (1998).
[0015] Pathological skin picking (PSP) is a severe and chronic
psychiatric and dermatologic problem with an average age of onset
around 15 years of age and mean duration of illness of 21 years.
Keuthen, W. S.; Deckersbach, T.; Engelhard, I. M.; et al.,
"Self-injurious skin picking: clinical characteristics and
comorbidity", J Clin Psychiatry 60:454-459 (1999). PSP can lead to
significant suffering, dysfunction, and disfigurement. Ko, S. M.,
"Under-diagnosed psychiatric syndrome II: Pathologic skin picking",
Ann Acad Med Singapore 28:557-559 (1999). Furthermore, there is
often psychiatric comorbidity. Keuthen, W. S.; Deckersbach, T.;
Engelhard, I. M.; et al., "Self-injurious skin picking: clinical
characteristics and comorbidity", J Clin Psychiatry 60:454-459
(1999). PSP is often considered an obsessive compulsive spectrum
disorder (Goldsmith, T. D.; Shapira, N. A.; Phillips, K. A.; et
al., "Obsessive Compulsive Spectrum Disorders"; in: Swinson, R. P.;
Antony, M. M.; Rachman, S.; Richter, M. A. (Eds).,
Obsessive-Compulsive Disorder: Theory, Research, and Treatment,
Guilford Publications, New York, pp.397-425 (1998)) and, as such,
there are several reports of serotonin receptor inhibitors (SSRI)
medication being helpful. Ko, S. M., "Under-diagnosed psychiatric
syndrome II: Pathologic skin picking", Ann Acad Med Singapore
28:557-559 (1999).
[0016] The literature points to topiramate having a negative impact
on cognitive functioning including impaired concentration,
attention, memory, slowed thinking, word finding, and verbal
fluency. Thompson, P. J.; Baxendale, S. A.; Duncan, J. S.; et al.;
"Effects of topiramate on cognitive function", J Neurol Neurosurg
Psychiatry 69:636-641 (2000); Privitera, M.; Fincham, R.; Penry,
J.; et al., "Topiramate placebo-controlled dose-ranging trial in
refractory partial epilepsy using 600-, 800-, and 1,000-mg daily
dosages", Topiramate YE Study Group. Neurology 46:1678-1683 (1996);
Crawford, P., "An audit of topiramate use in a general neurology
clinic", Seizure 7:207-211 (1998); Jones, M. W., "Topiramate-safety
and tolerability", Can J Neurol Sci 25:S13-15 (1998); Burton, L.
A.; Harden, C., "Effect of topiramate on attention", Epilepsy Res
27:29-32 (1997); Martin, R.; Kuzniecky, R.; Ho, S. "Cognitive
effects of topiramate, gabapentin, and lamotrigine in healthy young
adults", Neurology 52:321 (1999); Fraught, E.; Wilder, B. J.;
Ramsay, R. E.; et al., "Topiramate placebo-controlled dose-ranging
trial in refractory partial epilepsy using 200-, 400-, and 600-mg
daily dosages," Neurology 46:1684-1690 (1996); and Rosenfeld, W.
E.; Liao, S.; Kramer, L. D.; et al., "Comparison of the
steady-state pharmacokinetics of topiramate and valproate in
patients with epilepsy during monotherapy and concomitant therapy",
Epilepsia 38:324-333 (1997). A few studies have systematically
looked at cognitive changes using neuropsychological testing. In
one study (Burton, L. A.; Harden, C., "Effect of topiramate on
attention", Epilepsy Res 27:29-32 (1997)), 10 adult patients with
epilepsy were evaluated weekly for up to 13 weeks via a digit span
test. In 4 patients, there was an inverse correlation between
topiramate does and test performance. In another study, healthy
volunteers were treated with topiramate, gabapentin, or lamotrigine
for 4 weeks. Impaired cognitive functioning (attention and word
fluency) was seen in the topiramate treated subjects and not in
gabapentin or lamotrigine in these healthy young adults. Martin,
R.; Kuzniecky, R.; Ho, S. "Cognitive effects of topiramate,
gabapentin, and lamotrigine in healthy young adults", Neurology
52:321 (1999). Finally, in a recent study of 18 epilepsy patients
treated with topiramate and receiving repeat neuropsychological
assessments, patients on topiramate showed significant
deterioration in many cognitive domains, including verbal IQ,
verbal fluency, and verbal learning. Thompson, P. J.; Baxendale, S.
A.; Duncan, J. S.; et al.; "Effects of topiramate on cognitive
function", J Neurol Neurosurg Psychiatry 69:636-641 (2000).
Improvement in verbal fluency, verbal learning, and digit span
increased in patients where topiramate was withdrawn or
reduced.
[0017] The subject invention has, surprisingly, found improvements
in impulsivity control, without negative effects on attention and
concentration, in patients treated with topiramate. These
observations are unexpected and novel.
BRIEF SUMMARY OF THE INVENTION
[0018] The subject invention provides methods and compositions for
the treatment of neurogenetic disorders, particularly DSM-IV
impulse control disorders such as intermittent explosive disorder,
kleptomania, pyromania, pathologic gambling, trichotillomania, and
other impulse control disorders such as compulsive buying and
problematic Internet use. In a preferred embodiment, the subject
invention provides methods for treating or controlling symptoms
associated with ADHD or PWS comprising the administration of
therapeutically effective amounts of compositions containing
compounds of the formulas I-V. In another embodiment, the subject
invention provides for methods of promoting wound healing
comprising the administration of a therapeutically effective amount
of a composition comprising the compounds of formulas I-V.
Compositions are administered to a wound site via a salve,
ointment, or as a component of a bandage or bioadhesive applied to
the site of injury. The invention also provides therapeutically
effective compositions comprising one or more of the compounds of
formulas I-V.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication, with color drawing(s), will be provided by the Office
upon request and payment of the necessary fee.
[0020] FIGS. 1, 3, 5, and 7 depict the efficiency ratios of
patients treated with topiramate as measured by the Delay Task of
the Gordon Diagnostic.
[0021] FIGS. 2, 4, 6, and 8 depict the total correct responses of
patients treated with topiramate as measured by the Vigilance Task
of the Gordon Diagnostic.
[0022] FIGS. 9A-D and 10A-C depict the progression of wound healing
in patients treated with topiramate.
[0023] FIGS. 11A-B: Photographs of improvement in wound healing for
Ms. A on topiramate (75 mg/day) at week 4 (FIG. 11A) and 150 mg/day
topiramate at week 8 (FIG. 11B).
[0024] FIGS. 12A-B: Photographs of improvement for Mr. B. Mr. B. on
25 mg/day topiramate (FIG. 12A), Week 1; Mr. B. on 200 mg/day
topiramate (FIG. 12B), Week 8.
[0025] FIGS. 13A-B: Photographs of primary SIB lesions. Ms. C.
(right breast), baseline (FIG. 13A); Ms. C. on 175 mg/day (right
breast), Week 8 (FIG. 13B).
[0026] FIG. 14: Number of ulcerated SIB lesions for Ms. C. as
documented by group home staff utilizing systematic full body
surveys (* denotes lesions smaller than previous lesions and
appearing to result after insect bites).
[0027] FIGS. 15A-B: Photographic record of Ms. A hair loss at start
of treatment (FIG. 15A) and during treatment (FIG. 15B).
[0028] FIG. 16 illustrates the reported reduction in the urge of
Ms. A to pull hair.
[0029] FIG. 17 represents the improvement in impulse control for
Ms. A during treatment using the Gordon Diagnostic System.
[0030] FIG. 18 illustrates that Ms. A suffered no significant
change in cognitive ability during treatment.
DETAILED DISCLOSURE OF THE INVENTION
[0031] The subject invention provides methods and compositions for
the treatment of neurogenetic disorders, particularly DSM-IV
impulse control disorders such as intermittent explosive disorder,
kleptomania, pyromania, pathologic gambling, trichotillomania, and
other impulse control disorders such as compulsive buying and
problematic Internet use. In a preferred embodiment, an individual
is treated in methods comprising the administration of
therapeutically effective amounts of compositions comprising
compounds selected from the group consisting of formulas I-V. In
one embodiment, therapeutically effective amounts of topiramate are
administered to individuals topically or orally. In another
embodiment, compositions comprising one or more of the compounds
disclosed in formulas I-V are administered for the control or
treatment neurogenetic disorders. In preferred embodiments the
neurogenetic disorders include PWS and ADHD.
[0032] Thus, the subject invention provides methods and
compositions for the treatment or control of ADHD or PWS. In one
embodiment, the subject invention provides methods for controlling
symptoms associated with ADHD or PWS comprising the administration
of therapeutically effective amounts of compositions containing
compounds of the formulas I-V. One embodiment of the invention
provides therapeutically effective compositions comprising one or
more of the compounds of formulas I-V and acceptable carriers.
[0033] In another embodiment, the subject invention provides
methods of promoting wound healing comprising the administration of
a therapeutically effective amount of a composition comprising the
compounds of formulas I-V to an individual having a wound. In one
embodiment, compositions are topically administered to a wound. The
compositions may take the form of a salve, ointment, or aerosol
applied to the site of injury. Alternatively, the compositions may
be administered to the wound site as a component of a bandage or
transdermal patch. In these instances, the compositions may be an
integral component of the bandage or transdermal patch and are
thereby applied to the wound site. In another embodiment,
therapeutically effective amounts of the compounds comprising
formulas I-V are incorporated into bioadhesive compositions useful
in wound closure. In yet another embodiment, therapeutically
effective amounts compositions comprising the compounds of formulas
I-V are administered orally.
[0034] As the subject invention provides methods of promoting wound
healing or controlling impulsive behavior in an individual, the
subject invention provides methods having both human and veterinary
utility. The term "individual" includes animals of avian,
mammalian, or reptilian origin. Mammalian species which benefit
from the disclosed methods include, and are not limited to, apes,
chimpanzees, orangutans, humans, monkeys; domesticated animals
(pets) such as dogs, cats, guinea pigs, hamsters, Vietnamese
pot-bellied pigs, rabbits, and ferrets; domesticated farm animals
such as cows, buffalo, bison, horses, donkey, swine, sheep, and
goats; exotic animals typically found in zoos, such as bear, lions,
tigers, panthers, elephants, hippopotamus, rhinoceros, giraffes,
antelopes, sloth, gazelles, zebras, wildebeests, prairie dogs,
koala bears, kangaroo, opossums, raccoons, pandas, giant pandas,
hyena, seals, sea lions, and elephant seals. Reptiles include, and
are not limited to, alligators, crocodiles, turtles, tortoises,
snakes, iguanas, and/or other lizards. Avian species include, and
are not limited to, chickens, turkeys, pigeons, quail, parrots,
macaws, dove, Guinea hens, lovebirds, parakeets, flamingos, eagles,
hawks, falcons, condor, ostriches, peacocks, ducks, and swans.
Therefore, the subject invention provides methods of controlling
the impulse of an individual to scratch, pick, lick, or otherwise
cause self-injury by repeated mechanical irritation of an injured
area.
[0035] Bandages and wound dressings incorporating materials to
promote wound healing are well known in the art (see, for example,
U.S. Pat. Nos. 6,143,037; 6,142,982; 6,136,341; 6,132,759;
6,124,273; 6,096,709; 6,093,388; 6,087,549; 6,051,249; 6,033,684;
6,025,150; 6,022,556; 5,998,692; 5,989,577; 5,981,606; 5,977,428;
RE36,370; 5,972,332; 5,968,001; 5,960,795; 5,955,430; 5,914,125;
5,902,600; 5,897,516; 5,876,743; 5,874,479; 5,863,938; 5,856,364;
5,856,245; 5,834,432; 5,807,341; 5,807,300; 5,804,213; 5,780,048;
5,759,570; 5,735,812; 5,716,935; 5,716,337; 5,713,842; 5,707,647;
5,705,477; 5,692,302; 5,685,834; 5,674,912; 5,667,501; 5,663,208;
5,662,924; 5,662,904; 5,658,957; 5,658,956; 5,652,274; 5,648,380;
5,646,190; 5,641,814; 5,633,285; 5,632,727; 5,629,292; 5,614,561;
5,610,148; 5,603,946; 5,602,183; 5,578,022; 5,571,521; 5,525,335;
5,522,794; 5,520,926; 5,519,020; 5,512,291; 5,512,041; 5,507,775;
5,578,310, each of which is incorporated by reference in its
entirety).
[0036] Bioadhesives incorporating materials to promote wound
healing are well known in the art (see, for example, U.S. Pat. Nos.
5,981,606; 5,874,479; 5,863,938; 5,856,364; 5,692,302; 5,674,912;
5,663,208; 5,658,957; 5,658,956; 5,652,274; 5,648,380; 5,646,190;
5,641,814; 5,633,285; 5,631,019; 5,614,561; 5,602,183; 5,578,310,
each of which is incorporated by reference in its entirety).
[0037] Compounds of formulas I-V are anti-epileptic compounds,
which are highly effective anti-convulsants. The compounds useful
in the practice of the instant invention include the individual
isomers, analogs, and homologs of the disclosed anti-convulsant
compounds. Racemic mixtures, as well as the isolated enantiomeric
forms, of the compounds can also be used in the practice of the
subject invention.
[0038] In addition, the compounds useful for the practice of the
subject invention include pharmaceutically acceptable salts, for
example; alkali metal salts, such as sodium or potassium, ammonium
salts, dialkyammonium salts, trialkylammonium salts,
tetraalkylammonium salts, and tromethamine salts. Hydrates and
other solvates of the compounds are also included within the scope
of the compounds useful in the practice of this invention.
[0039] One such compound is taught and disclosed in U.S. Pat. No.
4,513,006, hereby incorporated by reference in its entirety.
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate, known as topiramate, has been demonstrated in clinical
trials of human epilepsy to be effective as adjunctive therapy or
as monotherapy in treating simple and complex partial seizures and
secondarily generalized seizures. Other useful compounds include
those described by formula I, including
(tetrahydro-2H-pyran-2-yl)methane sulfamate, and
2,3:4,5-bis-O-(1-methylethylidene) -.beta.-D-fructopyranose
methylsulfamate 1
[0040] wherein
[0041] X.sub.1 is CH.sub.2 or oxygen;
[0042] R.sub.1 is hydrogen or alkyl; and
[0043] R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently
hydrogen or lower alkyl and, when X.sub.1 is CH.sub.2, R.sub.4, and
R.sub.5 may be alkene groups joined to form a benzene ring and,
when X.sub.1 is oxygen, R.sub.2 and R.sub.3 and/or R.sub.4 and
R.sub.5 together may be a methylenedioxy group of the following
formula: 2
[0044] wherein R.sub.6 and R.sub.7 are the same or different and
are hydrogen, lower alkyl or are alkyl and are joined to form a
cyclopentyl or cyclohexyl ring.
[0045] For compounds of formula I, R.sub.1 may be hydrogen or an
alkyl of about 1 to 4 carbons, such as methyl, ethyl, and
isopropyl. Alkyl includes straight and branched chain alkyl. For
compounds of formula I, Alkyl groups for R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are of about 1 to 3 carbons and
include methyl, ethyl, isopropyl and N-propyl.
[0046] When X.sub.1 is CH.sub.2, R.sub.4 and R.sub.5 may combine to
form a benzene ring fused to the 6-membered X.sub.1-containing
ring, i.e., R.sub.4 and R.sub.5 are defined by the alkatrienyl
group .dbd.CH--CH.dbd.CH--CH.dbd..
[0047] In one embodiment, X.sub.1 is oxygen and both R.sub.2 and
R.sub.3 and R.sub.4 and R.sub.5 together are methylenedioxy groups
of the formula wherein R.sub.6 and R.sub.7 are both hydrogen, both
alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in
particularly where R.sub.6 and R.sub.7 are both alkyl such as
methyl. In another embodiment, X.sub.1 is CH.sub.2 and R.sub.4 and
R.sub.5 are joined to form a benzene ring. Another embodiment
provides compounds of formula (I) wherein both R.sub.2 and R.sub.3
are hydrogen.
[0048] Other compounds (formulas II-VI) and compositions useful in
the practice of the subject invention may be found in the teachings
of U.S. Pat. Nos. 5,384,327, 5,498,629, 5,654,461, 5,892,088, and
6,071,537, each of which is incorporated by reference in their
entireties.
[0049] These compounds include those provided by the structure:
3
[0050] wherein R.sub.6 and R.sub.7 may be the same or different and
are selected from any of hydrogen or C.sub.1 to C.sub.4 alkyl. In
one embodiment, R.sub.6 and R.sub.7 are each hydrogen.
[0051] R.sub.8 and R.sub.9 may be the same or different and are
selected from any of hydrogen or C.sub.1 to C.sub.4 alkyl. In one
embodiment, R.sub.8 and R.sub.9 are each C.sub.1 to C.sub.4
alkyl.
[0052] R.sub.10 and R.sub.11 may be the same or different and are
selected from any of azido, halogen, hydroxyl, sulfamoyl
(H.sub.2NSO.sub.2O), C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4
alkyl thiocarbonate (RSC(O)O), C.sub.1 to C.sub.4 alkyl carbonate
(ROC(O)O), or C.sub.1 to C.sub.4 alkyl carboxylate (RC(O)O),
wherein R is C.sub.1 to C.sub.4 alkyl. In one embodiment, R.sub.10
and R.sub.11 are selected from any of C.sub.1-C.sub.4 alkyl
thiocarbonate, halogen or hydroxyl.
[0053] For compounds of formula II, the terms alkyl and alkoxy
include straight and branched chains. For example, alkyl radicals
include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and
t-butyl. Halogen includes bromine, chlorine, fluoride and
iodine.
[0054] Preferred compounds of the formula (II) are those wherein
the pyran ring is in the L-sorbopyranose absolute configuration.
Particularly preferred compounds of formula (II) are those wherein
the pyran ring is in the L-sorbopyranose absolute configuration,
R.sub.6 and R.sub.7 are each hydrogen, R.sub.8 and R.sub.9 are each
methyl; R.sub.10 is methyl thiocarbonate (CH.sub.3SC(O)O) and
R.sub.11 is halogen; or R.sub.10 and R.sub.11 are both halogen; or
R.sub.10 is hydroxyl and R.sub.11 is halogen. Particularly
preferred halogens include bromine, chlorine, and iodine.
[0055] Specific examples of compounds of formula (II) are: (1)
5-deoxy-5-iodo-2,3-O-(1-methylethylidene)
-4-[methylthiocarbonyl)]-.alpha- .-L-sorbopyranose sulfamate,
(i.e., where the compound is in the L-sorbopyranose absolute
configuration, R.sub.6 and R.sub.7 are hydrogen, R.sub.8 and
R.sub.9 are methyl, R.sub.10 is CH.sub.3SC(O)O, and R.sub.11 is
iodine); (2) 4,5-dibromo-4,5-dideoxy-2,3-O-(1-methylethylidene)
-.alpha.-L-sorbopyranose sulfamate, (i.e., where the compound is in
the L-sorbopyranose absolute configuration, R.sub.6 and R.sub.7 are
hydrogen, R.sub.8 and R.sub.9 are methyl, R.sub.10 and R.sub.11 are
bromine); and (3)
5-chloro-5-deoxy-2,3-O-(1-methylethylidene)-.alpha.-L-sorbopyranose
sulfamate, (i.e., where the compound is in the L-sorbopyranose
absolute configuration, R.sub.6 and R.sub.7 are hydrogen, R.sub.8
and R.sub.9 are methyl, R.sub.10 is hydroxyl, and R.sub.11 is
chlorine).
[0056] Another compound useful in the practice of the invention is
described in Formula III: 4
[0057] wherein R.sub.12 and R.sub.13 are the same or different and
are selected from any of hydrogen, alkyl (C.sub.1 to C.sub.6),
cycloalkyl (C.sub.3-C.sub.7), allyl, or benzyl. In one embodiment,
R.sub.12 and R.sub.13 are each hydrogen. R.sub.14 and R.sub.15 are
the same or different and selected from hydrogen or lower
alkyl.
[0058] X.sub.2 may be chosen from carbon (C) or sulfur (S), with
the stipulation that when X.sub.2 is carbon, R.sub.16 and R.sub.17
are the same or different and are selected from hydrogen or lower
alkyl, whereas when X.sub.2 is sulfur one of R.sub.16 and R.sub.17
is oxygen and the other is a lone pair of electrons or both
R.sub.16 and R.sub.17 are oxygen.
[0059] For compounds of formula III, the term alkyl includes
straight and branched chains. For example, alkyl radicals include
methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and
t-butyl.
[0060] Particularly preferred compounds of formula III are: (1)
(1R,2R,3S,4S)-(1,2:3,4-di-O-methylethylidenecyclohexan
-1,2,3,4-tetraol-r-yl)methyl sulfamate, (i.e., where R.sub.12 and
R.sub.13 are hydrogen, R.sub.14, R.sub.15, R.sub.16, and R.sub.17
are methyl and X.sub.2 is carbon); (2)
(1R,2S,3S,4S)-(3,4-O-methylethylidene
-1,2-O-sulfonyl-cyclohexan-1,2,3,4-tetraol-4-yl) methyl sulfamate,
(i.e., where R.sub.12 and R.sub.13 are hydrogen, R.sub.14 and
R.sub.15 are methyl, R.sub.16 is oxygen and R.sub.17 is an electron
pair and X.sub.2 is sulfur); and (3)
(1R,2S,3S,4S)-(3,4-O-methylethylidene-1,2-O-sulfonyl--
cyclohexan-1,2,3,4-tetraol-4-yl)methyl sulfamate, (i.e., where
R.sub.12 and R.sub.13 are hydrogen, R.sub.14 and R.sub.15 are
methyl, R.sub.16 and R.sub.17 are both oxygen and X.sub.2 is
sulfur).
[0061] Another compound useful in the subject invention is 5
[0062] Other compounds useful in the practice of the invention
include those of Formula V 6
[0063] wherein, AR is represented by the following formulas: 7
[0064] Y is selected from the group consisting of halogens such as
F, Cl, Br and I, or trifluoromethyl and alkyl groups containing 1
to 3 carbon atoms when Y alone is attached to the benzene ring;
when X.sub.3, which may be S or O, is present, Y is selected from
the group consisting of trifluoromethyl and alkyl groups containing
1 to 3 carbon atoms.R.sub.18, R.sub.19, R.sub.20, and R.sub.21, may
be identical or different and are selected from the group
consisting of hydrogen, linear or branched alkyl groups containing
1 to 16 carbon atoms, cyclic alkyl groups containing 3 to 16 carbon
atoms and aryl groups containing 6 to 8 carbon atoms, and
NR.sub.18R.sub.19 and NR.sub.20R.sub.21, identical or different,
each may form a 3 to 7-membered aliphatic cyclic compound together
with another nitrogen atom or oxygen atom.
[0065] Compositions useful in the practice of this invention
comprise one or more of the compounds of formulas I-V admixed with
a pharmaceutical carrier. The compositions may be made according to
conventional pharmaceutical compounding techniques. Thus, the
carrier may take a wide variety of forms depending on the form of
preparation desired for administration, e.g., injection, oral,
suppository, topical, or parenteral.
[0066] In preparing the compositions in oral dosage form, any of
the usual pharmaceutical media may be employed. Thus, for liquid
oral preparations, such as for example, suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols,
oils, alcohols, flavoring agents, preservatives, coloring agents
and the like; for solid oral preparations such as, for example,
powders, capsules and tablets, suitable carriers and additives
include starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like.
[0067] Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are employed. If desired,
tablets may be sugar coated or enteric coated by standard
techniques. Suppositories may be prepared, in which case cocoa
butter could be used as the carrier.
[0068] For parenterals, the carrier will usually comprise sterile
water, though other ingredients, for example, for purposes such as
aiding solubility or for preservation, may be included. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed.
[0069] Other compositions useful in the practice of the subject
invention include salves, cosmetics, ointments, and the like. Such
compositions may be topically applied to a site or incorporated
into articles of manufacture including, but not limited to,
bandages, adhesive strips for the covering of wounds (e.g., BANDAID
brand adhesive strips), or transdermal patches. Carriers such as
cocoa butter, viscous polyethylene glycols, hydrogenated oils, and
such mixtures can be emulsified if desired.
[0070] Compounds of the subject invention may also be incorporated
into cosmetics. Additional materials and substances suitable as
carriers for the compounds of formulas I-V are described in the
International Cosmetic Ingredient Dictionary and Handbook, 8.sup.th
Edition (The Cosmetic, Toiletry, and Fragrance Association (CTFA),
2000), hereby incorporated by reference in its entirety.
[0071] Where the pharmaceutical compositions are aerosols, the
active ingredients can be packaged in pressurized aerosol
containers with a propellant, e.g., carbon dioxide, nitrogen,
propane, etc. with the usual adjuvants such as cosolvents, wetting
agents, etc.
[0072] In accordance with the invention, pharmaceutical
compositions comprise, as an inactive ingredient, an effective
amount of one or more non-toxic, pharmaceutically acceptable
ingredient(s). Examples of such ingredients for use in the
compositions include ethanol, dimethyl sulfoxide, glycerol, silica,
alumina, starch, calcium carbonate, talc, flour, and equivalent
non-toxic carriers and diluents.
[0073] The pharmaceutical compositions herein will contain, per
dosage unit, e.g., tablet, capsule, powder injection, teaspoonful,
suppository, bandage, and the like, from about 0.1 to about 400 mg
of the active ingredient. In a preferred embodiment, the
compositions comprise about 10 mg to 200 mg per dosage unit. In an
even more preferred embodiment, the compositions contain comprise
about 20 mg to about 100 mg of active ingredient. In another
embodiment, the compositions comprise about 25 mg of active
ingredient per unit dose.
[0074] Topiramate is currently available for oral administration in
round tablets containing 25 mg, 100 mg or 200 mg of active agent.
The tablets contain the following inactive ingredients: lactose
hydrous, pregelatinized starch, microcrystalline cellulose, sodium
starch glycolate, magnesium stearate, purified water, carnauba wax,
hydroxypropyl methyl cellulose, titanium dioxide, polyethylene
glycol, synthetic iron oxide, and polysorbate 80.
[0075] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application and the scope of the
appended claims. All publications and patents cited herein are
hereby incorporated by reference in their entireties.
EXAMPLE 1
Effects of topiramate on impulsivity and cognitive functioning
[0076] There are no reports of topiramate being utilized in PWS for
any behavior. Measurements of attention, concentration, and
impulsivity were assessed by the Delay and Vigilance tasks of the
Gordon Diagnostic System (GDS; Gordon, M.; McClure, F. D.; &
Aylward, G. P. (1996) Gordon Diagnostic System, Interpretive Guide
(Third Edition); Dewitt, N.Y.: Gordon Systems, Inc.), a mechanized
evaluator of cognitive functions, including attention and
concentration. The GDS was originally developed, and most commonly
used, to measure aspects of Attention-Deficit/Hyperacti- vity
Disorder (ADHD) (previously called Attention-Deficit Disorder). One
of the important components of the Vigilance test is the ability of
an individual to have sustained attention, and the Delay task in
part measures the subjects' ability to concentrate and focus on
hitting a button at appropriate time intervals and delay impulsive
behavioral responses.
[0077] The Delay Task requires that the subject inhibit responding
(pressing a button and then refraining from pressing the button
again for at least 6 seconds) in order to earn points. The Delay
Task measures the subject's ability to suppress and delay impulsive
behavioral responses. While focusing and sustaining attention
usually facilitate Delay Task performance, the Delay Task maximally
draws on a subject's ability to inhibit impulsive responses. The
Delay Task's total efficiency ratio (EF) is considered the best
indicator (score ranges from 0 to 1) of the level of impulsivity
with the lower the score (such as less than 0.5) indicating higher
impulsivity and poor self-control. The Vigilance Task measures the
subject's ability to focus attention on a task and to maintain this
attention over a period of time without reinforcement. The correct
responses (CR) of the Vigilance Task measures the level of
alertness and is a measure of the subjects attentional
processes.
[0078] JAS-002 (patient Number 2) had a baseline total efficiency
ratio (ER) of 0.02, approximately 8 standard deviations below the
normal range and well below the first percentile in regards to the
Delay task. This falls markedly within the range of an "abnormal"
performance as stated in the rating score manual provided by the
manufacturer of the GDS. At visit 4, approximately 1 month after
starting medication (at a dose of 100 mg/day), JAS-002 demonstrated
dramatic improvement in ER (a value of 0.98), well within the
normal range of performance. At 2 months (at a dose of 175 mg/day),
JAS-002 continued with improvements in ER (a value of 0.85), within
the normal range of performance. Attention as evaluated by the
Vigilance Task for JAS-002 showed essentially no change for CR from
39 at baseline to 38 (at a dose of 175 mg/day) at 2 months.
[0079] For patient Number 1 (MJG-001), a significant improvement
has been noted. At baseline, MJG-001's ER for the Delay Task was at
a value of 0.06 (approximately 7 standard deviations below the
average ER) demonstrating a severe impairment of impulsivity.
However, at the second testing session, MJG-001 showed moderate
improvement with a Delay Task ER of 0.24. At visit 5, approximately
1.5 months after starting medication (at a dose of 75 mg/day),
MJG-001 demonstrated a substantial improvement with an ER value of
0.46 and two weeks later (at a dose of 125 mg/day) had an ER value
of 0.70. At 2 months after starting medication (at a dose of 150
mg/day), MJG-001 demonstrated a substantial improvement with an ER
value of 0.50. The Vigilance Task for MJG-001 showed some
variability up and down during the study and, after approximately 2
months, showed a mild decrease of CR from 43 to 41 (at a dose of
150 mg/day).
[0080] Patient Number 3 (GFV-003) has also shown a severe deficit
in impulsivity and focusing; baseline ER was 0.02 (a value 8
standard deviations below the normal range). At visit 1, after one
week at a low dose of topiramate (25 mg/day), GFV-003 had improved
to an 0.09 ER and by week 4 (at a dose of 100 mg/day) to an ER of
0.19, and by 2 months (at a dose of 200 mg/day) the ER was at 0.10.
The Vigilance Task for GFV-003 showed variability on topiramate and
by the end of two months was essentially unchanged with a CR
decreasing from 16 at baseline to 15 at 2 months.
[0081] Patient #4 (MCK-004) also showed abnormal performance on the
Delay task (ER of 0.35). Within 1 week on low dose topiramate (25
mg/day) MCK-004 had improved to an ER of 0.51, by the 2.sup.nd week
on 50 mg/day topiramate, the ER was 0.76, and continued improvement
by the 3.sup.rd week on 75 mg/day with an ER of 0.65 and by two
months at a dose of 150 mg/day, her ER continued to be improved at
0.64. The Vigilance Task for MCK-004 shows mild decrease from
baseline CR of 38 to 34 (by the 8.sup.th week on 150 mg/day).
[0082] Thus, the use of topiramate for impulsivity, without
negative effects on attention and concentration, is both novel and
clinically applicable. Disorders with impulsivity and deficits in
attention and concentration are difficult to manage for both the
patient and their caregiver, especially in cases of dementia.
Impulsivity and lack of concentration can severely handicap
day-to-day functioning in all age groups affected by these
disorders. There are no reports in the literature of topiramate
specifically used to treat impulsivity and/or deficits in attention
and concentration.
EXAMPLE 2
Effect of topiramate on pathologic skin picking (PSP)
[0083] There are no reports of topiramate being utilized in PWS for
any behavior. Patient #3 (GFV-003) also has pathologic skin picking
(PSP) in addition to food seeking behavior. Patient #3 has a
chronic large lesion on his lower left arm. Within one week of
topiramate (25 mg/day), he had decreased skin picking and showed
healing of this lesion on his left arm. By the 4.sup.th week on
topiramate (at 100 mg/day), the lesion on his lower left arm had
completely healed over. The progression of wound healing is
provided in FIGS. 9A-D and 12A-B.
[0084] Patient #1 (MJG-001) has pathologic skin picking (PSP) in
addition to food seeking behavior. Unexpectedly and
serendipitously, it was observed that several large lesions (where
she skin picks) on her right arm, legs, and lips were clearing up
quickly (within 5 days) after topiramate was initiated at 25
mg/day. Furthermore, the patient has continued to do well in terms
of skin clearing. For example, a large lesion on her right arm
completely healed over after about 2 months on topiramate (at a
dose of 125 mg/day). The patient lives in a group home and workers
there, as well as her mother, have also commented to us that her
skin picking/skin has overall improved. The progression of wound
healing is provided in FIGS. 10A-C and 11A-B.
[0085] The use of topiramate for PSP and related disorders is also
novel and clinically applicable. There are no FDA approved
pharmacological treatments for pathologic skin picking (also
referred to as neurotic excoriation, repetitive skin picking,
compulsive skin picking, and dermatotillomania) and possible
related obsessive-compulsive spectrum disorders (i.e., repetitive
self-mutilation (RSM), oncophagia, rhinotillxomania,
trichotillomania) (Goldsmith, T. D.; Shapira, N. A.; Phillips, K.
A.; et al., "Obsessive compulsive spectrum disorders"; in: Swinson,
R. P.; Antony, M. M.; Rachman, S.; Richter, M. A. (Eds).,
Obsessive-Compulsive Disorder: Theory, Research, and Treatment,
Guilford Publications, New York, pp.397-425 (1998)).
EXAMPLE 3
Effects of Topiramate on patients with Prader-Willi Syndrome
[0086] In an 8-week, open-label, flexible-dose (maximum 350 mg/day)
study to evaluate the efficacy and safety of topiramate in PWS
adults, weekly evaluations were performed that included scales for
stereotypical behavior (Stereotypy Checklist, Y-BOCS checklist),
aberrant behavior (Aberrant Behavior Scale {ABS}, Severity of
Symptoms Scale, Self-Injury and Self-Restraint Checklist) and
cognitive functioning (Gordon Diagnostic, Controlled Oral Word
Association Test, Semantic Naming test). Subject safety measures
were also performed (e.g., monitoring blood pressure). Appetite was
assessed for one hour at four time points during the trial.
Measurements were made by investigator observation of the subject
with free access to low calorie food and a visual analogue scale
before and after observation.
[0087] Eight subjects (19-36 years of age; 4 males and 4 females)
entered the trial and six have completed the treatment regimen. A
mean weight loss of 0.3 pounds was observed over the course of the
study. Appetite tests show a mean increase of 255.8 calories/hour;
however, a dramatic reduction in self-injurious behavior was also
observed (e.g., skin picking). Five subjects have continued
long-term on topiramate for at least 6 months (mean of 8.2.+-.1.5
months) and, in these subjects, there has been mean 4.9 lb.+-.4.0
lb weight loss. Behavior evaluations have shown a reduction in
aberrant behaviors (such as irritability and noncompliance [Mean
ABS at baseline of 8.5.+-.7.2 and mean ABS at week 8 of 5.3.+-.5.1,
*Z=-2.0, df=1, P=0.042 {Wilcoxon signed-ranks test}]) and
self-injury in all four subjects exhibiting these behaviors.
Healing of skin lesions was also observed. Open-label
administration of topiramate has been shown to improve behavior and
decrease self-injury in PWS subjects. Longer treatment lengths
appear to result in steady weight decrease.
EXAMPLE 4
Effects of Topiramate on Prader-Willi Syndrome
[0088] In the above study was performed to assess the effects of
topiramate on PWS. All subjects provided written informed consent
for topiramate treatment and were between 18 and 65 years of age.
Criteria for exclusion included: clinically significant suicidality
or homicidality; current or recent (within 6 months of the start of
topiramate) DSM-IV diagnosis of substance abuse or dependence; a
clinically unstable disease that could interfere with treatment or
assessment of PWS; treatment with any drug that might interact
adversely with topiramate; and personal or family history of
nephrolithiasis. Women of childbearing potential who were not
taking adequate contraceptive measures were not included. Screening
measures included a physical examination, psychiatric background,
medication history, blood draw for laboratory assessment (CBC,
SMA-12, urinalysis, and a B-hCG for women of childbearing
potential), and the Structured Clinical Interview for DSM-IV,
Patient Edition (SCID-P). Weekly assessments of weight loss,
participant functioning, and safety measures including blood
pressure and pulse were taken by the investigators at each visit.
Participants are residents of group homes operated by the
Association of Retarded Citizens, Alachua County, Florida (ARC).
These homes are monitored, thereby allowing recording of
participants' behavioral and psychiatric manifestations as well as
their medication management. Participants began pharmacotherapy
with topiramate at 25 mg of drug given in the evening for 7 days.
After 14 days, their daily dose could be increased in increments of
up to 50 mg/week for the next 6 weeks.
[0089] Case 1: Ms. A. is a 19 year-old female who through DNA
methylation testing was positive for PWS and shown to have a
chromosomal deletion through FISH and DNA polymorphism analyses.
Ms. A. has a history of hoarding and severe skin picking dating to
childhood. Current concomitant psychiatric medications include
fluoxetine 60 mg/day and naltrexone 50 mg/day. Psychiatric
intervention dated back to 1992 when the subject began therapy with
clomipramine and fenfluramine, both of which were unsuccessful in
managing her behavior and weight problem.
[0090] Initial side effects (of topiramate) experienced included
mild sedation, word-finding difficulties, and unrelated lower back
pain that resolved by Week 8. Ms. A's weight remained stable with a
baseline of 129.5 lbs and weight of 128.5 lbs at Week 8. Ms. A had
a long-standing primary lesion on her right forearm that measured
approximately 4 cm by 1 cm and ulcerated at baseline. She
experienced a reduction in skin picking with improvement to the
lesions on her face, arm, and legs noted by Week 4 (75 mg/day). To
better follow the improvement in her skin, a photographic record of
Ms. A's lesion on her forearm was begun demonstrating healing of
this lesion by Week 8 of topiramate (150 mg/day). See FIGS. 10A-C
and 11A-B.
[0091] Case 2: Mr. B. is a 29 year-old male confirmed to be a
chromosomal deletion as described above. He has a history of severe
food seeking and skin picking dating to childhood. Mr. B does not
have a history of taking psychotropic medications and had declined
a previous recommendation to take fluoxetine. Initial healing of
his primary lesion (a round 1.5 cm diameter ulcerated lesion) was
noted within one week of initiating topiramate treatment (25
mg/day) at which point photographic records were started. Mr. B
also experienced some increased irritability when topiramate was
initiated. Irritability returned towards baseline by Week 8. Mr. B
also experienced a decrease in his weight from 180.0 lbs at
baseline to 176.8 lbs at Week 8. By Week 8 of topiramate (200
mg/day), Mr. B. had experienced remission of his self-injurious
behavior (SIB) with resultant healing and complete unulceration of
his primary lesion (FIGS. 9A-D and 12A-B).
[0092] Case 3: Ms. C. is a 32 year-old female confirmed to be a
chromosomal deletion. Concomitant psychotropic medications include
fluoxetine 20 mg/day. She has a history of food seeking and skin
picking dating to childhood. Due to her employment, Ms. C. picks in
multiple concealed locations (e.g., her chest, breasts, and the top
of her legs). Because of her secrecy regarding SIB, the staff
members of her group home daily perform full body surveys. As a
result of previous experience with Ms. A and Mr. B, photographic
records of her lesions were started prior to initiation of
topiramate (FIG. 13).
[0093] After beginning topiramate, an attenuation of SIB behavior
and number of ulcerated lesions (FIG. 14) was noted within 1 week
(25 mg/day) by photographs and by 2 weeks (50 mg/day) by her group
home staff. Side effects included word-finding difficulty, mild
confusion, sedation, and some mild tingling in her left heel. All
side effects resolved by Week 5. On topiramate, Ms. C experienced
an increased weight from 150 lbs at baseline to 154.5 lbs at Week
8. At Week 8, Ms. C. had continued attenuation of skin picking on a
dose of 175 mg/day (FIGS. 14 and 15). During participation, Ms. C.
experienced a period of three weeks where she was without any SIB.
However, reportedly as result of her picking at several insect
bites, small ulcerated lesions appeared on her forearm and lower
legs in Weeks 7 and 8.
[0094] These three cases further illustrate the beneficial effects
of the anti-epileptic drug topiramate. Topiramate is able to
attenuate self-injurious behavior in a patient population where SIB
is common and difficult to manage and treat. All three subjects
have longstanding histories of self-injury, and two subjects (Ms.
A. and C.) had failed previous psychotropic medication
interventions. Furthermore, all three PWS subjects have chosen to
continue on topiramate after the 8-week trial (8 months for Ms. A.,
7 months for Mr. B., and 4 months for Ms. C.) with continued
improvement in self-injury. Improvement in self-injury was noted by
both investigators and in systematic body evaluations by the group
home in one subject (Ms. C.). Additionally, while individuals with
PWS often pick surreptitiously and pick even when they describe
having no urges, all three subjects reported decreased urges to
pick while on topiramate.
[0095] In terms of an objective measurement of impulsivity,
subjects were also followed by the Delay Task of the computerized
Gordon Diagnostic System (Gordon et al., 1996). The Delay Task
measures a subject's ability to suppress and delay impulsive
behavioral responses (Gordon et al., 1996). All three subjects
demonstrated improvement in the Delay Task while on topiramate.
EXAMPLE 5
Effects of Topiramate on Impulsive Disorders in Mammals
[0096] Canine acral lick dermatitis (ALD), also known as lick
granuloma, acral pruritic nodule, and neurodermatitis, is a common
self-inflicted skin disorder in dogs in which localized alopecia
and epidermal hyperplasia and fibrosis are caused by continued
licking, biting, and/or scratching one or more areas usually near
the carpus or hock. When severe, the licking of the paws or flank
causes significant local trauma and, in extreme cases, may require
surgery and steroids. Occasionally, the animal must be put to death
because of chronic ulceration or osteomyelitis. The etiology of ALD
is unknown, although, commonly, it is considered to be psychogenic
in origin secondary to boredom, loneliness, or confinement. It can
also be provoked by local irritation. Certain large breeds appear
to be more susceptible, such as German Shepherds, Labrador
Retrievers, and Great Danes. The repetitive self-licking, chewing,
or scratching creates areas of hair loss and the production of
lesions which may range in size from several centimeters to the
entire surface of the limb. This stereotypic behavior prevents the
lesions from healing and may cause discomfort, pain and, in severe
cases, may prove crippling.
[0097] Twenty dogs will be recruited from the Veterinary Animal
Teaching Hospital. Other causes of licking will be ruled out by
examining the dogs' clinical history, typical lesion appearance,
and past history of treatment response. Dogs must exhibit chronic
licking of 6 months or more that has caused an observable
lesion(s). Reasons for exclusion from the study include: dogs
undergoing concurrent treatment for ALD, dogs weighing <5 kg,
dogs that have not been neutered or spayed, nephrolithiasis, and a
significant acute or chronic confounding disease. Once the
referring veterinarian has consented to the dogs' involvement,
letters inviting participation in the study will be sent out to the
owners of appropriate candidates. An informed consent documents
will also be obtained.
[0098] A double-blind placebo-controlled trial of 8 weeks duration
(6 week treatment and 2 week taper) will be conducted. One-half of
the dogs receive placebo. The dogs will start at 2 mg/kg in a split
dose (1 mg/kg twice a day) for the first two weeks. The dose will
be increased 2 mg/kg a week as tolerated for the next four weeks.
Thus, the maximum dosage will not exceed 10 mg/kg. This dosage
strategy is based upon the target dose for seizures, which is 5 to
10 mg/kg in split doses.
[0099] Topiramate or placebo will be administered via gelatin
capsules once daily (5 minutes before feeding). Owners will be
instructed to avoid feeding dogs anything in addition to their
regular diet. In addition to adhering to the dogs' routine (e.g.,
food, exercise, and training), owners will also be asked to
maintain environmental conditions for the duration of the
study.
[0100] A video camera will record the dogs' behavior for 1 hour
each week for the 6 weeks of the trial. The primary behavior of
interest is self-licking or self-chewing of the granulomatous
lesion. The measure of time the dogs are involved in licking or
chewing will be computerized. The evaluator will press the
designated key when the dog's tongue or lips first makes contact
with the lesion, and at the end of a continuous bout of licking or
chewing when the dog lifts its head from the lesion and transfers
its attention elsewhere.
[0101] In addition to videotaping, the owners will rate their dogs'
licking behavior on a 10-point scale, with 10 being the worst ever
observed and 0 indicating a complete absence of excess licking
(Acral Lick Dermatitis Severity Scale). Investigators will also
rate the dogs' behavior using a similar scale. Finally, photographs
of the lesions will be taken weekly. Additionally, at baseline, a
checklist for phobias will be done with the owners and the list
will be reviewed each week using clinical global impression scales
to rate phobias.
[0102] A 2-week taper period will follow the 6-week treatment
period. During week 7, study medication will be reduced by
approximately 25% for 3 days. On day 4, the dosage will be reduced
by another 25%. On day 11 the remaining dose will be reduced in
half again and on day 13 all study medication will be stopped. The
dogs' last visit will be day 14 of the taper period.
[0103] For each of the efficacy measures, a listing of each
patient's score at each study week during treatment will be
generated. The evaluation of change in efficacy measurements will
be carried out using standard analysis of variance techniques. All
statistical tests will be two-sided if not otherwise specified. A
test will be said to be significant if p<0.05. Analyses will be
preformed using the "intent-to-treat" population consisting of all
dogs randomized into the trial that take at least one capsule of
study medication and had at least one post-baseline evaluation. The
primary efficacy variable will be the number of self-injurious
behaviors observed by video camera during weekly visits. A dog's
self injury duration (in min/hr) is measured at the baseline and
six weeks after treatment. The improvement score is the percentage
of reduction (in ratio), i.e., improvement=(baseline-posttreat-
ment)/baseline.
EXAMPLE 6
Effects of topiramate on trichotillomania
[0104] Topiramate was used as an adjunct therapy in a 38 year-old
female with a 9-year history of trichotillomania. She was on a
stable dose combination of fluvoxamine and clomipramine. While the
fluvoxamine/clomipramine combination was therapeutic for 3 years, 6
months ago Ms. A experienced an increase in hair pulling
predominately on the left side of her head. The investigators have
made photographic records of Ms. A's hair loss (FIGS. 15A-B) and
she has been evaluated psychometrically for impulse control. Ms. A
was started on a 25 mg dose of topiramate at night and was
gradually titrated in increments of 25 mg to 150 mg at night.
Preliminary results suggest the addition of topiramate to this
combination therapy effective for trichotillomania.
[0105] Before topiramate was initiated, clomipramine blood levels
were as follows: clomipramine=354 ng/ml, DM clomipramine=118 ng/ml,
and clomipramine+DM clomipramine=472 ng/ml. Following the addition
of topiramate Ms. A reported a lessening of the urges to pull her
hair starting at a relatively low dose (approximately 50 mg/ day).
Ms. A reported a significant reduction in the urge to pull by 3
weeks following the addition of topiramate and this improvement has
been maintained for 14 weeks (FIG. 16). Although patient described
decreased urges to pull hair, her re-growth was minimal. Subsequent
laboratory assessments when patient was on 150 mg of topiramate,
100 mg of clomipramine and 50 mg of fluvoxamine showed that
although the ratio of parent to metabolite were the same as before
topiramate (0.69), both measurements were elevated:
clomipramine=514 ng/ml, DM clomipramine 181 ng/ml, clomipramine+DM
clomipramine=695 ng/ml.
[0106] After initial success with topiramate augmentation, the
patient is currently being weaned off clomipramine and is currently
on 25 mg/day from 100 mg/day without any increase in urges to hair
pull. Ms. A has experienced weight loss of approximately 5 lbs
which she reports as a positive side effect. Possible other side
effects of topiramate administration include disruption of
attention and concentration and cognitive deficits such as word
finding difficulties.
[0107] Ms. A has been evaluated psychometrically for these side
effects. Results from the Delay task of the Gordon Diagnostic
System, a widely used measurement of impulse control, have shown
improvements from baseline (FIG. 17). Subsequent testing of word
finding abilities through the Control Oral Word Association Test
(COWAT) and Semantic Category Naming test have shown no significant
changes from baseline (FIG. 18).
[0108] The patient has continued to see a reduction in the urge to,
as well as in the time, spent, pull her hair. Re-growth of hair at
the sites previously pulled has also been observed. The patient is
currently on 475 mg topiramate (p.o. q.h.s.).
EXAMPLE 7
Effects of Topiramate on Trichotillomania
[0109] A 19-year-old female with a history of trichotillomania and
skin picking has also been treated in accordance with the
invention. She presented with skin lesions on her hands and face
that resulted from picking at pimples (face) and pulling of hair on
the backs of her hands. Several medications, in various classes,
were previously tried without improvement (including mirtazapine,
citalopram, gabapentin, paroxetine, nefazadone, and sertaline). The
initiation of topiramate has resulted in the resolution of her
trichotillomania, with noticeable re-growth of hair on the backs of
her hands at 200 mg. p.o. q.h.s.) and has also resulted in
improvements in the facial skin lesions. She is currently on 300 mg
q.d. topiramate monotherapy.
* * * * *