U.S. patent application number 09/836156 was filed with the patent office on 2003-11-06 for treatment of disorders secondary to organic impairments.
Invention is credited to Mueller, Peter Sterling.
Application Number | 20030207943 09/836156 |
Document ID | / |
Family ID | 22756736 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030207943 |
Kind Code |
A1 |
Mueller, Peter Sterling |
November 6, 2003 |
Treatment of disorders secondary to organic impairments
Abstract
A method for treatment of neuropsychiatric symptoms or disorders
emanating from primary brain or systemic impairments includes
administration of an effective dose of a dopamine, serotonin, and
norepinephrine reuptake inhibitor to a human in need of such
treatment. The preferred reuptake inhibitor is sibutramine.
Inventors: |
Mueller, Peter Sterling;
(Princeton, NJ) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Family ID: |
22756736 |
Appl. No.: |
09/836156 |
Filed: |
April 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09836156 |
Apr 17, 2001 |
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09204124 |
Dec 2, 1998 |
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6323242 |
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Current U.S.
Class: |
514/659 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/08 20180101; A61P 25/20 20180101; A61P 31/12 20180101; A61K
31/135 20130101; A61P 25/30 20180101; A61K 31/00 20130101; A61P
3/00 20180101; A61P 27/02 20180101; A61P 25/18 20180101; A61P 5/00
20180101; A61P 15/00 20180101; A61P 25/36 20180101; A61P 25/14
20180101 |
Class at
Publication: |
514/659 |
International
Class: |
A61K 031/135 |
Claims
What is claimed:
1. A method of treatment for neurological, behavioral and cognitive
disorders or symptoms, emanating from primary organic impairments
which comprise temporal lobe epilepsy; brain disorders of
metabolic, endocrine, genetic, or chromosomal diseases, brain cysts
and tumors; or viral infection, said method comprising
administering to a human in need of such treatment a
pharmaceutically effective amount of a compound which is a
selective reuptake inhibitor for dopamine, serotonin and
norepinephrine.
2. The method of claim 1 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
3. The method of claim 2 wherein the treatment interrupts
endorphin-opioid pathology.
4. The method of claim 1 wherein the pharmaceutically effective
amount comprises from about 0.25 mg to about 45 mg per day.
5. A method for treatment of symptoms of Sick Building Syndrome
comprising administering a pharmaceutically effective amount of a
selective reuptake inhibitor for dopamine, serotonin and
norepinephrine thereof to a human in need of such treatment.
6. The method of claim 5 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
7. A method for treatment of symptoms of Gulf War Syndrome
comprising administering a pharmaceutically effective amount of a
selective reuptake inhibitor for dopamine, serotonin and
norepinephrine thereof to a human in need of such treatment.
8. The method of claim 7 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
9. A method for treatment of symptoms of Reflex Sympathetic
Dystrophy Syndrome or Complex Regional Pain Syndrome comprising
administering a pharmaceutically effective amount of a selective
reuptake inhibitor for dopamine, serotonin and norepinephrine
thereof to a human in need of such treatment.
10. The method of claim 9 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
11. A method for treatment of symptoms of Retinitis Pigmentosa
comprising administering a pharmaceutically effective amount of a
selective reuptake inhibitor for dopamine, serotonin and
norepinephrine thereof to a human in need of such treatment.
12. The method of claim 11 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
13. A method for treatment of symptoms of organic brain impairments
which result in stammering comprising administering a
pharmaceutically effective amount of a selective reuptake inhibitor
for dopamine, serotonin and norepinephrine thereof to a human in
need of such treatment.
14. The method of claim 13 wherein the dopamine, serotonin and
norepinephrine reuptake inhibitor is sibutramine, sibutramine salts
or derivatives of sibutramine.
15. A method for treatment of claims 6, 8, 10, 12 or 14 wherein the
pharmaceutically effective amount comprises about 0.25 mg to about
45 mg per day.
16. A method for treatment of claims 6, 8, 10, 12 or 14 further
comprising delivering said pharmaceutically acceptable amount in a
controlled or sustained release form.
17. The method for treatment of claims 6, 8, 10, 12, or 14 further
including an antiepileptic or anti-depressant medication.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part application of
U.S. application Ser. No. 09/204,124 filed Dec. 2, 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to the pharmacological
treatment of various secondary neurological, behavioral and
cognitive symptoms or disorders emanating out of brain or systemic
impairments, i.e, primary impairments.
[0003] The secondary symptoms and disorders include as non-limiting
examples, tic and behavioral disorders including Tourette's
syndrome and severe non-Tourette's motor or vocal tics;
Posttraumatic Stress Disorder (PTSD); a typical attention deficit
disorder with or without hyperactivity; frontal lobe defects of
executive function; oscillopsia; self-mutilation; violence or rage
such as in intermittent explosive disorder; asocial behavior;
sexual disorders (including gender choice difficulties or
hyposexuality); psychological (psychosis, violence, and confusion)
and motor symptoms of Huntington's Disease (Huntington's Chorea);
fatigue, exhaustion, sleep problems, and pain of Chronic Fatigue
Syndrome with or without Fibromyalgia; psychosis with multiple
hallucinations and delusions secondary to brain injury; opiate
narcotic addiction; Sick Building Syndrome (SBS); Gulf War Syndrome
(GWS); Reflex Sympathetic Dystophy Syndrome (RSDS), also known as
Complex Regional Pain Syndrome (CRPS); and Retinitis Pigmentosa
(RP). It should be noted that a symptom is a single manifestation
while a disorder involves more than one symptom or a cluster of
symptoms.
[0004] The symptoms and disorders are secondary to the primary
impairments and emanate from neurological diseases or brain lesions
including Tourette's Disease, non-Tourette's tic disorders,
Asperger's Syndrome, temporal lobe or other focal epilepsy,
Huntington's Disease, brain tumors or cysts, systemic lupus
erythematosus, viral infections and their resulting neurological
injuries, and various psychological disorders such as multiple
personality disorder, borderline personality, organic psychosis,
and severe traumatic experiences.
BACKGROUND OF RELATED TECHNOLOGY
[0005] Gilles De La Tourette's syndrome is characterized by motor
and vocal tics, i.e., involuntary, sudden, rapid, recurrent,
nonrhythmic, stereotyped motor movement or vocalization. Some
researchers hypothesize that there is a dysregulation in
presynaptic dopamine function in Tourette's disorder (T.D.) and
tics can be exacerbated by drugs that enhance synaptic dopamine
function. R. T. Madison et al., Am. J. Psychiatry 152(9):1359-1361,
1995. Pharmacologic therapy has included low doses of dopamine-2
blockers and dopamine-antagonists including haloperidol,
risperidone, or pimozide. T. M. Hyde et al., JAMA 273: 498-501,
1995. A problem with this dopamine-2 blockade is that this may
often produce decreased attention, hyperactivity, dysphoria, and
extrapyramidal symptoms in T.D. patients. Furthermore, if T.D.
patients are treated with dopamine-2 stimulating analeptics (such
as methylphenidate, dextroamphetamine, or pemoline) for their
cognitive, attention, and hyperactivity problems, their motor and
vocal tics are intensified. Non-Tourette's tic disorder most
commonly arises out of previous analeptic treatment and persists
after such treatment.
[0006] Posttraumatic Stress Disorder (PTSD) follows exposure to a
traumatic experience involving actual or threatened death or injury
or threat to the physical integrity of oneself or others. PTSD
includes characteristic symptoms of reexperience, avoidance of
stimuli associated with the trauma, and numbing of general
responsiveness or hyperarousal (sleep difficulty, anger, difficulty
concentrating, hypervigilance or exaggerated startle response) with
clinically significant distress or impairment. It has been
established that PTSD is associated with organic changes in the
limbic system. It has also been suggested that a kindling model or
a model of a paroxysmal disorder is applicable to PTSD (S. Liper et
al., Psychosomatics 27 (12): 849-854, 1986). In the kindling model
(R. M. Post et al, Clin. Neuropharmacol. 2:2542, 1977), cumulative
bioelectric changes, especially in the limbic area and secondary to
repeated biochemical or psychological stress, can result in
abnormal limbic or neuronal sensitization and major psychiatric
disturbances. Pharmacologic therapy for stress disorders has
included benzodiazepines (e.g., lorazepam, diazepam, clonazepam),
beta adrenergic blockers and anti-seizure medications such as
carbamazepine and valproic acid. It has been suggested that PTSD
can induce a long-lasting brainstem dysfunction resulting in loss
of the normal inhibitory modulation of startle response, (E. M.
Ornitz et al, Am. J Psychiatry 146(7): 866-870, 1989) and clonidine
has been used to decrease noradrenergic action and inhibit startle
response. Nevertheless, no successful dramatic treatment of PTSD
has been discovered for the severe, chronic cases of this crippling
disorder. A number of articles describing current developments in
PTSD appear in Psychiatric Annals 28:424-468, 1998.
[0007] Multiple Personality Disorder is a Dissociative Disorder
which includes the existence within the person of two or more
distinct personalities which recurrently take full control. There
is an extensive inability to recall personal information.
Dissociative disorders may occur as acute responses to overwhelming
trauma and are common in combat or disasters. There is probably
also a relationship between seizures and these disorders. Devinsky
et al., Neurology 39:835-840, 1989.
[0008] Borderline personality disorder is characterized by
tumultuous interpersonal relationships, labile mood status, and
behavioral dyscontrol. Self-mutilation and violent behavior can
also be seen with this disorder. Carbamazepine, an anti-convulsant
with preferential action on limbic foci, produced decrease in
severity of behavioral dyscontrol (R. W. Cowdry et al., Arch. Gen.
Psychiatry 45:111-119, 1988) but not in the other multiple
symptoms.
[0009] Primary attention deficit hyperactivity disorder (ADHD) is
characterized by developmentally inappropriate failures of
attention, hyperactivity, cognitive function, and impulsivity. The
ADHD syndrome is idiopathic (no known secondary cause such as brain
injury, dementia or known metabolic disease), begins at birth or
soon thereafter, and usually has a strong hereditary basis.
[0010] Violence or rage (intermittent explosive disorder) can also
be categorized as an impulse control disorder. There is a loss of
control grossly out of proportion to any precipitating psychosocial
stresses. Disabling outbursts of rage and violent behavior can be
related to chronic brain syndrome associated with irreversible CNS
(central nervous system) lesions. Yudofsky et al., Am. J Psychiatry
138:218-220, 1981. Disorders characterized by severe episodic
dyscontrol can result from brain dysfunction, e.g., resulting from
a failure of modulation of electrical disturbances in the limbic
system (amygdala, hippocampus, hypothalamus), temporal lobe
epilepsy (TLE), brain lesions or injuries which can have
neurological side effects. Other brain dysfunction disorders
include motor, personality, or behavior patterns arising from,
e.g., neurological impairment in the brain, TLE, viral infections,
neurotransmitter disorders, amino acid imbalance, brain tumors,
chromosomal abnormalities, metabolic disorders including endocrine
disorders, diabetes, and genetic disorders such as disease which
involves several genes, and chromosomal disorders.
[0011] Temporal lobe lesions may be brain damage produced by
injury, disease, viral infection, and surgery, and can produce
disturbances characterized, e.g., by seizures, which can include,
e.g., motor phenomena, impairment of external awareness,
depersonalization, emotional changes, behavioral disturbances,
psychosis, multiple cognitive disturbances, distortions or
hallucinations of any of the five senses, and autonomic
disturbances (gastrointestinal, cardiac, sweating, and headache
symptoms among others). The symptoms can be severe and difficult to
treat. The drugs used in treatment depend on the type of seizures
and have included phenytoin, carbamazepine, valproic acid,
phenobarbital, primidone, felbamate, gabapentin, and
lamotrigine.
[0012] Various pharmacological approaches have been taken in
treating the conditions described above. For example, a number of
medications such as lithium, neuroleptics, anticonvulsants,
buspirone and beta blockers have been used to reduce violent
behaviors as a symptom, but there are no officially labeled
treatments for violent behaviors. J. Fawcett, Psychiatric Annals
27(11):725, 1997. But, particularly when the symptoms are very
severe, the standard pharmacological approaches to alleviate the
symptoms of episodic dyscontrol are often unsuccessful.
[0013] Temporal lobe epilepsy poses particular problems which can
include simple partial seizures that can be manifested by motor
symptoms, sensory symptoms, or psychic symptoms including
impairment of consciousness, dysphasia, dysmnesia, illusions, and
hallucinations. Complex partial seizures include impaired
consciousness and psychic symptoms. The drugs used in treatment
depend on the type of seizures and have included phenytoin,
carbamazepine, valproic acid, phenobarbital, primidone, felbamate,
gabapentin, and lamotrigine.
[0014] Temporal lobe epilepsy (TLE), and other organic brain
disorders may be associated with various sexual impairments. See,
e.g., D. M. Bear, "Temporal Lobe Epilepsy--A Syndrome of
Sensory-Limbic Hyperconnection", Cortex 15:357-84, 1979. The most
common sexual effect of organic brain problems is a loss of sexual
interest and drive (hyposexuality). Less often sexual preference
changes can occur and rarely fetishistic, exhibitionistic, or
sadomasochistic problems occur. Some patients also develop an
obsessive concern about sex and sexual performance. Treatment for
these sexual problems is poor with antiepileptic or psychiatric
medications but at times has been altered by unilateral temporal
lobe surgery, a rather heroic procedure that many, if not most,
patients are unable to undergo.
[0015] Damage to frontal lobes can also impair the executive
function, that is the ability to plan, initiate, organize, carry
out, monitor, and correct one's own behavior. W. W. Beatty and N.
Monson, "Problem Solving By Patients With Multiple Sclerosis",
Journal of the International Neurological Society 2:134-140, 1996;
V. Goel and P. Grafman, "Are Frontal Lobes Involved With Planning
Functions? Interpreting Data From the Tower of Hanoi",
Neuropsychologia 5:623-642, 1995.
[0016] Sexual abnormalities can be associated with epilepsy or
other brain diseases. These include a loss of sexual interest and
drive (hyposexuality); fetishistic, exhibitionistic, or
sadomasochistic problems; sexual preference changes,
(homosexuality, transsexuality, or transvestism); obsessive
interest in sex or sexual performance; or compulsive sexual
activity. Homosexuality may become a problem for those patients who
have difficulty accepting this change or who are under societal
pressure. It has been long established that altered sexuality can
result from various brain impairments including temporal lobe
epilepsy. D. M. Bear, Cortex 15:357-384, 1979.
[0017] Another hereditary or genetic neurological disorder is RP, a
chronic progressive deterioration of vision that begins usually at
the age of 20-30 years and gradually leads to progressive loss of
vision and finally blindness at the age of 40-50 years. A
characteristic is that vision is particularly worse in poor light
and color vision goes first. Approximately 1 in 3000 in the
population suffer from inherited retinal degeneration. About one in
80 people carry a single copy of a recessive RP gene. There are no
known treatments for RP at this time.
[0018] Huntington's Disease (H.D.) is a relatively rare (6/10,000
in U.S. and Europe) fatal neurological disorder of a hereditary
nature. It is an autosomal chromosome 4 dominant disorder with full
penetrance (50% chance of all children of being affected) which
usually begins between age 35-40 years and kills the patient in
about 15 years with severe behavioral and neurological impairments
in this morbid period. There are no successful treatments of these
behavioral or neurological disorders of H.D. Neither gamma amino
butyric acid (GABA) agonists (i.e. carbamazepine or valproic acid)
nor antipsychotic medications repair the behavioral or neurological
problems of H.D. in any satisfactory fashion.
[0019] Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are
similar problems of unknown cause which lead to considerable
suffering and debility over 6 months or more and often for many
years. The incidence is approximately 250 per 100,000 for CFS and
as high as 5% of the general medical population for FM. There are
no reliably successful treatments and certainly no FDA approved
treatments for these two disorders. FM and CFS share in common
severe fatigue, impaired concentration and memory, exercise
intolerance, unrefreshing sleep, muscle and joint pain, malaise,
and headaches. FM is differentiated from CFS by specific point pain
spots in the muscles and CFS differs from FM by having a sore
throat, tender cervical or axillary lymph nodes, variably elevated
erythrocyte sedimentation rate, occasional low grade temperature,
and a variety of immunologic or neuroendocrinologic test values
(none of which are consistent or indicative of any known etiologic
agent) See, e.g., K. Fukuda et al., Ann. Intern. Med. 121:953-959,
1994; A. L. Komaroff et al., Rev. Infect. Dis. 13(Suppl. 1):S8-11,
1991. Both are clearly different from a depressive diagnosis. A
recent study by A. L. Komaroffet al, Am. J Med. 101:281-290, 1996,
showed marked impairment of the CFS patients vs. patients with
hypertension, acute myocardial infarction, multiple sclerosis,
NIDDM, diabetes, congestive heart failure, or depression. Moreover,
the degree and pattern of impairment CFS was different from that
seen in depression. This is also the case in Fibromyalgia. L. J.
Kirmayer et al., Am. J Psychiatry 145:950-954, 1988.
[0020] Gulf War Syndrome is a disorder of unknown etiology and
affecting about 1% of all Gulf War veterans according to Defense
Department research. One clue to the cause is that a number of
those veterans affected never reached the Gulf War area but
contracted the syndrome while training for the war in Europe. This
suggests that various injections or protective vaccines may have
had some etiological role. The symptoms of GWS are very similar to
those of Fibromyalgia/Chronic Fatigue Syndrome with the addition of
severe allergic complaints. According to the American Legion,
symptoms may include: chronic fatigue, headache, muscle pain, sleep
disturbance, neuropsychological signs or symptoms (such as memory
loss or encephalopathy), and various allergic signs and symptoms
including asthma, rash or gastrointestinal problems. There are no
successful treatments known for GWS.
[0021] Sick Building Syndrome (SBS) is another disorder with
multiple symptoms similar to GWS and perhaps Fibromyalgia/Chronic
Fatigue Syndrome. It is of unknown etiology other than it occurs
within certain building and produces allergic symptoms (skin
rashes, asthmatic symptoms, and flu-like complaints), fatigue,
cognitive problems, headaches, and muscle aches. It has been
assumed that there is some form of allergen or toxic substance that
affects those in the building involved, but no particular agent has
been identified. There are no successful treatments for SBS other
than leaving the building.
[0022] Opioid or narcotic abuse or addiction, most particularly
addiction to or involving the abuse of heroin, but which also may
involve other opiates such as propoxyphene, meperidine,
hydromorphine, codeine, levorphanol, methadone, oxycodone,
morphine, hydrocodone bitartrate and other opiate derivatives,
represents a major drug problem throughout the world. It probably
results from at least two events: 1.) a chance or purposeful
exposure of the addict or abuser to one of these opiates (either
through illegal sources or medical sources) with the intake by
oral, nasal, or intravenous routes, and 2.) the individual exposed
may have special needs for drugs which mute pain and distress. For
instance, it is an infrequent event for patients to whom narcotics
are administered for medical needs to develop dependence and
addiction although they may show transient tolerance during
treatment or withdrawal symptoms after cessation of the treatment.
The binding sites in the brain and elsewhere of these opiate drugs
are similar to the sites where our own endogenous pain-relieving
endorphins and enkephalins bind. It has been proposed (E. J.
Khantzian, Am. J. Psychiatry 142:1259-1264, 1985) that those who
abuse narcotics as a drug of choice for dependence abuse or
addiction are those who are subject to disorganizing and
threatening affects of rage and aggression, perhaps from inadequate
responses of their own endogenous pain-relieving endorphins. Many
of these patients do not feel relief of pain over time the way most
other people do. Treatment results for this serious addiction
problem are extremely poor, mainly because of the lack of any
non-addicting drug that can relieve the craving for narcotics in
these addicts. Methadone treatment has been used commonly but
methadone is just another addictive opiate which can be given
conveniently in an oral form. Nevertheless, methadone is frequently
abused and sold for abuse by addicts and others. There are no
FDA-approved non-narcotic treatments for the chronic abuse of
opiate narcotics.
[0023] Reflex Sympathetic Dystrophy Syndrome (RSDS) is a
progressive disease of the autonomic nervous system that can follow
trauma, a break or a fracture, a sharp force injury (such as a
knife or bullet wound), heart problems, infections, surgery, or
spinal injuries. RSDS is a multi-system disorder affecting nerves,
skin, muscles, blood vessels, bones and the central nervous system.
RSDS affects extremities, the face, shoulders, back, and eyes. The
initial symptoms are severe constant, burning pain with
inflammation and extreme sensitivity to touch. The skin appears
mottled, becomes easily bruised, and has a shiny red and tight look
to it. There is often profuse sweating in the areas involved. Later
in the course of the illness there is a constriction of the
vasculature with coldness, loss of skin integrity, low-grade fever,
edema, sores, dystonia, tremors, insomnia, emotional disturbance,
memory problems, and demineralization of the bones in the affected
limb. There are no successful treatments other than narcotics,
local anesthesia for the pain and the recent use of baclofen which
may temporarily relieve the dystonia. None of these treatments help
other multiple problems suffered by the RSDS patient.
[0024] Sibutramine hydrochloride monohydrate (N,
N-Dimethyl-1-[1-4-chlorop- henyl cyclobutyl]-3-methylbutylamine
hydrochloride monohydrate) available as MERIDIA.RTM. (Knoll
Pharmaceutical Co., Mount Olive, N.J.) has been described for the
treatment of obesity and depression (U.S. Pat. Nos. 4,746,680,
4,929,629 and 5,436,272), for diabetic hyperglycemia (WO 98/11884),
and for hyperlipidemia (WO 98/13034). In contrast to many of the
drugs mentioned above, sibutramine's mode of action is believed to
include, among other things, inhibition of serotonin,
norepinephrine, and dopamine reuptake. Accordingly, it intensifies
all three of these brain neurotransmitters at their post-synaptic
receptor sites. These results are described, e.g., in U.S. Pat. No.
4,939,175 which also discloses the use of
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine to
activate the central nervous system and thereby improve certain
cerebral functions involved with memory such as senile dementia,
amnestic syndrome, and learning, and to increase spontaneous
movement as in Parkinson's disease. There is no suggestion,
however, to treat the neuropsychiatric symptoms and disorders
treated according to the invention, i.e., neurological, behavioral
and cognitive symptoms, particularly symptoms refractory to
previous treatments.
[0025] It is an object of the invention to provide a treatment for
severe secondary symptoms and disorders which often have not been
successfully treated heretofore.
SUMMARY OF THE INVENTION
[0026] The invention provides a method of treating secondary
neurological, behavioral, and cognitive symptoms or disorders
emanating from primary organic impairments. The term
neuropsychiatric will be used herein to encompass these
neurological, behavioral and cognitive symptoms or disorders.
[0027] The conditions to be treated encompass symptoms and
disorders including symptoms of Sick Building Syndrome (SBS);
symptoms of Gulf War Syndrome (GWS); symptoms of Reflex Sympathetic
Dystrophy Syndrome (RSDS); symptoms of Retinitis Pigmentosa (RP);
vocal and motor tics, obsessive compulsive behavior, and cognitive
and behavior disorders of Tourette's syndrome and non-Tourette's
disorders; symptoms of Posttraumatic Stress Disorder (PTSD);
symptoms of multiple personality disorder; symptoms of Attention
Deficit Hyperactivity Disorder (ADHD) or Attention Deficit Disorder
(ADD); violence or rage such as seen with an intermittent explosive
disorder; adult or adolescent sexual disorder or sexual dysfunction
including hyposexuality, hypersexuality, obsessive-compulsive
sexual activity, gender choice problems (including homosexuality),
and sexual deviations (fetishism, transvestism, pedophilia,
sadomasochistic behavior, exhibitionistic behavior, and
frotteurism); self mutilation including self-laceration and other
self-abuse; oscillopsia; psychological, behavioral, emotional,
cognitive and motor symptoms of Huntington's Disease; severe
fatigue, sleep abnormalities, cognitive difficulties, and pain of
fibromyalgia and chronic fatigue syndrome; severe psychoses with
hallucinations and /or delusions refractory to conventional
antipsychotic treatment as caused by primary impairments including
trauma, brain tumors, amino acid imbalance, chromosomal
abnormalities, metabolic disorders including renal failure and
diabetes, and genetic disease; frontal lobe executive problems of
forming appropriate plans and carrying them out in prompt fashion
caused by various primary brain disorders; asocial behavior; and
opiate narcotic dependency, abuse, or addiction. Patients
advantageously treated have at least one of these symptoms or
disorders.
[0028] The primary impairments which give rise to these symptoms
include as non-limiting examples, temporal lobe epilepsy (TLE),
Huntington's Disease, Tourette's Disorder, nonTourette's Disorder,
a typical attention deficit disorder with or without hyperactivity,
adult or adolescent sexual disorders, Posttraumatic Stress Disorder
(PTSD), multiple personality disorder, borderline personality, and
organic psychosis. The primary impairments can be systemic such as
systemic lupus erythematosus; brain disorders from systemic causes
such as metabolic, genetic or chromosomal diseases, brain cysts,
and tumors; Fibromyalgia, Chronic Fatigue Syndrome; viral
infections and resulting neurological injuries.
[0029] The treatment includes administering a pharmacologically
effective dose of a dopamine, serotonin and norepinephrine reuptake
inhibitor, particularly sibutramine, to a human in need of such
treatment. The treatment has also been shown to interrupt
endorphinopioid pathology. Patients most advantageously treated are
those with severe symptoms. By severe is meant intractable symptoms
which have not responded to standard medication sufficiently to
control those symptoms.
DETAILED DESCRIPTION OF THE INVENTION
[0030] There are many secondary symptoms or disorders caused by or
excited by various primary excitatory factors or impairments
(diseases, illnesses, injuries, etc.). The primary impairments
include brain impairments such as brain disease, brain lesions, and
systemic impairments such as lupus erythematosus, fibromyalgia, and
chronic fatigue syndrome.
[0031] It has been discovered that administration of sibutramine
allows control of previously uncontrollable behavioral, cognitive,
and neurological problems in patients suffering from a spectrum of
neurological disorders. Clinical results show that symptoms
successfully controlled include tics manifested by motor or vocal
outbursts, episodic dyscontrol with anger and violence, self injury
or mutilation, asocial behaviors, problems of executive (frontal
lobe) function, severe posttraumatic stress disorder, panic
outbursts, a typical psychoses with florid hallucinations and
delusions refractory to previous treatments, the severe behavioral
motor and psychotic symptoms of Huntington's Disease (HD), a
typical attention deficit disorder, sexual disorders, sleep
problems, fatigue, cognitive dysfunction, or pain problems of
fibromyalgia or chronic fatigue syndrome, and the opiate narcotic
craving in opiate addiction.
[0032] Many of the disorders and symptoms are listed in The
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of
the American Psychiatric Association, Washington, D.C.
[0033] The term sibutramine as used herein means compounds of
sibutramine hydrochloride monohydrate, more specifically
N,N-dimethyl-1-[1-(4-chlorop- henyl)cyclobutyl]-3-methylbutylamine
hydrochloride preferably in its monohydrate form, and enantiomers
and analogues thereof, as described in U.S. Pat. Nos. 4,746,680,
4,929,629 and 5,436,272. Sibutramine is believed to inhibit
reuptake of norepinephrine, serotonin and dopamine thereby
intensifying their effects in the brain. Sibutramine is
commercially available as MERIDIA.RTM., Knoll Pharmaceutical
Company, Mount Olive, N.J. Capsules are presently available with
discrete dosages of 5, 10 and 15 mg for oral administration. The
sibutramine is administered in a pharmaceutically active dose. The
preferred dosage is about 5 mg three times a day but there is
variation between patients for the best dose. It is believed that
the cytochrome P450 system differs in individuals and the dose must
be determined empirically in each patient. The effect of the
cytochrome P450 system on metabolism of psychotropic drugs is
discussed in "Intercom: The Experts Converse", published by The
Journal of Clinical Psychiatry, November 1995. The lowest effective
dose has been shown to be 0.25 mg daily and the highest dose has
been shown to be 45 mg (15 mg 3 times daily). It is possible that
higher or lower doses can be used depending upon each individual.
Therefore, more flexibility in available dosage is needed.
Furthermore, means of administration such as injection, rectal
suppository, or transdermal patches may be utilized. Finally, a
long-acting slow-release means such as oral tablet or capsule would
be the preferred route in view of the rapid metabolism noted (5
hour duration of action usually) in most of the patients.
[0034] The sibutramine, sibutramine salt or derivative thereof, is
administered, preferably in a pharmaceutical carrier and in a
pharmaceutically effective dose, preferably about 5 mg three times
a day. The dose can vary depending upon the individual, e.g., from
about 0.25 mg to 45 mg or more per day.
[0035] Although the use of sibutramine has been described for the
treatment of conditions such as obesity, depression, diabetic
hyperglycemia, hyperlipidemia, senile dementia and related
conditions, and Parkinson's disease, it has been discovered that
sibutramine can be successfully used in treating other problems
unrelated to these conditions. In treating other problems according
to the invention, for example, rather than demonstrating an
anti-obesity effect, most patients gained weight when the changes
resulting from the method of the invention were taking place. For
example, patients with ADD previously treated with stimulants found
it easier to eat when treated with sibutramine and gained weight.
Moreover, the improvements according to the invention were rapid
and the symptoms were alleviated within minutes or hours of
treatment. Therefore, the improvements were seen in the short term,
and the improvements continued long term. In regard to depression,
most of the patients treated were not clinically depressed and
patients who were being treated with antidepressants became
depressed when removed from the anti-depressant medication and
treated with sibutramine alone. It was generally necessary to
continue anti-depressant therapy along with the sibutramine
therapy.
[0036] It has been discovered that sibutramine acts as a stabilizer
or normalizer of the secondary effects of various neuropsychiatric
conditions. Sibutramine appears to correct multiple secondary,
ancillary neurophysiological signs and symptoms of many
neuropsychiatric disorders. While it is not intended to be bound by
theory, this may be through a "damping" neurological effect which
would restrict or mute abnormal impulses emanating from the area of
pathology or injury (such as the temporal lobe) to peripheral areas
(such as the hypothalamus, the amygdala, the hippocampus, other
limbic structures, or motor areas). Sibutramine is therefore
usually an "add-on" medication to other medications, such as
antiepileptic or anti-depressant medications. It appears to be one
of those very rare if not unique medicines that calms without
sedating, activates without agitating, or, in sum, corrects these
multiple severe neurophysiological problems toward normal. For many
of the patients it also helps frontal lobe planning in executive
function, thereby not only helping attention, but also
intention.
[0037] Above and beyond the known effects of sibutramine on
serotonin, dopamine and norepinephrine activation, there is
believed to be an effect of this medication on the endorphic opiate
neurotransmitter system which is evident in the patients who have
been relieved of pain, rage, anger, self-mutilation and
particularly addiction to heroin. Moreover, self-injury appears to
activate the opioid system and the relief through sibutramine of
the need to cut themselves in these patients strongly suggests
endorphic involvement of some sort. It would appear that
sibutrarnine activates endorphins or, at the very least, modifies
the endorphinergic opioid systems to promote serenity and lack of
pain and stress, and to reduce craving for heroin. Such a mechanism
which was previously unsuspected may have also contributed to the
therapeutic effects of sibutramine herein described for PTSD,
asocial behavior and fibromyalgic pain which have not been helped
by serotonin, dopamine and norepinephrine potentiators. This is in
contradistinction to the therapeutic effects of sibutramine on
ADHD, chronic fatigue, and the symptoms of Tourette's and
non-Tourette's diseases. Finally, a differentiation between the
serotonin, dopamine and norepinephrine potentiation versus the
opiate-like therapeutic effects of sibutramine may be made in terms
of duration of action, whereas the serotonin, dopamine,
norepinephrine agonist effects lasted in most patients for only 4-6
hours (therefore requiring tid dosage), the opiate effects appear
to last all day and require only a single AM dosage.
[0038] Furthermore, for most of these disorders, at this time there
are no other known nor FDA approved medications currently
available. The following nonlimiting examples illustrate the
invention. In the following case histories, problems (symptoms or
disorders) helped included:
[0039] 1. Rage, violence, self-abuse. (Case Nos. 3, 47, 54, 97,
100, and 113)
[0040] 2. Organically-based sexual dysfunction (including
hyposexuality, obsessive-compulsive sexual preoccupation, and
gender choice problems). (Case Nos. 20, 54, 77, 99, 100, and
109)
[0041] 3. Severe post-traumatic stress disorder (PTSD). (Case
No.74)
[0042] 4. The behavioral-emotional problems of Huntington's
Disease. (Case No.113)
[0043] 5. The cognitive and visual problems of Retinitis Pigmentosa
(RP).
[0044] 6. Oscillopsia associated with brain injury. (Case
No.111)
[0045] 7. Treatment refractory Attention Deficit Disorder (ADHD) or
(ADD) with or without hyperactivity. (Case Nos. 16, 20, 41, 47, 76,
77, 78, 100 and 109)
[0046] 8. Tics, concentration problems, and behavioral problems of
Tourette's Disease. (Case Nos. 20 and 47) and non-Tourette's
Disease (Case No. 76).
[0047] 9. Asocial behavior. (Case Nos.20 and 54)
[0048] 10. Severe a typical and neuroleptic refractory psychoses
with delusions, hallucinations, and dyscontrol. (Case No.97)
[0049] 11. Enhancement of frontal lobe (executive planning)
function (Case Nos. 41 and 78).
[0050] 12. The fatigue, cognitive problems, sleep disorders, and
pain of fibromyalgia, and chronic fatigue syndrome. (Case No.
141).
[0051] 13. The symptoms due to Gulf War Syndrome (GWS).
[0052] 14. The symptoms due to Sick Building Syndrome (SBS).
[0053] 15. The craving for opiates in the dependent patient (case
No. 165)
[0054] 16. The symptoms due to Reflex Sympathetic Dystrophy
Syndrome (RSDS), also known as Complex Regional Pain Syndrome
(CRPS).
[0055] Some of the cases illustrate multiple problems.
EXAMPLES
[0056] 1. Severe Atypical Psychosis (Problem No.9)
[0057] Sibutramine Patient No.97:
[0058] A 33-year-old male patient had been treated for a severe
psychosis which emanated from a motor vehicle accident with head
trauma. Symptoms included multiple hallucinations (visual,
auditory, smell, and touch), paranoid delusions, confusion,
impaired memory, and discontinuity in awareness. He had received
various a psychiatric diagnoses and had been treated without
success with haloperidol, risperidone, olanzapine, trifluoperazine,
buspirone, paroxetine, lorazepam, amantadine, and fluoxetine. SPECT
brain scan showed multiple foci of dysfunctions in the right
hemisphere indicative of right hemisphere encephalopathy (rather
than a primary psychiatric disorder). Treatment with carbamazepine
and quetiapine did not control his symptoms and valproic acid was
also added. Finally, the patient was started on sibutramine 10 mg
orally three times a day and the patient noted a marked decrease in
hallucinations, confusion, paranoia, and anxiety. He continued on
this treatment for seven weeks and beyond with gradual and
consistent improvements.
[0059] 2. Violence and Self-Laceration (Problem No. 1)
[0060] Sibutramine Patient No.3
[0061] A 49-year-woman had been treated for over eleven years for a
complex partial seizure disorder with marked mood swings, frequent
suicide attempts, out-of-body experiences, auditory, visual, and
smell hallucinations, violent periods, and self-abuse (cutting
herself). She required large doses of carbamazepine, valproic acid,
gabapentin, trazodone, fenfluramine, nadolol, olanzapine, and
venlafaxine to minimize her seizures (several per week) and to keep
her out of psychiatric hospitals (a number of admissions), but she
continuously suffered from self-abuse, rage attacks, loss of
energy, and violent mood swings. She was rejected for brain surgery
because of multiple foci for her seizure disorder.
[0062] She was started on sibutramine 10 mg orally every morning
for her violence, self-abuse and obesity. Within less than a week,
the patient gained new energy, had fewer seizures, and was no
longer violent or self-abusive. Her dose of sibutramine was
adjusted to 5 mg orally three times a day within the first two
weeks of treatment due to a rapid wear-off of effects within 5-6
hours of administration. The patient had little weight change,
actually gaining four pounds during the first month of treatment
when these rapid behavioral and psychological changes were noted
and therefore were clearly not related to the approved uses of
sibutramine.
[0063] 3. to 7. Repair of Altered Sexuality (Problem No. 2)
[0064] As discussed above, head injury temporal lobe epilepsy
(TLE), and other organic brain disorders may be associated with
various sexual impairments. The most common sexual effect of
organic brain problems is a loss of sexual interest and drive
(hyposexuality). Less often sexual preference changes can occur and
rarely fetishistic, exhibitionistic, or sadomasochistic problems
occur. Some patients also develop an obsessive concern about sex
and sexual performance. The following case histories 3 through 7
illustrate the rapid repair of these organically based sexual
problems with sibutramine.
[0065] 3. Sexual Function, ADD, and Rage Outbursts (Problem Nos. 1,
2, and 6)
[0066] Sibutramine Patient No. 100
[0067] A 51-year-old married man was treated for over two years for
a simple partial seizure disorder of post-traumatic TLE (three
automobile accidents) with severe mood swings, suicide attempts,
obesity (over 300 lbs., and a body mass index of 41), memory
problems, decreased organization, concentration problems, decreased
sexual drive, and rage attacks. SPECT and EEG studies showed
diffuse abnormalities in both frontal and parietal lobes. Previous
treatment for his mood swings with lithium carbonate was
unsuccessful and made his obesity worse. Treatment for his
cognitive problems with bupropion, imipramine, nortriptyline,
methylphenidate, and dextroamphetamine were unsuccessful.
[0068] Treated with carbamazepine helped with his mood swings but
not with his anger, sexual, or cognitive problems. Treatment with
phenteramine 15 mg twice a day helped him lose a small amount of
weight but did not affect his other problems. Treatment with
magnesium pemoline, lamotrigine, desipramine, selegiline,
olanzapine, valproic acid, donepezil, thyroxine, fenfluramine and
long-acting amphetamine salts were also not helpful. A trial of
sildenafil (Viagra) did not help his sexual libido.
[0069] The patient was started on sibutramine 10 mg twice a day and
he soon noted an increase in his sexual drive and interest in
distinct contrast to his lack of response to sildenafil. He was
able to concentrate better and had fewer and less severe anger
outbursts.
[0070] 4. Sexual Function and ADD (Problem Nos. 2 and 6)
[0071] Sibutramine Patient No. 109
[0072] A 56-year-old married man had been treated for a year and a
half for a simple partial seizure disorder of TLE with visual
illusions, mood swings, anger attacks, and a loss of sexual
interest and drive. He also had a separate problem with a
prostatitis, urethritis, and prostatic calculi which further
impaired his sexual life. Valproic acid helped his anger attacks
but interfered with his concentration considerably and did not help
his sexual problems. Other unsuccessful treatments included
magnesium pemoline, lamotrigine, propranolol, and donepezil.
Prostatic surgery with the removal of calculi helped his sexual
performance marginally but not his sexual interest. Other
unsuccessful treatments included yohimbine, testosterone patches,
and sildenafil, which only increased sexual function but not
libido. He was started on sibutramine 5 mg three times daily and
immediately noted a new-found interest and ability to engage in
sex. Finally, he no longer had the concentration and fatigue
problems he had suffered from with the continuing valproic acid
treatment.
[0073] 5. Tourette's Tics, Asocial Behavior, and Relief of
Hyposexuality (Problem Nos. 2, 6, 7, and 8)
[0074] Sibutramine Patient No. 20
[0075] A boy was diagnosed at age 4 with ADHD (Attention Deficit
Hyperactivity Disorder) and at age 61/2 years with Tourette's
Disease. He had developmental delays as well as severe learning
disabilities. He had violent behavior, dangerous impulsive behavior
(jumping out of a second story window), marked social
inappropriateness, and asocial behaviors of odd communication. He
has been on medications since the age of four and at the time of
this writing is now 16.
[0076] He was extremely difficult to medicate because any
medication which helped the ADHD worsened his Tourette's Disease
symptoms. Likewise, any effective Tourette's medication worsened
his ADHD or his cognitive function. He had been given numerous
medications over the years and none could improve his function
without causing severe side effects or worsening other symptoms. In
fact, he was hospitalized twice (103 days and 35 days) and in both
cases it was reported that it was next to impossible to medicate
him correctly. He was completely dysfunctional without medications
or on the wrong medications and nearly required placement out of
the home in an institution. Medications that were tried without
success included: haloperidol, pimozide, fluphenazine, olanzapine,
fenfluramine, dextrofenfluramine, carbamazepine, valproic acid,
clomipramine, methylphenidate, magnesium pemoline, fluvoxamine,
tacrine, donepezil, dextroamphetamine, felbamate, gabapentin,
lamotrigine and seligiline. Clozapine was helpful in controlling
his behavior and helped somewhat with his verbal tics but produced
sedation, worse ADHD, and cognitive problems. (IQ fell 30 points).
It also did not help his social behavior.
[0077] He was started on sibutramine (5 mg three times a day) and
improvement was shown in many ways. First, the motor and vocal tics
associated with Tourette's Disease were decreased as well as the
obsessive compulsive component. Secondly, his ADHD improved; he
became calmer and his thought processes clearer (decreased racing
thoughts). Thirdly, his communication and social skills improved.
He began dating girls for the first time. Prior to this he had no
interest in sexual matters. He began attending regular mainstream
school. Finally, many of the inappropriate behaviors ceased. These
improvements included looking at people when he talked, directed
rather than circumstantial speech, and appropriate social behavior
which permitted him to be popular with his peer group. Prior to
sibutramine treatment he had not begun to cope with the problems of
adolescence but had remained sexually undifferentiated and socially
remote.
[0078] 6. Sexual Obsessive-Compulsive Behavior, ADD and Executive
Function (Problem Nos. 2, 6 and 10)
[0079] Sibutramine Patient No. 77
[0080] A 47-year-old married man had been treated for TLE simple
partial seizure disorder for about six months. Among his complaints
were inattention, poor organization, mood swings, sexual
preoccupation, compulsive sexual behavior, visual illusions, and
discontinuities in awareness. He had a past history of alcoholism
but had been abstinent for ten years. He had been treated for a
number of "psychiatric" disorders including "schizophrenia,"
"depression," "mania," and "ADD." Past unsuccessful medicines had
included haloperidol, dextroamphetamine, buproprion, and valproic
acid.
[0081] Treatment with carbamazepine corrected the mood swings,
breaks in awareness, and visual illusions, but not his lack of
concentration, his disorganization, nor his sexual preoccupations
and compulsive activity. Trials of added methylphenidate,
long-acting amphetamine salts, and magnesium pemoline were also
unsuccessful in this regard. He was started on sibutramine 10 mg
every morning by mouth and after a month the dose was increased to
5 mg three times a day by mouth because the duration of effects of
each dose was about five hours. On this medication, he could
concentrate, organize, and no longer had the sexual
obsessive-compulsive problems. Despite this decreased sexual
activity, he has a more enjoyable sexual life with his wife with
sibutramine treatment.
[0082] 7. Sexual Gender Choice Change: Homosexuality (Problem No.
2)
[0083] Sibutramine Patient No. 99
[0084] A 20-year-old young man had been treated for TLE with
partial seizures, disorganization, and suicidal behavior
(particularly when abandoned by a male lover). He had a history of
head injury at age 11/2 years when he fell off a dresser while
having a diaper change. He had been seen by multiple psychiatrists
since age 13 years for depression that was refractory to
imipramine, sertraline, lithium carbonate, fluoxetine,
methylphenidate, gabapentin, donepezil, and olanzapine. The
patient's impulsive behaviors, mood swings, and epileptic symptoms
were relieved by carbamazepine.
[0085] His sexual history was significant in that he was completely
asexual with no interest in either males or females until age 14
years when he began autoerogenous activity with thoughts of men. At
age 16 years, he began homosexual activity. The sexual behavior
continued for the 11/2 years he was treated with carbamazepine. A
marked change occurred after he was started on sibutramine 10 mg
every morning. He first noted an increased interest in sex
generally, but for the first time this interest included females as
well as males. His interest in women became heightened with a
differentiation between "attractive" and "non-attractive" girls,
something he had not even considered previously. He became
interested in female anatomy for the first time. A major issue
became his complete lack of knowledge of dating and sexual
conventions with girls. As a result, he gave up sexual activity
(but not interest) until he could acquire the necessary social
skills with girls. Most recently he had intercourse with a woman.
His present dose of sibutramine is 5 mg three times a day.
[0086] 8. Tourette's Disease Tics, Violence, and ADHD (Problem Nos.
1, 6, and 7)
[0087] Sibutramine Patient No. 47
[0088] An 18-year-old male was treated for Tourette's Disease with
vocal and motor tics, attention deficit disorder, and episodic
anger and violence, for over six years. Treatment had included
phenytoin, phenobarbital, clonidine, carbamazepine, fenfluramine,
magnesium penoline, valproic acid, hydroxyzine, methylphenidate,
bromocriptine, clomipramine, desipramine, selegiline, propranolol,
clozapine, felbamate, tacrine, gabapentin, risperidone,
lamotrigine, olanzapine, donepezil, and quetiapine without any good
results. The medicines that helped the tics made his violent
outbursts and cognitive problems worse and vice versa. The one
exception was donepezil 5 mg bid p.o. which helped his cognitive
problems without aggravating his tics or his outbursts; yet
donepezil did not relieve the outbursts nor the tics.
[0089] The patient was started on sibutramine 10 mg every morning.
This rapidly relieved his tics, his aggressive outbursts, and
helped his concentration. The donepezil was continued. The effects
of the sibutramine wore off quickly after noon with a rapid return
of all symptoms. The dose of sibutramine was readjusted to 10 mg
three times daily and he has continued on this medication to date
with the loss of verbal and motor tics, violence, and concentration
problems.
[0090] 9. Non-Tourette's tics, obsessive-compulsive rituals, and
attention deficit hyperactive disorder (ADHD). (Problem Nos. 6,
7)
[0091] Sibutramine Case #76
[0092] An 11-year-old boy had been treated since the age of five
years for attention deficit disorder with hyperactivity. He had a
difficult birth in that his mother suffered from disseminated
intravascular coagulation (presumably secondary to amniotic
infusion) with kidney, cardiac, and pulmonary failure. The patient
himself had pulmonary and cardiac arrest at birth but was restored
back to life by resuscitation and artificial life support. His
development was normal except for his hyperactivity, attention
deficit, and impulsivity (from which his older brother also
suffered).
[0093] He was initially treated successfully with methylphenidate
until age eight years when premoline was added because of the rapid
wear-off from the effects of methylphenidate. Lamotrigine was added
at age nine years in an attempt to help his cognitive problems
without success. At age 10 years, the patient developed multiple
obsessive-compulsive (OCD) symptoms of trichotillomania and
lip-licking, and fluvoxamine was added. SPECT scan was negative as
was his MRI. The methylphenidate was discontinued and he was
treated with amphetamine salts. Although the amphetamine and
fluvoxamine helped his hyperactivity and OCD symptoms in part, he
went on to develop multiple vocal and motor tics. Carbamazepine,
donepezil, and ropinirole were unsuccessful. Finally, sibutramine
was started at 5 mg tid. This stopped both the tics and the OCD
symptoms, but only for a few hours. When the sibutramine dose was
increased to 10 mg tid, he was free of symptoms throughout the day.
Sleep and appetite were not affected. Furthermore, his
concentration at school was better than with any of the analeptics
(dextroamphetamine, methylphenidate, or pemoline) which were all
discontinued. Finally, if he misses a single dose of sibutramine,
the vocal and motor tics return immediately; this clearly
identified the duration of action of sibutramine and was typical
for most of the 170 patients treated to date.
[0094] 10. Asocial Behavior, Violence, and Hyposexuality (Problem
Nos. 1, 2, and 8)
[0095] Sibutramine Patient No. 54
[0096] A 31-year-old man had a life-long history of asocial
behavior, violence, and mental retardation. His parents noted that
he had been relatively normal until age 31/2 when he became asocial
and withdrawn and had problems with eye/hand coordination. He went
on to become episodically violent. He also developed limited speech
and inappropriate communication with no eye contact and lack of
affect with others. He had been given multiple medications since
the age of 5 years including methylphenidate, thioridazine, chloral
hydrate, haloperidol, carbamazepine, nadolol, fenfluramine,
propranolol, olanzapine, and quetiapine without any changes in his
speech or mode of communication. The carbamazepine, high-dose
propranolol, and fenfluramine combination was successful in curbing
his violence but not his asocial behavior or hyposexuality. In the
late fall of 1997 fenfluramine was removed from the market and the
patient became episodically violent again.
[0097] In the spring of 1998 the patient was tried on sibutramine
10 mg daily and he again became calm and manageable. The dose was
then changed to 5 mg tid and other changes became noticeable. These
included a decrease in repetitive speech, hissing, and compulsive
acts, an increase in social activity and sexual interest, and
increased speech generally. Furthermore, for the first time he
began to look directly and intently at the person he was talking to
and made sense in his speech and oriented to the situations around
him. Finally, he now was accepting change without upset for the
first time.
[0098] 11. Severe Post-Traumatic Stress Reaction (Problem No.3)
[0099] Sibutramine Patient No. 74
[0100] A married 53-year-old woman was seen for a very severe
post-traumatic stress disorder (PTSD) which stemmed from her
witnessing the murder of her employer and the suicide of the
murderer by pistol shots close to her ear. The brain single photo
emission computed tomography (SPECT) scan was abnormal with
decreased left frontal lobe perfusion. The patient had psychotic
decompensation when confronted with pistol shot-like sounds such as
backfires, shots from TV or movies, and particularly thunder.
During the first thunderstorm after the trauma she described rain
coming down the color of blood, and she ended up curled up in a
fetal position in a corner of the room with her hands over her ears
in a grossly psychotic state. Treatment with carbamazepine,
phenytoin, various benzodiazepines, valproic acid, various
antipsychotics (including clozapine), buspirone, oxcarbazepine,
various antidepressants, dextroamphetamine, pemoline,
methylphenidate, and fenfluramine were all unsuccessful in
preventing her severe PTSD symptoms and particularly the reactions
to thunder. She frequently was suicidal and was hospitalized once
for these severe problems.
[0101] The patient was started on sibutramine 10 mg in the morning
and was seen two days after a very severe thunderstorm with the
threat of tornadoes. The patient reported she stayed up four hours
of that night watching for tornadoes, completely oblivious of her
former psychotic fear of thunder.
[0102] After one and a half months sibutramine was stopped due to
problems of dosage due to her deficiency in P-450 cytochrome system
enzymes. Even one-half of the smallest capsule (5 mg) was too much
and produced drowsiness, sugar craving, and weight gain. She also
had not had any PTSD symptoms in many weeks and felt she might be
over the disorder. Unfortunately, she immediately noted a rapid
return of the fear of thunder, sound and light sensitivity,
exaggerated startle reflex, headaches, and nightmares of life and
death situations. She had to wear ear plugs and be sedated for the
psychoses caused by thunderstorms or even the threat of such.
Within one and a half months of the cessation of the sibutramine,
the patient was returned to sibutramine but at a much lower dosage
(less than 1 mg once a day). This provided relief again from her
PTSD symptoms but without the sedation she had noted before with
higher doses of sibutramine. Finally, this patient was taken off of
fluoxetine 20 mg when sibutramine treatment was initiated. She
became severely depressed despite the relief from PTSD. When the
fluoxetine was reinstated, the depression and PTSD were relieved.
Therefore, the effect of sibutramine on PTSD was different from any
antidepressant action.
[0103] 12. Huntington's Disease (Problem No. 4)
[0104] Sibutramine Patient No. 113
[0105] A 39-year-old single woman had been treated for an organic
behavioral disorder with mood swings, violence, concentration
problems, and psychosis for over eleven years. She had been managed
well and worked full-time with great success with carbamazepine,
gabapentin, and fluoxetine, but she then developed staggering gait,
confusion, disorganization, rage outbursts, and severe hopelessness
with suicidal impulses that no longer responded to the previous
medications. She was then started on sibutramine 5 mg three times a
day and within 20 minutes of the first capsule she noted complete
relief of the cognitive, emotional, and behavioral problems but not
with the ataxic gait. These effects lasted only five hours and
required at least three times a day dosage. A dosage of 5 mg at
5:30 AM and 10:30 AM and 10 mg at 3:30 PM permitted her relief
until bedtime at 10:30 PM. Gradually she noted improvements in her
ataxic gait and was able to continue her responsible work as a boat
captain without staggering or falling. Her dose was adjusted to 10
mg tid po due to rapid wear-off of the smaller 5 mg doses. A review
of her family history revealed that the patient's uncle and father
had H.D. and her younger brother also has the behavior and
emotional complaints that the patient had prior to the worsening of
the initial symptoms (without the ataxic neurological
symptoms).
[0106] 13. Retinitis Pigmentosa
[0107] A 76-year-old woman presented with a 40 year history of
gradual loss of vision due to RP. For the past 10 years she had
been almost completely blind except for well-lit large shapes
visible to her right eye. She has been prone to falls with head
injury and had developed a focal seizure disorder which had been
also associated with "visions", stammering, and confusion. Multiple
treatments had been tried unsuccessfully by other physicians, and
she was then referred to me. After trials with various
antiepileptics, she was treated with sibutramine 5 mgs. t.i.d. The
patient not only rapidly showed better organization and alertness,
decreased stammering, but also better vision by visual testing and
observations of her husband, family, and herself.
[0108] She was able to read gravestones of her family and also lost
the "visions" which had upset her so. One problem was that the
effects faded after 4-6 hours and required multiple dosing. Her
sleep was aided as well because of the relief from the frightening
visual apparitions. The relief from stammering was also
unexpected.
[0109] 14. Intracerebral Porencephalic Cyst With Oscillopsia
(Problem No. 5)
[0110] Sibutramine Patient No. 111
[0111] A 58-year-old man suffered a severe head injury in 1976 with
a fractured skull, coma, and an intracerebral (porencephalic) cyst
caused by the traumatic blockage of his cerebral spinal fluid in
his brain. This cyst was repaired surgically with a brain
ventricular--jugular vein shunt. This had permitted him to work
continuously with concomitant treatment with carbamazepine,
valproic acid, and dextroamphetamine until early 1998 when he began
to suffer severe attacks of bizarrely altered vision, dizziness,
ataxia, and confusion. The attacks progressed to several times per
week, lasting 4-24 hours in duration. Examination revealed he was
suffering from oscillopsia produced by the rapid oscillation of his
eyes produced by irritation from his injury and his shunt. There is
no known treatment for these attacks and he was therefore unable to
drive or work safely. He was placed on total disability. He was
started on 10 mg of sibutramine as needed for these oscillopsia
attacks. When this appeared to help, his dose of sibutramine was
increased to 5 mg three times daily. In the next four weeks he had
only one such attack, and this began early in the morning prior to
his initial dose of sibutramine. After 2 months at the 5 mg tid
dosage, the patient again noted a recurrence of oscillopsia on a
2-3 times weekly basis. His dosage of sibutramine was increased to
10 mg tid and this was followed by an absence of attacks.
[0112] 15. Severe ADHD Refractory to All Other Medications With
Executive (Frontal Lobe) Problems (Problem Nos. 6 and 10)
[0113] Sibutramine Patient No. 41
[0114] A 25-year-old male was seen first for a life-long history of
severe hyperactivity, distractibility, disorganization, poor memory
of studied material, very poor concentration, and school failure
despite a high IQ. There was no known history of head injury, other
neurological disease, nor metabolic disease. He had had multiple
trials (both singly and in combination and in a wide range of
doses) of methylphenidate, magnesium pemoline, dextroamphetamine,
venlafaxine, valproic acid, carbamazepine, lamotrigine, nefazodone,
lithium carbonate, fluoxetine, imipramine, nortriptyline,
buproprion, and donepezil. He was started on sibutramine, finally
reaching a dose of 15 mg three times a day (due to his rapid
catabolism of this medicine with a maximum duration of a single
dose effect of only 4-5 hours). This was the first medication to
calm him and permit careful, quiet concentration and retention of
information. He now plans graduate school for the first time with
confidence. The only complaints relate to being "too calm" with a
loss of the exciting high-risk behavior of the past. He also noted
for the first time a marked improvement in his ability to form
appropriate, organized plans and execute them promptly without
procrastination or distraction.
[0115] 16. ADHD Refractory to Other Treatments (Problem No. 6)
[0116] Sibutramine Patient No. 16
[0117] A 46-year-old married woman with a lifelong history of ADHD
was treated for four years with multiple medications including
methylphenidate, magnesium pemoline, dextroamphetamine, and
long-acting amphetamine salts without success and negative side
effects. The amphetamines made her nervous, jittery, and unable to
sleep. The methylphenidate and magnesium pemoline, on the other
hand, made her sleepy. These medications did not calm her
hyperactivity without sedating her. She was started on sibutramine
10 mg every morning by mouth. Immediately she noted a calming and
an alerting effect not seen with the dopamine agonist analeptics.
After the first month, her dose was changed to 5 mg three times
daily due to a five hour duration of effects. She has continued on
the medication to date (over six months) as did her daughter who
also failed to respond to all of the various analeptic dopaminergic
drugs used for ADHD.
[0118] 17. Enhancement in Frontal Lobe Executive Function, ADHD,
and Hyposexuality (Problems Nos. 2, 6, and 10)
[0119] Sibutramine Patient No. 78
[0120] A 65-year-old man with a lifelong history of ADHD had been
treated for eight years with multiple medications. Initially his
attention problems responded to methylphenidate but then required
the addition of pemoline. On the other hand, his work continued to
suffer due to difficulties making decisions.
[0121] Trials of adding lamotrigine, donepezil, fluoxetine, or
selegiline were unsuccessful. He was then started on sibutramine 10
mg. bid p.o. and noted immediate repair of concentration, and
particularly his ability to plan and carry out these plans
effectively for the first time in many years. Due to dry mouth and
some insomnia his dose of sibutramine was decreased to 5 mg bid and
the pemoline and methylphenidate were discontinued without a loss
of efficacy.
[0122] In 1997 the patient had a radical prostatectomy for
adenocarcinoma of the prostate. This resulted in a lack of sexual
drive and erectile dysfunction. Treatment with sildenafil helped
correct the mechanical dysfunction but not the libido. With
sibutramine this problem of sexual drive was repaired for the first
time since his prostate surgery.
[0123] 18. Fibromyalgia--Chronic Fatigue Syndrome (Problem No.
11)
[0124] As discussed above, both FM and CFS share in common severe
fatigue, impaired concentration and memory, exercise intolerance,
unrefreshing sleep, muscle and joint pain, malaise, and headaches.
FM is differentiated from CFS by specific point pain spots in the
muscles and CFS differs from FM by having a sore throat, tender
cervical or axillary lymph nodes, variably elevated erythrocyte
sedimentation rate, occasional low grade temperature, and a variety
of immunologic or neuroendocrinologic test values.
[0125] Sibutramine Case #141
[0126] A 52-year-old married woman had a 10 year history of
fibromyalgia with multiple areas of point tenderness in her
muscles, severe fatigue, marked exercise intolerance, malaise, poor
concentration and memory, weight gain, headaches, and poor and
unrefreshing sleep. She was tried unsuccessfully on multiple
medications including most of the non-steroid anti-inflammatory
disease drugs and most recently nabumetone, tramadol, and
oxaprozin. The patient was started on sibutramine 5 mg tid p.o.
[0127] Within 2 hours of the first 5 mg capsule the patient noted
that her fatigue diminished and her energy increased substantially.
She was able to eliminate her multiple rest periods and naps and
able to walk up 2 levels of steps without effort as compared to her
previous total exhaustion. She reported that "simple tasks became
easy instead of monumentally strenuous." Despite difficulty in
getting to sleep that first night after sibutramine, she woke up
feeling "human" and was able to cope with the various demands of
her life without fatigue or need for rest periods. She also became
alert and able to concentrate. She did note that her pain points
were still tender but that the burning sensation at these points
had abated within 4 days. She has not have sleep problems since the
first 2 days on sibutramine.
[0128] 19. Gulf War Syndrome (GWS)
[0129] This 47-year-old totally disabled veteran was entirely well
until just after a series of injections for anthrax exposure and
against various chemical and biological toxins in France in 1988.
He was being prepared for duty in the Gulf War as a member of the
U.S. Army Calvary motorized corps. He developed asthma, rash,
cognitive dysfunction, multiple body pains with trigger spots, poor
sleep, confusion, and marked fatigue. Over the next ten years he
received both antiallergic and neuropsychiatric treatments with no
notable success and with marked deterioration of physical and
mental function secondary to steroid toxicity He gained over 100
lbs. in weight and was hospitalized many times, finally being
declared totally disabled. Treatment of 10 mg. b.i.d. of
sibutramine rapidly repaired his pain, cognitive problems, and
confusion. His allergic symptoms had already abated gradually over
the previous decade.
[0130] 20. Sick Building Syndrome (SBS)
[0131] This 40-year-old woman began to note an increasing fatigue,
poor concentration, rash, and wheezing which she related to
exposure to unknown foreigns in the large building in which she
worked. She also noted that more than 40 other employees had
similar symptoms. She was treated for obesity with sibutramine 5
mg. t.i.d. She then noted rapid relief of the cognitive and fatigue
symptoms, but no relief from the allergic symptomatology. She was
then forced to leave her job in this building with a gradual relief
of all symptoms over the next several weeks.
[0132] 21. Relief of Heroin Craving and Abuse (Problem No. 12)
[0133] Sibutramine Patient No.165
[0134] A 19 year old single woman was introduced to heroin by
snorting at age 18 years when she was particularly stressed with
the anger and pain of losing a boyfriend. She had always had
difficulty recovering from pain, anger and loss but the heroin
rapidly made her feel "normal". She quickly moved to the
intravenous route and reached a maximum intake of 5 bags per day
(approximately $100/day in cost) for the next 6 months when she was
discovered to have charged large amounts on her charge cards. She
was then hospitalized in a drug detoxification hospital for three
weeks but soon relapsed after discharge. After her second round of
treatment she was referred to the care of a psychiatrist (the
inventor herein). The patient described constant, unrelenting
cravings for heroin and expressed that it would be "next to
impossible" to remain free of the drug for any length of time. She
was started on sibutramine 5 mg tid po with no relief from her
anger and hurt nor from her narcotic craving. Out of desperation,
the dose was increased to 15 mg in the AM and within an hour she
noted a marked change. She now felt a complete relief for the first
time since her first exposure to heroin a year before. She now felt
the "normal" feeling that heroin had given her and no longer noted
any anger, hurt or distress. Furthermore, this effect was extended
for the whole day without the rapid wear-off and tolerance that
heroin had produced.
[0135] Her side effects were a dry mouth and a craving for food.
She gained 15 pounds the first 2 weeks on the 15 mg of sibutramine
in the morning. This was partially relieved by adding a 5 mg dose
of sibutramine in the afternoon. This effect on the heroin craving
and hurt is therefore clearly separate from the FDA-approved
anorexic effect of sibutramine. Finally, she has had none of the
negative "nodding out" side effects with sibutramine that she noted
with heroin. She is now working at two jobs to pay her back
debts.
[0136] 22. Reflex Sympathetic Dystrophy Syndrome (RSDS)
[0137] A 34-year-old woman injured her left ankle 14 months prior
to her initial visit. The left lower leg then became red and then
black, hot, swollen, and extremely painful. RSD was diagnosed and
multiple treatments were unsuccessful. After nine months the skin
gradually sloughed and the limb turned cold but remained painful,
especially to touch. The patient also noted profuse swelling of the
affected left leg, a tremor of the left hand, and many
visual-spatial problems characteristic of right cerebral
dysfunction. She was declared totally disabled. After various
unsuccessful treatments, the patient was treated with sibutramine
10 mg. b.i.d. After the sibutramine the patient rapidly became
cognitive and had pain relief. This enabled her to discontinue her
other medication.
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