Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/4035—Isoindoles, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants

Definitions

• the present invention is in the field of pharmacotherapy of nicotine-responsive neuropsychiatric disorders by administering a nicotine antagonist alone, particularly mecamylamine, or in combination with a neuroleptic agent.
• a nicotine antagonist alone, particularly mecamylamine, or in combination with a neuroleptic agent.
• Examples of such disorders are schizophrenia, bipolar disorder, obsessive compulsive disorder, attention deficit hyperactivity disorder, Tourette's syndrome, and other movement disorders.
• Tourette's syndrome is an autosomal dominant neuropsychiatric disorder characterized by a range of symptoms, including multiple motor and phonic tics. It is a hyperkinetic movement disorder expressed largely by sudden, rapid, brief, recurrent, nonrhythmic, stereotyped motor movements (motor tics) or sounds (phonic tics), experienced as irresistible impulses but which can be suppressed for varying lengths of time (Tourette Syndrome Classification Study Group, Arch Neurol 50: 1013-16). Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing, while phonic or vocal tics include throat clearing, sniffling, yelping, tongue clicking and coprolalia.
• TS is frequently treated with the dopamine antagonist haloperidol (Haldol®, McNeil Pharmaceutical, Raritan, NJ), which is effective in about 70% of cases (Erenberg G, Cruse RP, Rothner, AD, Ann Neurol, 22:383-385, 1987; Shapiro AK, Shapiro E, Wiley series in child and adolescent mental health, Eds. Cohen DJ, Bruun RD, Leckman JF, New York City, John Wiley and Sons, pp. 267-280, 1988).
• Other neuroleptics include pimozide (Shapiro ES et al.
• haloperidol has frequent side effects that affect compliance, including difficulty in concentration, drowsiness, depression, weight gain, parkinsonian-like symptoms - and with long-term use - tardive dyskinesia (Shapiro AK, Shapiro E, Tourette's syndrome and Tic Disorders: Clinical Understanding and Treatment. Wiley series in child and adolescent mental health. Eds. Cohen, DJ, Bruun, RD, Leckman JF, New York City, John Wiley and Sons, pp. 267-298, 1988).
• the side effect of tardive dyskinesia is particularly bothersome because it may add additional abnormal, involuntary movements of the tongue, jaw, trunk and/or extremities.
• the 7 mg, 24-hour transdermal nicotine patch (Nicoderm® TNP) was tested in 11 TS patients who were not responding optimally to current neuroleptic treatment (Silver AA et al. The Effects of Nicotine on Biological Systems II. PBS Clarke, M. Quik and K. Thurau, (Eds.); Advances in Pharmacological Sciences, Birkhauser Publishers, pp. 293-299, 1995).
• Patients' tics were videotaped before treatment began and 3 hours after the start of treatment. The frequency and severity of tics were reduced 47% and 34%, respectively, at three hours.
• Patients with the least control by neuroleptic treatment showed more dramatic improvement than did patients whose neuroleptic treatment alone had been more effective.
• the effects of the TNP persisted longer than the expected 24 hours.
• transdermal nicotine was an effective adjunct to neuroleptic therapy of TS, and helped when administered alone to two patients.
• ADHD Attention Deficit Hyperactivity Disorder
• the current patent application is concerned with the administration of nicotine antagonists, particularly mecamylamine (3-methylamino-2,2,3-trimethylnorcamphane).
• Mecamylamine is well known as a nicotine antagonist and blocks ganglia which nicotine stimulates.
• mecamylamine blocks sympathetic ganglia transmission and thereby causes vasodilatation and a fall in blood pressure (Taylor P, In: Goodman LS, Gilman A (eds) The Pharmacological Basis of Therapeutics, McMillan Publishing Co., New York City, pp. 193-95, 1996).
• ganglionic blockade may result also in atony of the bladder and gastrointestinal tract, impaired sexual function, cycloplegia, xerostomia, diminished perspiration and postural hypotension. While the clinical use of mecamylamine as a ganglionic agent has largely been replaced by more effective antihypertensive medications, scientists remain interested in mecamylamine because of its ability to block nicotine binding sites in the brain (see, e.g., Martin BR, Onaivi ES, Martin TJ, Biochemical Pharmacology 38: 3391-3397, 1989; and Banerjee S et al, Biochemical Pharmacology 40(9): 2105-2110, 1990). These nicotine binding sites, known as nicotinic acetylcholinergic receptors (nAChr), are normally activated in the brain by acetylcholine, a prominent neurotransmitter.
• nAChr nicotinic acetylcholinergic receptors
• Nicotine via tobacco in various forms, has been one of the most widely utilized drugs for centuries (Wilbert J, J Ethnopharmacol 32(1-3): 179-186, 1991). Nicotine is a potent modulator of nAChrs (Changeux JP, Sci Amer (November) pp. 58-62, 1993). Through these receptors, nicotine activates the presynaptic release of several neurotransmitters including acetylcholine, norepinephrine, serotonin and dopamine (Balfour DJK, Pharmacological Therapeutics 16: 269-
• SUBSTITUTE SHEET (RULE 26 ⁇ on nAChrs may be useful therapeutically for treating neuropsychiatric disorders (Jarvick ME, Br J Addict 86: 571-575, 1991; Newhouse PA, Hughes JR, Br J Addict 86: 521-526, 1991; and Hughes J, Clarke PBS (Eds): The effects of nicotine on biological systems II. Abstract S40, 1994; Decker MW et al, Life Sci 56: 545-570, 1995).
• mecamylamine has been reported to produce central effects in humans, such as blocking the CNS actions of nicotine (Martin BR, Onaivi ES, Martin TJ, Biochemical Pharmacology 38:3391-3397, 1989) and in altering cognitive functioning (Newhouse PA et al, Neuropsychopharmacology 10: 93-107, 1994), electrical brain waves (Pickworth WB, Herning RI, Henningfield JE, Pharmacology Biochemistry & Behavior 30: 149-153, 1988) and cortical blood flow (Gitalman DR, Prohovnik I, Neurobiology of Aging 13: 313-318, 1992).
• OCD obsessive-compulsive disorder
• TS tylcholine
• nAChrs nAChrs in the basal ganglia
• DA dopamine
• U.S. Patent No. 5,774,052 to Rose and Levin discloses agonist-antagonist combinations to reduce the use of nicotine and other drugs.
• the nicotinic antagonist mecamylamine was given to treat tobacco dependency.
• Rose and Levin proposed including both nicotine and mecamylamine in a patch.
• Rose and Levin also suggested that such agonist-antagonist combinations could be used in other psychopathological disorders and cases involving neuronal dysfunction (e.g., manic depression, schizophrenia and hypertension due to sympathetic autonomic disorder).
• a method of treating an individual with nicotine-responsive neuropsychiatric disorders comprising administering to the individual an effective amount of a nicotine antagonist.
• the nicotine antagonist is mecamylamine, a stereoisomer, or a mecamylamine analog .
• the effective amount of mecamylamine is that which improves the individual's signs and symptoms.
• the effective amount is the amount which decreases the frequency and/or severity of tics in the individual.
• neuroleptic drugs are haloperidol, pimozide, fluphenazine, and risperidone.
• nicotine-responsive disorders are movement disorders such as Tourette's
• Figure 1 shows the chemical structures of mecamylamine and several other nicotinic antagonists.
• LE26 such as attention deficit hyperactivity disorder (ADHD), Obsessive Compulsive Disorder (OCD), Essential Tremor (ET), Tardive Dyskinesia (TD), Depression (D), and Huntington's Disease (HD). Nicotine antagonists can also be expected to affect other nicotine-responsive disorders (e.g., schizophrenia, depression, bipolar disorder, rage outbursts and panic states). Hemidystonia also is nicotine responsive and is a focal movement disorder involving an arm and a leg on one side of the body. It generally develops in adulthood, remains stable and rarely spreads to other body parts. It is part of a family of syndromes which also include spasmodic torticollis (intermittent spasms turning or bowing the head).
• Nicotine Antagonists of which mecamylamine is but one example are a large and growing category. A truly exhaustive list of such compounds would take up too much space here. The following discussion is not intended to be exhaustive but to teach how to identify compounds which are encompassed by this term.
• “Beneficial effect” is an observable improvement over the baseline clinically observable signs and symptoms.
• a beneficial effect in motor disorders includes decreases in tic frequency or severity, but improvements also can be manifested indirectly through reductions in anxiety, aggressive outbursts, and premonitory urges which often precede or compound the severity of abnormal movements.
• Treatment effects can be quantified by clinical observations and video tape scoring.
• Beneficial effects in obsessive compulsive disorders include diminution in the obsessive or compulsive behavior, which can be confirmed by patient's reports.
• Suemaru et al ibid
• Suemaru et al has proposed that the nicotine-induced rat tail tremor can be used to screen for compounds to treat tremors.
• the Yale Global Tic Severity Scale is the most widely used clinical assessment rating scale used to assess tic symptoms. It provides an objective measure of tic frequency of severity based on clinical observations. This scale includes a tic symptom inventory which is filled out based on the patient's personal recall of tics occurring over the previous week. Using this inventory as a guide, the clinician then rates the severity of both motor and vocal tics on five separate dimensions: number, frequency, intensity, complexity, and interference. In addition, there is also a separate rating of global impairment which characterizes the impact of the disorder on the patient's social function, self esteem, etc., over the previous week.
• An objective method for rating tic symptoms employs video recording of patients. A videotape of at least five minutes is viewed and the frequency and severity of both motor and vocal tics are recorded. Video taping has proven a valuable adjunct to clinical rating systems for drug trials (Leckman JF, et al., Arch Gen Psychiatry, 48: 324-328, 1991; Shapiro ES, et al, Arch Gen Psychiatry, 46: 722-730, 1989; McConville BJ, Fogelson MH, Norman AB, Klykylo WM, Manderborg MA, Parker KW, Sanberg PR, Am J Psychiatry, 148: 793-794, 1991; Silver AA, Shytle RD, Philipp MK, Sanberg PR, The Effects of Nicotine on Biological Systems II. PBS Clarke, M. Quik and K. Thurau, (Eds.); Advances in Pharmacological Sciences, Birkhauser
• Chappell PB et al., Adv Neurol 58: 253-262, 1992; Lombroso PJ et al. Neurology 41: 1984-1987, 1991.
• Chappell and colleagues validated both motor and vocal tic frequency by video tape and found that such data correlated well with established clinical rating scales.
• Neuroleptic drug as used herein is a drug which affects thinking, feeling and neurological status, particularly movement and posture (as in TS). Almost all neuroleptic drugs have a strong extrapyramidal effect, resulting in Tardive dyskinesia (see above). Examples of neuroleptic drugs are haloperidol (Haldol®, McNeil Pharmaceutical, Raritan, NJ), pimozide (Orap®, Teva Pharmaceuticals, Kulpsville, PA), fluphenazine, and risperidone (Risperdal®, Janssen Pharmaceutical, Titusville, NJ).
• an effective amount refers to the amount of nicotine antagonist that is necessary to provide benefit.
• the precise amount required will vary depending upon the particular compound selected, the age and weight of the subject, severity of the disorder, route of administration, and so forth, but may easily be determined by routine experimentation, as described below in the clinical examples. In general, however, an effective amount will range from about 0.001 mg/kg to about 6 mg/kg per day, preferably about 0.002 mg/kg to about 3 mg/kg, more preferably about 0.005 mg/kg to about 2 mg/kg, and most preferably about 0.01 to about 1.5 mg/kg.
• a starting dose for adults with drug-resistant TS is about 2.5 mg per day, with dosage adjusted according to return of symptoms (see case histories below).
• a small child with mild ADHD preferably starts with 1 mg per day or less.
• the effective amount of a neuroleptic drug is the least amount which when combined with a nicotine antagonist relieves symptoms. Our clinical experience suggests some patients may not require any neuroleptic drug to achieve maximum benefit.
• pharmaceutically acceptable refers to a lack of unacceptable toxicity in a compound, such as a salt or excipient.
• Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and the like, and organic anions such as acetate, malonate, pyruvate, propionate, cinnamate, tosylate, citrate, and the like.
• Pharmaceutically acceptable excipients are described at length by E.W. Martin, in Remington's Pharmaceutical Sciences (Mack Pub. Co.).
• compositions containing nicotine antagonists may contain one or more pharmaceutical carriers.
• pharmaceutically acceptable carrier refers to any generally acceptable excipient that is relatively inert, non-toxic and non-irritating. When the carrier serves as a diluent, it may be solid, semisolid, or liquid material acting as a vehicle, excipient, or medium for the active ingredient.
• Pharmaceutical unit dosage forms may be prepared for administration by any of several routes, including, but not limited to, oral and parenteral (especially by intramuscular and intravenous injection, or by subcutaneous implant or transdermal administration).
• compositions containing nicotine antagonists may be formulated by procedures known in the art so as to provide rapid, sustained, or delayed release of any or all of the compounds after administration.
• preferred carriers facilitate formulation in tablet or capsule form.
• Solid pharmaceutical excipients such as magnesium stearate, calcium carbonate, silica, starch, sucrose, dextrose, polyethylene glycol (PEG), talc, and the like may be used with other conventional pharmaceutical adjuvants including fillers, lubricants, wetting agents, preserving agents, disintegrating agents, flavoring agents, and binders such as gelatin, gum arabic, cellulose, methylcellulose, and the like, to form admixtures which may be used as such or may be tabulated, encapsulated, or prepared in other suitable forms as noted above.
• a general description of formulation is given in Remington's Pharmaceutical Sciences (Mack Pub. Co.).
• Modes of Administration is preferably by oral dosage but may be by transdermal application, intranasal spray, bronchial inhalation, suppository, parenteral injection (e.g., intramuscular or intravenous injection), and the like.
• Carriers for parenteral administration include, without limitation, aqueous solutions of dextrose, mannitol, mannose, sorbitol, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-polyoxypropylene block polymers, and the like.
• suitable preservatives for example, BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
• Other devices include indwelling catheters and devices such as the Alzet® minipump.
• Patient 1 was a tall, 173-pound, 15-year-old male diagnosed with TS. He had been a patient in our clinic, receiving 2 mg of haloperidol daily and two transdermal nicotine patches (14 mg/24 hr) each week for approximately one year for effective control of severe symptoms of TS. However, approximately two months before a scheduled follow-up visit, his tics, which had been under excellent control, had emerged again. At that time, his haloperidol dose was increased to 3 mg/day and the frequency of nicotine patch application was increased to every other day, with some improvement noted. However, the side effects of the nicotine patch, particularly nausea, were disturbing to the patient, resulting in his refusal to wear the patch. In addition, because of the increased risk of nicotine addiction with daily use, we were reluctant to subject the patient to continued use of the patch.
• Mecamylamine (5 mg) was given orally at about 11:30 AM. Approximately two hours later, the patient reported that his urge to tic was reduced. The YGTSS score was 6/20. Although tics were still present, there was a 25%> decrease in tic frequency. Overall tic severity was reduced by 50%. By 6:00 PM, his mother reported that the patient felt better, there were virtually no tics present, and there were no side effects. However, by the next morning, his tics were beginning to return. One month later, on a daily dose of 5 mg mecamylamine at breakfast, his tics were still under control, and the patient reported that he was more relaxed and alert. The shy, taciturn youth of 30 days earlier was now more outgoing and voluble.
• Mecamylamine was prescribed and the patient was told to take it after dinner. His mother, a nurse, reported that two hours after taking 5 mg of mecamylamine he started to study math. This time, he was patient, felt his "mind is clearer", was more relaxed, and worked on math problems for three hours without distraction. His tics had subsided in intensity and frequency. The following morning, he felt restless; and tics started to return, though not as disturbing as previously. He had eye blinking and gross, jerky body movements. He was prescribed 5 mg mecamylamine at breakfast and 2.5 mg after dinner daily. Twelve days later, the patient reported that with the medication, he was not "hyper” and could concentrate on his schoolwork. The tics, although occasionally present, had subsided.
• Patient 3 was a 35-year-old, who has had TS with severe motor and vocal tics, obsessions and compulsions since the age of six. She is the mother of three children, the oldest of whom, a girl aged 12, also had TS. Over several years, a variety of medications had been tried, including Zoloft (sertraline hydrochloride, Roerig Div, Pfizer, New York City) to limit her depression and mood swings.
• Zoloft sodiumline hydrochloride, Roerig Div, Pfizer, New York City
• Patient 4 was a 43-year-old salesman with a history of TS since age 14. He had received haloperidol (0.5 mg bid) and a 14 mg transdermal nicotine patch twice each week for the previous 6 months, without complete control of motor or vocal tics. Rather than increase the haloperidol dose or increase the frequency of nicotine patch, the nicotine patch was discontinued and mecamylamine (5 mg per day) was prescribed.
• the YGTSS was 27/30, and a 5- minute segment of videotape revealed a total tic count of 207 with an overall severity of 4 (very noticeable) on a 7-point scale.
• Patient 4 reported that his primary care physician could not find a cause for his chronic fatigue which had started before mecamylamine treatment. There was no change in blood pressure. However, the patient discontinued mecamylamine and resumed the nicotine patch.
• Patient 5 was an 18-year-old male who was first seen in our clinic at age 15. His TS symptoms had been treated with pimozide (Orap, Teva Pharmaceuticals, Kulpsville, PA) up to 16 mg daily since age 10. He had a strong family history of tic spectrum disorders. His mother, maternal grandfather, maternal uncle and a male cousin all had evidence of Tourette symptoms. At his initial clinic visit, he was receiving 12 mg of pimozide together with Prozac® (fluoxetine hydrochloride, Eli Lilly & Co., Indianapolis IN).
• Patient 6 was a 23-year-old male, who had had severe Tourette symptoms since he was in second grade. Over the years he had been treated with a variety of neuroleptic medications as well as clonidine and clonazepam (Klonopin®, Roche Laboratories, Nutley, NJ.) At his first visit to our clinic, he had been receiving 12 mg of pimozide daily for at least two years, and was working as a counselor at a camp for emotionally disturbed children. Twice he had failed his courses to become an Emergency Medical Technician. His Tourette symptoms were among the most severe seen at our clinic.
• Mecamylamine 2.5 mg daily was started on 7/1/97. The patient reported that he was "more relaxed, speaks better [coprolalia diminished], and speech more fluent". However, he complained of "headaches and heartburn”. Mecamylamine was tried again on 12/8/97. On initial dose of 2.5 mg, coprolalia was under control for about 1 hour, following which the patient complained of "getting jittery and nervous”. Mecamylamine was discontinued. Patient 11 was a 14-year-old boy with Tourette's Syndrome, ADHD, OCD, severe visual and motor dysfunction, anxiety, and low self esteem. An avulsion of his thumb contributed to his feeling of being "incomplete” and physically different from his class mates. His symptoms were under moderate control with haloperidol.
• mecamylamine at 2.5 mg per day was started. Within 3 hours of the first dose the patient was less restless and felt calm. His tics had markedly decreased in severity. There were no adverse effects and blood pressure remained at 110-114/70-76. Within the week after mecamylamine was started, his mother reported a marked improvement in mood and behavior, decreased irritability and pleasant interactions with parents. "He does not hit his little brother any more.” Haloperidol and clonidine, which had been continued, were decreased in dose. Mecamylamine was continued for 215 days.
• Tics began within months of starting methylphenidate.
• the symptoms of Tourette's syndrome, OCD, and ADHD had become progressively worse. He had received a combination of medication including pimozide, haloperidol, Prozac, and Paxil, together which caused mild control of his tics, increased depression and sleeping in school, so much so that he was removed from his current grade (8th) at school and was home-schooled for 2 months before he was brought to our clinic at age 14.5 years. Gradually decreasing his various medications to haloperidol 2 mg and adding clonidine did not significantly alter his symptoms. Transdermal nicotine patch (7 mg) twice weekly did obtund his symptoms.
• Patient 13 was a 12-year-old boy had been seen in our clinic since he was 9 years of age. Motor and vocal tics, and compulsions have become increasingly worse after the age of 4 years, more so after 7 years.
• EEG's were abnormal "dysrhythmia grade III, bilateral synchronous and independent central, parietal temporal spikes". Tegretol aggravated all symptoms. His motor and vocal tics have been difficult to control with standard medication; he was sensitive to nicotine which, although helping obtund his tics, caused intolerable side effects.
• mecamylamine 2.5 mg/day, was started.
• Dosages for these TS patients whose condition was not under control with conventional therapy are summarized below in Table 1. Dosages ranged from about 0.03 to 0.10 mg/kg. This range was used to calculate Table 2.
• nAChr blocker which has been disclosed herein with the example of mecamylamine, a nAChr blocker, which reduced the symptoms in the nicotine responsive disorders, TS and ADHD.
• Schizophrenia a psychiatric disorder theorized to involve hyperdopaminergic tone, is most often treated with neuroleptics, but there is now speculation that it is a nicotine-responsive disorder. For example, surveys of schizophrenic patients have demonstrated rates of smoking between 74% and 92%, compared to 35% to 54% for all psychiatric patients and 30%-35% for the general population. It has been speculated that cigarette smoking may improve underlying psychopathology by enhancing concentration and reducing anxiety from hyperarousal (Gopalaswamy AK, Morgan R, Br J Psychiatry, 149: 523, 1986). In addition, nicotine may have some role to play in reducing the cognitive deficits associated with schizophrenia and neuroleptic treatment.
• Cigarette smoking has been found to normalize sensory gating deficits in schizophrenic patients (Adler LE et al, Am J Psychiatry 150:1856-1861, 1993) and a recent study found that transdermal nicotine reversed some of the adverse cognitive effects of standard anti-psychotic medication and improved cognitive performance in general for schizophrenic patients (Levin ED et al, Psychopharmacology 123:55-63, 1996). If as we now hypothesize that nicotine administration may actually have a similar effect as a nAChr blocker, then it is possible that a nAChr blocker such as mecamylamine and related compounds would also reverse the adverse cognitive effects of the anti-psychotic medication and improve cognitive performance in schizophrenic patients.
• a nAChr blocker such as mecamylamine and related compounds would also reverse the adverse cognitive effects of the anti-psychotic medication and improve cognitive performance in schizophrenic patients.

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• Neurology (AREA)
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• Epidemiology (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
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• 1998
  • 1998-08-11 WO PCT/US1998/016634 patent/WO1999007378A1/en active IP Right Grant
  • 1998-08-11 AU AU87784/98A patent/AU8778498A/en not_active Abandoned
  • 1998-08-11 DK DK98939328T patent/DK1011678T3/da active
  • 1998-08-11 JP JP2000506968A patent/JP4640888B2/ja not_active Expired - Fee Related
  • 1998-08-11 ES ES98939328T patent/ES2299214T3/es not_active Expired - Lifetime
  • 1998-08-11 CA CA002300148A patent/CA2300148C/en not_active Expired - Fee Related

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