Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-12
2001-04-24
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06221883
ABSTRACT:
BACKGROUND OF THE INVENTION
Racemic methylphenidate (MPH) is a central nervous system stimulant that has pharmacological activity qualitatively similar to amphetamines and is widely used in the treatment of attention deficient disorder (ADD) and attention-deficient hyperactivity disorder (ADHD) (l-threo isomer shown in FIG.
1
). Symptoms of these disorders include distractability and impulsivity; ADHD is further associated with increased activity of the body. MPH has also been used to treat cognitive defects, including dementia, that manifest in at least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (Navia et al. Ann. Neurol. 1986; 19:517-524). Additionally, d-threo-methylphenidate is used to treat hypersomnia (Aoyama et al. Clin. Pharmacol. Ther., 1994; 55:270-276)
Originally MPH was sold pharmaceutically as a mixture of two racemates, 80% dl-erthro and 20% dl-threo. Subsequent studies revealed that the central stimulant activity residues in the threo racemate, and thus the erythro racemate was removed from the pharmaceutical to improve its therapeutic index.
dl-threo-MPH appears to facilitate dopaminergic and noradrenergic transmission (Maxwell et al. J. Pharmacol. Exp. Ther. 1970;173:158-165; Breese et al., Paychopharmacology 1975; 44:5-10; Janowsky et al. Eur. J. Pharmacol. 1985; 108:187-191). Patrick et al. found that d-threo-MPH produced greater induction of locomotor activity in rats and greater inhibition of tritiated dopamine and l-norepinephrine uptake into striatal and hypothalamic synaptosomes, respectively, than the l-isomer (Patrick et al. J. Pharmacol. Exp. Therap. 1987; 241:152-158). Additionally, Srinivas et al. showed that the pharmacodynamic activity of the racemic threo-MPH in treating ADHD resides in the d-threo isomer (Srinivas et al.
Clin. Pharmacol. Ther.
1992; 52:561-568). Administration of d-threo-MPH instead of dl-threo-MPH in patients suffering from ADD, ADHD, AIDS cognitive decline, and AIDS Dementia Complex resulted in less severe side effects. These include a reduction in the euphoric effect that is produced when dl-threo-MPH is administered intravenously or through inhalation, to create a potential for substance abuse in patients (U.S. Pat. No. 5,908,850). In rats, baboons, and humans, [
11
C]d-threo-MPH demonstrated highest regional accumulation in the basal ganglia; in contrast, [
11
C]d-threo-MPH displayed similar uptake in all brain regions, suggesting that its distribution in the brain is less specific. This result further supports the hypothesis that the pharmacological specificity of racemic threo-MPH in elevating striatal dopamine concentration resides in the d-threo isomer (Ding et al.
Psychopharmacology
1997; 131:71-78; Aoyama et al.
Pharm. Res.
1994; 11:407-411).
SUMMARY OF THE INVENTION
The invention features a method of effecting dopamine inhibition in a mammal, such as a human, by administering an effective inhibiting amount of l-threo-MPH which is substantially free from d-threo-MPH. This method can be used for the treatment or prevention of a manic disorder, a psychotic disorder, or an anxiety disorder.
In a related aspect, the invention further includes a method of inhibiting the effect of a stimulant by administering to a mammal l-threo-MPH which is free from d-threo-MPH to a mammal. Stimulants that can be inhibited according to the invention include cocaine, amphetamines, caffeine, and d-threo-MPH. The methods of the invention can also be used for treating or preventing the toxic effects of an overdose of a stimulant. By “effect of a stimulant” is meant induction of dopamine or l-norepinephrine uptake, distractibitlity, impulsivity, or hyperactivity.
l-threo-MPH is administered orally, intramuscularly, intravenously, or subcutaneously to the mammal. l-threo-MPH generally is administered together with a pharmaceutically acceptable carrier. Generally, dosage is in the same range as the dosage currently used for d-threo-MPH.
REFERENCES:
patent: 5874090 (1999-02-01), Baker et al.
patent: 5908850 (1999-06-01), Zeitlin et al.
Aoyama et al., “Stereospecific distribution of methylphenidate enantiomers in rat brain: Specific binding to dopamine reuptake sites,”Pharm. Res.11:407-411 (1994).
Aoyama et al., “Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats,”Psychopharmacology127:117-122 (1996).
Breese et al., “Involvement of brain monoamines in the stimulant and paradoxical inhibitory effects of methylphenidate,”Psychopharmacologia(Berl) 44:5-10 (1975).
Ding et al., “Chiral drugs: Comparison of the pharmacokinetics of [11C]d-threo and l-threo-methylphenidate in the human and baboon brain,”Psychopharmacology131:71-78 (1997).
Eckerman et al., “Enantioselective behavioral effects of threo-methylphenidate in rats,”Pharmacology, Biochemistry&Behavior40(4):875-880 (1991).
Ferris et al., “Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradrol on the uptake of 1-[3H] norepinephrine and [3H]dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus,”J. Pharmacol. Exp. Ther.210(3):422-428 (1979).
Ferris et al., “A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta,”J. Pharmacol. Exp. Ther.181(3):407-416 (1972).
Froimowitz et al., “Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT,”Pharm. Res.12(10):1430-1434 (1995).
Janowsky et al., “The effects of surgical and chemical lesions on striatal [3H] threo-(±)- methylphenidate binding: Correlation with [3H] dopamine uptake,”Eur. J. Pharmacol.108:187-191 (1985).
Jonkman et al., “Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder,”Psych. Res.78(1-2):115-118 (1998).
Leith et al., “Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate,”Psychopharmacology74(1):23-28 (1981).
Maxwell et al., “Conformational similarities between molecular models of phenethylamine and of potent inhibitors of the uptake of tritiated norepinephrine by adrenergic nerves in rabbit aorta,”J. Pharmacol. Exp. Ther.173:158-165 (1970).
Navia et al., “The AIDS dementia complex: I. Clinical Features,” Ann. Neurol. 19:517-524 (1986).
Patrick et al., “Pharmacology of the Enantiomers of threo-Methylphenidate,”J. Pharmacol. Exp. Ther.241:152-158 (1987).
Schweri, “N-ethylmaleimide irreversibly inhibits the binding of [3H]threo-(+−)methylphenidate to the stimulant recognition site,”Neuropharmacology29(10):901-908 (1990).
Srinivas et al., “Enantioselective pharmacokinetics and pharmacodynamics of dl-threo- methylphenidate in children with attention deficit hyperactivity disorder,”Clin. Pharmacol. Ther.52:561-568 (1992).
Srinivas et al., “Stereoselective disposition of methylphenidate in children with attention-deficit disorder,”J. Pharmacol. Exp. Ther.241(1):300-306 (1987).
Baldessarini Ross
Campbell Alexander
Clark & Elbing LLP
Jarvis William R. A.
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