Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-04
2001-12-25
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S400000
Reexamination Certificate
active
06333345
ABSTRACT:
1. FIELD OF THE INVENTION
The invention relates to compositions and methods for the treatment and prevention of sleep, convulsive, and related disorders.
2. BACKGROUND OF THE INVENTION
Zolpidem, chemically named N,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide, is a non-benzodiazepine hypnotic which has the following structure:
A 2:1 tartrate complex of zolpidem is sold under the tradename AMBIEN® and is indicated for the short-term treatment of insomnia.
Physicians' Desk Reference,
2929-2933 (53
rd
ed. 1999). The synthesis of zolpidem is described by U.S. Pat. Nos. 4,382,938 and 4,794,185.
Zolpidem binds at or near benzodiazepine receptors, particularly those found within GABA
A
receptor chloride channel macromolecular complexes located in the central nervous system. Scatton, B., et al.,
J. Pharmacol. Exp. Ther.
237(2):659-665 (1986); Criswell, H. E., et al.,
Neuropharmacology
36(11-12):1641-1652 (1997); Buhr, A. and Sigel, E.,
Proc Natl. Acad Sci USA
94(16):8824-8829 (1997). At least three subtypes of benzodiazepine, or omega (&ohgr;), receptors are believed to exist within GABA
A
receptor complexes, but zolpidem preferentially binds in vitro to the &ohgr;
1
receptor.
Physicians' Desk Reference,
2929 (53
rd
ed. 1999). The sedative, anticonvulsant, anxiolytic, and myorelaxant properties of zolpidem are believed to be due to its ability to allosterically modulate the activity of GABA
A
complexes by increasing trans-membrane conductance of chloride ions. This stabilizes neuronal membrane potentials and dampens excitatory input. Id.;
Goodman
&
Gilman's The Pharmacological Basis of Therapeutics,
Hardman, J. G., et al., eds., 365-372 (9
th
ed., 1996).
Zolpidem is chemically unrelated to the benzodiazepines but possesses a similar spectrum of activity. Id.; Depoortere, H. et al.,
J. Pharmacol. Exp. Ther.
237(2):649-658 (1985). In addition to the treatment of insomnia, zolpidem has been claimed to be useful in the treatment of other conditions such as convulsions (U.S. Pat. No. 4,382,938), migraine headaches (U.S. Pat. No. 5,767,117), and parkinsonian and related extrapyramidal symptoms (WO 96/31210).
Zolpidem is readily absorbed through the gastrointestinal tract, and is reportedly eliminated almost entirely in the-liver largely by oxidation of the methyl groups on the phenyl and imidazopyridine rings to the corresponding carboxylic acids.
Goodman
&
Gilman's The Pharmacological Basis of Therapeutics,
Hardman, J. G., et al., eds., 372 (9
th
ed., 1996). Metabolism of zolpidem is primarily attributed to CYP3A4, and it has been found that inducers of CYP3A4 such as rifampicin, phenytoin, and carbamazepine reduce the pharmacodynamics of zolpidem. Villikka, K., et al.,
Clin. Pharmacol. Ther.
62(6):629-634 (1997).
The metabolites of zolpidem are reportedly inactive. See, e.g.,
Goodman
&
Gilman's The Pharmacological Basis of Therapeutics,
Hardman, J. G., et al., eds., 372 (9
th
ed., 1996);
Physicians' Desk Reference,
2930 (53
rd
ed. 1999).
While zolpidem is effective in the treatment of insomnia, unfortunately, there are adverse effects associated with both short term and chronic use of the drug. These include, but are not limited to, headache, dizziness, vertigo, confusion, lack of coordination, lethargy or drowsiness the day after use, and gastrointestinal problems such as nausea and diarrhea.
3. SUMMARY OF THE INVENTION
The invention is directed to compositions comprising, and methods of using, N-desmethylzolpidem in the treatment and prevention of diseases and conditions in mammals.
Zolpidem metabolites are reported to be pharmacologically inactive. According to this invention, however, N-desmethylzolpidem can be used in the treatment or prevention of a disease or condition in a mammal which is affected by the modulation of one or more benzodiazepine receptors. Further, N-desmethylzolpidem can be used in the treatment or prevention of such diseases and conditions while avoiding adverse effects associated with zolpidem. Further still, N-desmethylzolpidem can be adjunctively administered with drugs that affect the activity of the enzyme CYP3A4 to provide pharmacological effects that differ from those of zolpidem when it is adjunctively administered with such drugs.
One embodiment of the invention encompasses a method of treating or preventing a sleep disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of insomnia.
Another embodiment of the invention encompasses a method of treating or preventing an affective disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of depression. Another method of this embodiment is the treatment or prevention of attention deficit disorder or attention deficit disorder with hyperactivity.
Yet another embodiment of the invention encompasses a method of treating or preventing a convulsive state in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of epilepsy or epileptic seizures.
Still another embodiment of the invention encompasses a method of treating or preventing anxiety in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof. A particular method of this embodiment is the treatment or prevention of acute anxiety. Another method of this embodiment is the treatment or prevention of chronic anxiety.
Another embodiment of the invention encompasses a method of treating or preventing aggressive behavior in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof.
Yet another embodiment of the invention encompasses a method of treating or preventing spasticity or acute muscle spasm spasticity in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof.
Still another embodiment of the invention encompasses a method of treating or preventing a behavioral disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof.
Another embodiment of the invention encompasses a method of treating a schizophrenic disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof.
Yet another embodiment of the invention encompasses a method of treating or preventing a disease or condition associated with abnormal plasma hormone levels in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically effective amount of N-desmethylzolpidem or a pharmaceutically acceptable salt, solvate, or clathrate thereof. In a particular method of this embodiment, the disorder is an endocrine disorder.
Patients who may receive the therapeutic or prophylactic benefits of the methods of the invention include those suffe
Jones Dwayne C.
Pennie & Edmonds LLP
Sepracor Inc.
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