Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-11
2002-05-28
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S315000
Reexamination Certificate
active
06395752
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of treating depression in a patient by oral or non-oral administration of 2S,2′S-methyl 2-phenyl-2-(2′-piperidyl) acetate, commonly known as 1-threo-methylphenidate, hereinafter referred to as 1-MPH and to pharmaceutical compositions containing 1-MPH designed to deliver 1-MPH to the central nervous system. More particularly the method of treatment is designed to provide relief to a depressed patient who is awaiting the onset of the antidepressive action of an antidepressant such as a selective serotonin re-uptake inhibitor, or any other class of antidepressant that requires administration over 2 to 6 weeks to demonstrate therapeutic effect.
BACKGROUND OF THE INVENTION
Orally administered racemic d1-threo-methylphenidate (d1-MPH) is widely used in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in children and adults and also in the treatment of depression in patients suffering from cancer or AIDS, compulsive shopping disorder, narcolepsy, and hypersomnia. It is known that the therapeutic effect of d1-MPH in the treatment of ADHD in children is attributable to d-MPH (Srinivas et al, Clin. Pharmacol. Therap. 52, 561 to 568, 1992). Until recently, however, little was known about the potential pharmacological and/or therapeutic roles of 1-MPH because concentrations of 1-MPH in plasma and brain are very low due to extensive enantioselective first pass metabolism of 1-MPH after oral administration of d1-MPH (Srinivas et al, Pharm. Res. 10, 14 to 21, 1993). After intravenous administration of d1-MPH, however, both enantiomers of threo-methylphenidate are taken up into the brain although their patterns of distribution are different (Ding et al, Psychopharmacology 131, 71 to 78, 1997).
The use of oral stimulants such as dextroamphetamine or d1-MPH in the treatment of severe depressive disorders in the elderly or terminally ill depressed patients has been the subject of many studies over the years. After reviewing 85 publications on the subject, Satel and Nelson (J. Clin. Psychiat. 50, 241 to 249, 1989) were critical of the fact that many of the studies reported were methodologically unsophisticated and/or uncontrolled. They concluded that while stimulants are no more effective than a placebo in the treatment of primary depression, stimulants may be of value in the treatment of refractory patients and medically ill patients. Similarly, Chiarello and Cole (Arch. Gen. Psychiat. 44, 276 to 285, 1997) reviewed 81 publications and concluded that many of the older studies are inadequate although there was some evidence to support the use of psychostimulants in selected clinical instances. Emptage and Smith (Annals of Pharmacotherapy, 30, 151 to 157, 1996) reviewed 43 studies published from 1986 to 1995 and concluded that oral—MPH appears to be a safe and effective treatment for depressed, medically ill, elderly patients to provoke a rapid onset of antidepressant activity. Recently Wallace and co-workers (Am. J. Psychiat. 152, 929 to 931, 1995) conducted what they termed the first placebo-controlled double blind trial to demonstrate the efficacy of oral d1-MPH in older, medically ill depressed patients. The benefit of oral d1-MPH was statistically and clinically significant despite the small number of patients in the study (n=16). Depressive symptoms decreased markedly in 7 subjects (Hamilton depression scale decreased by >55%), moderately in a further 3 subjects (Hamilton depression scale decreased by 30 to 55%), minimally in 3 subjects (Hamilton depression scale decreased by <30%) and three patients were dropped from the study.
OBJECTS OF THE INVENTION
It is an objective of the invention to provide a method of treating a depressed patient to provide immediate relief from intense dysphoria by administering to the patient via an oral or non-oral route, a therapeutically effective amount of 1-MPH which refers herein to the base or hydrochloride salt or any other pharmaceutically acceptable salts thereof.
A further objective of the invention is to provide a method of treating a depressed mammal and particularly a depressed human patient with repeated doses of 1-MPH, either in immediate release form or sustained release form to provide relief while the patient awaits the onset of action of a conventional antidepressant drug.
A further objective of the invention to provide a test to ascertain how responsive a patient may be to certain forms of antidepressant therapy by administering 1-MPH orally or non-orally to the patient, observing the patient's response to the 1-MHP and utilizing that information to predict how effectively such a patient would be expected to respond to treatment with conventional anti-depressants which take 2 to 6 weeks to become optimally effective.
SUMMARY OF THE INVENTION
According to this invention, 1-MPH and/or its salts is a valuable rapidly acting anti-depressant and/or anti-dysphoric when administered by a route that avoids first pass metabolism or given orally in large enough doses to saturate and overwhelm the first pass metabolism. It may be used according to the present invention to treat a patient suffering from depression by systemically administering to the patient, in an oral or non-oral form, a clinically effective dose of 1-MPH. The 1-MPH may either be in the form of its free base or in the form of a pharmaceutically acceptable salt, such as the hydrochloride salt, the acetate salt, the maleate salt or any other pharmaceutically acceptable acid addition salt.
The oral routes of administration that avoid the first pass metabolism are preferably parenteral, sub-lingual or intra-nasal administration or via the buccal mucosae.
The 1-MPH used according to the present invention has an enantiomeric purity of at least 95% and therefore contains no more than 5% d-MPH; the latter enantiomer may potentially be abused. Preferably the 1-MPH is enantiomerically pure.
The 1-MPH may be used to provide rapid antidepressant action for the relief of severe depression in, for example terminal cancer patients, patients with AIDS depression, or in severely depressed patients with suicidal ideation. The 1-MPH may also be useful as a diagnostic tool to identify severely depressed patients who are responders to serotonin re-uptake inhibitors (SSRIs). Examples of these SSRIs include fluoxetine hydrochloride, venlafaxine hydrochloride, paroxetine hydrochloride, nefazodone hydrochloride, and sertraline hydrochloride.
The drug is particularly useful in the treatment of severely depressed hospitalized patients and in depressed suicidal patients to provide immediate relief from their intense dysphoria. The drug may be given repeatedly, either as an immediate release or as a sustained release formulation to provide relief while the patient awaits the onset of conventional antidepressants which typically take 3 to 6 weeks to become effective. These conventional antidepressants can include serotonin re-uptake inhibitors (SSRIs) which have been discussed hereinabove as well as any other pharmaceutical composition that is recognized as safe and effective in the treatment of depression. Such other pharmaceutical compositions include atypical antidepressants which are antidepressant compounds with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors. Examples of such compounds are nefazodone and bupropion. Such other pharmaceutical compositions also include tricyclic antidepressants such as amitriptyline, imipramine, doxepin, maprotiline, protriptyline, nortriptyline, desimipramine, clomipramine, trimipramine or any other conventional tricyclic antidepressant.
The 1-MPH may be used to help severely depressed patients to recover a sufficiently euthymic mood to restore in them feelings of hope and a renewed will to live.
Another feature of the present invention is a diagnostic test which includes the 1-MPH in a method to determine how responsive a patient may be to certain forms of anti-depressant therapy. Patients
Kumar Vijai
Midha Kamal K.
Teicher Martin
Dubno Herbert
Myers Jonathan
Pharmaquest Limited
Rose Shep K.
LandOfFree
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