Drug combinations

Details Drug combinations Drug combinations

2001-07-11

2002-12-31

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S236200, C514S247000, C514S249000

Reexamination Certificate

active

06500827

ABSTRACT:

FIELD OF THE INVENTION
This invention describes new treatments that should provide for a fast acting rapid onset of relief from several nervous system disorders, and it involves the administration of the drug reboxetine in combination with the drug pindolol.
BACKGROUND
The introduction of tricyclic antidepressants in the early 1960s has provided a major advance in the treatment of neuropsychiatric disorders. Reactive and endogenous depressions, diagnoses formerly carrying grave prognostic implications, have become, with the introduction of the tricyclics, manageable disorders with a much smaller toll on the patient and the society as a whole.
The early tricyclic compounds were reuptake inhibitors of all the catecholamines released in the synaptic cleft, thus resulting in prolongation and enhancement of the dopamine (DA), noradrenaline (NA) and serotonin (5-hydroxytryptamine=5-HT) action. Lack of selectivity also causes undesired side effects particularly on the acetylcholine (especially the muscarinic component), and histamine mediated neurotransmission.
Because of these unwanted pharmacodynamic activities, cognitive impairment, sedation, urinary and gastrointestinal tract disturbances, increased intraocular pressure were limiting factors in the clinical use of these compounds and often required discontinuation of treatment. Of utmost concern were also the cardiac toxic effects and the proconvulsant activity of this group of drugs.
More recently, selective reuptake inhibitors for serotonin (SSRI) have been introduced with definite advantages in regard to fewer side effects without loss of efficacy.
SUMMARY OF THE INVENTION
Here we present the surprising finding that when the drug pindolol is given to a patient concurrently with a drug from a new category of antidepressants, a so called noradrenaline (NA) reuptake inhibitor (NARI), the combination of drugs act with surprising speed in relieving the symptoms of depression and it may be used for treating the symptoms of other central nervous system disorders including, but not only, general anxiety, Addictive Disorders, attention deficit hyperactivity disorder (ADHD), anxiety disorders such as obsessive compulsive disorders (OCD), panic disorders (PD), social phobia (SP) and the like.
One particular NARI that is preferred is reboxetine. Reboxetine is the generic name of the pharmaceutical substance with the chemical name of 2-(I-((2-ethoxyphenoxy)benzyl)-morpholine, and its pharmaceutically acceptable salts. Reboxetine can be a free base, or it can include reboxetine methanesulfonate (also called reboxetine mesylate) or any other pharmaceutically acceptable salt that does not significantly affect the pharmaceutical activity of the substance.
The chemical name of pindolol is 1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol; 4-[2-hydroxy-3-(isopropylamino)-propoxy]indole; pinodolol. Pindolol is described in U.S. Pat. No. 3,471,515, incorporated by reference and process steps are described in Swiss patents 469,002 and 472,404, assigned to the Sandoz Company, now the Novartis company, all documents incorporated into this document by reference. It has the trade name VISKEN®.
The present invention provides for the dosing of both reboxetine and pindolol, concurrently. The dosages for reboxetine and pindolol can be measured separately. The two drugs can be given as a single combined dose or given separately. They may be given at the same or at different times as long as both drugs are in the patient at one time over a 24 hour period. The two drugs will preferably be given to the patient, concomitantly, concurrently, at or about the same time, within about 5, 10, or 30 minutes, or they may be given within 1, 2, 3, 4, 5, 6, 8, 10, 12, 18 or about 24 hours, or fractions of minutes or of hours of each other. Concomitant or concurrent administration means the patient takes one drug within about 5 minutes of taking the other drug. Because the goal here is to provide rapid symptomatic relief to the patient, in most cases when treatment is started the two drugs would be administered to the patient close in time and typically concomitantly; thereafter, the timing of each drug's administration may not be as important.
A preferred dose range of reboxetine is 4 to 10 mg per patient per day and the more preferred dose is 6 to 8 mg or 8 to 10 mg per patient daily, depending upon the patient, delivered twice a day (b.i.d.). The reboxetine should be given to a patient concurrently with pindolol.
A preferred dose range of pindolol is 10-60 mg per patient per day and the more preferred dose is about 10 mg per patient daily, depending upon the patient, delivered twice a day (b.i.d.). Preferably the pindolol should be given concurrently with reboxetine as described above.


REFERENCES:
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patent: 5532268 (1996-07-01), Wong et al.
patent: 5798393 (1998-08-01), Swartz
patent: 6028070 (2000-02-01), Helligenstein
patent: 6046193 (2000-04-01), Helligenstein
patent: 6184222 (2001-02-01), Helligenstein
“Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors”, Artigas et al., 1994, Arch Gen Psychiatry.

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