Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-06
2001-07-03
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...
C514S647000
Reexamination Certificate
active
06255329
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an agent with an antidepressant activity containing 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, the (+) or (−) enantiomer thereof, the pharmacologically acceptable acid addition salts thereof and a conventional antidepressant. The combination of pramipexole and sertraline is of particular interest.
BACKGROUND OF THE INVENTION
Pramipexole—(−)-2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole—is a dopamine-D
3
/D
2
agonist, the synthesis of which is described in European Patent 186 087 and U.S. Pat. No. 4,886,812. Pramipexole is known primarily for treating schizophrenia and particularly for the treatment of Parkinson's disease. German Patent Application DE 38 43 227 discloses that pramipexole lowers the prolactin serum level, and it is also known from German Patent Application DE 39 33 738 to use pramipexole to lower high TSH levels. Its transdermal administration is disclosed in U.S. Pat. No. 5,112,842, and WO Patent Application PCT/EP93/03389 describes the use of pramipexole as an antidepressant.
Details of the preparation of the title compound can be found in EP-A 85 116 016, and reference is hereby made specifically to the literature cited therein.
DESCRIPTION OF THE INVENTION
It has now been found that, surprisingly, pramipexole, the (+) or (−) enantiomer thereof, or the pharmacologically acceptable acid addition salts thereof, combined with another antidepressant has a significantly greater antidepressant activity than either of the two individual components taken alone. The fact that the combination of active substances takes effect immediately should be particularly emphasised.
The improvement in the effect of pramipexole by the simultaneous administration of another antidepressant was discovered by administering to rats a combination of pramipexole and sertraline and then subsequently testing them according to the so-called “forced swimming test”. Details of this test method can be found, for example, in Willner, Psychopharmacology 83, 1-16 (1984) or Borsini and Meli, Psychopharmacology 94, 147-160 (1988).
For the particular preferred combination of pramipexole and sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, their acid addition salts respectively, the test was carried out as follows. The animals were divided up into different groups and each group was given either a saline solution, a therapeutically effective amount of pramipexole, a therapeutic amount of sertraline or a combined dose of both antidepressants in the same therapeutic amount as the animals that received only one of the two active substances.
The combination of 2-amino-4,5,6,7-tetrahydro-6-n-propyl-amino-benzothiazole, the (+) or (−)-enantiomer thereof, the acceptable acid addition salts thereof and (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline) and the acid addition salts thereof is particularly preferred, while the combination of pramipexole and sertraline in the form of their hydrochlorides is most particularly preferred.
The invention also encompasses the combined use of pramipexole with antidepressants other than sertraline. Preferably these other antidepressants are selected from the following known compounds: alprazolam, chlordiazepoxide, clomipramine, chinpirol, dibenzepin, doxepin, fluvoxamine, lofepramine, maprotiline, mirtazapine, mianserin, moclobemide, nefazodone, nortriptyline, opipramol, paroxetine, sertraline, sulpiride, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine and viloxazine.
The term “combination” for the purposes of the invention refers to either the co-administration of pramipexolc and the second antidepressant agent (with both agents being administered separately, but such that both agents will exert their therapeutic in concert) or to the administration of both agents together, as components of a single pharmaceutical dosage form.
Orally administered pharmaceutical formulations for pramipexole are known from the prior art and are obtainable in the German and U.S. markets.
The individual active substances may also be packaged in kit form as a combined pack of the individual drugs, as well as separately.
The combination of pramipexole and another antidepressant may be formulated analogously to conventional pharmaceutical preparations, generally together with a pharmaceutical carrier. In other words, an effective dose of the individual components and optionally a pharmaceutical carrier are formulated as plain or coated tablets, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories etc. For pramipexole the pharmaceutically effective dose per patient is between 0.01 and 10 mg, preferably between 0.08 and 5 mg.
The therapeutically effective doses of the second antidepressant in the combination are given in the Table which follows.
Alprazolam
(25-100 mg)
Nefazodone
(100-300 mg)
Chlordiazepoxide
(5 mg)
Nortriptyline
(10-25 mg)
Clomipramine
(10-25 mg)
Opipramol
(50 mg)
Chinpirol
(1-5 mg)
Paroxetin
(20 mg)
Dibenzepin
(10-250 mg)
Sertraline
(50 mg)
Doxepin
(5-50 mg)
Sulpiride
(50-200 mg)
Fluvoxamine
(50-100 mg)
Tranylcypromine
(10 mg)
Lofepramine
(35-75 mg)
Trazodone
(25-100 mg)
Maprotiline
(10-75 mg)
Trimipramine
(25-250 mg)
Mianserin
(10-30 mg)
Tryptophan
(500 mg-2.5 g)
Mirtazapine
(30 mg)
Venlafaxine
(30-75 mg)
Moclobemide
(150-300 mg)
Viloxazine
(100 mg)
In the combination according to the invention the recommended dose may in individual cases be below the single dose previously recommended for the monopreparation.
REFERENCES:
patent: 4536518 (1985-08-01), Welch et al.
patent: 4843086 (1989-06-01), Griss et al.
patent: 4886812 (1989-12-01), Griss et al.
patent: 4962128 (1990-10-01), Doogan et al.
patent: 5248699 (1993-09-01), Sysko et al.
patent: 6191153 (2001-02-01), Hammer et al.
Maj et al Eur. J. Pharmacol. 324(1):31-37 Pra Antipsychotic & Sulpiride, 1997.*
Ferrari et al Psychopharmacology(Berlin) 113(2):172-176 Pra & Sulpiride, 1993.*
Carter et al Eur. J. Pharmacol. 200(1):65-72 Pra & Sulpiride, 1991.*
Borsini et al Psychopharmacology (Berlin) 97(2):183-188 Forced Swimming Test Discovers Antidepressant Activity, 1989.*
Piercey et al Clinical Neuropharmacology 18 Suppl. 1 534-542 Pra & Quinpirole, 1995.*
Willner Psycyhopharmacology 83(1):1-16 Learned Helplessness Test for Antidepress, 1984.*
Borsini et al Psychopharmacology 94(2):147-160 FST in Rats, not Mice Detects Antidepressants, 1988.*
Skrebuhhova et al Methods & Findings Exp. Clin. Pharmacol. 21(3):173-178 FST 4, 1999.*
Harkin et al Eur. J. Pharmacol. 364 2-3 123-132 Sertraline FST, Jan. 1999.*
J. Maj, Z. Rogoz, G. Skuza & K. Kolodziejczyk; “Antidepressant Effects Of Pramipexole, A Novel Dopamine Receptor Agonist”; Journal of Neural Transmission; Aug. 6, 1997; pp. 525-533; vol. 104; Pub. Springer-Verlag; Austria.
J. Maj, Z. Rogoz, G. Skuza & K. Kolodziejczyk; “Pramipexole Given Repeatedly Increases Responsiveness Of Dopamine D2 and D3 Receptors”; Abstrac—XIIIth International Congress Of Pharmacology; Jul. 26-31, 1998; Poster Topic p. 35; Germany.
O. Benkert, G. Gruender & H. Wetzel; “Dopamine Autoreceptor Agonists In The Treatment of Schizophrenia and Major Depression*”; Review—Pharmacopsychiatry; Nov. 1992; Review pp. 254-260; Georg Thieme Verlag Stuttgart; Germany.
Boehringer Ingelheim Pharma KG
Raymond R.P.
Rose Shep K.
Stempel A. R.
Witkowski T. X.
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