Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-02-11
1999-09-14
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
A61K 31135
Patent
active
059523883
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of selegiline (=L-N-(1-phenylisopropyl)-N-methyl-N-propynylamine) or its pharmaceutically utilizable salts in pharmaceuticals with an antiepileptic effect.
It is known that selegiline is a blocker of monoamine oxidase type B. This enzyme breaks down monoaminergic neurotransmitters (especially dopamine) in gliacytes, which leads to termination of the effect of dopamine. Blockade of the enzyme results in an increase in the dopamine level in the brain. Because of this effect, selegiline is used as adjunct treatment together with levodopa in the therapy of Parkinson's disease (marketed under the proprietary name Deprenyl for example).
Further effects of N-(1-phenylisopropyl)-N-methyl-N-propynylamine and of the L form (selegiline) are described in the literature.
WO 92/17 169 A1 describes a neuroprotective effect with an as yet undefined mechanism of action. It is therefore proposed for use as neuroprotective agent (prevention of nerve cell loss in disorders of the CNS, in particular Parkinson's disease, cerebral trauma and spinal cord trauma).
Furthermore the following effects of selegiline, with or without combination partners, are patented, but no clear mechanisms of action are known for these:
Therapy of addiction; U.S. Pat. No. 4,861,800, U.S. Pat. No. 4,868,218, U.S. Pat. No. 4,579,870, CA 1 322 530, WO 92/21333 A1, WO 91/18592 A1, WO 90/04387, WO 90/01928, WO 88/04552, EP 252 290 A1)
A further use for which a patent has been applied for is as marker for glioses in degenerative disorders using labelled selegiline as marker of gliacytes (U.S. Pat. No. 7,052,921, U.S. Pat. No. 6,853,119). In this indication there is also mention of the diagnosis of gliotic centres before surgical removal of these scars from the brain of epilepsy patients. However, this is exclusively a diagnostic use. The authors state that there are no indications whatsoever of a pathogenetic involvement of monoamine oxidase B in epilepsy, selegiline is suitable only as marker for gliacytes (Kumlien E. et al., Epilepsia, Vol. 33, No. 4. 1992, 610 ff).
There are a number of anticonvulsants on the market for the treatment of epilepsies. Phenytoin and carbamezepine may be mentioned as the principal representatives. The anticonvulsants used to date for therapy lead to suppression of the convulsion but have no effect on the development of the actual epileptic focus.
It is an object of the present invention to provide pharmaceuticals with good anticonvulsant and antiepileptogenic effects.
It has been found, surprisingly, that selegiline shows a potent anticonvulsant and antiepileptogenic effect. The threshold for the induction of focal and generalized convulsions was raised to a similar extent as by the standard anticonvulsants carbamazepine and phenytoin. The convulsion threshold is regarded as the most important characteristic of an anticonvulsant effect. Epilepsy is a threshold phenomenon, and a convulsion is induced in humans by the threshold being exceeded by endogeneous or exogenous stimuli. Drugs of first choice for the treatment of epilepsy raise the threshold, while drugs of second choice often do not influence the threshold but only reduce the severity of the convulsions in the individual episode. An effect of selegiline on the threshold has also been demonstrated in a classical model of epilepsy, the maximum electric shock.
On the basis of the pharmacological investigations, selegiline shows an effect similar to that of drugs of first choice.
In epilepsy patients there is often a progression of the disorder with time, the attacks become more severe and the patient responds less well to the treatment.
It is therefore of particular interest that selegiline is also able to slow down the development of epileptic focus and thus halt progression of the disorder.
The antiepileptic effect of N-(1-phenylisopropyl)-N-methyl-N-propynylamine is strictly stereospecific. Only the L form (selegiline) has an antiepileptic effect. The D form is inactive. At doses at which the L form has no side effects, it induces seve
REFERENCES:
patent: 5462740 (1995-10-01), Evenstad et al.
The Journal of Pharmacology and Experimental Therapeutics, vol. 274, No. 1, Mar. 2, 1995, pp. 307-314, Loscher, W., et al. "Anticonvulsant and Antiepileptogenic Effect . . . Epilepsy".
Indian Journal of Experimental Biology, vol. 25, No. 11, 1987, pp.761-770, Mukhopadhyay, M. et al., "Neuropharmacoligical Studies on Selective Monoamine . . . Inhibitors".
Pharamacology Biochemistry and Behaviour, vol. 23, No. 5, 1985, pp. 753-757, Sparks, D.L., et al. "Combined Inhibition Of Serotonin Uptake . . . Mice".
Mukhopadhyay et al., Indian Journal of Experimental Biology, vol. 25, pp. 761-770, 1987.
Sparks et al., Pharmacology Biochemistry & Behavior, vol. 23, pp. 753-757, 1985.
Arzneimittelwerk Dresden GmbH
Henley III Raymond
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