MXPA97001031A - Utilization of selegiline for the treatment of epilepti diseases - Google Patents

Abstract

The present invention relates to the use of L-N- (1-phenylisopropyl) -4-methyl-N-2-propylamine (selegiline) or its pharmaceutically usable salts, for the preparation of a medicament for the treatment of epileptic diseases.

Description

USE OF SELEGILIN FOR THE TREATMENT OF EPYPETIC DISEASES The invention relates to the use of selegiline (L-N- (1-phenyl-isopropyl) -N-methyl-N-propylamine) or its pharmaceutically usable salts, in drugs with an anti-epileptic effect. It is known that selegiline is a blocker of the I or monoaminooxidases of type B. This enzyme metabolizes or breaks down neuroglia cells monoaminergenic neurotransmitters (especially dopamine), which leads to the termination of the effect of dopamine. Due to the blocking of the enzyme, the level of dopamine in the brain is raised. Because of this effect selegiline is applied as an additional treatment along with levodopa in the therapy of Parkinson's Disease (commercially available, under the designation Deprenil). Other effects of N- (1-phenyl-isopropyl) N-methyl-N-propylamine, specifically of the L-form (selegiline). In WO 92/17 169 A 12 a neuroprotective effect is described with a mechanism of action that has not been defined up to the present. For this reason it has been proposed to be applied as a neuroprotector (inhibition of nerve cell loss in the case of diseases of the SNCL, especially in the case of Parkinson's Disease, brain trauma and spinal cord traumas). On the other hand, the following effects of selegiline have been patented with combination co-components, or without them, for which, however, well-defined mechanisms of action are not known: Therapy of: a) dysfunctions of the immune system; b) Cushing's syndrome; c) psychic symptoms of abstinence after addition to cocaine, alcohol and opiates; d) aging phenomena; e) Alzheimer's disease; f) psychic symptoms of tobacco withdrawal; g) schizophrenia; h) psychic symptoms of the pre-menstrual syndrome; i) sickness in travel by boat or plane (motion sickness); j) high blood pressure; k) depression, in combination with other preparations (US 5, 192,808, US 4,861, 800, US 4,868,218, US 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 A l) Another of the claimed uses, is the labeling of glioses in degenerative diseases by means of selegiline labeled as a marker of neuroglia cells (US 7,052,921, US 6,853,119). With this same indication is also mentioned the diagnosis of the glyiotic centers before the surgical removal of said scarring, from the brain of patients affected by epilepsy. However, in this case, it is exclusively used for diagnostic purposes. The authors confirm that there is no indication of a pathogenic involvement of monoamine oxidase B in epilepsy; selegiline is only suitable for the labeling of neuroglia cells (Kumlien E. and Col. (s), Epilepsy, Vol. 33, No. 4, 1992. 610 et seq.). For the treatment of epilepsies there is a series of anticonvulsants in the market. Phenytoin and carbamazepine should be considered as the main representatives. The anticonvulsants hitherto applied in therapy lead to the suppression or repression of seizures, but have no effect on the development of the epileptic focus itself. The object of the present invention is to prepare drugs with good anticonvulsant and anti-epileptogenic effects. With some surprise it has been discovered that selegiline has an energetic anticonvulsant and antiepileptogenic action. The threshold for the onset of focal and generalized seizures is inhibited to a degree that is similar to that of the standard anticonvulsant carbamazepine and phenytoin. The threshold of seizures is considered the most important characteristic of an anticonvulsant effect. Epilepsy is a threshold phenomenon, and in humans a seizure is triggered when the threshold is exceeded by endogenous or exogenous excitations. The drugs of first selection for the treatment of epilepsy, raise the threshold; Second-line medications often do not influence the threshold, but are limited to reducing the intensity or severity of seizures of individual attacks. Also in the case of a classic model of epilepsy, the maximum electroshock, an effect of selegiline on the threshold could be verified. Pharmacological investigations show that selegiline has an action similar to that of first-line drugs. In the case of epileptic patients, it is common that in the course of time advances (worsens) the disease, the access or attacks are increasingly severe, and the patient reacts increasingly worse to treatment. Therefore, it is especially interesting that selegiline is also able to stop the development of the epileptic focus and with it the advance of the disease. The anti-epileptic effect of N- (l-phenyl-isopropyl) N-methyl-N-propylamine), is highly stereo-specific. Only the L-form (selegiline) has an anti-epileptic effect. The D-form has no effect. If it is applied in doses that for the L-form lack side effects, it results in strong side effects similar to those of the amphetamines. Pharmacological Investigations The starting point for the investigation of selegiline in the Amygdala-Kindling as a model of focal epilepsy and as a model of epileptogenesis consisted of current knowledge about the neuroprotective action of selegiline. In the Amygdala-Kindling, an epileptic focus is induced by repeated weak stimulation of a cerebral area of the rats, by means of depth electrodes. This focus is permanent, and animals that have been kindelized completely, must be considered as epileptic. Only anticonvulsants can be investigated in this model. If they are administered to completely kindelized animals and if a seizure is triggered, then it is possible to raise the threshold for seizure triggering (it is necessary to apply a more vigorous stimulus to trigger a seizure), and the seizure that in spite of it it is triggered, it may be weaker. However, by means of said model, drugs can also be investigated that, independently of their effect against the seizure triggered, inhibit the development of the epileptic focus. The anticonvulsant effect is independent of the effect against the development of the epileptic focus. Data Concerning the Anticonvulsive Effect Method of Freemann FG and Other (s), Brain Res. Bull. 1981; 7; 629-633, modified according to Rundfeldt C and Other (s), Neuropharmacology 1990: 29; 845-851 Kindling Amygdala, Elevation of the Threshold for the Unchaining of Focal Convulsions in the case of completely kindelized rats: Influence of the Development of the Epileptic Focus in the Kindelized Method according to Racine R. and other (s), Electroencephalograph Clin Neurophysiol. 1975: 38; 355-365, see also: Silver JM and Other (s), Ann Neurol. 1991: 29; 356-363. When the epileptic focus originates in the kindelized, plastic changes occur in the brain. For the complete expression of the epileptic focus, epileptic discharges of a given total duration are necessary. Under treatment with selegiline (5 and 10 mg / kg, 1 x / day), 35% and 53% more stimulations are used, until the first generalized seizure occurs. On the one hand, significantly longer epileptic discharges are necessary to establish the focus (52% and 1 1 7%). This indicates that selegiline delays the plastic modifications of the brain, necessary for the establishment of the focus. Once the treatment is finished, it is observed that the duration of the epileptic discharges, which can be triggered in completely kindelized animals, is significantly shorter than for the control animals. It is observed that the epileptic focus is less pronounced than in the case of the control group. Therefore, selegiline can be applied as a highly specific effective medication for the treatment of epileptic diseases. Not only is the seizure repressed, but the progression of the disease is also slowed down. The compound according to the invention and the process for its preparation are known. The compounds can be prepared in a known manner in the form of customary formulations such as tablets, capsules, dragees, pills, granules, syrups, emulsions, suspensions and solutions, together using inert, non-toxic, pharmaceutically suitable materials-carriers or solvents. The daily dose of selegiline for oral or parenteral administration should be 5 to 20 mg. If necessary, it is possible to depart from the aforementioned amounts, taking into account specifically the body weight and the specific type of administration route.

Claims (3)

1 .- Use of Selegiline or its pharmaceutically usable salts, for the preparation of a medicine for the treatment of epileptic diseases.

2. - Use of selegiline or its pharmaceutically usable salts, for the preparation of a medicament according to claim 1, especially to suppress seizures and to slow down the progression (development) of the disease.

3. - Drug with anti-epileptic effect containing compounds according to claim 1.