Application selegilina for the treatment of epileptic disorders


(57) Abstract:

The invention relates to medicine, in particular, neurology, and is the application selegilina (L-N-(1-phenylisopropyl)-N-methyl-N-Propylamine) or its pharmaceutically acceptable salts for the treatment of epileptic disorders. Application selegilina can significantly reduce the duration of epileptic seizures, as well as slow down the progression of the disease. 2 S. and 1 C.p. f-crystals, 1 table.

The subject of the invention is the use of selegilina (=L-N-(1-phenylisopropyl)-N-methyl-N-Propylamine) or its pharmaceutically acceptable salts for the preparation of drugs anti-epileptic actions.

It is known that selegiline blocks monoaminoxidase type B. This enzyme breaks down in glial cells monoamine neurotransmitters, especially dopamine, which leads to the termination of dopamine. Blockade of the enzyme increases levels of dopamine in the brain. This effect underlies the application of selegilina in the treatment of Parkinson's disease as an additional treatment in combination with the drug levodopa (for example, available as a drug under the trademark "Deprenyl").

In the literature upgarade application N WO 92/17169 A1 describes the neuroprotective effect is still not certain of the mechanism. Therefore, this enzyme is suggested to use as a neuroprotector (prevention of neuronal cell death in the Central nervous system diseases, in particular Parkinson's disease, brain injury and spinal cord injury).

In addition, patented the following selegilina or selegilina in combination with other drugs, but the mechanism of these actions is not uniquely defined: therapy

a) disruption of the immune system;

b) Cushing's syndrome;

c) mental symptoms during abstinence from cocaine, alcohol, and opium funds when addiction to them;

d) senile phenomena;

e) Alzheimer's disease;

f) mental symptoms during abstinence from Smoking;

g) schizophrenia;

h) mental symptoms of premenstrual syndrome;

i) locomotion sickness (travel sickness);

k) hypertension;

l) depression in combination with other drugs

(U.S. patent N 5192808, U.S. patent N 4861800, U.S. patent N 4868218, U.S. patent N 4579870, patent Canada N 1322530, the international application N WO 92/21333 A1, international patent application N WO 91/18592 A1, international patent application N WO 90/04387, the international application N WO 90/01928, the international application N WO 88/04552, European patent N 252290 A1).

The market offers a number of anticonvulsive drugs for the treatment of epilepsy. As the most important representatives should be called phenytoin and carbamazepine. Still used anticonvulsive drugs inhibit seizures, but have no influence on the initial development of the epileptic focus.

The present invention is the development of a medicinal product with good anticonvulsive and anti-epileptic effect.

Unexpectedly, it was found that selegiline has a strong anticonvulsive and antiepileptogenic action. The threshold of occurrence of focal and General convulsions greatly increased, the effect of selegiline is rogovy threshold is considered to be the most important characteristic of anticonvulsive action. Epilepsy is a threshold phenomenon, and cramp in humans is a consequence of the transition of the threshold caused by endogenous or exogenous stimuli. Medicines of the first type for the treatment of epilepsy the threshold increases, the drugs of the second type often do not affect the threshold, they only reduce the severity of seizures in some cases seizure.

Influence selegilina on the threshold could be proved in the classical model of epilepsy, the maximum electroshock.

Based on pharmacological studies, it was found that selegiline has an effect similar to drugs of the first type.

Patients suffering from epilepsy, the disease during his often progresses, the attacks become harder, and the patient is worse to respond to treatment.

Of particular interest is the fact that selegiline can slow the development focus of epilepsy and thereby slow down the progression of the disease.

Anti-epileptic action of N-(1-phenylisopropyl)-N-methyl-N-propanolamine strictly stereospetsifichno. Only the L-form (selegiline) acts of anti-epileptic.

D-form is not applicable. In doses in which the L-shape has no side effects, D-form in dnim point for research selegilina for initiating the tonsils as a model of focal epilepsy and as a model epileptogenesis was information about neuroprotective action selegilina.

When initiating tonsils repeated very weak stimulation of brain areas of the rat deep electrodes formed epileptic focus. This focus is fixed and fully initiated animals should be characterized as epileptic. In this model may be analyzed anticonvulsants. If they are fully initiated animals and is called a cramp, it is possible to increase the threshold of excitation, convulsions (should strengthen the stimulation to cause a seizure), and caused despite this spasm may be weaker.

However, in this model, you can explore and drugs that regardless of its impact on caused cramp inhibit the development of the epileptic focus. Anticonvulsive action is not dependent on the effect of impeding the development of the epileptic focus.

Data related to anticonvulsive effects

Method F. Freeman and others (Freemann FG u.a., Brain Res. Bull 1981; 7; 629 - 633), modified on Roundfield K. and others neuropharmacology, environmental pollutants and 1990; 29; 845-851.

The initiation of the tonsils, raising the threshold of occurrence of focal seizures in fully initiated rat - see table.

Influence on the development of the epileptic focus p is icatio: J. M. Silver (and others ), Ann Neurol 1991; 29; 356 - 363.

The occurrence of the epileptic focus during initiation leads to plastic changes in the brain. For the full expression (manifestation) of the epileptic focus necessary epileptic discharge certain total duration.

When treating selegiline (5 and 10 mg/kg; 1 per day) is required by 35% and 53% more stimulation before it becomes the first General cramp. In addition, to initiate the hearth required significantly longer epileptic discharge (52% and 117%). This indicates that selegiline slows plastic changes in the brain, necessary for the formation of the hearth.

After cessation of treatment the duration of epileptic discharges, which could be due to the fully initiated by the animals, is much shorter than the animals of the control group.

This suggests that epileptic focus is less pronounced than in the control group.

Thus, selegiline can be used as a highly effective drug for the treatment of epileptic disorders.

Not only suppressed cramp, but also slows the progression zabalegui to have known method of production, i.e., to be issued in the form of conventional tablets, capsules, coated tablets, pills, granules, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable vehicles and solvents.

This daily dose selegilina in oral or parenteral admission should be 5 to 20 mg.

If necessary, the possible deviations from the above dosages, namely depending on the body weight and special application.

1. Application selegilina or its pharmaceutically acceptable salt as a vehicle for the treatment of epileptic disorders.

2. Application under item (1 selegilina or its pharmaceutical salt as a means to suppress seizures and slow the progression of the disease.

3. Anti-epileptic drug that contains a carrier and an active ingredient, characterized in that the active substance is selegiline or its pharmaceutically acceptable salt.


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