The use of atipamezole for the treatment of male sexual impotence


(57) Abstract:

The invention relates to medicine. A method for treatment of male sexual impotence by introducing atipamezole in certain ways in certain doses. Technical result: a new method for the treatment of male impotence. 1 Il.

The present invention relates to a new therapeutic treatment of male sexual impotence by introducing atipamezole, which is the INN-approved generic name for 4-/2-ethyl-2,3-dihydro-1H-inden-2-yl/-IH-imidazole or its pharmaceutically acceptable salt accession acid.

Male impotence is a sexual dysfunction related to the difficulties of achieving and/or maintain sufficient penile erection. It may occur as a result of various causes from a purely psychogenic to fully physical disorders. For the treatment of impotence has been used in both surgical and pharmacological treatment. Surgical treatment (implantation penisnula prostatic device) has been successfully used mainly in the case of pure organic disease. Various agents have been proposed for use as medicaments for lecheniena drug therapy for impotence, therefore, so far not found any wide approval.

A significant number of works were devoted to the identification of neurotransmitters that are included in the facilitation and inhibition of male sexual behavior (see, e.g., Bitran, Hull, 1987. Neuroscience and Behavioral reotens. Noradrenalina neurotransmission obviously plays an important role.

However, according to Bitran & Hull, as dopaminergic transmission, and serotonergically transmission also regulate the sexual behavior of men. Thus, mechanisms other than antagonism against alpha-2-adrenergic receptors may play a major role in the regulation of sexual behavior in men.

Patent DE N 3943519 describes the use for the treatment of erectile dysfunction peptides genetically related to calcitonin. It also States that genetically related to the calcitonin peptides at the above indications may be used in combination with the alpha blocker receptors. However, it does not mention that atipamezol or selective antagonist of alpha-2-recetaron may be one applied for the treatment of erectile dysfunction.

Atipamezol is a selective and potent2-adrenoreceptor antagonist is amatol was described, for example, in European patent EP 183492 as useful for the termination of detomidine.

We have now discovered that this compound is also very effective to increase men's sexual ability on the model of the apes. This discovery confirms that atipamezole can be effective also for the effective therapy of male impotence in people.

Other2-adrenoretseptory antagonist, yohimbine, usually used to treat male impotence. Yohimbine increases noradrenergicheskoy neurotransmission and has been reported about the increase in sexual ability in males animals, although results from different studies are contradictory.

MacDonald et al (Ann. Clin. Res. 20, 1988, 298-310) indicate that it is not clear whether therapeutic effect of yohimbine through antagonism against alpha-2 receptors. If fentolamina, which is not selective alpha-I-adrenergic antagonist, local introduction in the cavernous body of the penis causes long-lasting and strong erection, and at the same time more specific antagonist of alpha-2-adrenoreceptor - idazoxan - with this introduction has no effect. Therefore, the effects of yohimbine p is the research Institute of the alpha-2-adrenergic receptors.

Reid et al (Zancet, August 22, 1987, 421-423) argue that the beneficial effect of yohimbine detected for the first time only after 2-3 weeks of treatment. Unusual, but the effect of atipamezole detected almost immediately after injection, as shown by the following experiments.

Atipamezol clearly has advantages over yohimbinum for this application because of its distinctive selectivity. The ratio of the selectivity 2/1for atipamezole 200-300 times higher than for yohimbine.

In the experiment studied three males and one female macaques with amputated tails. The age of the males was 13, 16 and about 24 years. Age females - 6 years.

During the period of the study, the test pair was placed in one square (0.6 x 0.9 x 1.2 m) with two departments. Between sessions and during the first 10 min of each session moving wall separates the male and female in each cage. The moving wall is made of iron rods. Monkeys can see and touch each other through the sliding wall. After intramuscular dose of the investigational drug (saline control) begin monitoring sexual behavior of the male, as described below. After 10 min of drug administration removed the sliding of stee observation period (30 min after drug administration) moving the wall back to the place. Each time exploring a new pair, the first three sessions were conducted as above, but without the introduction of drugs that allows you to habituate the animals to each other. These first three sessions are not included in the results.

See the time availability and the duration of the next behavior: a study of the perineum, lifting, ejaculation, communication, courtship, direct aggression towards the female, yawning, scratching, gnashing of teeth, shaking the cells and Masturbation. This report provides only the number of ejaculations in each session, because it gives the most accurate indicator of the willingness of male sexual behavior. For the same reason, ejaculation, obtained by Masturbation and intercourse, were combined in the results.

The experiments were conducted only once a day for seven days. Atipamezol was given every second day and the saline control during other days. Preliminary results on one monkey showed that there are no differences in the effect of atipamezole, if he is given every third or second day.

The dose of atipamezole range from 0.01 to 0.3 mg/kg dissolved in saline to a final volume of approximately 0.2 ml of Each dose was tested 5-15 times on each monkey. Usignolo month. The order of testing each dose varies between monkeys for a possible counterweight to the serial effect. The difference in the number of ejaculations obtained for a given dose of atipamezole and the corresponding days of saline control, was used as a measure of the impact of atipamezole on sexual behavior. Now possible variation of the primary sexual activity /corresponding ejaculation during salt days can be minimized. Cases of ejaculations /percentage salt of days with one or more ejaculation/ during salt days were used as the main indicator of sexual activity each male. When the statistical evaluation of the data was used one way analysis of variance /ANOVA and student's t test. P < 0.05 is considered as significant difference.

In the case of the introduction of saline /=control/ sexual activity /percentage of sessions with ejaculations obtained in respect of and/or Masturbation/ three male monkeys were 7%, 12% and 26%. The oldest male had the lowest, and the young male is the highest sexual activity in the control /= saline conditions/. Sexual activity of males in saline conditions or atipamezole not depended on estratega cyclical the number of ejaculations, depending on the dose, all three male monkeys /for each individually; P < 0,05 ANOVA; drawing a-C/. The lowest effective dose of atipamezole ranges from 0.01 to 0.08 mg/kg depending on the individual; the younger male, the lower the lowest effective dose. The average increase ejaculations caused by atipamezole three males, also depends on the dose and is trustworthy (P < 0,05, ANOVA; drawing D/. There have been no other behavioral effects caused by atipamezole, except for the increase of alertness /alertness/.

The drug is preferably administered orally, through the mucous, intravenous, intramuscular, or transdermal. The preferred interval daily dose of approximately 0.01 to 1 mg/kg, preferably 0.05 to 0.3 mg/kg for intravenous, intramuscular, transmucosal or TRANS-dermal and 0.03-10 mg/kg for oral administration.

A method for the treatment of sexual impotence in men, including the introduction of antagonist alpha-2-adrenergic receptors, characterized in that antagonists alpha-2-adrenergic receptors is atipamezol or its pharmaceutically acceptable salt accession acid, and when administered orally to a person the amount specified connection is 0.3 - 10 mg/kg/day, intravenous, intramuscular, transmutes


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