Treatment of disorders relating to the serotonergic system

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The possible antidepressant activity of deramciclane has also been evaluated in various conventional animal models. In learned helplessness tests in rats (Giral et al. Reversal of helpless behavior in rats by putative 5-HT1A agonists. Biol. psychiatry 23: 237-242), deramciclane dose dependently attenuated helpless behaviour induced by inescapable electric foot shocks, when given intraperitoneally 1 or 10 mg/kg, repeatedly 8 times, twice a day, before the test. The effect of deramciclane was found to be negligible, even at relatively high oral doses, 48-160 mg/kg, when evaluated for tetrabenazine-induced ptosis in mice according to the method of Howard et al. (Howard, J. L. et al., (1981) Empirical behavioral models of depression with emphasis on tetrabenazine antagonism. In Enna S. J., Malick J. B., Richelson E. (eds.): Antidepressants: Neurochemical, Behavioral, and Clinical Perspectives. New York: Raven Press, p 107). In the forced swimming test in rats deramciclane was clearly ineffective at oral doses of 25 and 100 mg/kg.

Thus, deramciclane has been effective in some animal models of anxiety after oral doses in a range from 1 mg/kg to 30 mg/kg in mice and rats. Further, deramciclane has shown negligible effects in animal models of depression even after high peroral doses in mice and rats, which is in line with the results reporting that 5-HT2C-receptor agonists are effective in animal models of depression.

In a whole body autoradiography distribution study with tritium labeled deramciclane in rats at a dose of 3 mg/kg, it was found that after intravenous administration there was high radioactivity (reflecting amount of deramciclane) in several organs including blood and the brain, but after oral administration the amount was substantially lower, especially in the brain.

In a comparative pharmacokinetic study of orally administered deramciclane in rats, dogs, rabbits and humans, it was shown that the plasma concentration curves obtained after the administration of a single 3 mg/kg oral dose of deramciclane to rats (dogs, rabbits) and human show considerable species specific differences. In the peak plasma concentration (Cmax) values there were significant differences: Cmax was 5.4 ng/ml in rat and 217.5 ng/ml in human after the same 3 mg/kg oral dose. Thus a 40-times lower oral dose of deramciclane could be used in man to result in the same maximal plasma concentration as in rat. Furthermore, the total amount of deramciclane absorbed into blood, calculated as Area Under Curve values (AUC 0-∞) from plasma concentrations as a function of time, showed more considerable species difference. The mean AUC 0-∞ values after single oral administration of deramciclane were 11.9 ng h/ml and 3737.8 ng h/ml in rat and human, respectively. Thus, over 300 times lower oral doses should result in equal exposure in humans than in rats. Basing only the Cmax difference between rat and man, it can be predicted that considerably lower doses should be centrally active in humans than in rat. The minimum oral effective anti-anxiety dose in rats was 1 mg/kg (1-30 mg/kg the full range; see above), i.e. in a 70 kg-man this would mean 70 mg dose. To reach the same pharmacologically active plasma concentration in humans as was shown to be efficacious in rat, one should divide the rat dose by 40. This would result in 70 mg/40=1.75 mg (i.e. 0.025 mg/kg) as an effective dose in man.

The binding of deramciclane to serotonin 5-HT2A-receptors in frontal cortex of healthy male volunteers after a single oral dose of 20, 50 and 150 mg of deramciclane is discussed in Kanerva, H. et al., Psychopharmacology (1999) 145:76-81. The determination of the brain 5HT2A-receptor occupancy of deramciclane in humans has shown that 90% and 50% receptor occupancies were reached at a deramciclane plasma concentration of about 70 ng/ml and 21 ng/ml, respectively. The pharmacokinetics of a single dose of deramciclane and during oral dosing of 10 mg, 30 mg and 60 mg twice a day for seven days are discussed in Kanerva, H., Pharmacokinetic studies on deramciclane. Kuopio University Publications A. Pharmaceutical Sciences 39.1999. After a single oral administration of 20 mg and 30 mg doses of deramciclane, the Cmax-values were 24±9.4 ng/ml and 27±6.1 ng/ml, respectively. During repeated administration of deramciclane for one week the Cmin and Cmax for 60 mg and 20 mg daily doses were shown to range between 48-91 ng/ml and 16-33 ng/ml, respectively.

As the above experimental animal and human data does not disclose repeated administration of deramciclane rendering steady state plasma concentrations in treated patients, it was impossible to predict the oral dosages of deramciclane that would be effective in treating anxiety in humans. Furthermore, it was totally unexpected that deramciclane would be effective in treating depressive symptoms.

Anxiety is a normal emotional feeling related to different situations of threat or fear. External threat is experienced as a fear whereas obscure and unidentified feeling of threat may be experienced as anxiety. When anxiety persists it can develop into a pathological disorder. Anxiety disorders are divided more specifically in diagnostic disorders e.g., panic disorder, phobias, and GAD. GAD is a chronic illness associated with excessive anxiety and worry lasting for at least six months. In addition, the anxiety and worry are associated with restlessness, fatigue, difficulties in concentrating or mind going blank, irritability, muscle tension, and sleeping disturbances. The symptoms may be triggered by different events of life, and the control of anxiety is very difficult for the patient.

Anxiety is currently treated with benzodiazepines, SSRI's and buspirone, which are not optimal treatments due to adverse drug reactions and their efficacy profiles. Moreover, relapse of the disease, different kinds of withdrawal effects, development of tolerance, as well as relapse and recurrence, often happen when traditional anxiolytics are used. For example, to avoid withdrawal effects, doctors usually gradually taper the dosage of the medicine (i.e. gradually diminish its daily dosage) before the treatment may be stopped. Patients tend to develop tolerance to those traditional compounds as well. Development of tolerance occurs when, for example, a patient requires greater quantities of a compound over time to achieve the same therapeutic effect.

In the treatment of psychiatric disorders with a chronic course, such as anxiety, it is important to prevent the relapse and recurrence of the disease. After the acute treatment phase, the improved condition can be maintained, and relapses can thus be prevented by continuing the treatment in those who have responded to the treatment or who have reached remission during it. After the continuation treatment phase, when recovery has been reached, the disease can be prevented by continuing the treatment further by the so-called maintenance treatment, during which the daily dosage may be decreased, for example, to a half from the original.

There has thus been a long felt need in the art to obtain an anxiolytic medicament, which is void of withdrawal and discontinuation effects and does not cause development of tolerance in patients. Furthermore, sufficient efficacy in relapse and recurrence prevention are important qualities of a well functioning anxiolytic drug. It is believed that deramciclane satisfies this need in the art.

Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.