Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-03-16
2003-07-08
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S645000, C514S657000, C514S661000
Reexamination Certificate
active
06589996
ABSTRACT:
FIELD OF THE INVENTION
An embodiment of the present invention is directed to the treatment of disorders relating to the serotonergic system with deramciclane, (1R,2S,4R)-(−)-2-[N,N-(dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethyl-bicyclo [2.2.1]heptane, in humans.
Another embodiment of the present invention is directed to the treatment of depression with deramciclane in humans.
Another embodiment of the present invention is directed to the treatment of anxiety, for example, chronic anxiety, including generalized anxiety disorder (GAD), in an oral daily dosage of about 20 mg to about 60 mg in humans. The daily dosage may be given as a once-a-day formulation, or it may be divided. For example, a once-a-day formulation may be used, and may lead to greater patient compliance than a multiple-dose daily formulation.
BACKGROUND
The preparation of deramciclane as a free base and as a fumarate salt has been described in Hungarian Patent No. 212,547, the contents of which are incorporated by reference herein. Other pharmaceutically acceptable acid addition salts of deramciclane may be formed with inorganic (e.g., hydrochloric acid, sulfuric acid) or organic acids (e.g., acetic acid, tartaric acid). The fumarate salt is an example of such a pharmaceutically acceptable acid addition salt.
Deramciclane has shown anxiolytic-like effects in some conventional animal models with various routes of administration, and in receptor binding studies in vitro deramciclane has shown to bind with high affinity to serotonin 5HT
2A
- and 5-HT
2C
-receptor subtypes, being a potent antagonist of these receptors (Gacsalyi, I. et al., Drug Dv Res (1997) 40:333-348). In punished drinking tests in rats (Vogel, J. R. et al., Psychopharmacologia (1971) 21:1-7) deramciclane was active, after single oral administration at doses of 1 mg/kg and 10 mg/kg. In social interaction tests in rats (File, S. E. J. Neurosci Methods (1980) 2:219-238) deramciclane enhanced the social interaction time, and the minimum effective dose after single intraperitoneal administration was 0.7 mg/kg. In two compartment tests in mice (Crawley, J. and F. K. Goodwin, Pharmacol Biochem Behav. (1980) 13, 167-170. & Crawley, J. N., Pharmacol. Biochem. and Behav. (1981) 15,695-699) deramciclane was active after single subcutaneous administration at a dose of 3 mg/kg. In marble-burying test in mice (Broekkamp, C. L. et al., Eur J. Pharmacol. (1986) 126:223-229) the effective doses were 10 mg/kg and 30 mg/kg orally. Nevertheless, deramciclane was totally ineffective in elevated plus maze test in rats (Handley, S. L. and S. Mithani, 1984, Effects of Alpha-Adrenoceptor Agonists and Antagonists in a Maze-Exploration Model of “Fear”-Motivated Behaviour, Naunyn-Schmiedeberg's Archives of Pharmacology. 327, 1-5) after single intraperitoneal doses at a range of 0.1 mg/kg-5 mg/kg. However, deramciclane was able to attenuate the caerulein-induced decrease in exploratory behavior at an intraperitoneal dose of 0.5 mg/kg in the elevated plus maze test.
The possible antidepressant activity of deramciclane has also been evaluated in various conventional animal models (Gacsalyi, I. Et al, Drug Rv. Res. (1997) 40:333-348). 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 (Porsolt R. D. et al., Eur. J. Pharmacol. (1978) 47:379-391) 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-HT
2C
-receptor agonists are effective in animal models of depression (Moreau J-L. et al. European Neuropsychopharmacology 6:169-175, 1996).
In a whole body autoradiography distribution study with tritium labeled deramciclane in rats (Hazai, I, et al. J. Pharm. Pharmacol. 51: 165-174, 1999) 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 (Klebovich et al Pharm. Pharmacol. Commun., 4:129-136, 1998), 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-HT
2A
-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 5HT
2A
-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 i
Kanerva Harri
Mäki-Ikola Outi
Finnegan Henderson Farabow Garrett & Dunner LLP
Krass Frederick
Orion Corporation
LandOfFree
Treatment of disorders relating to the serotonergic system does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of disorders relating to the serotonergic system, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of disorders relating to the serotonergic system will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3054233