Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1995-03-02
1997-03-25
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514 85, 514 89, 514 93, 514114, 514120, 514220, 514221, 514289, 514312, 514317, 514383, 514425, 514647, 514662, 514674, A61K 31675, A61K 3166, A61K 3147, A61K 31445, A61K 3141, A61K 3140, A61K 31135, A61K 3113
Patent
active
056145098
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of NMDA antagonists or their physiological salts for the production of pharmaceutical agents for preventing the development of tolerance during the treatment with benzodiazepine-receptor-binding active ingredients as well as for the suppression of dependence.
Both in clinical studies and in practice, long-term treatments with benzodiazepine-receptor-binding pharmaceutical agents, such as, e.g., diazepam (valium) are frequently performed in the case of convulsive disorders and sleep disturbances or for sedation and anxiolytic purposes. The greatest problem for the patients is the tolerance occurring during the treatment and the withdrawal symptoms occurring after these substances are discontinued, such as muscular stiffness, tremors, cramps and states of anxiety, under which the patients suffer.
The role of excitatory amino acids in the central nervous system has received increasing interest in recent years. Glutamate thus was identified as a neurotransmitter and three other receptor subtypes have been found and characterized for excitatory amino acids, which were named according to the specifically effective glutamate-analogous amino acids N-methyl-D-aspartate (NMDA), kainate and quisqualate receptors.
Surprisingly, it has been found that excitatory amino acids are involved in the development of tolerance relative to benzodiazepine-receptor-binding active ingredients and that the blocking of the NMDA receptor prevents or reduces the development of tolerance.
The object of the invention is the use of NMDA antagonists or their physiologically compatible salts for the production of pharmaceutical agents for preventing the development of tolerance, which results during the treatment with benzodiazepine-receptor-binding active ingredients.
BRIEF DESCRIPTION OF THE DRAWING
Various other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawing, wherein:
FIG. 1 shows the amount of exploratory activity (COUNTS) in mice treated s.c. for 12 days with diazepam in sesame oil (DIAZ), sesame oil alone (SOLVENT), the competitive NMDA antagonist 3-((.+-.)2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), and diazepam and CPP together (DIAZ+CPP). The amount of exploratory activity shows the sedative effect of diazepam; treatment with diazepam at first causes sedation, which is abolished by the development of tolerance; co-treatment with CPP prevents the development of tolerance.
The methods for determining the tolerance are based on the measurement of the exploratory locomotor activity in mice during long-term treatment with BDZ-receptor-binding active ingredients, as is shown by the example of benzodiazepines.
The suppression of the exploratory activity is part of the most known sedative effects. During long-term treatment with BDZ, a loss of the sedative effect takes place in mice. To examine the development of tolerance during the long-term administration of benzodiazepines, male NMRI mice weighing 20-24 g were treated under daily controlled conditions (0600-1800 hours of a light/dark cycle, 45-55% atmospheric humidity and free access to water and food) for 12 days with 15 mg/kg of diazepam in sesame oil. The control animals were treated subcutaneously with the vehicle under the same conditions for 12 days. In the case of mice, the 12-day treatment with 15 mg/kg of diazepam results in a total tolerance in the sedative property.
To examine the role of the excitatory amino acids in the development of tolerance, the animals were treated with NMDA antagonists. In this case, minipumps having an osmotic effect were implanted intraperitoneally under a slight ether anesthesia and the behavior of mice in the locomotion unit was examined from day one to day twelve. The pumps were filled in advance with NMDA antagonists. The pumping rate was 1 mg/kg/h over 12 days.
The development of tolerance is prevented by the treatment with NMDA antagonists during
REFERENCES:
patent: 5474990 (1995-12-01), Olney
The Merek Manual, 15th edition, 1987, pp. 1476-1495.
Khanna et al, Chemical Abstracts, vol. 116, No. 23, abstract No. 230028h, 1992, p. 278.
Schneider Herbert
Stephens David N.
Steppuhn Karin G.
Turski Lechoslaw
Cintins Marianne M.
Jarvis William R. A.
Schering Aktiengesellschaft
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