STUDIES OF PHYSICAL DEPENDENCE ON CINEPAZIDE IN RATS

• Published in: Journal of toxicological sciences Vol. 5; no. 2; pp. 123 - 140
• Main Authors: TAGASHIRA, Eijiro, AKIYAMA, Yoshihiro, URANO, Tomoko, YANAURA, Saizo
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 1980; Japan Science and Technology Agency
• Subjects: Animals; Barbiturates; Behavior, Animal - drug effects; Body Weight - drug effects; Central Nervous System Depressants; Dose-Response Relationship, Drug; Humans; Levallorphan - pharmacology; Morphine; Naloxone - pharmacology; nonspecific action for dependence; Piperazines; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.5.123

Physical dependence liability to cinepazide was studied, and the following were found : 1. Rats were applied cinepazide for 96 days by the cinepazide-admixed food method (DAF method) on gradedly increasing dosage schedules from low cinepazide dose; of 1/4 and 1/2 mg/g food (the average intake being 40 mg/kg/day) to 6 and 8 mg/g food (the average intake being 277 mg/kg/day) which caused toxic signs to evolve, e.g., suppressed righting reflex, urinary incontinence, dacryohemorrhed, hypothermia, and weight loss. No abstinence signs evolved on withdrawal at any dosage level. 2. The challenge with levallorphan (2 mg/kg, s.c.) at each dosage level during the application of cinepazide on the gradedly increasing dosage schedules precipitated no abstinence signs. 3. Cross-application at 3- to 6-hour intervals of 0 (the vehicle only), 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide (doses prolonging the duration of hexobarbital-induced sleep) to animals with the manifestation of moderate to severe barbital abstinence signs, unlike the similar application of diazepam (10, 30 and 100 mg/kg, p.o.) as the positive control, failed to suppress but rather tended to aggravate the abstinence signs. 4. Cross-application at 3- and 6-hour intervals of 0, 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide and similar s.c. application of 30 mg/kg of pethidine resulted in a significant suppression of weight loss due to withdrawal of morphine in the groups of animals treated with 100 and 300 mg/kg of cinepazide. Naloxone challenge at the stage when weight loss was suppressed significantly (p<0.05) in the animals on the cross-application of pethidine precipitated the abstinence signs but no significant weight loss in the groups on the cross-application of cinepazide. Thus, the suppressive action of cinepazide on the morphine abstinence signs proved to be derived from its non-specific action on drug dependence, and failed to maintain morphine dependence. In conclusion, cinepazide cannot be considered either to have physical dependence liability or maintain barbital- or morphine-dependence.