[Endogenous formation of carcinogenic-N-nitroso compounds in rats after application of drugs and nitrite (author's transl)].

UNLABELLED

During the last years in vitro investigations have demonstrated the possibility of nitrosation of different amines and amides including a number of drugs. The aim of the presented investigations was to test whether an endogenous nitrosation of piperazine, Obesin (propyhexedrine), and ephedrine is possible in long term experiments with rats.

MATERIAL AND METHODS

With the exception of group No. 3, the experiments were carried out with hooded rats (table 1). Group No. 1: 15 rats were given 100 mg/kg b.w. piperazine (Merck, Darmstadt) and 80 mg/kg b.w. NaNO2 by gastric tube. After the fourth application because of intoxication a reduction to 80 mg/kg b.w. piperazine and 50 mg/kg b.w. NaNO2 was necessary. Duration of treatment (in two weeks intervals): 7 months. Group No. 2: Pregnant rats received 80 mg/kg b.w. piperazine and 50 mg/kg b.w. NaNO2 by gastric tube once in the last third of pregnancy. In 13 offsprings the carcinogenic action was tested. Group No. 3: Pregnant Wistar rats were given 100 mg/kg b.w. piperazine and 70 mg/kg b.w. NaN92 by gastric tube once in the last third of pregnancy. Group No. 4: 20 hooded rats received 40 mg/kg b.w. Obesin (propylhexedrine, Fahlberg-List Magdeburg) and 40 mg/kg b.w. NaM92 once in two weekly intervals by gastric tube. Duration of the treatment: 6 months. 5 controls received 40 mg/kg b.w. Obesin or 40 mg/kg b.w. NaNO2 resp. Group No. 5: Hooded rats were given 40 mg/kg b.w. Obesin and 40 mg/kg b.w. NaNO2 by gastric tube once in the last third of pregnancy. 32 offsprings were observed. Group No. 6: 26 animals received 80 mg/kg b.w. ephedrine (D,L-Ephedrin "Fahlberg" DAB 7) and 50 mg/kg b.w. NaNO2 once per two weeks by gastric tube. Duration of the experiment: 6 months. 5 controls were applied 80 mg/kg b.w. ephedrine. Group No. 7: 30 hooded rats received a standard diet containing 0.5 per cent ephedrine and 0.2 per cent NaNO2. Duration of the experiment: 50 days. Only ephedrine was added in the same concentration to the diet of 10 control animals. results (tables 2--7): All animals that survived for more than 80 days were included in the analysis. In group No. 1 after a latency of 254--432 days 5 out of 14 rats developed malignant tumours of the nasal cavities (1), esophagus (1), leukoses (2), or soft tissue sarcoma (1). The spectrum of tumours indicates the endogenous formation of N-nitrosopiperazines. In groups 2 and 3 no significant carcinogenic action can be verified. In 56 per cent of hooded rats of group 4 reticulum-cell sarcomas, that were mainly localized in the paracoecal region (7) as well as leukoses (3) were registered. These findings were regarded as a carcinogenic action of the N-nitroso derivative of Obesin. In group No. 5 there is an insignificant carcinogenic effect. 2 paracoecal reticulum-cell sarcomas, 2 leukoses, 1 soft tissue sarcoma, 1 palsma-cytosis and 1 spindle cell sarcoma of the heart were found. After application of ephedrine and nitrite in group No. 6 and group No...