Endogene bildung kanzerogener N-Nitrosoverbindungen nach Gabe von pharmaka und Nitrit an Ratten

Abstract

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. NaNO 2 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. NaNO 2 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. NaNO 2 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 NaNO 2 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. NaNO 2 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. NaNO 2 resp. Group No. 5: Hooded rats were given 40 mg/kg b.w. Obesin® and 40 mg/kg b.w. NaNO 2 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. NaNO 2 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 NaNO 2. 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 plasmacytosis and 1 spindle cell sarcoma of the heart were found. After application of ephedrine and nitrite in group No. 6 and group No. 7 the formation of N-nitrosoephedrine may be supposed because in 21 and 43 per cent, resp. malignant neoplasms (mostly paracoecal reticulum-cell sarcomas and leukoses) were observed. The experiments indicate, that in rats the formation of carcinogens from nitrosable drugs is possible in the digestive tract. The transplacental effect of Obesin® and nitrite leads to an insignificant increase in tumour frequency whereas a carcinogenic transplacental activity of piperazine and nitrite cannot be demonstrated. Preventive oncological consequences are discussed.