Mechanisms of the production and release of leucocytic pyrogen (LP) from peritoneal polymorphonuclear leucocytes (PMN) from rabbits were studied in vitro. The following results were obtained. 1) The fever curves of the microsomal and the lysosomal fractions had a later onset and were longer lasting than those from the extracellular fluid. The fever curves of the supernatant of 105, 000 g showed the typical response of endogenous pyrogen characterized by a rapid onset and short lasting fever, as shown by the extracellular fluid. 2) The pyrogenicity of LP was the most potent at 60 min while the 105, 000 g supernatant was most potent at 30 min after PMN incubation at 37°C. 3) The extracellular protein attained the maximum level at 30 min after incubation of PMN, while the protein content in the supernatant of 105, 000 g of PMN decreased gradually to the constant level at 30 min. 4) It was observed that the lysosomal degradation was stimulated with bacterial pyrogen (LPS) at 37°C but LPS did not directly affect the lysosomal fraction of PMN.

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Injection of a low dose of clonidine showed the biphasic blood pressure response which comprises a delayed onset of long lasting hypotension and a quick onset of hypertension of short duration followed by the former, in the a-chloralose-urethanized rat. A second injection of a low dose of clonidine administered 90 min after the first showed only two peaks of pressor response, no longer a depressor one, and tachyphylaxis occurred with repeated injections of the same dose of clonidine, together with a gradual elevation of blood pressure level. Furthermore, the depressor action was inhibited by pretreatment with cocaine or imipramine. In contrast, injection of a high dose of clonidine exhibited pressor response with only two peaks, duration of which was markedly potentiated by pretreatment with cocaine or imipramine, and also by guanethidine, but inhibited in reserpinized and spinal rats. While the blood pressure was sustained at a high level after the injection of a high dose of clonidine, blood pressure reversal was produced by tyramine, due to possible β-mimetic action of much greater amounts of catecholamines released by tyramine. The isolated guinea-pig vas deferens contracted when treated with clonidine, and this contraction was inhibited in the reserpinized preparation. This inhibition was recovered by incubation with norepinephrine. Interaction between tyramine and clonidine was also seen in vitro, but it disappeared in the reserpinized, denervated or propranolol-pretreated guinea-pig vas deferens. The contraction of the vas deferens induced by clonidine was potentiated by pretreatment with cocaine, but not by pretreatment with guanethidine, and was inhibited by treatment with α-adrenergic blocking agents, phentolamine and phenoxybenzamine, but not by tolazoline.

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Results of a previous experiment indicated that naive rats given a choice between morphine-admixed food (0.5 ?? 1 mg/g of food) and quinine-admixed food (0.5 ?? 1 mg/g of food) for 3 weeks gradually and spontaneously preferred the morphine-admixed food, and this choice behavior revealed one of the psychological aspects of morphine dependent rats. In the present work, the ability of preference formation was detected for morphine, phenobarbital and diazepam by a different choice test using drug dependent rats. Rats were pretreated with morphine, phenobarbital, and/or diazepam by drugadmixed food ingestion method for 12 ?? 15 weeks, and the choice test was practiced for one week at 3 weeks intervals (4 ?? 5 trials). Control groups of rats were given the same choice test as the naive rats. Results indicated that (a) of all the drugs employed, morphine showed the most rapid and intensive preference formation. (b) Phenobarbital and diazepam had almost the same degree of preference formation. (c) Phenobarbital showed no dose-dependent intensity of preference formation in the 50 ?? 90 mg/kg/day dose range, however, a more rapid development of preference was observed dose-dependently among the 80 ?? 120 mg/kg/day dose range of diazepam. Thus these studies utilizing a choice test provide a clear demonstration of drug-seeking behavior in rats. In addition, the present method is useful for drug screening tests involving weak psychological dependence liability, and moreover, the data could be analyzed statistically.

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Effects of drugs were studied on L-cell line: L, of mouse subcutaneous tissue origin. Results are as follows: the concentrations of 62.50 ?? 500 μg/ml for each drug were examined regarding inhibition of the growth of L-cell line. ID50 values of ibuprofen, naproxen, Y-5554, dichlofenac and aminopyrine were found to be 185, 185, 175, 145 and >500 μg/ml respectively. Minimum concentration, caused by the detachment of the cell from the vessel wall, was as follows: ibuprofen 125 ?? 250, naproxen 250 ?? 500, Y-5554 125 ?? 250, dichlofenac 62.50 and aminopyrine 1, 000 ?? 2, 000 pg/ml respectively.

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The toxicity of drugs was determined using embryonic skin and muscle from humans (Flow 1, 000). The dosage causing a 50% inhibition culture growth (ID50) and minimum concentration, caused by the detachment of the cell from the vessel wall, were determined. ID50 values of ibuprofen, naproxen, Y-5554, dichlofenac and aminopyrine were found to be 150, 320, 220, 110 and >500 μg/ ml respectively. Minimum concentration, caused by the detachment of the from the vessel wall, was as follows: ibuprofen 250, naproxen 250 ?? 500, Y-5554 250 ?? 500, dichlofenac 62.50 ?? 125 and aminopyrine 1, 000 ?? 2, 000 μg/ml respectively.

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