HCO-60, a polyoxyethylene castor oil derivative, is used as a solubilizer in the injectable formulations of lipophilic agents. This study was performed to examine the toxicity of HCO-60 in various experimental animals including dogs, monkeys, rabbits, guinea pigs and rats. With 1.25 or 2.5 mg/kg of HCO-60 injected i.v. to dogs, blood pressure decreased, flush, swelling and itching appeared after injection, and with 10 mg/kg of HCO-60 there was additionally a decrease of spontaneous motility. In the two higher dose groups, these symptoms paralleled an increase of histamine levels. Since degranulation was observed after injection in the mast cells of the skin, but not in the liver of dogs, the histamine in the plasma was considered to be released from the mast cells of the skin. Pretreatment with diphenhydramine, a H1-receptor antagonist, suppressed the decrease of blood pressure induced by HCO-60. These findings show that the toxicity of HCO-60 is associated with histamine release from the mast cells. No symptoms occurred in monkeys, rabbits, guinea pigs or rats with 50 or 100 mg/kg of i.v. of HCO-60, and there was no change in plasma histamine levels. This study demonstrated that the toxicity of HCO-60 is species specific to dogs among the animals tested.
As part of the safety assessment of (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil)(BOF-A2), a new 5-fluorouracil (5-FU) derivative with anti-tumour activity, its potential genotoxicity was studied in 3 different tests. BOF-A2 was negative in a reverse mutation (Ames) test in strains of S. typhimurium and E. coli. BOF-A2 induced chromosomal aberrations in Chinese hamster cells in vitro especially in the presence of exogenous metabolic activation, and was clastogenic in vivo, inducing micronuclei in mouse bone marrow. The clastogenic activity of BOF-A2 was similar to that of 5-FU.
Using spontaneously hypertensive rats (SHR), we studied the effects of a new calcium antagonist, (±)-(R*)-3-[(R*)-1-benzyl-3-piperidyl] methyl 1, 4-dihydro-2, 6-dimethyl-4-(m-nitrophenyl)-3, 5-pyridinedicarboxylate hydrochloride (KW-3049) on the development of hypertension and cardiac hypertrophy. When KW-3049 was administered orally to 5-week-old SHR, a stage before the onset of hypertension, for 12 consecutive weeks, it showed a dose-dependent and marked antihypertensive action. Administration of 3 mg/kg of KW-3049, once a day, significantly suppressed the rise in blood pressure to a similar extent to 15 mg/kg of nicardipine, twice a day. After 12 weeks of administration, the heart weight was decreased or tended to be decreased. Co-administration with propranolol markedly decreased the heart rate, but little affected the heart weight, suggesting changes in the heart rate during the long-term administration of KW-3049 did not largely affect cardiac hypertrophy. KW-3049 did not increase plasma renin activity (PRA) or plasma aldosterone concentration (PAC). There was no significant change in the myocardial DNA and RNA contents. These results suggest the clinical usefulness of KW-3049 as an antihypertensive drug.