The effect of α-naphthylisothiocyanate (ANIT) on blood clearance of <99m>Tc-phytate (<99m>Tc-P) in dogs was examined, and blood c1earance test of <99m>Tc-P was compared with the cases of serum transaminase test or serum bilirubin test. Serum transaminase and bilirubin levels in dogs increased after ANIT administration, however, the degree of increase in these parameters was much lower than the cases in rats. The disappearance rate of <99m>Tc-P from blood in dogs decreased with the increase in dose of ANIT and with the passage of time after the ANIT administration. Changes of the blood Clearance of <99m<Tc-P after ANIT treatment in dogs may be influenced by the disorder in the hepatocytes rather than in the bile ductule cells. The blood clearance test of <99m>Tc-P in dogs showed a sensitive reaction for the acute hepatic dysfunction induced by ANIT equally to the serum transaminase test or the serum bilirubin test.
The modifying effects of 2, 2'-[(4-aminophenyl) imino] bisethanol sulfate (4APE) on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given 4APE at dietary levels of 1, 000, 330 and 110 parts per million (ppm), or 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) at 600 ppm as a positive control for 6 weeks. At week 3 following DEN administration, all animals were subjected to partial hepatectomy. No adverse effects on survival and body weight were seen in rats treated with 4APE, even at the highest dietary levels. Marked growth retardation and significant increase of relative liver weight were found in animals treated with the known hepatocarcinogen 3'-Me-DAB, which demonstrated marked promoting activity as evidenced by significantly increased values for γ-glutamyl transpeptidase (γ-GT) positive foci as compared with the controls given DEN alone. In contrast, 4APE did not significantly increase the level of γ-GT positive foci over that induced by DEN initiation alone. From these results, it is concluded that 4APE does not possess promoting activity for liver carcinogenesis.
The multiplicity of the spontaneous lung tumor in CD-1 mice was investigated in 413 males from 6 different control groups of 2-year carcinogenicity studies with agrochemicals. Among a total of 152 lung tumor bearers, 95 (62.5%) were seen with 1 nodule, 36 (23.7%) with 2 nodules, and 14 (9.2%) with 3 nodules. Three males bore 4 nodules and each of 5, 7, 9 and 10 nodules was seen in one male, respectively. In one control group 20 out of 30 lung tumor bearers had 2 or more nodules presenting a significant heterogeneity among the control groups in terms of the multiplicity of lung tumor nodule.
Corneas isolated from the pig eyeball have been treated in vitro with varying concentrations of befunolol hydrochloride, in order to test the topical effect of befunolol on the cornea in terms of opacity. Experiments were carried out with the corneas treated as follows : intact, epithelium-removed. endothelium-removed, and both epithelium- and endothelium-removed. Solutions of the drug were applied to both epithelial and endothelidl surfaces, to the epithelial surface only, or to the endothelial surface only. When the drug was applied either to both surfaces or to the endothelial surface only, there was a significant increase in opacity. However, when applied to the epithelial surface only, befunolol caused an insignificant increase in opacity as compared with that of control. It is suggested, therefore, that corneal opacity due to befunolol hydrochloride topically administered to the eye, is concerned mainly with the epithelium in cornea, since the drug is uncapable of passing barrier probably existing in surface layer of epithelium but it easily penetrates in corneal layers from endothelial side to attain reversely to epithelial cells. Thus, it is probable that the risk to induce opacity is minor in cade that befunolol is topically given in drops to the eye.
Methyl isocyanate (MIC) either inhaled (5, 10 mg/lit) or administered by intravenous (5, 10, 28 mg/kg) or subcutaneous (1300, 1500 mg/kg) routes produced a dose dependent fall in blood pressure (BP) and heart fate (HR) in anaesthetised rats. Higher doses (10 mg/lit inhalation, 10&28 mg/kg i. v., 1500 mg/kg s. c.) increased the lung body weight index (LBI) and tracheobronchial resistance (TBR) concomitant with gross pulmonary damage and edema. However, lower doses (5 mg/lit inhalation, 5 mg/kg i.v., 1300 mg/kg s. c.) produced the cardiovascular depressant effect without affecting LBI, lung morphology and TBR. The effects of MIC on BP, HR and TBR were not counteracted by muscarinic, histaminic and 5-HT receptor blockers and by vagotomy. Studies with hydrolysis products of MIC showed that relatively large doses of methylamine (MA) and dimethylurea (DMU) (i.v.) produced cardiovascular depressant effects, without affectint the LBI & TBR. The results indicate that the cardiovascular depressant effect of MIC may not be entirely a sequel to its effect on respiratory organs, release of vasoactive substances or its hydrolysis pro-ducts. A non-specific cardiovascular depressant effect of MIC is suggested.
In the preceding study, no teratological effects against rat fetuses were observed when carboplatin, an oncostatic platinum coordination complex, was dosed to their dams from days 7 to 17 of gestation at a dose level of 4 mg/kg/day. However, there are a few reports which show the teratogenic action of carboplatin injected from days 6 to 15 of pregnancy at a dose level of 6 mg/kg/day. In the present study, carboplatin was administered intravenously to pregnant female Crj : CD (Sbrague-Dawley) rats from days 6 to 9 or 7 to 10 of gestation at a dose level of 6 mg/kg/day in order to know the teratogenicity of this drug. Carboplatin were highly embryolethal in dams when dosed from days 6 to 9 of gestation, but not in animals when injected from days 7 to 10 of pregnancy. Carboplatin also produced external, internal and skeletal anomalies in fetuses such as gastroschisis, dilatation of cerebral ventricles, cleft sternum, fused ribs, malformed thoracic vertebra when administered from days 6 to 9 of gestation, but not in conceptuses when dosed from days 7 to 10 of pregnancy. However, the delayed ossification which was ascribed to the fetal growth retardation was observed in rats treated with this drug during both administration periods. These results suggest that carboplatin is embryotoxic, inducing intrauterine death and congenital malformations in rats, when injected during fhe early stages of gestation including day 6 of pregnancy.
1. The reverse mutation test was carried out on propiverine hydrochloride (P-4) at dose range of 5-500 μg/plate using Salmonella typbimurium strains, TA100, TA98, TA1535 and TA1537, and Escbericbia coli strain WP2uvrA. -As compared with so1vent-treated control, no significant increases were observed in the number of revertant colonies in all tester strains in both systems with and without mammalian metabolic activation (S9 Mix). 2. The chromosomal aberration test was also carried out on P-4 using cultured Chinese hamster lung cells (CHL). The cells were treated with P-4 at the doses of 5, 10, 20 and 40 μM without S9 Mix and at 62.5, 125, 250 and 500 μM with S9 Mix. No significant differences were found in the incidence of structural- and numeral-aberrations of chromosomes in both systems with and without S9 Mix. 3. These rebults indicate that P-4 has no mutagenic activity.
Antigenicity of propiverine hydrochloride (P-4), a newly developed drug for pollakisuria, was investigated in guinea pigs and mice. 1. Two strains of mice (BALB/c and C3H/He) showed no production of antibodies against P-4 inoculated with aluminum hydroxide gel (alum) as an adjuvant, judged by the heterologous passive cutaneous anaphylaxis (PCA) test tising rats. On the other hand, antibodies against P-4-ovalbumin (OVA) conjugate inoculated with alum was definitely detected. 2. In the studies with guinea pigs, both the inoculation of P-4 alone and of P-4 with Freund's complete adjuvant (FCA) as an adjuvant did not produce positive reactions in any of homologous passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA) and passive hemagglutination (PHA) tests. On the other hand, the inoculation of P-4-OVA conjugate with FCA produced positive reaction in all of PCA, ASA and PHA tests. 3. In the active cutaneous anaphylaxis (ACA) test in guinea pigs inoculated with P-4-OVA conjugate with FCA, positive reaction was produced by eliciting injection of P-4-human serum albumin (HSA). 4. In the Schultz-Dale reaction test, any animals in any groups showed no positive reaction to both eliciting antigens, P-4 and P-4-HSA. 5. These findings showed that P-4 had no antigenicity in guinea pigs and mice.