Acute, subacute, and chronic toxicity studies, carcinogenicity bioassays, and reproductive and genetic toxicology studies were performed with quinapril, an ACE inhibitor used in the treatment of hypertension. Acute toxicity is minimal in rodents, and repeated dosing elicits gastric irritation, juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia and tubular degenerative changes in the kidney, and reduced red cell parameters and heart weights in rodents and/or dogs. Other manifestations of toxicity, including hepatic lesions in dogs, reduced offspring weights in rats, marked sensitivity of the rabbit, and clastogenic effects at cytotoxic doses in the in vitro V79 chromosome aberration assay, have been reported with other drugs of this class.
Roxithromycin and erythromycin were incubated with rat and human liver microsomal or reconstituted cytochrome P450 (P450 or CYP) monooxygenase systems in the presence of an NADPH-generating system, and the effects of these chemicals on testosterone 6β-hydroxylation and nifedipine oxidation activities were compared with those of typical CYP3A4 inhibitors including ketoconazole, troleandomycin, and gestodene. Roxithromycin and erythromycin were found to be relatively weak inhibitors of testosterone 6β-hydroxylation and nifedipine oxidation activities by rat and human liver microsomes or by reconstituted systems containing CYP3A4/5. Formation of an inhibitory P450-metabolite complex was determined spectrally by incubating troleandomycin with human liver microsomes; the extents of the complex formation were lesser in liver microsomes of humans than those of rats treated with dexamethasone. Erythromycin and roxithromycin were also activated slightly by rat liver microsomes to form P450·Fe(II)-metabolite complex, although these chemicals caused very little or undetectable levels, respectively, of spectral changes by human liver microsomes even when a human sample which contained relatively high levels of CYP3A4 was used. These results suggested that roxithromycin and erythromycin were relatively less potent to inhibit CYP3A4-catalytic activities in human liver microsomes, because of their low capabilities to form P450·Fe(II)-metabolite complex.
The immunosuppressive effects of cisplatin at relatively low doses were investigated in CD-1 mice. Mice were injected intraperitoneally with 8, 40 and 200 μg/kg cisplatin for 10 days. A decrease in body and thymus weights was observed at 200 μg/kg. Though there were no dose-related effects on the IgM antibody response to sheep erythrocytcs, a statistically significant reduction of the contact hypersensitivity response (CHR) was seen at 200 μg/kg. In vivo and in vitro effects of cisplatin on T- and B-lymphocyte function were assessed by proliferative response to concanavalin A and lipopolysaccharide, respectively. Cisplatin inhibited splenic T-lymphocyte function more than splenic B-lymphocyte function. These data indicate that a relatively low dose of cisplatin induce immunosuppressive effects in mice with a greater effect on T-lymphocytes than the B-lymphocytes.
We examined the effect of nicardipine, a calcium antagonist, on the induction of peroxisomal enzymes, such as acyl-CoA oxidase and carnitine acetyltransferase, by dehydroepiandrosterone sulfate (DHEAS) and clofibric acid (CPIB), in primary cultured rat hepatocytes. Peroxisomal β-oxidation and carnitine acetyltransferase activities were increased 11- and 20-fold, respectively, after 5 days of treatment with DHEAS (40 μM). However, 60 μM nicardipine significantly suppressed the induction of both of these activities by DHEAS to about 2-fold that of the control. This suppression was found to be both dose- and time-dependent. Immunoblot and Northern blot analyses of acyl-CoA oxidase revealed that suppression by nicardipine of the induction of peroxisomal β-oxidation activity would be responsible for an increase in the amount of mRNA. In addition, the manner in which nicardipine suppressed the induction of peroxisomal β-oxidation and carnitine acetyltransferase activity, was similar to that of clofibric acid. These findings suggest that in the calcium-dependent pathway, the mechanism for the induction of peroxisomal enzymes by DHEAS is basically the same as that by clofibric acid, a typical peroxisome proliferator. The present results also support our previous hypothesis that calcium may play an important role in the induction of these enzymes by peroxisome proliferators.
Indomethacin has been used to treat patent ductus arteriosus (PDA). Re-opening of the ductus arteriosus (DA) after indomethacin therapy, however, is common, although the reason is unclear. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE2 in fetuses and nenonates. The enzyme, 15-hydroxy prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reactions converting the biologically active PGE2 to its inactive metabolite 15-keto-PGE2, and the lungs are a major site of this inactivation. In the present study, the effect of prenatal indomethacin treatment on the activity of neonatal rat lung 15-PGDH, and the effect of prenatal indomethacin on the re-opening of the DA induced by PGE2 were examined in rats. Indomethacin treatment at 3 mg/kg/day from day 18 to day 20 of gestation significantly decreased the activity of 15-PGDH in neonatal lungs. In a subsequent experiment, subcutaneous injection of PGE2 (4 μg) was given to newborn rats 3hr after Cesarean delivery from pregnant females administered indomethacin (1, 3 mg/kg/day) as in the above experiment. The ratio of the DA to pulmonary artery was determined at intervals after injection. Maternal indomethacin treatment significantly increased the re-opening of the DA and prolonged the duration of re-opening induced by PGE2. These results suggest that the decrease in the catabolism of PGE2 in the lung is partly responsible for the failure of indomethacin therapy for PDA.
To assess the reliability of noninvasive measurement of intraocular pressure (IOP) in rats, a Perkin's applanation tonometer was calibrated against direct manometry. The normal values of IOP in male Wistar rats were then detected. The mean tonometer readings against the transducer IOP produced regression formula: y=-0.198+1.071x (r2=0.987). The mean IOP with standard deviation in rats was 17.7±3.5 mm Hg (95% and 99% confidence intervals: 17.2 and 18.1 mm Hg, 17.0 and 18.3 mm Hg for the lower and upper limits of the normal rat IOP, respectively). The IOP could be measured accurately using Perkin's applanation tonometer in anesthetized rats each weighing 300 g and over. Measurement of IOP using this tonometer was considered to be valuable allowing, repeated use in rats because of its smal1 size, portability and noninvasiveness.
This study was designed to specify the toxicity of amiodarone toward mouse pulmonary endothelial cells in comparison with that of another cationic amphiphilic drug, i.e., mianserin. These examinations were performed in the absence and presence of mouse alveolar macrophages under transmembrane co-culture or in direct contact with the endothelial cells to assess the contribution of macrophages to the toxicities toward the endothelial cells. As a result of 24-hr treatment, amiodarone caused a decrease in cell viability, in H+-ATPase, acid sphingomyelinase, and acid phospholipase A2 activities, and in neutral red uptake, and an increase in permeability of the endothelial cells. Because the magnitude of changes in the endothelial cells was the greatest under direct contact with macrophages, and was the mildest without macrophages, macrophages were considered to enhance the toxicity of amiodarone toward the endothelial cells. Additionally, the toxic effect of amiodarone on the cells was depressed by pretreatment of them with docosahexaenoic acid (DHA) or α-tocopherol for 2 days and co-treatment with these agents for 1 day, but not with prednisolone or indomethacin co-treatment. DHA and α-tocopherol protected endothelial cells from the toxicity of amiodarone. The effect was more potent for DHA than α-tocopherol.