The authors have studied the effects of dimethyl sulfoxide (DMSO) on the plasma α-amylase activity in mice that sustained a pancreatic injury induced by an oral administration of adenine. In mice given a 5% solution of DMSO as drinking water for 3 d prior to the administration of adenine (175 mg/kg), and also drank this DMSO solution until the end of the experiment, hyperemia of the pancreas was observed and the level of plasma α-amylase activity became significantly higher than the level seen in the control mice. A pathological examination also revealed vacuolation and zymogenic degranulation. Further, the plasma α-amylase activity level increased only in mice given this 5% DMSO solution, and no increase was noted in mice given a 3% or a 1% DMSO solution for drinking water. Further, the pancreatic lipid peroxide level of mice given this 5% DMSO solution was significantly higher than the level seen in the control group. Based on the above results and associated data, it is thought that an oral administration of adenine can induce a pancreatic injury in the mouse, and that this injury is sustained with the assistance of DMSO.

抄録全体を表示

Disulfide bridges in fibrinogen (Fbg) were cleaved by cis-diamminedichloroplatinum (II) (cis-DDP). Incubation with 120 molar excess of cis-DDP at pH 7.4 and 37°C in the presence of EDTA resulted in cleavage of seven disulfide bridges out of 29. In the presence of calcium, however, the number of cleavages were reduced to four. The result indicates that calcium, which has three high affinity sites on Fbg, protects disulfide bridges from the rupture. Thrombin clottability was examined by turbidity measurement. The cis-DDP treated Fbg was shown to give a decreased fiber thickness. As the cleavage proceeded, the clotting ability of Fbg decreased.

抄録全体を表示

Paramylon, a β-(1→3)-D-glucan, isolated from Euglena gracilis, was tested for its adjuvant activity on the antibody response to sheep red blood cell (SRBC) in mice. Paramylon markedly enhanced anti-SRBC plaque-forming cell production at a dose of 10 mg/kg. It was also found that in vitro addition of lipopolysaccharide in culture to macrophages from paramylon-treated mice produced a large amount of interleukin 1 (IL-1) and there was a significant level of interleukin 6 (IL-6) induced transiently in the blood of these mice. As IL-1 and IL-6 play crucial roles in the immune response to T cell-dependent antigens like SRBC, the immunopotentiating effect of paramylon might be expressed through the action of these cytokines.

抄録全体を表示

The effects of halothane on the effective refractory period (ERP) and the ventricular activation were examined in a canine myocardial infarction model, and compared with those of propranolol. Halothane reduced the heart rate and prolonged the ERP in both normal and infarcted zones. A prolongation of ERP with halothane was also observed during atrial pacing at the same rate as in control, but the effect was less than during sinus rhythm. Halothane (1 MAC) further delayed or blocked the delayed activation in the infarcted zones with only slight effects on the activation of the normal zones. Propranolol (0.2 mg/kg) prolonged ERP during sinus rhythm, but it did not affect either the ERP or ventricular activation during atrial pacing. In conclusion, halothane produced a selective depression of the delayed activation and the prolongation of ERP, which may be caused by both direct effects on the myocardium and secondary effects such as a reduction of the heart rate. These effects of halothane may contribute to its antiarrhythmic effects in the myocardial infarction model which have been previously reported.

抄録全体を表示

The pharmacokinetics of zonisamide (ZNS) and the effects of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) on ZNS kinetics were investigated in rats. The effects of other antiepileptics on the serum protein binding, erythrocyte distribution and metabolism of ZNS were also studied in vitro to elucidate the mechanism of pharmacokinetic interaction of ZNS. ZNS showed a linear disposition kinetics after oral administration of ZNS within the dose examined. Moreover, the pharmacokinetic behaviors of ZNS were not altered after multiple dosing. The decreased t_1/2 value of ZNS by PB or CBZ pretreatment and the increased Vd/F value of ZNS by VPA pretreatment were observed, although it showed no marked effect of PHT on ZNS kinetics. The enhanced metabolism of ZNS was observed by PB or CBZ pretreatmtent from an in vitro metabolism study. The serum protein binding and erythrocyte distribution of ZNS showed no significant change in the presence of other antiepileptics in vitro. These results indicate that the decreased t_1/2 value of ZNS is attributable to the enzyme inducing effect of PB or CBZ, and that neither protein binding nor erythrocyte distribution of ZNS could be the reason for the increased Vd/F value of ZNS by VPA coadministration.

抄録全体を表示

In order to elucidate the analgesic mechanism of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (T-614), its effects on the kinin-forming system were examined both in vivo and in vitro. T-614, at doses more than 10 mg/kg p.o., exhibited a significant inhibitory effect on the increased levels of bradykinin released into the pouch fluid of kaolin-induced inflammation in rats. In the kaolin-induced writhing response in mice, which is shown to be mainly dependent on the action of bradykinin, T-614 reduced not only the writhing frequency but also the peritoneal levels of bradykinin in a dose-dependent manner. Whereas, in the zymosan-induced writhing response in which prostaglandin I₂ (PGI₂) is shown to be an important mediator, it did not exert an obvious inhibition on either writhing responses or peritoneal PGI₂ levels at a highest dose of 100 mg/kg. T-614 did not inhibit the activities of serine proteases, such as trypsin, thrombin, kallikrein and plasmin. Furthermore, it did not affect the kinin-forming enzymes of rat plasma in vitro. The above results suggest that the analgesic effects of T-614 may be partly mediated by the inhibition of bradykinin release in the local inflamed tissue.

抄録全体を表示

In vitro effects of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (T-614), a novel antiinflammatory compound, on the production of interleukin-1 (IL-1) and/or interleukin-6 (IL-6) by human monocytes and the THP-1 cells of a human monocytic cell line, were examined. T-614 inhibited the release of immunoreactive IL-1β from these cells stimulated with lipopolysaccharides (LPS) in a dose-dependent manner (0.3-30 μg/ml). The release of IL-6 from THP-1 cells, as detrmined by the assays for its hepatocyte-stimulating activities and immunoreactivities, was inhibited by T-614 with the IC₅₀ values of 2.0 and 6.6 μg/ml, respectively. Northern blotting analysis using LPS-stimulated THP-1 cells indicated that the inhibitory effect of T-614 on IL-1β production is caused by the suppression of IL-1β mRNA expression. The inhibition of cytokine production by T-614 may provide an important insight into the additional mechanisms contributing to its antiinflammatory activities.

抄録全体を表示

Effects of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl}-2-oxoimidazolidine-4-carboxylic acid hydrochloride (TA-6366) on morphological change and mechanical property related to sodium ion permeability in the aorta of spontaneously hypertensive rats (SHRs) were examined, as compared with those of enalapril and captopril. Ten-week oral administration of TA-6366 (1 and 5 mg/kg/d) from 4 weeks of age impeded aortic media-thickening together with a rise in blood pressure in SHRs. Concomitantly, aorta weights in both groups were markedly decreased. The higher dose of TA-6366 almost fully suppressed the accelerated tension development induced by K⁺-free medium and decreased total sodium ion content in the aorta. These vascular effects of TA-6366 was more prominent than those of enalapril and captopril at 5 mg/kg/d. The difference in potencies on the above vascular parameters between TA-6366 and these drugs seemed to be mainly related to the difference in their antihypertensive activities. These results suggest that TA-6366 has preventive effects against progression of vascular diseases, particularly atherosclerosis, accompanied with hypertension.

抄録全体を表示