In rats exposed to restraint and water immersion stress, inhibitory effects of atropine (ATR) and chlorpromazine (CPZ) on stress-induced gastric ulceration and motility were studied to clarify which of central and peripheral origins was responsible for these effects. The drug dose ration of peripheral (intravenous, i. v.) route versus central (intracerebroventricular, i. c. v.) route required to produce an approx. 50% inhibition of gastric ulceration or motility was estimated. Gastric ulceration was prevented by pretreatment with each drug via either route, and there was no great difference in the dose ratio of each drug (i. v. : i. c. v.=4 : 1) for the inhibition. The stress-enhanced gastric motility was immediately depressed by each drug via either route. This inhibitory effect of CPZ was short-lasting as compared with that of ATR, and the complete blockade was observed after administration of i. v. ATR or i. c. v. CPZ at higher doses. The ATR dose ratio for this inhibition was less than 10, while the CPZ dose ratio was from 10 to 25. The treatment with CPZ, but not with ATR, caused a definite change in EEG patterns, along with a decrease in body temperatue or heart rate. The effect of pretreatment with ATR or CPZ on gastric motility during stress was also investigated. Only the administration of ATR, via either route, appreciably inhibited the gastric motility. Thus, it was suggested that : (1) the inhibitory effect of ATR on gastric motility may be of peripheral rather than central origin, while that of CPZ predominantly of central origin ; (2) the anti-ulcerogenic effect of ATR and CPZ may be predominantly of peripheral origin, and the mechanisms involved in ATR may be associated with inhibition of gastric motility, which is different from those in CPZ.

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Electrical and mechanical activities of the isolated guinea pig papillary muscle were measured simultaneously, and the effects of various degrees of hypoxia and metabolic inhibitors were examined. Hypoxia selectively diminished the action potential duration (APD) dependently upon the degree of hypoxia with little affecting the other parameters of the action potential. Hypoxia concomitantly depressed the contractile force (CF), but the decrease in CF always preceded the decrease in APD ; thus, the complete excitation-contraction uncoupling was sometimes observed. Metabolic inhibitors (dinitrophenol, DNP and monoiodoacetic acid, IAA) produced qualitatively the same changes in the electrical and mechanical activities. However, DNP mimicked hypoxia better than IAA which produced rather parallel decreases in CF and APD. The slow response action potential (elicited after inactivation of the excitatory fast Na system of the membrane) was completely blocked by hypoxia and metabolic inhibitors, which was partially restored by isoproterenol, histamine and tetraethylammonium. When isoproterenol was present in the bathing solution, the decreases in CF and APD produced by hypoxia were accelerated, but ATP and propranolol did not significantly modify the hypoxically induced changes.

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To evaluate the distribution of creatinine in rats, urinary, fecal and expiratory excretion, plasma levels and whole-body autoradiography following intravenous or oral administration of [carbonyl-¹⁴C] creatinine was investigated. More than 90% of the exogeneous creatinine was excreted in the urine in 24 hr following intravenous administration, and both fecal and expiratory excretion were only about 1%. In case of oral administration, however, it was found that expiratory excretion could not be neglected, ranging from about 1 to 30%. Plasma creatinine concentration-time curves following the intravenous administration (70.4 μg/kg or 400 mg/kg as creatinine) were analyzed according to a two-compartment open model. There were significant but very small differences in the pharmacokinetic parameters for these two doses. When these parameters were compared with those of urea, k₁₂ and k₂₁, which are transfer rate constants between compartment 1 and 2, for creatinine were significantly smaller than those of urea. On the other hand, k₁₀ was larger in creatinine. Furthermore, (V'_d)_extrap for creatinine was about three times that of urea. Whole-body autoradiograms at 5 minutes following intravenous administration showed that exogeneous creatinine distributes with higher concentrations in liver, lung and kidney than in muscle and fat. This results was remarkably different from that of urea which distributes almost uniformly throughout the body at the same time. This difference observed in the autoradiograms would be the consequence of the fact that urea has larger k₁₂ and k₂₁ than creatinine.

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Parotid saliva (Pr) and mandibular-sublingual saliva (MS) were collected separately by means of permanent fistulae in order to investigate the excretion of indomethacin in saliva of dogs receiving a single intravenous dose of 20 mg/kg. Drops of citric acid solution were placed on the tongue to stimulate salivary secretion. The concentrations of indomethacin both in saliva and plasma declined biexponentially with time. There was a good linear relationship between the drug concentration in each saliva and plasma. The Pr and MS levels were 7.4% and 4.4% of the plasma levels, respectively. Indomethacin concentrations in Pr were significantly higher than in MS (p < 0.05). The roles of salivary pH and salivary protein binding were discussed in respect to the mechanism of salivary excretion of the drug.

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The competitive binding of phenylbutazone (PB) and mefenamic acid (MF) with 2-(4'-hydroxyphenylazo) benzoic acid (HABA) on bovine serum albumin (BSA) was studied by the investigation of the effects of these drugs on two bound forms of HABA, the azo and hydrazone forms. PB displaced preferentially the hydrazone form. MF displaced both the azo and hydrazone forms, though the azo form was preferentially displaced at the small molar ratio of MF to BSA. The binding constants of PB and MF obtained from the convenient spectrophotometry were dependent on the concentration of added drugs. These facts reflect the selective displacement of the azo and hydrazone forms. In connection with the absorption spectra of bound HABA, induced circular dichroism (CD) spectra of HABA-BAS complex were investigated. The induced CD spectra varied with the change of the molar ratio of HABA to BSA, indicating the presence of at least three differently perturbed HABA molecules by BSA. The addition of PB and MF caused dramatic changes of the induced CD spectra of HABA-BSA complex. These spectral changes were discussed with the displacement of the azo and hydrazone forms.

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The LD₅₀ values of dibekacin to mice were determined following three different methods of administration, namely, intravenous constant infusion, intravenous bolus injection, and intramuscular injection. The serum levels of dibekacin were pharmacokinetically analyzed. The differences in LD₅₀ values between the methods of administration were discussed from the viewpoints of pharmacokinetics. 1) The LD₅₀ value following the intravenous constant infusion was higher than that following the intravenous bolus injection and approached the level of that following the intramuscular injection, when the infusion rate of the drug was decreased by increasing the infusion period. 2) The biological half-life of dibekacin in mice was 24-45 min. 3) The volume of distribution increased as its dose increased, and a linear correlation was noted between log V_d and log (dose). 4) The difference among the maximum serum concentrations calculated with dibekacin following the administration of LD₅₀ was small, which coincided with the results of the experiment that the serum concentrations of dibekacin at the death following the administration of LD₁₀₀ were almost the same regardless of the method of administration.

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The behaviors of dibekacin after three administration methods to rabbits and dogs were pharmacokinetically analysed. 1) In both rabbits and dogs, the pharmacokinetic constants for the intravenous constant infusion and intramuscular injection were similar to each other, and the serum levels after the intravenous constant infusion for 1 hr were similar to those after the intramuscular injection except the peak time. 2) In both rabbits and dogs, V_d increased with the dose and a linear correlation was noted between log V_d and log (dose). 3) The tissue concentrations of dibekacin decreased with the decrease in the serum concentration. 4) A correlation equation, log T_1/2=0.194·log B+1.128, was obtained, where T_1/2 and B represent the biological half-life of dibekacin and the body weight of animals, respectively. It was suggested that the pharmacokinetic behaviors of dibekacin in human beings can be predicted from the results of the animal experiments.

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After a single treatment with d-methamphetamine (philopon) at a dose of 8 mg/kg in 10 weeks old female Wistar rats, heme oxygenase activity was enhanced at 3 hr and reached its peak level at 12 hr, whereas cytochrome P-450 content showed the lowest level at 12 hr. However, activity of δ-aminolevulinic acid synthetase was not affected. Twenty-four hr later, all measured parameters returned to nearly initial levels at zero time. The pretreatment with cycloheximide blocked the increase of heme oxygenase activity in philopon-treated animals.

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We examined the effect of cyclo (His-Pro) and its analogs on pentobarbital narcosis in mice. Cyclo (His-Pro), 500 nmol/mouse, administered via intracerebroventricular (i. c. v.) route significantly prolonged the sleeping time. Methylation of histidine in the structure of cyclo (His-Pro) did not increase the activity of cyclo (His-Pro). Some of other cyclo (His-Pro) analogs, of which proline was replaced with other amino acids, cyclo (His-Phe), cyclo (His-Tyr), cyclo (His-His) and cyclo (D-His-Leu) produced significant prologation of the sleeping time as compared with cyclo (His-Pro). These results suggest that cyclo (His-Pro) has opposing effect to that of thyrotropin releasing hormone (TRH) and the prolongation of pentobarbital narcosis by cyclic dipeptides might be caused by their central action.

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