Ethylacetoacetate promoted the colonic and the jejunal absorption of amino acids such as L-phenylalanine and D-phenylalanine when administered in aqueous solution. Enhanced absorption of these isomers of amino acid might occur via a formation of enamine, which was observed in aqueous solution by monitoring ultraviolet absorbance at 288 nm. Since mixture of L-or D-phenylalanine and ethylacetoacetate in aqueous solution enhanced colonic absorption of cefmetazole while the solution did not affect so much on the jejunal absorption of cefmetazole compared to the colonic absorption of it, enhancing action of enamine probably produced in aqueous solution may be more effective at the colonic compartment.

View full abstract

Mice exhibited marked suppression of motor activity when placed in the same environment where they had previously received electric shocks. Morphine-HCl (20 mg/kg) markedly attenuated such a conditioned suppression in mice. The morphine-induced reduction of the conditioned suppression was antagonized by pretreatment with reserpine (0.1 and 0.5 mg/kg), haloperiodol, pimozide and α-methyl-p-tyrosine, but not atropine-sulfate, p-chlorophenylalanine, phenoxybenzamine-HCl or propranolol. Thus, it is possible that the potentiation of the dopaminergic neurotransmission in the brain is involved in the morphine-induced reduction of the conditioned suppression in mice.

View full abstract

Griseofulvin and its sixteen derivatives were investigated by viscometry to examine their effects on in vitro polymerization and aggregation of microtubule proteins and depolymerization of microtubules. Of these compounds, eight pairs of enantiomers were compared in their activities. Electron microscopic studies were performed in several samples. The results indicate that in the C ring moiety of griseofulvin derivatives natural (+)-griseofulvin structure is essential to show their functions on microtubule proteins and microtubules.

View full abstract

The disposition and metabolism of iodochlorhydroxyquin (clioquinol), an amebicidal drug with neurotoxic properties, were studied in dogs and rats with ¹⁴C-labelled drug. Pharmacokinetic studies in the dog demonstrated that the compound was well absorbed ; the bioavailability was 36% of the dose of 1 mg/kg. The serum half-life was 1.3-1.8 h. In both the dog and the rat, biliary excretion was a major route of elimination. The dog excreted 27% of an intravenously administered dose (1 mg/kg) in the bile within 2 h ; the rat excreted 39% of the dose (5 mg/kg i.v.) in less than 3 h. Elimination via the renal route was also substantial in both species. Urinary and biliary metabolites were separated by TLC (thin layer chromatography) and identified as sulfate and glucuronide conjugates in both species. No evidence for any other metabolites was found. A significant difference was observed between the dog and the rat in the extent of conjugation ; the percentage radioactivity in the urine accounted for by the unchanged compound was six to twenty times greater for the dog than for the rat. The species differences in the disposition and metabolism of the compound might explain its greater toxicity in the dog than in the rat.

View full abstract

The participation of local anesthetic action in spinal reflex inhibition produced by mephenesin-type muscle relaxants was examined by comparing the local anesthetic effects (in vitro), the depressant effects on muscle afferent discharges (in situ) and the depressant effects on spinal reflexes (in situ) of the drugs in rats. At doses producing depression of spinal reflexes, mephenesin, tolperisone (mephenesin-type) and lidocaine (local anesthetic) reduced the frequency of afferent discharges from the muscle. The order of reducing afferent discharges by these drugs corresponded to that of their conduction blocking activities in the isolated sciatic nerve of rats. These results suggest the participation of a membrane stabilizing action in spinal reflex inhibition produced by mephenesin-type muscle relaxants. Baclofen (non-mephenesin-type) did not show any local anesthetic action.

View full abstract

Effects of brovincamine (BV) on peripheral nerves were studied in dogs and rats. 1) In pentobarbital-anesthetized dogs, BV (6.4 mg/kg) administered i.v. did not affect the changes of blood pressure and heart rate induced by noradrenaline and adrenaline, but slightly inhibited the hypotensive effect of acetylcholine. BV had no effect on the hypertension elicited by carotid sinus reflex, but diminished the bradycardia by vagus nerve stimulation. BV did not influence the tachycardia elicited by stimulation of the postganglionic nerve to stellate ganglion, but slightly inhibited that by the preganglionic stimulation. 2) In spinal dogs, BV (6.4 mg/kg) given i.v. slightly inhibited the increases of blood pressure and heart rate induced by i.v. dimethylphenylpiperazinium (DMPP). When i.v. administered in divided doses of 2 and 4 mg/kg, BV induced a slight but stepwise inhibition of the tachycardia elicited by direct administration of DMPP, bethanechol (BCH) and angiotension II (AT II) to the cardiac sympathetic ganglia via the subclavian artery. 3) In rat isolated diaphragm nerve preparations, BV at 10^-5 and 10^-4 g/ml dose-dependently reduced the twitch response to nerve stimulation. 4) In conclusion, BV does not affect the sympathetic activities but inhibits the cholinergic function in the autonomic nervous system.

View full abstract

The possible effects of digoxin on the elimination and anticoagulant action of warfarin were examined in rats. The pharmacokinetic parameters of warfarin after a single i.v. (1.2 mg/kg) or repeated oral coadministration with anticoagulant (0.6 mg/kg on day 1, thereafter 0.3 mg/kg) and digoxin (50 μg/kg) were not significantly different as compared with those in the group treated with warfarin alone. However, prothrombin complex activity (PCA) following coadministration with the diuretic was significantly and relatively rapidly recovered as compared with that in the warfarin group. The amounts of warfarin extracted by liver 2 and 6 h after a single i.v. dosing or 3 and 8 h after repeated oral dosing in the coadministered group were significantly decreased as compared with those in the group received warfarin alone. The renal function (renal plasma flow rate (RPF) and glomerular filtration rate) in the group coadministered with digoxin was significantly higher than that in the group receiving warfarin alone. On the other hand, the fraction of warfarin bound to BSA or rat plasma and the plasma water were little changed in the presence of digoxin. These results suggest that a pharmacological interaction, the decrease in the anticoagulant action, is induced between warfarin and digoxin coadministered.

View full abstract

The absorption of carboxyfluorescein (CF) entrapped in liposomes from the small intestine was investigated in vivo using bile fistula rats. Within the intestine CF was not metabolized, but 32% of the entrapped CF was released for 3 h from the liposomes when incubated with luminal incubation solution. The data of CF disappearance from the intestinal lumen and of CF plasma concentration showed that no apparent difference was observed between administration of the liposomal CF and that of free dye. Especially in initial 60 min after administration of liposomal CF, the plasma concentration was obviously lower than that in free CF administration. On the contrary, the coadministration of 40 mM lipid-surfactant mixed micelles induced a remarkable promotive effect on the absorption of free CF already in the early periods of the initial 60 min. When liposomal CF was administered into the intestinal lumen of thoracic ductcannulated rats, the concentration in lymph was lower than that in plasma. Intramural injection of liposomal CF into intestinal wall, however, showed a much higher concentration in lymph than that in plasma. These findings suggest that liposomal entrapment of CF has rather difficulty to be absorbed through the intestinal mucosa, while lipid-surfactant mixed micelles exert a remarkable promotive effect on the absorption of CF.

View full abstract

Specific enzyme immunoassays for cationic and anionic glutathione S-transferases were established using the specific antibodies which were purified by antigen-bound adsorbent column chromatography. The enzyme immunoassay for cationic glutathione Stransferase had high specificity to cationic enzyme, but showed no cross reactivity with anionic one, and vice versa. The recovery of cationic glutathione S-transferase by the enzyme immunoassay was 94.7%, and coefficient of variation for within day and day-to-day precision were 7.8-10.4% and 8.5-12.5%, respectively. The enzyme immunoassay for anionic glutathione S-transferase also had a good recovery and precision. Using these enzyme immunoassays for glutathione S-transferases, sera of various patients were analyzed. Serum cationic glutathione S-transferase was increased in patients with hepatitis and hepatoma, and anionic glutathione S-transferase in serum was increased in patients with liver cirrhosis.

View full abstract

The effects of the administration routes on the biliary excretion of gentamicin and cefazolin were investigated in male white rabbits. The administration routes studied were intravenous, intramuscular injection and injection into portal vein. In both antibiotics, total excretion into bile was the highest when drug was administered by the injection into portal vein. In case of gentamicin, the bile level above MIC (against P. aeruginosa) could be obtained only by the administration into portal vein. These results indicate that the administration into portal vein is useful clinically, for the drug delivery to biliary tract, especially in drugs like aminoglycoside antibiotics which have an extremely low rate of transfer to the bile.

View full abstract

Effect of sodium selenite on renal toxicity and antitumor activity of cisdiamminedichloroplatinum (Cisplatin ; CDDP) repeatedly administered to mice inoculated with Ehrlich ascites tumor cells were examined. Simultaneous repeated administration of selenite with CDDP markedly improved the growth depression, the renal toxicity indicated by blood urea nitrogen value and the diarrhea caused by CDDP, and inhibited the growth of Ehrlich ascites tumor cells cooperatively with CDDP. This results suggest that selenium compounds are useful for prevention of the toxic side effects of CDDP.

View full abstract