The effects of Glycyrrhiza extract and one of its components, glycyrrhizin, on the mutagenicities of several mutagens were investigated by means of a modification of the Ames test. Both inhibited the mutagenicities of 3-amino-1, 4-dimethyl-5 H-pyrido [4, 3-b]-indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido [4, 3-b] indole. Since the Glycyrrhiza extract and glycyrrhizin inhibited the mutagenicity of activated Trp-P-1, it was clear that their inhibitory effects were not due to inhibition of the enzyme activity of the S9 fraction. Both Glycyrrhiza extract and glycyrrhizin also inhibited the mutagenicities of benzo [α] pyrene, 3-methylcholanthrene, 2-naphthylamine, 2-amino-6-methyldipyrido [1, 2-α : 3', 2'-d]-imidazole, dimethylnitrosoamine and dimethylaminoazobenzene. The mutagenicity of 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2) was inhibited by the Glycyrrhiza extract but not by glycyrrhizin. This suggested that a component different from glycyrrhizin, present in the Glycyrrhiza extract, inhibited the mutagenicity of AF-2.

抄録全体を表示

The effects of oral administration of methyl (+) (3S)-1, 2, 3, 4-tetrahydro-3-hydroxymethyl-β-carboline-2-carbodithioate (THC) on protein synthesis in the liver and chronic liver injury induced by carbon tetrachloride (CCl₄) in rats were studied. THC increased liver weight and the contents of protein and ribonucleic acid, but not deoxyribonucleic acid, in the liver. THC also accelerated the ¹⁴C-leucine incorporation into hepatic microsomal and cytosol proteins in rats when the animals were treated with THC 24 h before sacrifice. In addition, when the animals were treated with THC during the latter half of a 5 weeks CCl₄-treatment period, THC had a marked therapeutic effect on CCl₄-induced chronic liver injury in rats by an improvement of the decreased body weight gain, suppression of the elevated serum enzyme activities (glutamic pyruvic transaminase, glutamic oxaloacetic transaminase and alkaline phosphatase) and increases in the decreased serum total protein and glucose contents. In the liver, THC also improved the decreased protein content, the increased triglyceride content and histopathological changes. These results suggested that THC stimulates protein synthesis in the liver and has a therapeutic effect on chronic liver injury induced by CCl₄.

抄録全体を表示

The effect of allopurinol, a xanthine oxidase inhibitor, on the intestinal absorption characteristics of 6-mercaptopurine was investigated by in situ and in vitro absorption techniques in rats. In the in situ experiment, the percent disappearance of 6-mercaptopurine from the lumen showed a dependency on initial drug concentration. Most of the 6-mercaptopurine that was lost from the lumen appeared as its metabolite, 6-thiouric acid, in the lumen. Dose-dependency of 6-mercaptopurine disappearance from the lumen and the biotransformation of drug to 6-thiouric acid were not observed in the presence of allopurinol. The in vitro data supported the results of the in situ experiment. In addition, allopurinol increased the serosal transfer in vitro and the mesenteric appearance of 6-mercaptopurine in situ by inhibiting the biotransformation to 6-thiouric acid. These results suggested that the type of absorption characteristics observed with 6-mercaptopurine was due to its metabolism by xanthine oxidase in the intestine.

抄録全体を表示

PEDA, an integrated program in BASIC for implementation on microcomputers, has been developed for use in clinical practice to assist dosage adjustment for individual patients. A parameter optimization for individual patients is based on the principle of Bayes' theory and Maximum Likelihood Estimation, and utilizes a prior information on the distribution of population pharmacokinetic parameters, means and variances, as well as serum drug concentrations. The program can accommodate a one-compartment open linear model and a non-linear model at steady state (Michaelis-Menten model) and handle both uniform and non-uniform multiple dosage regimens mostly arising from clinical settings. Clinical examples which demonstrate the ability and the flexibility of the program are provided. The program may also be used as an aid for instruction in clinical pharmacokinetics.

抄録全体を表示

The effects of cimetidine on the time course of plasma concentration, plasma protein binding and tissue distribution of quinidine were studied in rats. The plasma disappearance of quinidine after a 25 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of quinidine, such as the plasma total body clearance (Cl_rot), the volume of distribution at steady state (V_dss) and the elimination rate constant of the central compartment (k_el) decreased to 62, 60 and 73%, respectively of those of the non-treated rats. The plasma concentration of quinidine at steady state, after an intravenous injection (20 mg/kg body weight) followed by a constant rate infusion (0.2 mg/min/kg), increased from 3.02 to 5.11 μg/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (K_p) of heart, brain and muscle, determined in homogenates at steady state, decreased after cimetidine treatment. The effect of cimetidine lasted several hours after a cimetidine bolus intravenous injection. These decreases of K_p could satisfy quantitatively the decrease of V_dss. It may be concluded that the decrease of V_dss was due to the inhibition of tissue distribution (binding and/or partition to tissue components) of quinidine by cimetidine treatment.

抄録全体を表示

Release of endogenous glutamate, γ-aminobutyric acid (GABA) and glycine was investigated in the caudal dorsomedial (CDM) region of the rat medulla oblongata. High potassium stimulation (50 mM) produced an increase in release of glutamate, GABA and glycine by 579.1, 303.4 and 774.5 (pmol/mg protein), respectively. The release was abolished by Ca²⁺ deprivation. These results indicate a possible neurotransmitter role for glutamate, GABA and glycine in the CDM medulla of the rat.

抄録全体を表示

Several peptides and peptide derivatives were tested for their inhibitory effect on prolyl endopeptidase and possible properties as anti-amnesic agents. Among the compounds tested, Z-Gly-Pro-CH₂Cl, Z-Val-prolinal, Boc-Pro-prolinal, Z-Pro-prolinal, aniracetam and pramiracetam inhibited the enzyme activities at K_i values in the order of nM to μM, and the effect of the prolinal-containing peptide derivatives was specific for prolyl endopeptidase. Z-Pro-prolinal was the most effective inhibitor in vitro (K_i=5 nM) and in vivo (50 to 70% inhibition in various organs of rat at a dose of 1 μmol/animal i.p.). Regional differences were observed in the effect of inhibitors on the brain enzyme activities : most active in mesencephalon, followed by striatum, cerebellum, hippocampus, hypothalamus ; and inactive in cerebral cortex and medulla oblongata. In the passive avoidance learning test using rats, pretreatment with Z-Pro-prolinal prevented the induction of amnesia by scopolamine at the dose of 1 μmol/animal, i.p. Z-Val-prolinal, Z-Pyr-prolinal and Z-Gly-Pro-CH₂Cl were also effective in the retention test at 24 and 48 h after the training trial. The antiamnesic effect of these compounds was approximately parallel to the in vitro inhibitory activities on prolyl endopeptidase. These results suggest the possibility that the inhibitors exhibit their anti-amnesic effect through the regulation of the enzyme activity in the brain.

抄録全体を表示

Rat liver aryl sulfotransferase was purified by chromatography on diethylaminoethyl-cellulose or chromatofocusing and three fractions, referred to by Sekura and Jakoby as I, II and IV, were obtained in the order of their elution, each containing sulfation activity. p-Nitrophenol (PNP) at mM order and β-naphthol were substrates common to all three fractions, but PNP at μM order and tyramine were substrates only for IV. IV corresponded to the enzyme designated M by Rein et al. and was active with monoamine, as predicted from our previous results with rat liver cytosol. However, the effectiveness of IV in bringing about the sulfation of PNP at mM order was not evident from our previous results. The characteristics of aryl sulfotransferase multiplicity on the basis of thermostability of sulfation activity could not be determined since essentially the characteristics were the same for all three purified fractions. The multiplicity of aryl sulfotransferase purified from rat liver was different from that of human platelets, indicating possible species and/or tissue differences in this enzyme.

抄録全体を表示

The bioavailability of percutaneous nifedipine was studied in rats. To improve the transdermal delivery of nifedipine, concentration changes due to loss of a volatile component in the vehicle were utilized. The percutaneous absorption of nifedipine was enhanced from binary solvent systems of acetone and propylene glycol (PG) or isopropyl myristate (IPM), compared with the results from simple PG or IPM saturated with the drug. In contrast, no appreciable increases in the percutaneous absorption of nifedipine from PG or IPM above controls were observed for pretreatment of the dosing site with acetone. From a ternary vehicle of volatile/nonvolatile-hydrophile/nonvolatile-lipophile solvent system, i.e., acetone-PG-IPM, a very dramatic enhancement in the bioavailability of nifedipine was noted. In addition, a marked increase in the penetration of PG from the ternary solvent system was found, compared with the result from the binary solvent system of acetone and PG. Nifedipine solutions with the volatile component eventually caused precipitaion at the dosing site and so reduced the plasma nifedipine concentration. The precipitation was inhibited or retarded when polymer additives were incorporated in the ternary solvent system, and the high plasma nifedipine concentrations were maintained. This effect was not diminished when the formulation was administered immediately after the evaporation of acetone. The area under the plasma nifedipine concentration-time curve from the ternary solvent system with a polymer additive was higher by about 75 times than that from PG saturated with the drug. From these observations, we conclude that the increase in the transdermal delivery of nifedipine was caused by the increase in the thermodynamic activity of the drug in the nonvolatile vehicle following the evaporation of the volatile component.

抄録全体を表示

When examining the level of esterolysis and that of cathepsin B or H, a significant positive correlation was found in the rat pancreas with inflammation induced by a closed duodenal loop, whereas there was a significant negative correlation between the activity of cathepsin B or H and that of its endogenous inhibitors. The levels of endogenous inhibitors of cathepsin B and H in rats with a pancreatitis were lower than in the sham-treated group. The endogenous inhibitors of cathepsins B and H were destroyed by incubation with the supernatant fraction obtained from the inflamed pancreas. These observations indicate that the activities of pancreatic cathepsins B and H are closely related to the severity of acute pancreatitis and that lesser levels of thiol proteinase inhibitors in the pancreatitis group than in the sham-treated group are due to destruction of the inhibitors by the enhanced protease activity.

抄録全体を表示

A radioimmunoassay has been developed which makes possible sensitive and specific determination of an active metabolite of cadralazine, (±)-6-[ethyl (2-hydroxypropyl) amino]-3-hydrazinopyridazine (ISF-2405), in plasma and tissues. On account of its lability in a sample solution, ISF-2405 in biological samples was selectively derivatized to a stable form, (±)-6-[ethyl (2-hydroxypropyl) amino]-3-(3, 5-dimethyl-1-pyrazolyl) pyridazine (ISF-3349), by treatment with acetylacetone. The concentration of ISF-2405 was determined by the assay of the resultant ISF-3349. Antiserum against ISF-3349 was elicited in guinea pigs immunized with the ISF-3349 derivative coupled with bovine serum albumin. The obtained antiserum was highly specific for ISF-3349, and did not cross-react with either cadralazine or its metabolites. [Pyrazole-4-³H] labeled ISF-3349 with a specific activity of 13.9 Ci/mmol was used as the radioligand. Assays of ISF-2405 in plasma and tissues were possible over the concentration range from 0.4 to 6.4 ng/ml with 1 ml of plasma, and from 2 to 64 ng/g with 100 mg of tissue. Plasma and blood vessel levels of ISF-2405 in rats after single oral administration of cadralazine have also been determined by the present method.

抄録全体を表示