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Biomedical subjects

H Yoshimura

Publications and source records attributed to H Yoshimura.

At least 433 records · Page 24Linked to original sources
PubMed1987

Comparative embryolethal effect of bromofenofos and dephosphate bromofenofos in rats.

Bromofenofos (BF) and dephosphate bromofenofos (DBF) were administered at equimolar doses to rats on day 10 of pregnancy. The dams were killed on day 21, and the fetuses were removed, weighted and examined by routine teratological methods. BF caused a significant increase in fetal resorptions at 58.2 mg/kg. Approximately 69% of the implants were resorbed at this dose level. In rats given DBF equimolar to 58.2 mg/kg BF, the resorption rate was 81.9%. Administration of BF resulted in a dose-dependent decrease in fetal body weights which was significant at 29.1 mg/kg or more. DBF caused a significant decrease in fetal body weights, beginning at 25.1 mg/kg equimolar to 29.1 mg/kg BF, and the decreased fetal body weights were almost the same between BF and DBF. BF at 58.2 mg/kg induced significant gross and skeletal malformations, with incidences of 35.6 and 27.6%, respectively. In rats given DBF equimolar to 58.2 mg/kg BF, gross and skeletal malformations were seen in 54.5 and 61.5% of the fetuses, respectively. There were similarities in the types of malformations observed between BF and DBF. Both compounds induced no significant internal malformations. It was concluded from these results that the embryolethal and teratogenic effects of BF is due to its metabolite, DBF, which cannot respond to cholinesterase inhibition.

Animals↗
PubMed1987

Teratogenicity of flubendazole in rats.

Flubendazole, the p-fluoroderivative of mebendazole, was suspended in deionized water, and administered by gavage once daily to pregnant rats on days 8 through 15 of pregnancy at 0 (control), 2.5, 10, 40 or 160 mg/kg. Fetuses were removed on day 21 of pregnancy by caesarian section, and examined by routine teratological methods. The highest dose (160 mg/kg) was embryocidal and resulted in a significant increase in the fetal resorption rate. There was a dose-dependent decrease in fetal body weights which was significant at 40 mg/kg or more. The 40 and 160 mg/kg doses induced significant fetal (gross, skeletal and internal) malformations. A variety of gross malformations occurred, i.e. encephalocele, cranial meningocele, omphalocele, ectrodactyly, club foot, defects in tail, anal atresia, shortened backbone and Spina bifida occulta. The skeletal malformations mainly affected the vertebrae and ribs. The most frequently observed internal malformation was hydrocephaly, followed by anophthalmia and/or microphthalmia.

Abnormalities, Drug-Induced↗
PubMed1987

Teratogenic evaluation of triclabendazole in rats.

Triclabendazole, a new benzimidazole anthelmintic, was administered by gavage to pregnant rats at 0 (control), 10, 25, 50, 100 or 200 mg/kg on days 8 through 15 of pregnancy. The dams were killed on day 21 of pregnancy, and the fetuses were examined by routine teratological methods. As the results, no increase in the incidence of resorptions was observed even at 200 mg/kg corresponding to 20 times the recommended therapeutic dose. There was a dose-related decrease in fetal body weights which was statistically significant at 100 mg/kg or more. Examinations of the fetuses revealed no significant increase in the incidences of gross, skeletal and internal malformations at any dose in comparison with the controls. Thus, no evidence of embryocidal and teratogenic effects was observed with this anthelmintic in rats.

Animals↗
PubMed1987

Comparison of DT-diaphorases purified from the liver cytosol of untreated, and 3,4,5,3',4'-pentachlorobiphenyl- and 3-methylcholanthrene-treated rats.

DT-Diaphorase purified from the liver cytosol of rats treated with a highly toxic PCB congener, 3,4,5,3',4'-pentachlorobiphenyl (PenCB), was compared to those from 3-methylcholanthrene (MC)-treated and untreated rats. Treatments with PenCB and MC resulted in about 8- and 7-fold increases of cytosolic DT-diaphorase activity, respectively. Purification of the enzyme preparations from untreated, and PenCB- and MC-treated rats were conducted by using DE-52, DEAE-Sephadex A-50, hydroxylapatite, and Bio-Gel P-150 column chromatographies. Both Sephadex G-100 gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that all of the final preparations from the three origins were homogeneous and had the same molecular weight of 59,000, consisting of two subunits with molecular weights of 30,000. Further studies on amino acid composition, Km value, optimum pH, and catalytic activities for various substrates also indicated that both PenCB- and MC-inducible DT-diaphorases were identical with that from the untreated rats. All three DT-diaphorases contained about 2 mol of FAD per mol of enzyme. Partial digestion of the enzymes by trypsin and subsequent analysis by HPLC revealed that the three preparations were indistinguishable. The identity among the three purified DT-diaphorases was finally confirmed by Ouchterlony immunodiffusion employing anti-serum raised against each enzyme preparation.

Amino Acids↗
PubMed1987

Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension.

A single dose of doxazosin, a long-acting postsynaptic alpha 1-adrenoceptor antagonist, was administered to seven patients with essential hypertension. Following administration of a single dose, all the patients except one who was forced to be discharged from the hospital for work, continuously received doxazosin once daily (o.d.) for evaluation of its consecutive dosing effect. The antihypertensive effect, pharmacokinetics, and effects on the plasma renin activity (PRA) of doxazosin were investigated. Following a 2-mg single dose of doxazosin, the systolic blood pressure (SBP) decreased significantly up to 12 h, whereas consecutive dosing produced a significant decrease in the SBP up to 24 h and a significant decrease in the mean blood pressure up to 24 h as compared with placebo. The pharmacokinetic parameters of doxazosin in both single- and consecutive-dose study were 18.9 and 25.8 ng/ml in Cmax, 11.1 and 12.9 h in half life (t1/2), and 182.0 and 273.0 ng h/ml in area under the curve (AUC)24(0), respectively. No significant changes were observed in PRA and plasma concentration of catecholamines. Neither were there any observable changes in endogenous creatinine clearance and in the urinary excretion rates of Na, K, and Cl. Doxazosin was well tolerated by all patients, and no untoward effects were observed. Doxazosin effectively reduces blood pressure and, because of its long t1/2 and minimal effects on PRA catecholamines, and electrolytes, seems to be a useful antihypertensive agent in patients with essential hypertension.

Adult↗
PubMed1987

Cross-tolerance development to the prolongation of pentobarbitone-induced sleep by delta 8-tetrahydrocannabinol and 11-hydroxy-delta 8-tetrahydrocannabinol in mice.

Repeated administration (5 mg kg-1 day-1 i.v.) of delta 8-tetrahydrocannabinol and its active metabolite, 11-hydroxy-delta 8-tetrahydrocannabinol caused tolerance to develop to their prolonging effect on pentobarbitone-induced sleep in mice. Reciprocal cross-tolerance also developed after seven daily doses of these cannabinoids. The magnitude of the tolerance developed by the metabolite was greater than that by delta 8-tetrahydrocannabinol. The results suggest that 11-hydroxy-delta 8-tetrahydrocannabinol plays an important role both in the sleep-prolonging effect of delta 8-tetrahydrocannabinol and its tolerance development.

Animals↗
PubMed1987

In vivo effects of tetrahydrocannabinols and their eight monooxygenated metabolites of the hepatic microsomal drug-metabolizing enzyme systems of mice.

In vivo effects of tetrahydrocannabinols (THCs) and their eight monooxygenated metabolites on the hepatic microsomal drug-metabolizing enzymes in mice were studied. delta 8-THC and its metabolites (7 alpha-hydroxy-, 7 beta-hydroxy- and 7-oxo-delta 8-THC, and 8 alpha, 9 alpha- and 8 beta, 9 beta-epoxyhexahydrocannabinol) tended to increase the enzyme contents or activities except for 7 beta-hydroxy-delta 8-THC which affected the microsomal enzymes in a different manner between the single and subchronic treatments. Single administration (5 mg/kg, i.v.) of 7-oxo-delta 8-THC, 8 alpha, 9 alpha- and 8 beta, 9 beta-epoxyhexahydrocannabinol led to the significant increase in hepatic microsomal p-nitroanisole O-demethylase and aniline hydroxylase activities accompanying a significant increase in cytochrome P-450 content in hepatic microsomes. The same results were obtained with subchronic treatment of mice with these metabolites (5 mg/kg/d, i.v. for 7 d), although the effect of 8 beta, 9 beta-epoxyhexahydrocannabinol on cytochrome P-450 was not statistically significant. 7 beta-Hydroxy-delta 8-THC significantly increased nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and aniline hydroxylase activities by single administration, while the metabolite significantly decreased the contents of cytochrome b5 and P-450 and p-nitrophenol uridine diphosphate-glucuronyltransferase activity by the subchronic treatment. In contrast, delta 9-THC and its metabolites (8 alpha-hydroxy-, 8 beta-hydroxy- and 8-oxo-delta 9-THC) did not significantly affect the microsomal enzymes by both treatments except that the single administration of 8 alpha-hydroxy-delta 9-THC and the subchronic treatment of delta 9-THC significantly decreased NADPH-cytochrome c reductase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Metabolism in vivo of 3,4,3',4'-tetrachlorobiphenyl and toxicological assessment of the metabolites in rats.

1. Metabolism in vivo of 3,4,3',4'-tetrachlorobiphenyl (TCB) and toxicological assessment of the metabolites were investigated in the rat. 2. Four metabolites were isolated from faeces of rats dosed with 3,4,3',4'-TCB. Two were identified as 5-hydroxy-3,4,3',4'-TCB and a chlorine-shift metabolite, 4-hydroxy-3,5,3',4'-TCB, by comparison of melting points, chromatographic mobilities and spectral features with those of the synthetic samples. A dihydroxy-TCB and monohydroxy-trichlorobiphenyl were also indicated by mass spectrometry to be excreted in faeces as minor metabolites. 3. Faecal excretion of unchanged 3,4,3',4'-TCB, 5-hydroxy-3,4,3',4'-TCB and 4-hydroxy-3,5,3',4'-TCB was 0.8%, 19.6% and 11.6% of dose, respectively, in 5 days after i.p. injection of 3,4,3',4'-TCB at a dose of 50 mg/kg. 4. From the inability to cause the liver hypertrophy and thymus atrophy, both monohydroxy-metabolites of 3,4,3',4'-TCB are much less toxic than the parent 3,4,3',4'-TCB. In addition, these phenolic metabolites did not induce the activities of benzo[a]pyrene hydroxylase and DT-diaphorase, whereas 3,4,3',4'-TCB greatly induced these activities. These results indicated that unlike PCB congeners with phenobarbital-type inducing ability, 3,4,3',4'-TCB, a prototype of 3-methylcholanthrene-type inducers, is detoxified by metabolic hydroxylation.

Animals↗
PubMed1987

A new metabolite of methamphetamine; evidence for formation of N-[(1-methyl-2-phenyl)ethyl]ethanimine N-oxide.

1. N-Hydroxyamphetamine and N-hydroxymethamphetamine, metabolic intermediates of amphetamine and methamphetamine, showed no reactivity towards endogeneous protein, amino acids, nucleic acids and fatty acids. In contrast, formaldehyde, acetaldehyde and propionaldehyde reacted well with N-hydroxyamphetamine and slightly with N-hydroxymethamphetamine under mild conditions (pH 7.4, 37 degrees C). 2. Two products were isolated from the reaction mixture of acetaldehyde and N-hydroxyamphetamine. These were characterized as N-[(1-methyl-2-phenyl)ethyl]ethanimine N-oxide and N-[(1-methyl-2-phenyl)ethyl]butenimine N-oxide by mass and n.m.r. spectrometries. 3. N-[(1-Methyl-2-phenyl)ethyl]ethanimine N-oxide was formed by incubating methamphetamine with liver 9000 g supernatants of rats and guinea-pigs. The butenimine N-oxide derivative, however, could not be detected as a metabolite of methamphetamine in vitro. 4. N-[(1-Methyl-2-phenyl)ethyl]ethanimine N-oxide was also detected as a urinary metabolite of methamphetamine in rats and guinea-pigs. Thus, the ethanimine N-oxide was established as a novel metabolite of methamphetamine.

Amphetamine↗
PubMed1987

Comparison of effects of vegetable protein diet and animal protein diet on the initiation of anemia during vigorous physical training (sports anemia) in dogs and rats.

The effect of the quality of dietary protein on the initiation of temporary anemia during vigorous physical training (sports anemia) was studied in dogs and rats. In the dog experiment, one group of dogs was fed a crude animal protein (AP) diet and the other a crude vegetable protein (VP) diet. After 6 weeks on the diets in a sedentary state (rest period), all the dogs were forced to run every day for two weeks (exercise period). The rat experiment was carried out using purified nutrient mixtures. Casein (C) was used as AP and gluten (G) as VP. Feeding was done for two weeks in two series with two diet groups of rats. One series was 15% protein feeding (15% C and 15% G) groups and the other 24% protein feeding (24% C and 24% G) groups. In each group, one group remained in a sedentary state (rest group), and the other ran vigorously on a treadmill every day for one week (exercise group). In a sedentary state, there was a slight tendency for the hemoglobin content or erythrocyte count to be reduced, even when the values remained within the normal range, in dogs and rats fed VP. On the other hand, after vigorous running, significant anemia (reduction of hemoglobin) appeared in the VP diet dogs and in all exercise rat groups except the 24% C group. It was confirmed that the anemia was caused by a reduction of erythrocyte resistance to hemolysis, which was closely related to changes in the lipid composition of blood (serum and especially erythrocytes). The change in lipid profile revealed by the experiments was a reduction of free cholesterol in blood associated with an increase of lysolecithin in dogs during the exercise period and in the rat exercise groups. It was suggested that repeated physical exercise increased the activity of LCAT (lecithin-cholesterol-acyltransferase) in the liver, spleen, etc., resulting in the above changes in lipid patterns in the blood. In dogs of AP and rats of 24% C, however, those changes in lipid pattern caused by exercise and sports anemia did not appear significantly. The different effects of the AP diet seemed to be due to the antagonistic effects of lysine, which was present in sufficient amounts in the diet. Thus the theoretical basis for our recommendation of a high amount of AP in the diet to prevent sports anemia was clarified by the present experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Anemia↗
PubMed1987

Pharmacokinetics and acute effect on the renin-angiotensin system of delapril in patients with chronic renal failure.

The acute effect on the renin-angiotensin system and the pharmacokinetic properties of delapril, a new angiotensin converting enzyme inhibitor and its active diacid metabolites (delapril diacid and 5-hydroxy delapril diacid) arising from delapril in vivo were investigated in 4 hypertensive patients with chronic renal failure (CRF: 4 males, average age 49.5 (37-64) years, mean Ccr 22.2 ml/min/1.73 m2) and 9 patients with essential hypertension (EH: 6 males, 3 females, average age 42.8 (28-61) years, mean Ccr 79.3 ml/min/1.73 m2). In CRF, following a single dose of delapril hydrochloride (30 mg), the biological half lives (t1/2) of delapril diacid and 5-OH-delapril diacid were 4.69, 12.88 hours, the maximum serum concentration (Cmax) and the area under the plasma concentration-time curve ([AUC]24(0)) of delapril and its diacid metabolites were 414, 797 and 435 ng/ml, and 658, 6400 and 5068 ng X h/ml, respectively. In EH, the t1/2 of delapril diacid and 5-OH-delapril diacid were 1.21, 1.40 hours and the Cmax and [AUC]24(0) of delapril and its diacid metabolites were 489, 635 and 229 ng/ml, and 572, 1859 and 948 ng X h/ml, respectively. The [AUC]24(0) in CRF were significantly increased as compared with those in EH. The cumulative urinary excretions were significantly lower in CRF than in EH. The serum angiotensin converting enzyme (ACE) was markedly inhibited in both groups up to 24 hours. The plasma concentration of angiotensin II decreased in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗