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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 181 records · Page 10Linked to original sources
PubMed1998

Chronopharmacological study of KE-SI-TO components in mice.

Influence of dosing time on pharmacological effects and toxicity of KE-SI-TO (KST) components, as well as the role of each component in the circadian rhythms of KST, was investigated in ICR male mice under an LD (12:12) cycle. The mice given Cinnamomi Cortex (258 mg/kg, i.p.) or Paeoniae Radix (258 mg/kg, i.p.) showed a significant circadian rhythm in the time spent on the hot plate with the shortest latency at 0900 and the longest one at 0100 (p<0.01, respectively). The mice given Cinnamomi Cortex or Glycyrrhizae Radix (129 mg/kg, i.p.) showed a significant circadian rhythm with the lowest rectal temperature (RT) at 1700 and the highest one at 0500 (p<0.01, respectively). Cinnamomi Cortex (850 mg/kg, i.p.)- or Glycyrrhizae Radix (2500 mg/kg, i.p.)-induced toxicity showed a significant circadian rhythm with the highest mortality at 1700 and the lowest one at 0500 (p<0.05, respectively). The rhythmic patterns of the drug-induced analgesia, hypothermia and toxicity resembled the overall rhythms occurring after KST (1000 or 6000 mg/kg, i.p.) injection. These results suggest that the circadian rhythms in actions of Cinnamomi Cortex, Paeoniae Radix and Glycyrrhizae Radix are mainly responsible for the rhythm in the effects and toxicity of KST.

Analgesics↗
PubMed1998

Ex vivo occupancy by tamsulosin of alpha1-adrenoceptors in rat tissues in relation to the plasma concentration.

At 0.5-12 h after oral administration of tamsulosin (2.3 micromol/kg) in rats, there was a significant decrease in specific [3H]prazosin binding in the prostate as compared to the control value. The greater decrease occurred in the submaxillary gland. The effect of tamsulosin was mainly due to a marked reduction of [3H]prazosin binding sites (Bmax) rather than to an increase in the dissociation constant (Kd). In contrast, there was only a slight decrease or no change in the [3H]prazosin binding in the spleen, heart, and cerebral cortex of tamsulosin-administered rats at 0.5-12 h. Oral administration of terazosin (21.7 micromol/kg) significantly increased Kd values for [3H]prazosin binding with little effect on Bmax values in the rat prostate at 3 and 6 h. The greater increases in Kd values were observed in the submaxillary gland, spleen and heart at 0.5-12 h. Terazosin had a slight effect on Kd values for the cerebral cortical [3H]prazosin binding. Tamsulosin was absorbed rapidly after oral administration at a dose of 2.3 micromol/kg in rats, and at 6 h, plasma concentration decreased markedly to approximately one-twentieth of the 0.5 h peak level. alpha1-Adrenoceptor occupancy was estimated as a percentage of decrease in Bmax values for [3H]prazosin binding in tissues of tamsulosin-treated rats compared with control rats. The alpha1-adrenoceptor occupancy by tamsulosin in the prostate and submaxillary gland occurred rapidly in parallel with the rise in plasma concentration of tamsulosin, and lasted for over 12 h despite the marked decrease in plasma concentration. Consequently, it is suggested that tamsulosin produces more selective and sustained occupancy in vivo of alpha1-adrenoceptors in the submaxillary gland and prostate of rats than in other tissues.

Administration, Oral↗
PubMed1998

Role of nitric oxide and prostaglandin in the protective effect of pibutidine hydrochloride, a novel histamine H2-receptor antagonist, on the gastric mucosal lesions in rats.

1. The role of endogenous nitric oxide (NO) and prostaglandins (PGs) in the gastric mucosal protective action of pibutidine hydrochloride (IT-066), a novel histamine H2-receptor antagonist, was investigated in a 0.15 N hydrochloride (HCl) + 60% ethanol (EtOH)-induced gastric lesion model. 2. The 0.15 N HCl + 60% EtOH-induced lesion formation was reduced significantly by IT-066 (3 mg/kg, PO), NOR3 (spontaneous NO releaser; 0.03-0.1 mg/kg, SC) or PGE2 (0.01 mg/kg, PO) but was not reduced by famotidine (1-10 mg/kg, PO). 3. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg, IV), an inhibitor of NO synthase, inhibited the protective action of IT-066 (3 mg/kg, PO), and the inhibitory effect of L-NAME was reversed by L-arginine (300 mg/kg, IV). The protective effect of PGE2 (0.01 mg/kg, PO) was not affected by the pretreatment with L-NAME (3 mg/kg, IV). 4. Infusion of carboxy-PTIO (1 mg/kg/min), a direct NO scavenger, inhibited the protective effect of IT-066 (3 mg/kg, SC) or NOR3 (0.1 mg/kg, SC). Pretreatment with indomethacin (5 mg/kg, SC) markedly reduced the protective effect of IT-066 (3 mg/kg, PO) or NOR3 (0.1 mg/kg, SC). 5. These results suggest that endogenous NO and PGs may be implicated in the gastric mucosal protection induced by IT-066 and that the endogenous PGs may contribute to the protective effect of NO.

Animals↗
PubMed1998

The ACAT inhibitor HL-004 inhibits cholesterol absorption and lowers serum cholesterol in rats.

1. HL-004 decreased absorption of cholesteryl ester from the intestine into the lymph in a rat lymph-fistula model. 2. HL-004 reduced serum cholesterol level in acute cholesterol-fed rats. 3. HL-004 simultaneously decreased hepatic cholesteryl ester content and increased free cholesterol in cholesterol-fed rats. 4. These findings suggest that: (1) the hypocholesterolemic effect of HL-004 is principally due to inhibition of cholesterol absorption via inhibition of ACAT in the intestine; and (2) changes in hepatic cholesterol metabolism due to direct inhibition by HL-004 of hepatic ACAT may account in part for reduction of serum cholesterol level by HL-004.

Absorption↗
PubMed1998

Pharmacokinetic analysis of subcutaneous erythropoietin administration with nonlinear mixed effect model including endogenous production.

AIMS: Erythropoietin, a glycoprotein hormone is produced by the kidney and targeted to erythrocyte precursors. Recombinant human erythropoietin (Epoetin beta) has been utilized for therapeutic purposes in renal anaemia or anaemia occurring after auto blood donation or chemotherapy. The administration routes for erythropoietin are normally subcutaneous or intravenous. No population pharmacokinetic analysis, however, has been performed following subcutaneous administration with consideration given for endogenous production. METHODS: In the present study, we have attempted to analyze the pharmacokinetics of erythropoietin after subcutaneous administration in healthy adult male volunteers by using the Nonlinear Mixed Effect Model program (NONMEM) with a model including endogenous erythropoietin production. RESULTS: It has been established that the final estimation of the population mean values of the absorption rate constant (ka), the elimination rate constant (ke), the distribution volume (V) and the endogenous production are 0.0430 h(-1), 0.206 h(-1), 3.141 and 15.7IU h(-1), respectively. For the circadian rhythm of endogenous production, the amplitude was calculated as 9.86% and the peak appeared around 24.00 h. CONCLUSIONS: The values for ke and V are very similar to those previously reported for intravenous administration. The circadian rhythm of endogenous production are also able to be substantiated. The factors influencing ke were found to be serum creatinine and age.

Adult↗
PubMed1998

Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes.

1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Cloning and expression analysis of a cDNA coding for a dexamethasone-inducible cytochrome P450 in Xenopus laevis liver.

We previously purified a cytochrome P450 (P450) from liver microsomes of adult female Xenopus laevis. In this study, we screened a cDNA library of Xenopus liver to isolate the cDNA clone coding for this P450. The 5'-end of the resultant cDNA was truncated at the N-terminal region and extended by method of rapid amplification of cDNA end to give the complete coding sequence. Amino acid sequence showed this clone to be 36% to 55% identical to members of the CYP2 family and less than 31% identical to members of other gene families, and to belong to the CYP2Q subfamily. This gene is expressed constitutively in the livers of adult male and female frogs, and is significantly induced by dexamethasone administration.

Amino Acid Sequence↗
PubMed1998

Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics.

Aldehyde dehydrogenase-2 (ALDH2) eliminates most of the acetaldehyde produced during alcohol metabolism. In some drinkers, a mutant ALDH2 allele contributes to diminished activity of the enzyme, dramatically increasing the risk for esophageal cancer. This study was designed to evaluate the ALDH2 gene polymorphism as a predictor of the development of cancers prevalent in Japanese alcoholics. We performed ALDH2 genotyping on lymphocyte DNA samples from Japanese alcoholic men (487 cancer-free; 237 with cancer, including 34 oropharyngolaryngeal, 87 esophageal, 58 stomach, 46 colon, 18 liver, 7 lung, 9 other sites, and 19 multiple primary cancers in two or three organs). The frequencies of the mutant ALDH2*2 allele were significantly higher in alcoholics with oropharyngolaryngeal (52.9%), esophageal (52.9%), stomach (22.4%), colon (21.7%) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (78.6%), than in cancer-free alcoholics (9.0%). After adjustment for age, daily alcohol consumption and amount of cigarette smoking, significantly increased risks (odds ratios) in the presence of the ALDH2 *2 allele were found for oropharyngolaryngeal (11.14), esophageal (12.50), stomach (3.49), colon (3.35), lung (8.20) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (54.20) but not for liver or other cancers. These results suggest a general role of acetaldehyde, a recognized animal carcinogen, in the development of human cancers.

Adult↗
PubMed1998

Alteration of circadian time structure of blood pressure caused by night shift schedule.

The effects of night shift schedules on circadian time structure of blood pressure were studied in seven healthy young subjects by continuous monitoring of blood pressure every 30 min for 72 h. In the control experiment, subjects were instructed to sleep at regular times with the light off at 00.00 h and the light on at 07.00 h. In the shift experiment, they were instructed to go to bed at 06.00 h and wake up at 11.00 h. The circadian rhythm of blood pressure rapidly phase delayed by 3.5 h in the second night shift day as a group phenomenon. Individual differences in changes in power spectral patterns of blood pressure were found in the night shift schedule. Ultradian rhythmicity of blood pressure was more pronounced in three subjects, whereas the circadian rhythmicity was maintained in four subjects. These findings held when the adaptation to shift work was taken into account.

Adult↗
PubMed1998

Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population.

Genotypings of two mutations (*2 and *3) in CYP2C19 and the amino acid variants (Arg144/Cys, Tyr358/Cys, Ile359/Leu, and Gly417/Asp) in CYP2C9 were carried out in 140 unrelated Japanese subjects. Thirty-three subjects (23.6%) were genotypically identified as poor metabolizers of CYP2C19, and the allele frequencies of the CYP2C19*2 and CYP2C19*3 were 0.35 and 0.11, respectively. The authors' findings are in agreement with the 18% to 23% prevalence of poor metabolizers in the Japanese populations previously phenotyped. In CYP2C9, all subjects were homozygous (CYP2C9*1) for Arg144, Tyr358, Ile359, and Gly417, except for five subjects (3.6%) who were heterozygous for the Leu359 (CYP2C9*3). The frequencies of Arg144, Tyr358, Ile359, Leu359, and Gly417 variants were 1.0, 1.0, 0.982, 0.018, and 1.0, respectively. The low frequency of the Cys144 allele (CYP2C9*2) in the Japanese population is different from the frequency recently found in British subjects (allele frequency, 0.125 to 0.192). The results suggest that the known interindividual variations in the CYP2C9 sequence among Japanese subjects is small, and that Ile359/Leu is one possible site showing interracial polymorphism.

Adult↗
PubMed1998

Genetic and epidemiological research at the National Institute on Alcoholism, Kurihama National Hospital.

The National Institute on Alcoholism, Kurihama National Hospital, Japan, was designated as a WHO Collaborating Center on Research and Training of alcohol-related problems in 1988. As part of the collaboration and contribution to the WHO, the institute has made significant efforts for the advancement of alcohol research. This article summarizes recent research activities at the institute, focusing on two areas of research: epidemiological and genetic studies.

Academies and Institutes↗
PubMed1998

The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.

PURPOSE: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed. METHODS: The genotype of CYP2C9 (Arg144/Cys, Ile359/Leu) and CYP2C19(*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data. RESULTS: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (Km) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (S)-p-HPPH/PHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations. CONCLUSIONS: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

In-vitro negative chronotropic and inotropic effects of a novel dihydropyridine derivative, CD-832, in the guinea-pig: comparison with calcium-channel antagonists.

The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro -2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate) , a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca2+-channel antagonists. All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 > nicardipine = gallopamil > clentiazem > nifedipine = efonidipine > amlodipine = semotiadil > verapamil > diltiazem; that for the negative inotropic effect was nicardipine = gallopamil > nifedipine > verapamil > CD-832 > diltiazem > clentiazem > efonidipine = semotiadil > amlodipine. The ratio of the EC50 (the concentration of Ca2+ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca2+ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11.4, 0.29, 0.87, 35.4, 37.1, 0.65, 0.87, 0.92, 7.11 and 30.0, respectively. These findings indicate that CD-832 and the newly developed Ca2+ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This 'chrono-selective' effect of these drugs might be of benefit in the treatment of cardiovascular disorders.

Animals↗
PubMed1998

Possibility of partial absorption of nicardipine by routes other than the hepato-portal system after oral administration in rats.

The systemic availability of nicardipine after different routes of administration has been examined in rats, with particular attention to differentiating oral absorption from intestinal and hepatic metabolism. The quantities of nicardipine and its metabolite were determined by capillary column gas chromatography. A linear relationship was shown between the hepatic first-pass effect and dose after hepato-portal administration of nicardipine; the hepatic first-pass effect was calculated to be approximately 80%. However, the availability after oral and rectal administration was found to be more than twice that observed after hepato-portal administration. Partial avoidance of the hepatic first-pass effect after oral and rectal administration are estimated to be 37.3% and 35.2%, respectively, assuming that all absorbed molecules pass through the liver. These findings suggest that the absorption of nicardipine after oral administration also occurs by routes other than the hepato-portal system.

Administration, Oral↗
PubMed1998

Induction of human osteoclast-like cells by treatment of blood monocytes with anti-fusion regulatory protein-1/CD98 monoclonal antibodies.

We have developed a new and simple system of human osteoclast formation by fusing peripheral blood monocytes with anti-Fusion Regulatory Protein-1 (anti-FRP-1) monoclonal antibody (mAb). When human blood monocytes were cultured in the presence of anti-FRP-1/CD98 mAbs, polykaryocytes began to appear at approximately 15 h and increased in size with time until 3-4 days of incubation with anti-FRP-1 mAb. These fused cells showed positive staining in tartrate-resistant acid phosphatase, possessed numerous calcitonin receptors, and were capable of bone resorption. These results strongly suggest that anti-FRP-1 antibody-induced multinucleated cells are osteoclasts. Furthermore, FRP-1 antigens were detected in osteoclasts isolated from human bone and in the osteoclast-like cells obtained from human giant cell tumors of bone.

Acid Phosphatase↗