Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 55 records · Page 3Linked to original sources

PubMed2001

Homozygosity and linkage disequilibrium mapping of autosomal recessive distal myopathy (Nonaka distal myopathy).

Autosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.

Adult↗

PubMed2001

Identification of 197 genetic variations in six human methyltranferase genes in the Japanese population.

Methylation is an important event in the biotransformation pathway for many drugs and xenobiotic compounds. We screened DNA from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in six methyltransferase (MT) genes (catechol-O-MT, COMT; guanidinoacetate N-MT, GAMT; histamine N-MT, HNMT; nicotinamide N-MT, NNMT; phosphatidylethanolamine N-MT, PEMT; and phenylethanolamine N-MT, PNMT) by direct sequencing of their entire genomic regions except for repetitive elements. This approach identified 190 SNPs and seven insertion/deletion polymorphisms among the six genes. Of the 190 SNPs, 33 were identified in the COMT gene, 6 in GAMT, 41 in HNMT, 8 in NNMT, 98 in PEMT, and 4 in PNMT. Nine were located in 5' flanking regions, 156 in introns, 10 in exons, and 15 in 3' flanking regions. These variants may contribute to a more precise understanding of possible correlations between genotypes and disease-susceptibility phenotypes or risk for side effects from drugs.

3' Untranslated Regions↗

PubMed2001

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1 and L1CAM in the Japanese population.

By direct sequencing of regions of the human genome containing five genes belonging to the acetyltransferase family, arylamine N-acetyltransferase (NAT1), arylamine N-acetyltransferase (NAT2), arylalkylamine N-acetyltransferase (AANAT), L1 cell adhesion molecule (L1CAM), and the human homolog of Saccharomyces cerevisiae N-acetyltransferase ARD1, we identified 53 single-nucleotide polymorphisms (SNPs) and two insertion/ deletion polymorphisms in 48 healthy Japanese volunteers. NAT1 and NAT2 are so-called drug-metabolizing enzymes. In the NAT1 gene we found two SNPs and a 3-bp insertion/ deletion polymorphism that corresponded to the NAT1*3, *10, and *18A/*18B alleles reported in other populations. The frequencies of NAT1* alleles in our Japanese subjects were 52.6% for NAT1*4, 1.0% for NAT1*3, 40.6% for NAT1*10, 2.6% for NAT1*18A and 3.1% for NAT1*18B. In the NAT2 gene we found 32 SNPs and a 1-bp insertion/ deletion polymorphism; 6 SNPs within the coding region were reported previously and belonged to the slow acetylator group (NAT2*5, NAT2*6 and NAT2*7), and 2 of the 8 SNPs in the 5' flanking region were reported in the dbSNP of GenBank, but the remaining 24 SNPs and the insertion/deletion polymorphism were novel. The frequencies of NAT2* alleles in Japanese (51.3% for NAT2*4, 1.6% for *5B, 26.1% for *6A, 2.2% for *6B, 1.2% for *7A, 10.1% for *7B, 7.4% for *12A, and 1.1% for *13) were significantly different from those reported in Caucasian populations. In the AANAT gene we found 4 novel SNPs: 2 in the 5' flanking region, 1 in exon 4, and 1 in intron 3. In the two genes belonging to the N-terminal N-acetyltransferase family, we identified 9 SNPs, 7 of them novel, for ARD1, and six novel SNPs for L1CAM. Variations at these loci may contribute to an understanding of the way in which different genotypes may affect the activities of human N-acetyltransferases, especially as regards the therapeutic efficacy of certain drugs and antibiotics.

Acetyltransferases↗

PubMed2001

Estimation of rhG-CSF absorption kinetics after subcutaneous administration using a modified Wagner-Nelson method with a nonlinear elimination model.

The clearance of recombinant human granulocyte-colony stimulating factor (rhG-CSF) is known to decrease with dose increase, and to be saturable. The average clearance after intravenous administration will be lower than that after subcutaneous administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be an underestimate. The absorption pharmacokinetics after subcutaneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 microg/kg. The analysis was performed using a modified Wagner-Nelson method with the nonlinear elimination model. The apparent absolute bioavailability for subcutaneous administration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, however, estimated to be 89.8 and 96.9%, respectively, and the ratio was approximately 108%. The absorption pattern was applied to other doses, and the predicted clearance values for subcutaneous and intravenous administrations were then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%, and the amplification of difference was 2.5 times, from 8 to 20%, because of the nonlinear pharmacokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably that the amount eliminated through the saturable process, which might indicate the amount consumed by the G-CSF receptor, was identical for each formulation.

Absorption↗

PubMed2001

Diurnal variations in alpha power density and subjective sleepiness while performing repeated vigilance tasks.

OBJECTIVE: Diurnal variations in EEG activity and subjectively rated sleepiness while performing repeated vigilance tasks were examined. METHODS: Nine diurnally active healthy males underwent repeated vigilance tasks at 08:00, 11:00, 14:00, 17:00 and 20:00 h. An electroencephalogram (EEG) was taken while the subjects performed the tasks with their eyes open. The alpha power spectra (8.6-13.3 Hz) of EEG was integrated. Subjectively rated sleepiness, reaction time and oral temperature were also measured. RESULTS: Significant diurnal variations were found for alpha power, subjectively rated sleepiness and oral temperature. The alpha power was significantly smaller at 08:00 than at 11:00, 14:00, 17:00 and 20:00 h. The subjectively rated sleepiness was significantly larger at 08:00 than at 11:00, 17:00 and 20:00 h. The diurnal variation in alpha power did not correspond to that in subjectively rated sleepiness. On the other hand, repeated vigilance tasks increased the alpha power, subjectively rated sleepiness and reaction time at each time of day. The increase in alpha power was significantly greater at 14:00 than at 08:00 and 20:00 h. CONCLUSIONS: The diurnal variation was found in alpha power while performing vigilance tasks. Furthermore, the increase in alpha power with repetition of the task depended on the time of day.

Adult↗

PubMed2001

Changing the dosing schedule minimizes the disruptive effects of interferon on clock function.

The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-alpha on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-alpha. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.

Animals↗

PubMed2001

Influence of age and comedication on steady-state clonazepam serum level-dose ratios in Japanese epileptic patients.

BACKGROUND: In antiepileptic drugs, the marked inter- and intrapatient variability of the level-dose ratio makes it difficult to predict serum concentrations from the administered per kg dose. It is therefore important to identify factors, such as age and comedication, that could contribute to this observed variability. OBJECTIVE: To investigate the effect of age and comedication on clonazepam (CZP) level-dose (L/D) ratios. METHOD: A retrospective evaluation of data from 137 epileptic patients who had received clonazepam. RESULTS: The CZP L/D ratio increased slowly with age up to 15 years in patients on monotherapy. Associated antiepileptic therapy affected the CZP L/D ratio, which was significantly reduced in patients on polytherapy as compared to patients on monotherapy. CONCLUSION: The study therefore suggests that routine monitoring of CZP serum levels is extremely useful, especially in the paediatric age group, and in patients who require associated antiepileptic medication.

Adolescent↗

PubMed2001

Genetic polymorphisms and functional characterization of the 5'-flanking region of the human CYP2C9 gene: in vitro and in vivo studies.

OBJECTIVE: Genetic polymorphisms were identified in the 5'-flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformational polymorphism analysis, following sequencing with DNA samples obtained from 50 healthy volunteers and 133 adult epileptic patients. HepG2 hepatoma cells were cotransfected with various sequence patterns of 5'-flanking region-luciferase reporter gene constructs. Pharmacokinetic parameters of phenytoin in relation to the corresponding sequence patterns were estimated by the Bayesian method, and the results were compared with in vitro activities. RESULTS: Genetic analysis revealed the existence of 7 single nucleotide polymorphisms (SNPs). Allele frequencies of T-->C transition at position -1912 (T-1912C), C-1886G, C-1566T, G-1538A, C-1189T, G-982A, and A-162G were 0.019, 0.019, 0.077, 0.019, 0.579, 0.019, and 0.003, respectively. Some mutations occurred simultaneously, and a total of 6 sequence patterns (patterns 1-6) were observed. The luciferase reporter gene assay indicated that the presence of mutation(s) resulted in a reduction in luciferase activity of 41.4% (pattern 2) to 86.8% (pattern 5) compared with the activity of the wild-type construct. The calculated intrinsic clearance of phenytoin was also lower (up to a 40% reduction for pattern 2) when a mutation(s) was present. CONCLUSION: In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.

Adult↗

PubMed2001

Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics.

Alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) gene polymorphisms play roles in ethanol metabolism, drinking behavior and esophageal carcinogenesis in Japanese; however, the combined influence of ADH2 and ALDH2 genotypes on other aerodigestive tract cancers have not been investigated. ADH2/ALDH2 genotyping was performed on lymphocyte DNA samples from Japanese alcoholic men (526 cancer-free; 159 with solitary or multiple aerodigestive tract cancers, including 33 oropharyngolaryngeal, 112 esophageal, 38 stomach and 22 multiple primary cancers in two or three organs). After adjustment for age, drinking and smoking habits, and ADH2/ALDH2 genotypes, the presence of either ADH2*1/2*1 or ALDH2*1/2*2 significantly increased the risk for oropharyngolaryngeal cancer [odds ratios (ORs), 6.68 with ADH2*1/2*1 and 18.52 with ALDH2*1/2*2] and esophageal cancer (ORs, 2.64 and 13.50, respectively). For patients with both ADH2*1/2*1 and ALDH2*1/2*2, the risks for oropharyngolaryngeal and esophageal cancers were enhanced in a multiplicative fashion (OR = 121.77 and 40.40, respectively). A positive association with ALDH2*1/2*2 alone was observed for stomach cancer patients who also had oropharyngolaryngeal and/or esophageal cancer (OR = 110.58), but it was not observed for those with stomach cancer alone. Furthermore, in the presence of ALDH2*1/2*2, the risks for multiple intra-esophageal cancers (OR = 3.43) and for esophageal cancer with oropharyngolaryngeal and/or stomach cancer (OR = 3.95) were higher than the risks for solitary intra-esophageal cancer and for esophageal cancer alone, but these tendencies were not observed for ADH2*1/2*1 genotype. Alcoholics' population attributable risks due to ADH2/ALDH2 polymorphisms were estimated to be 82.0% for oropharyngolaryngeal cancer and 63.9% for esophageal cancer.

Adult↗

PubMed2001

Effects of lansoprazole, clarithromycin and pH gradient on uptake of [14C]amoxycillin into rat gastric tissue.

The effect of lansoprazole and clarithromycin on the uptake of [(14)C]amoxycillin into rat gastric tissue was investigated. After oral administration of [(14)C]amoxycillin, the levels of radioactivity in gastrointestinal tissue were two to 15 times higher than those in plasma. The level of radioactivity in glandular stomach was significantly higher when lansoprazole and [(14)C]amoxycillin were administered together. After intravenous administration of [(14)C]amoxycillin, there was less radioactivity in gastric tissue than after oral administration, and co-administration of lansoprazole and clarithromycin had no obvious effect. The gastric emptying rate of [(14)C]amoxycillin was not apparently affected by the co-administration of lansoprazole and clarithromycin. In vitro uptake of [(14)C]amoxycillin into gastric tissue depended on the pH, with uptake at pH 7.4 being four times greater than that at pH 4.0. The apparent synergic effects of lansoprazole are due to enhanced penetration of amoxycillin in gastric mucus and tissue by increasing intragastric pH and play an important role in the eradication of H. pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2001

Localization of [14C]amoxicillin in rat gastric tissue when administered with lansoprazole and clarithromycin.

The gastric mucosal distribution of [14C]amoxicillin when administered to rats with or without lansoprazole and clarithromycin was investigated. After oral administration, the amount found in the gastric mucosa was higher than after iv administration. Co-administration of lansoprazole and clarithromycin had no apparent effect on the distribution pattern of [14C]amoxicillin within the deeper stomach layers. About 50-60% of the radioactivity in the gastric tissue was present in the mucosal layer, irrespective of the route of administration. Microautoradiograms of the gastric mucosa indicated that [14C]amoxicillin was distributed in both the mucous layer and surface epithelial cells following oral administration. [14C]amoxicillin was secreted mainly by surface epithelial cells after iv administration, although only in small quantities.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2001

Changes in postural sway during a period of sustained wakefulness in male adults.

Nocturnal variations in postural sway during a period of sustained wakefulness were studied in seven healthy male adults. Postural sways with the subject's eyes open and with them closed were measured every hour from 22:00 to 04:00 h the following day. Parameters of postural sway [rectangle area (RA), root mean square of length in the anterior-posterior direction (RMSL-y), and medium-frequency-band (0.2-1.0 Hz) power of postural sway in the lateral (MF-x) and anterior-posterior (MF-y) directions] showed significant nocturnal variations. RA, RMSL-y, MF-x and MF-y increased after midnight and reached peaks at 04:00 h. Moreover, changes in RA and MF-y depended on visual conditions. The increases in RA and MF-y were larger with the eyes closed than with them open. These postural sway parameters showed positive correlations with subjectively rated sleepiness and negative correlations with electroencephalographic alpha activity. The results suggest that changes in postural sway during the night are influenced by the increase in sleepiness.

Activity Cycles↗

PubMed2001

Metabolic and ethnic determinants of alcohol drinking habits and vulnerability to alcohol-related disorder.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Shoji Harada and Dharam P. Agarwal. The presentations were (1) Mutations in the exons, exon-intron junctions, and promoter regions of human CYP2E1 gene and alcoholism, by Fumio Nomura; (2) Genetic variability in alcohol metabolism and drinking habits in Japanese, by Shoji Harada; (3) Genetic studies of alcohol dependence using alcoholics with inactive ALDH2, by Susumu Higuchi; and (4) Alcohol consumption, apolipoprotein polymorphisms, and cardiovascular disorders, by Dharam P. Agarwal.

Alcohol Drinking↗

PubMed2001

Functional relevance of human adh polymorphism.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were C. J. Peter Eriksson and Tatsushige Fukunaga. The presentations were (1) 4-Methylpyrazole as a tool in the investigation of the role of ADH in the actions of alcohol in humans, by Taisto Sarkola and C. J. Peter Eriksson; (2) ADH2 polymorphism and flushing in Asian populations, by Wei J. Chen, C. C. Chen, J. M. Ju, and Andrew T. A. Cheng; (3) Role of ADH3 genotypes in the acute effects of alcohol in a Finnish population, by Hidetaka Yamamoto, Kathrin Kohlenberg-Müller, and C. J. Peter Eriksson; (4) Clinical characteristics and disease course of alcoholics with different ADH2 genotypes, by Mitsuru Kimura, Masanobu Murayama, Sachio Matsushita, Haruo Kashima, and Susumu Higuchi; (5) ADH2 polymorphism, alcohol drinking, and birth defects, by Lucinda Carr, D. Viljoen, L. Brooke, T. Stewart, T. Foroud, J. Su, and Ting-Kai Li; and (6) ADH genotypes and alcohol use in Europeans, by John B. Whitfield.

Adult↗

PubMed2001

Recent research on alcohol tolerance and dependence.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hiroshi Suwaki and Harold Kalant. The presentations were (1) Influence of ADH genotypes on acute alcohol withdrawal syndrome in Japanese, by Susumu Higuchi; (2) Use of genetic analyses to refine phenotypes related to alcohol tolerance and dependence, by John C. Crabbe; (3) Neurochemical basis for alcohol dependence, by Seitaro Ohkuma and Masashi Katsura; (4) Adenylyl cyclase and development of tolerance to addictive drugs, by Masami Yoshimura; (5) Tolerance in rat lines selectively bred for alcohol preference, by Robert C. Stewart and Ting-Kai Li; and (6) Ethanol reinforcement, dependence, and vulnerability to relapse: Interactions between neuroadaptive and conditioning factors, by Friedbert Weiss.

Alcohol Dehydrogenase↗

PubMed2001

Postural sway during cane use by patients with stroke.

OBJECTIVE: To quantitatively evaluate the effects of body support with a cane on postural sway by measuring gravity-center sway of patients with stroke who reside at home. DESIGN: The subjects were 41 patients with stroke and 36 healthy independent elderly people. Each subject stood in the standard Romberg position on a gravicorder under two conditions: without support and with a cane. RESULTS: In both groups, the largest area of gravity-center sway occurred when the subjects stood without support. The area of gravity-center sway of the patients with stroke was significantly greater than that of the healthy independent elderly. In the patients with stroke group, the percentage decrease in the standing position with the cane was 58.0% in the men and 53.9% in the women, as opposed to 67.7% in the men and 67.8% in the women in the group of healthy independent elderly. CONCLUSION: The authors quantitatively evaluated the effects of body support with a cane on postural sway of patients with stroke. The effect of body support with cane on postural sway of patients with stroke was more effective than that of healthy independent elderly.

Aged↗

PubMed2001

Pharmacoepidemiologic investigation of a clonazepam-carbamazepine interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients.

Nonlinear mixed effects modeling was used to estimate the effects of clonazepam-carbamazepine interaction on clearance values using 359 serum levels gathered from 183 pediatric and adult epileptic patients (age range, 0.3-26.8 years) during their clinical routine care. Patients received the administration of clonazepam and/or carbamazepine. The final model describing clonazepam clearance was CL = 179.0 x TBW(-0.231) x 1.22(CBZ), where CL is total body clearance (mL/kg/h) and TBW is total body weight (kg); CBZ = 1 for concomitant administration of carbamazepine and CBZ = zero otherwise. The final model describing carbamazepine clearance was CL = 92.7 x TBW(-0.394) x DOSE(0-397) x 0.795(CZP), where DOSE is the daily dose of carbamazepine (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance and a 20.5% decrease in carbamazepine clearance.

Adolescent↗

PubMed2001

Phenytoin intoxication induced by fluvoxamine.

A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.

Alleles↗