Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus.
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Alleles↗
Biomedical subjects
S Higuchi
Publications and source records attributed to S Higuchi.
Pharmacokinetic interactions among phenobarbital, carbamazepine, and valproic acid in pediatric Japanese patients: clinical considerations on steady-state serum concentration-dose ratios.
With antiepileptic drugs, the marked inter- and intrapatient variability of the concentration-dose ratio makes it difficult to predict serum concentrations from the dose administered per kilogram. The effects of comedication on steady-state serum concentration/dose ratios of antiepileptic drugs were evaluated retrospectively in 669 pediatric patients. To avoid complex pharmacokinetic interactions among multiple antiepileptic drugs, the data on serum concentrations in the current study were collected from patients who were co-administered only one additional antiepileptic drug (phenobarbital-carbamazepine, phenobarbital-valproic acid, or carbamazepine-valproic acid) or who received monotherapy. The concentration/dose ratio for the antiepileptic drugs increased significantly with body weight in children up to 15 years old. Associated therapy with antiepileptic drugs affected the concentration/dose ratio. Therefore, routine monitoring of serum concentrations of the antiepileptic drugs is extremely useful, particularly in children and in patients who require associated antiepileptic medication.
Adolescent↗
Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats.
Renal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrononephrotoxicity in rats after weekly or daily cisplatin injections. Weekly high doses (5 mg kg(-1)) or daily low doses (1.2 mg kg(-1)) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P < 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.
Animals↗
Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice.
The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.
Animals↗
Characterization of microsomal alcohol oxygenase catalyzing the oxidation of 7-hydroxy-delta 8-tetrahydrocannabinol to 7-oxo-delta 8-tetrahydrocannabinol in rat liver.
The formation of 7-oxo-delta8-tetrahydrocannabinol (7-oxo-delta8-THC) from 7beta-hydroxy-delta8-THC was found in hepatic microsomes of rats. The activity was stereoselective and about 3-fold higher than that from 7alpha-hydroxy-delta8-THC. The oxidative activity of 7alpha- and 7beta-hydroxy-delta8-THC to 7-oxo-delta8-THC was significantly higher in male than in female, and significantly enhanced by both dexamethasone and phenobarbital, and then inhibited up to about 20% of the control value by antibody against P450GPF-B, presumably a member of the 3A subfamily, a major enzyme responsible for the formation of 7-oxo-delta8-THC in guinea pigs. This antibody also inhibited the formation of 7alpha- and 7beta-hydroxy-delta8-THC, and 7-oxo-delta8-THC from delta8-THC by hepatic microsomes of rats. These results indicate that there is a sex-related difference in the oxidation of 7-hydroxy-delta8-THC to 7-oxo-delta8-THC and the reaction is mainly catalyzed by P450 enzyme(s) belonging to the 3A subfamily as major enzyme(s) of microsomal alcohol oxygenase in rats.
Animals↗
Evaluation of intracranial pressure by transcranial Doppler ultrasonography in dogs with intracranial hypertension.
Transcranial Doppler ultrasonography (TCD) has been used to confirm changes in cerebral hemodynamics. In this study, we investigated whether the parameters for the basilar artery measured by TCD were correlated with the intracranial and cerebral perfusion pressures in extreme intracranial hypertension. An intracranial hypertension model was produced in seven dogs by inflating a balloon inserted into the epidural space. The resistance index was compared with the corresponding intracranial pressure and cerebral perfusion pressure values during intracranial hypertension. A significant correlation was recognized between the resistance index and cerebral perfusion pressure. Therefore, measurement of the basilar artery by TCD in the dog with intracranial hypertension is useful in estimating the intracranial circulation in cases where the measurement of intracranial pressure is not available or not indicated.
Animals↗
Purification of bovine urinary beta2-microglobulin and its biochemical characteristics.
In this study, bovine beta2-m was purified from urine by ion-exchange chromatography and gel chromatography, and the characteristics were compared with those of colostral beta2-m by the immunological reactivity, isoelectric points, peptide map, and amino acid sequence. The characteristics of purified urinary beta2-m were consistent with those of the colostral beta2-m. The urinary and colostral beta2-m possessed the same polypeptide chain consisting of 98 amino acids, and its molecular weight is 11.8 kDa. Furthermore, four isoforms of beta2-m were found. The isoelectric points were different from each other.
Amino Acid Sequence↗
Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males.
Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males were studied. Ethanol (0.5 g/kg) or control drink was orally administered to nine healthy males at 10:00 and 18:00. The alpha 2 amplitude was significantly lower than that of the control at 0.5, 2.5 and 4.5 hours after ethanol consumption in the morning. These effects were observed in the left hemisphere and were only found after consumption in the morning. The subjectively rated attention was significantly lower than that of the control at 0.5 and 2.5 hours after ethanol consumption in the morning and at 0.5 hours after ethanol consumption in the evening. In contrast, the search speed of serial search task and P300 amplitude was significantly lower than that of the control at 2.5 hours after ethanol consumption in the evening. These results demonstrate that effects of ethanol are dependent on time-of-day of consumption. Ethanol consumption significantly lowered the alpha 2 amplitude when consumed in the morning, and lowered P300 amplitude when consumed in the evening.
Adult↗
Reliability and validity of the questionnaire to determine the biosocial rhythms of daily living in the disabled elderly.
The questionnaire to determine the biosocial rhythms of daily living in the disabled elderly was newly developed. This questionnaire was aimed to evaluate a state of synchronization of biological rhythms in the disabled elderly. Eighteen items of the questionnaire relating to the synchronization of biological rhythms were finally selected by the test-retest method that was conducted for 68 disabled elderly living in a community with a duration of one year. The factor analysis showed that the questionnaire consisted of five factors: outdoor activities, ultradian rhythms, subjective evaluation of health status, social support, and sleep habits. The cumulative contribution rate of five factors was 53.2%. Reliability of the questionnaire was confirmed by a calculation of the Equal-length Spearman-Brown coefficients ranging from 0.60 to 0.80. Regarding the construct validity of the questionnaire, results of factor analysis showed five factors that were consistent with the synchronizers known in chronobiology. The total score of the questionnaire was significantly correlated to Barthel Index score and the competence score, suggesting that it partly reflects the activities of daily living of the disabled elderly. We conclude that a new questionnaire to determine the biosocial rhythm of daily living in the disabled elderly is useful to evaluate the biosocial synchronization of the disabled elderly because of its high reliability and validity.
Activities of Daily Living↗
Alcohol and aldehyde dehydrogenase genotypes in Korsakoff syndrome.
BACKGROUND: Previous studies have suggested a genetic predisposition to the development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor. METHODS: To test the hypothesis that altered alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls. RESULTS: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS. CONCLUSIONS: These findings suggest that the ADH2*1/2*1 genotype is a risk factor for the development of WKS in alcoholic patients.
Aged↗
Is heavy alcohol consumption an attributable risk factor for cancer-related deaths among Japanese men?
BACKGROUND: Over the past four decades, per capita alcohol consumption in Japan has increased 4-fold. Age-adjusted cirrhosis mortality rates for men have also increased, whereas the rates for women have declined gradually. This widening difference in mortality could be due to a decreasing prevalence of viral hepatitis infection for both sexes and to differences in alcohol consumption between the sexes. Difficulties in estimating the impact of increased alcohol consumption on mortality rates in Japan also arise from changes in the prevalence of non-alcohol-related risk factors. METHODS: To measure the relative contribution of alcohol to death from cirrhosis, liver cancer, esophageal cancer, and head and neck cancer among Japanese men, we used the mortality rate for Japanese women as the standard because alcohol consumption for women has been low. We used published vital statistics data from 1992 to 1996 to calculate the attributable risk percent (ARP) in 5-year cohorts of Japanese men age 20 and older. RESULTS: Among Japanese men, heavy alcohol consumption accounted for 70.7% of deaths due to cirrhosis, 76.8% of liver cancer deaths, 88.5% of esophageal cancer deaths, and 87.4% of head and neck cancer deaths. When we examined ARPs by age group, ARPs for these four diseases were approximately 80% in the middle age groups. However, for older groups, the ARPs for cirrhosis and liver cancer were much lower than those for esophageal cancer and head and neck cancer. The prevalence of previous hepatitis C virus infection, considered to be the major cause of cirrhosis and liver cancer, increased with age. CONCLUSIONS: The results support previous epidemiologic studies conducted in Japan. Heavy alcohol consumption is a major public health problem among younger Japanese men, accounting for approximately 80% of the deaths for the four diseases examined.
Adult↗
Genetic polymorphism of the CCK gene in patients with alcohol withdrawal symptoms.
BACKGROUND: Cholecystokinin (CCK) is considered to play an important role in the central nervous system via its interaction with other neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid, substance P, and enkephalins. We investigated the relationship between the C to T substitution in the Sp1 binding cis-element of the CCK gene promoter region (at position -45 numbered from initiation codon) and alcohol withdrawal symptoms. METHODS: We examined 214 Japanese men with alcoholism (93 with delirium tremens, 49 with hallucination, 38 with seizure, and 93 with none of these symptoms) and 98 age-matched Japanese male controls by using a polymerase chain reaction-based single strand conformational polymorphism analysis. RESULTS: Patients who displayed hallucination were significantly more likely to possess the C allele than control subjects (chi2 = 8.17, p = 0.017, Bonferroni correction: p = 0.064). In addition, we investigated the influence of CCK gene polymorphism on alcohol consumption among the control subjects but found no significant relationship. CONCLUSIONS: Our data suggested that the C allele at -45 locus of the CCK gene was higher in patients with hallucination than the control group at a rate that was not quite significant after Bonferroni correction for multiple testing.
Adult↗
Population pharmacokinetics and pharmacodynamics of TS-943 for selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist in normal healthy subjects.
The pharmacokinetics and pharmacodynamics of TS-943 were evaluated with use of NONMEM in 36 healthy male subjects after constant infusion of five different single-dose regimens. Population analysis showed the plasma concentration-time profiles of TS-943 to be best-fit characterized by a two-compartment open model with constant infusion and first-order elimination. The pharmacodynamic model that best fitted the platelet aggregation was a sigmoid Emax model. The final estimates for baseline effect, 50% inhibitory concentration (IC50), and the Hill coefficient were 79.4%, 23.4 ng/mL and 1.63, respectively. The maximum effect (Emax) was fixed at 80% (submaximal aggregation response). In addition, correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The model estimates that the TS-943 plasma concentration necessary to double template bleeding time is approximately 63 ng/mL (ie, 2.7-fold greater than the IC50). The population approaches for pharmacokinetic-pharmacodynamic investigation can be useful for the analysis of concentration-effect relationships and concentration-adverse event relationships for a platelet glycoprotein IIb/IIIa receptor antagonist.
Adult↗
Basis for dosing time-dependent changes in the antiviral activity of interferon-alpha in mice.
The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM). 2'-5'Oligoadenylate synthetase activity in plasma at 24 h after IFN-alpha (10 MI.U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P <.05). The uptake of [(3)H]thymidine by lymphocytes after 24-h incubation with IFN-alpha, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9:00 AM than in the cells obtained at 9:00 PM (P <.01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P <.05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-alpha, which showed higher clearance for injections given at 9:00 PM than for those at 9:00 AM (P <.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9:00 PM than at 9:00 AM (P <.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.
2',5'-Oligoadenylate Synthetase↗
Chronopharmacology of antitumor effect induced by interferon-beta in tumor-bearing mice.
The mechanisms underlying the dosing time-dependent change in the antitumor effect of interferon-beta (IFN-beta) were investigated based on the sensitivity of tumor cells and the pharmacokinetics of the drug. Tumor-bearing mice were housed under standardized light-dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water available ad libitum. The antitumor effect of IFN-beta (0.5 MI.U./kg, intratumoral) was more efficient in early light phase than in early dark phase. The higher antitumor effect of IFN-beta was observed when specific binding of IFN receptor and DNA synthesis in tumor cells increased, and the lower effect was observed when these levels decreased. The dosing time-dependent effect of IFN-beta was supported by the time-dependent expression of transcription factor (signal transducers and activators of transcription 1) and cell proliferation inhibitor (p21 wild-type p53-activated fragment 1) protein induced by IFN-beta. There was a significant dosing time-dependent change in IFN-beta concentration in tumor, with a higher level in early light phase and a lower level in early dark phase. The dosing time-dependent change of IFN-beta concentration in tumor was associated with that of IFN-beta-induced antitumor effect. These results suggest that by choosing the most suitable dosing time for IFN-beta, the efficacy of the drug can be increased in certain experimental and clinical situations.
Animals↗
Comparison of drug disposition between wild-type and novel tissue-type plasminogen activator pamiteplase in rats.
The pharmacokinetics of pamiteplase in rats was compared with the pharmacokinetics of recombinant wild-type tissue-type plasminogen activator (rwt-PA). The half-life in the beta-phase and total clearance after administration of (125)I-labeled pamiteplase ((125)I-pamiteplase) to rats were 480 and 22% of those of (125)I-labeled rwt-PA ((125)I-rwt-PA), respectively. The amount of radioactivity distributed in the liver after administration of (125)I-pamiteplase was lower than that of (125)I-rwt-PA; consequently, a possible difference in metabolism between the drugs was assessed by an integration plot and a tissue-sampling single-injection technique. Use of these two methods revealed that the hepatic clearances of both compounds accounted for almost all of the total clearance and also revealed that the hepatic clearance of (125)I-pamiteplase was markedly lower than that of (125)I-rwt-PA. Therefore, the lower distribution of pamiteplase in the liver compared with rwt-PA is thought to contribute greatly to the higher plasma concentration of pamiteplase. Additionally, the uptake of (125)I-pamiteplase in the liver was inhibited by rwt-PA, suggesting that there is a common uptake mechanism for both compounds.
Animals↗
NOS3 polymorphism not associated with Alzheimer's disease in Japanese.
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Aged↗
CYP3A4 is a major isoform responsible for oxidation of 7-hydroxy-Delta(8)-tetrahydrocannabinol to 7-oxo-delta(8)-tetrahydrocannabinol in human liver microsomes.
The human liver enzyme microsomal alcohol oxygenase was able to oxidize both 7alpha- and 7beta-hydroxy-Delta(8)-tetrahydrocannabinol (7alpha- and 7beta-hydroxy-Delta(8)-THC) to 7-oxo-Delta(8)-THC. The oxidative activity was determined by using a panel of 12 individual cDNA-expressed human cytochrome P450s (CYPs) (1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1 and 3A4). Among the CYP isoforms examined, CYP3A4 showed the highest activity for both of substrates. The metabolism of 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-THC was also detected for CYPs 1A1 (4.8% of CYP3A4), 1A2 (4.7%), 2A6 (2.3%), 2C8 (16.6%), and 2C9-Cys (5.4%), and CYPs 1A1 (0.4%), 2C8 (1.3%), 2C9-Arg (4.3%), and 2C9-Cys (0.9%), respectively. The 7alpha- and 7beta-hydroxy-Delta(8)-THC microsomal alcohol oxygenase activities in human liver were significantly inhibited by addition of 100 microM troleandomycin, 1 microM ketoconazole, and anti-CYP3A antibody, although these activities were not inhibited by 1 microM 7, 8-benzoflavone and 50 microM sulfaphenazole. When the substrates were incubated with the CYP3A4-expressed microsomes under oxygen-18 gas phase, atmospheric oxygen was incorporated into 35% of 7-oxo-Delta(8)-THC formed from 7alpha-OH-Delta(8)-THC, but only 12% of 7-oxo-Delta(8)-THC formed from 7beta-OH-Delta(8)-THC. These results indicate that CYP3A4 is a major isoform responsible for the oxidation of 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-THC in liver microsomes of humans, although the oxidation mechanisms for 7alpha- and 7beta-hydroxy-Delta(8)-THC might be different.
Adolescent↗