Biomedical subjects

E Yukawa

Publications and source records attributed to E Yukawa.

At least 37 records · Page 2Linked to original sources

PubMed2000

Investigation of phenobarbital-carbamazepine-valproic acid interactions using population pharmacokinetic analysis for optimisation of antiepileptic drug therapy: an overview.

Antiepileptic drugs are associated with a wide range of drug interactions. Although monotherapy with antiepileptic drugs is preferred, patients with multiple seizure types or refractory disease generally require various combinations of antiepileptic drugs. Pharmacokinetic interactions between antiepileptic drugs represent a major complication of epilepsy treatment with polytherapy. It is important to be aware of possible interactions, so as to anticipate clinical effects and to reduce the risk of both toxicity and seizures worsening when a drug is added to, or withdrawn from, the patient's antiepileptic drug regimen. This report is an overview of the drug-drug interactions between antiepileptic drugs (phenobarbital<-->carbamazepine, carbamazepine<-->valproic acid and phenobarbital<-->valproic acid) by population pharmacokinetic analysis.

Adolescent↗

PubMed2000

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↗

PubMed2000

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↗

PubMed1999

Population-based investigations of drug relative clearance using nonlinear mixed-effect modelling from information generated during the routine clinical care of patients.

Interpatient variability in drug disposition and response is a therapeutic premise, and thus evaluation and management of such variability are the basis for individualized pharmacotherapy. If the mathematical approach to determining drug doses were accurate and practical, the use of calculated doses could reduce the potential for toxicity and decrease the need for repetitious drug assays. The major strength of the population pharmacokinetics approach is that useful information can be extracted from sparse data collected during routine clinical care. Population pharmacokinetics can be defined as the study of the variability in serum drug concentrations between individuals when standard dosage regimens are administered. An approach to population pharmacokinetic data analysis has been implemented in the Nonlinear Mixed Effects Model (NONMEM) computer program. This report shows the feasibility of using a simple pharmacokinetic screen approach to estimate the population mean relative drug clearance and detecting drug-drug interaction by use of NONMEM. In clinical application of multiple trough screen or multiple peak screen, the variability of drug relative clearance within the population is assessed and a mathematical relationship between drug relative clearance and individual patient characteristics, such as age, body weight, gender, disease state or drug interaction with concomitant drug is derived. In this report I describe this approach and its application using several examples previously reported by us and others.

Electronic Data Processing↗

PubMed1999

Population analysis for the optimization of digoxin treatment in Japanese paediatric patients.

BACKGROUND AND OBJECTIVES: Information about the pharmacokinetics of digoxin in paediatric patients is limited. We therefore aimed to investigate the effects of physiological factors on the digoxin clearance in Japanese paediatric patients. METHOD: We used routinely collected therapeutic drug monitoring data (n=544), derived from the steady-state serum concentrations of digoxin in 181 hospitalized paediatric patients. RESULTS: Of those physiological factors which have been examined in this study, age and total body weight were most closely correlated with digoxin clearance. Data on neonates within the first postnatal month indicated a tendency towards lower clearance for premature neonates than full-term neonates (P<0.01). Digoxin clearance was reduced by spironolactone in patients younger than 4 months (P<0.05). Patients with congestive heart failure showed a lower digoxin clearance than the others (P<0.001). Serum creatinine and gender did not have a statistically significant effect on digoxin clearance. CONCLUSION: Age and total body weight are important factors influencing digoxin clearance in children. Spironolactone affected digoxin clearance and needs to be considered when dosing paediatric subjects.

Age Factors↗

PubMed1999

Predictive performance of equations to estimate creatinine clearance from serum creatinine in Japanese patients with congestive heart failure.

Seven methods using patient's age, weight, gender, and serum creatinine concentration were evaluated for mathematical and clinical predictive performance in estimating the creatinine clearance of Japanese patients. We compared the measured and estimated creatinine clearance in 179 hospitalized heart failure patients. The Gates equation was the most biased (mean prediction error, 17.9 mL/min), and the Yukawa equation was the most precise (mean absolute prediction error, 10.4 mL/min), followed by the Jelliffe, Bjornsson, Cockcroft and Gault, and Mawer equations. For all methods, precision was less when serum creatinine concentrations of <0.6 mg/dL were rounded than when serum creatinine concentrations of >/=0.6 mg/dL were rounded. We conclude that in clinical practice where the renal function can vary widely, any of the published formulas can give satisfactory results. The Yukawa formula is concise and gives better results in Japanese patients.

Adolescent↗

PubMed1999

Pharmacokinetic and pharmacodynamic analysis of subcutaneous recombinant human granulocyte colony stimulating factor (lenograstim) administration.

A total of 72 adult healthy volunteers were administered 1 microgram/kg of rhG-CSF. There was no correlation between Cmax and an increase in peripheral neutrophil count, and there was a negative correlation between AUC and this increase. The mechanism of this is probably based on the correlation between the elimination rate constant (ke) and neutrophil increase. The ke probably has a close relationship with uptake by neutrophil and its progenitor via the G-CSF receptor. An individual with higher ke should therefore show a greater increase in neutrophil count. Therefore, AUC is proportional to the rhG-CSF remainder, that is, the proportion that is not consumed in the course of increasing the neutrophil count. In such a situation, the bioavailability calculated from the AUC is unlikely to indicate the absorbed amount. The authors also analyzed the pharmacokinetics using a two-compartment model with zero-order absorption and first-order elimination. This model was sufficient to obtain a good curve fit, and this demonstrates that the absorption process is not a first-order but a zero-order process. Therefore, there might be an upper limit to the rhG-CSF transfer rate from subcutaneous tissue to blood.

Adjuvants, Immunologic↗

PubMed1998

Detection of a drug-drug interaction on population-based phenobarbitone clearance using nonlinear mixed-effects modeling.

OBJECTIVE: Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effects of drug drug interaction on phenobarbitone clearance values, using 648 serum levels gathered during the routine clinical care of 349 pediatric and adult epileptic patients (age range, 0.4-33.3 years). Patients received phenobarbitone as monotherapy or in combination with either of the antiepileptic drugs carbamazepine or valproic acid. RESULTS: The final model describing phenobarbitone clearance was CL = 52.3 x TBW(-0.567) x CO, where CL is clearance (ml x kg(-1) x h(-1)), TBW is total body weight (kg) and CO is a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 46.4(-1/TBW) for those patients receiving concomitant carbamazepine and 0.642 for those patients receiving concomitant valproic acid. Phenobarbitone CL was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether phenobarbitone was administered alone or coadministered with carbamazepine or valproic acid. When phenobarbitone was coadministered with carbamazepine or valproic acid, phenobarbitone CL decreased compared with that in monotherapy. Its magnitudes in the presence of carbamazepine are maximal in early childhood (about 54%) and decreased in a weight-related fashion in older children, with minimal changes observed in adults. Concomitant administration of phenobarbitone and valproic acid resulted in a 35.8% decrease of phenobarbitone CL.

Adolescent↗

PubMed1998

Influence of dosing time on pharmacological action of G-CSF in mice.

The role of the susceptibility of living organisms and the pharmacokinetics of G-CSF on the rhythm of granulocyte colony-stimulating factor (G-CSF) activity was investigated. ICR male mice were housed in a standardized light-dark cycle (lights on at 0700, off at 1900) with food and water ad libitum. The leukocyte counts at 2 and 24 hr after G-CSF (250 microg/kg, i.v.) injection were significantly higher in mice injected with the drug at 0700 than at 1900 (p<0.01, respectively). The higher leukocyte-increasing effect corresponded to drug dosing at the time in which the granulocyte colony formation stimulated by G-CSF and DNA synthesis increased and the lower effect corresponded to drug dosing at the time in which they decreased. The rhythmicity corresponded to that in plasma G-CSF concentration. The present study suggests that the rhythm of G-CSF activity is caused by that of the sensitivity of bone marrow cells to the drug and the pharmacokinetics of the drug.

Animals↗

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

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

Chronopharmacology of granulocyte colony-stimulating factor in mice.

The role of the sensitivity of bone marrow cells to, and the pharmacokinetics of granulocyte colony-stimulating factor (G-CSF) on the rhythm of leukocyte-increasing effect was investigated in ICR male mice housed under a standardized light-dark cycle (lights on at 0700, off at 1900). A significant circadian rhythm was demonstrated for leukocyte counts at 24 hr after G-CSF (250 microg/kg, s.c.) injection at six different circadian times (P < .01). The leukocyte counts of mice given G-CSF at 0500, 0900, 1300 or 1700 were significantly higher than those of mice given G-CSF at 2100 (P < .01, respectively). The rhythmic pattern resembled overall the rhythm occurring after saline injection. In the comparison between leukocyte counts after G-CSF injection at 0700 and 1900, the time when leukocyte counts are equal in nondrugged state, the leukocyte counts at 24 hr after G-CSF (250 microg/kg, i.v.) injection were approximately 50% higher in mice injected with the drug at 0700 than at 1900 (P < .01). Bone marrow cultures obtained at two times of day resulted in different numbers of myeloid colonies even when treated with the same concentrations of G-CSF in vitro. The colony-forming activity of G-CSF was significantly more potent at 0700 than at 1900 (P < .01). The plasma G-CSF concentrations after G-CSF (250 or 5 microg/kg, i.v.) injection were significantly higher in mice receiving injections with the drug at 0700 than at 1900 (P < .05, respectively). The area under the curve and mean residence time were significantly larger in mice injected with the drug at 0700 than at 1900 (P < .01, P < .05, respectively). Our suggests that the rhythm of G-CSF activity is caused by that of the sensitivity of bone marrow cells to, and the pharmacokinetics of the drug.

Animals↗

PubMed1997

Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of drug-drug interaction and patient characteristics.

Nonlinear mixed effects modeling (NONMEM) was used to estimate the effects of drug-drug interaction on valproic acid relative clearance values using 792 serum levels gathered from 400 pediatric and adult patients with epilepsy (age range, 0.3-54.8 years) during their clinical routine care. Patients received valproic acid as monopharmacy or in combination with either the antiepileptic drugs, phenobarbital, or carbamazepine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6.TBW (kg)-0.252.DOSE (mg/kg/day)0.183.0.898GEN.COPB.COCBZ, where COPB equals 1.10 if the patient is treated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769.DOSE (mg/kg/day)0.179 if the patient is treated with carbamazepine, a value of unity otherwise. Valproic acid relative clearance was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether valproic acid was administered alone or coadministered with phenobarbital or carbamazepine. When valproic acid was coadministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnitude in the presence of carbamazepine increased in a valproic acid daily dose-related fashion. Concomitant administration of phenobarbital and valproic acid resulted in a 10% increase on valproic acid relative clearance. The clearance in female patients was approximately 10% less than that in male patients.

Adolescent↗

PubMed1997

Population-based investigation of relative clearance of digoxin in Japanese patients by multiple trough screen analysis: an update.

The steady-state concentrations of digoxin at trough levels were studied to reestablish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug-monitoring data. The data (n = 548) showing steady-state serum concentrations of digoxin after repetitive oral administration in 385 hospitalized patients were analyzed using NONMEM, a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished with a simple steady-state pharmacokinetic model. The effect of a variety of developmental and demographic factors on the clearance of digoxin was investigated. Estimates generated by NONMEM indicated that clearance of digoxin was influenced by the demographic variables of age, total body weight, serum creatinine, estimated creatinine clearance, gender, the coadministration of spironolactone, the presence or absence of congestive heart failure, and the administration of a half-tablet. The interindividual variability in the clearance of digoxin was modeled with proportional error with an estimated coefficient of variation of approximately 22%; the residual variability was approximately 25.0%. An a priori method, based on the value for clearance of digoxin obtained by NONMEM analysis, was proposed as a useful adjunct for the prediction of the steady-state concentration of digoxin at trough level as a function of the maintenance dose of digoxin.

Adolescent↗

PubMed1997

Circadian rhythm of fever induced by interferon-alpha in mice.

The influence of dosing time on the fever induced by interferon-alpha (IFN-alpha) was investigated in ICR male mice under light-dark cycle. There was a significant circadian rhythm in rectal temperature, as an index of fever, at 1 hr after IFN-alpha (10 MIU/kg, i.v.) injection. The rhythmic pattern resembled overall the rhythm occurring in the nondrugged state. IFN-alpha increased rectal temperature during the light phase, but not during the dark phase. The fever induced by IFN-alpha was blocked by indomethacin (10 mg/kg, i.p.) pretreatment. There was no significant difference of plasma IFN-alpha concentrations at 0.167, 0.5 and 1 hr after IFN-alpha injection. Therefore the dosing time dependent difference of fever induced by IFN-alpha may be caused via that of PGE2 level elevated by IFN-alpha. The choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of IFN-alpha.

Analgesics, Non-Narcotic↗

PubMed1997

Detection of carbamazepine-induced changes in valproic acid relative clearance in man by simple pharmacokinetic screening.

Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and comedication (carbamazepine-induced change) on population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 6.06TBW-0.168 x DOSE0.414 x CBZDOSE0.093 x 0.943GEN x 1.10CO, where CL is the clearance (mL kg-1 h-1), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs. This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.

Adolescent↗

PubMed1997

Chronotoxicity of methotrexate in mice and its relation to circadian rhythm of DNA synthesis and pharmacokinetics.

The mechanisms underlying the circadian rhythm of methotrexate (MTX)-induced toxicity (body weight loss and leukopenia) were investigated from the viewpoints of the sensitivity of living organisms to the drug and the pharmacokinetics of the drug. ICR male mice were housed in a standardized light-dark cycle (lights on at 0700, off at 1900) with food and water ad libitum. The body weight loss after an intraperitoneal injection of MTX (400 mg/kg) was more serious in the late dark period and the early light period and milder in the late light period and the early dark period. The MTX-induced leukopenia was more serious in the late dark period and the light period and milder in the early dark period. Lower toxicity was observed when DNA synthesis, dihydrofolate reductase (DHFR) activity in bone marrow cells and folate level in plasma decreased, and higher toxicity was observed when they increased. There was a significant circadian rhythm in plasma MTX concentration, with a higher level in the light period and a lower level in the dark period. The circadian rhythm of plasma MTX concentration was associated with that of MTX-induced toxicity. The present study suggests that the circadian rhythm of MTX-induced toxicity is caused by that of the sensitivity of living organisms to the drug and the pharmacokinetics of the drug.

Animals↗

PubMed1997

Chronopharmacological study of interferon-alpha in mice.

The influence of dosing time on the pharmacological effects (fever and antiviral activity) and the pharmacokinetics of interferon-alpha (IFN-alpha) was investigated in ICR male mice under light-dark (12:12) cycle. There was a significant circadian rhythm in rectal temperature, as an index of fever, at 0.5 hr after IFN-alpha (10.0 MIU/kg i.v.) injection. The rhythmic pattern resembled overall the rhythm that occurs in the nondrugged state. However, the percent change from basal level of rectal temperature varied according to the dosing time. The rhythmicity corresponded to the dosing time-dependent difference of PGE2 levels in thalamus after IFN-alpha injection, but it did not correspond to that of plasma IFN-alpha concentrations. A significant dosing time-dependent difference was also demonstrated for 2'-5'oligoadenylate synthetase activities, as an index of antiviral activity, in plasma and liver at 24 hr after IFN-alpha injection. It was related to the rhythmicity in plasma IFN-alpha concentrations that was caused by the rhythmicity in clearance of IFN-alpha. The choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of IFN-alpha in certain experimental and clinical situations.

2',5'-Oligoadenylate Synthetase↗