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S Ohdo

Publications and source records attributed to S Ohdo.

At least 37 records · Page 2Linked to original sources
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

Chronopharmacological study of KE-SI-TO in mice.

Influence of dosing time on pharmacological effects and toxicity of KE-SI-TO (KST), analgesic and antipyretic drug, was investigated in ICR male mice under LD (12:12) cycle. Significant circadian rhythms were demonstrated for analgesic and hypothermal effects of KST (1 g/kg, i.p.) with higher values in the dark and lower ones in the light (p<0.01, respectively). The rhythmic patterns of KST-induced analgesia and hypothermia resembled overall the rhythms occuring in the nondrugged state. Injection of KST resulted in a parallel increasing in latency to hot plate and a parallel decreasing in rectal temperature. KST (6 g/kg, i.p.)-induced toxicity also showed a significant circadian rhythm with the highest mortality at 1700 and the lowest one at 0500 (p<0.05). The principles and concepts of biological rhythm should be included in the consideration of the actions of KST.

Analgesics↗
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

Utility of a rectal suppository containing the antiepileptic drug zonisamide.

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15:S-55 = 3:1) as a lipophilic base and the other polyethylene glycol (PEG, 4000:1500 = 4:1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

Administration, Oral↗
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↗
PubMed1997

Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice.

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the sensitivity of living organisms and the pharmacokinetics of the drug. ICR male mice were housed under standardized light-dark cycle conditions (lights on at 0700, off at 1900) with food and water ad libitum. The loss of body weight after an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late dark and the early light and milder in the late light and the early dark. The CPT-11-induced leukopenia was more serious in the late dark and milder in the late light. The lower toxicity of CPT-11 was observed when DNA synthesis and type I DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity was observed when these activities began to increase. There were circadian stage-dependent changes in the concentrations of CPT-11 and its major metabolite (SN-38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT-11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhythm-dependent processes.

Animals↗
PubMed1996

Basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol.

The objective of the present study was to determine the basis for dosing time-dependent changes in the ocular and systemic absorption of topically applied timolol in pigmented rabbits. The gamma scintigraphic technique was used to monitor the changes in precorneal solution retention following instillation. Changes in timolol concentration in the plasma over 120 min and in various anterior segment eye tissues at 30 min following the topical instillation of 25 microliters of 0.65% timolol maleate solutions at various dosing times were monitored using reversed phase HPLC. Corneal and conjunctival permeability at various dosing times was evaluated in the modified Ussing chamber. The results indicated that precorneal solution drainage was slowest at noon. Suppressing tear production by anesthesia led to an increase in ocular timolol absorption at 6 a.m. but not at other dosing times, in spite of the lowest corneal permeability then. There was no statistically significant dosing time influence on systemic timolol absorption following nasal or conjunctival dosing. In conclusion, possible diurnal changes in precorneal solution clearance may be the main factor underlying the diurnal changes in ocular as well as systemic timolol absorption in rabbits. In addition, diurnal changes in corneal permeability may also contribute to diurnal changes in ocular timolol absorption.

Absorption↗
PubMed1996

Partial deletion of the long arm of chromosome 11: ten Japanese children.

The clinical features of partial deletion 11q were correlated with the size of the deleted region. Ten Japanese children with partial deletion of 11q were investigated. They were divided into three groups. Three patients in the first group had interstitial deletions and preserved subband q24.1. Six patients in the second group demonstrated terminal deletion of 11q including subband q24.1, with typical features of 11q- syndrome (Jacobsen syndrome). The third group included only one patient, who had terminal deletion of 11q without characteristics of typical 11q- syndrome. Prominent features of patients in the first group included severe mental and motor developmental delay, seizures, cleft lip and palate, and ophthalmological findings. Patients in the second group showed mild to moderate developmental delays without deterioration. Abnormalities in neuroimages, high intensity in the cerebral white matter in T2-weighted magnetic resonance (MR) images, and recurrent infections were not observed after the age of 7 years. The subject in the third group, with the smallest amount of deleted chromosome, did not show developmental delays, suggesting that some unknown genes related to developmental delays may be located adjacent to subband q24.1. Variation in the deleted parts of 11q resulted in different clinical features in each group.

Abnormalities, Multiple↗
PubMed1996

Chronotoxicity of sodium valproate in pregnant mouse and embryo.

The influence of dosing time on the embryotoxicity of sodium valproate (valproic acid, VPA) was investigated in ICR mice under a light-dark (12:12) cycle. A significant circadian rhythm was shown for VPA-induced embryotoxicity, with the highest value at 1700 and the lowest at 0100. A similar pattern of rhythm was also shown for VPA-induced toxicity in pregnant and nonpregnant mice. No significant dosing time-dependent difference between injection at 1700 and 0100 was demonstrated for VPA concentrations in the embryo, plasma and brain. The rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity of the embryo and dam to the drug. Embryotoxicity and VPA concentrations were significantly higher on gestational day 13 than day 7. The pharmacokinetics of VPA contribute, at least partly, to the gestational stage-dependent embryotoxicity of VPA. The timing of drug administration (i.e., gestational stage and circadian phase) appears to be essential for studies on the embryotoxicity of VPA in mice.

Animals↗
PubMed1996

[A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1].

We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.

Adult↗
PubMed1996

Influence of feeding schedule on the chronopharmacological aspects of sodium valproate in mice.

The role of feeding schedule on the chronopharmacological aspects of sodium valproate (valproic acid; VPA) was examined. ICR male mice were housed in a 12-hr light and 12-hr dark cycle (lights on at 0700, off at 1900) with food and water ad libitum, under a repeated time restricted feeding (feeding time: 0900-1700) for 2 wk, under fasting for 12 hr or under fasting for 12 hr and feeding for 2 hr before the experiment. VPA was used at an i.p. dose of 1200 mg/kg for toxicity, an oral dose of 600 mg/kg for electroshock seizure threshold and plasma VPA concentration, an i.v. dose of 50 mg/kg for pharmacokinetic study and at a rate of 1072.6 micrograms/hr for constant-rate administration using an osmotic minipump. The toxicity, electroshock seizure threshold and VPA concentration (probably at the absorption phase) were significantly higher in the light and lower in the dark showing rhythmicity. The rhythmicity in VPA concentration during constant-rate administration was related to that of clearance and volume of distribution. The rhythms of electroshock seizure threshold and VPA absorption were controlled easily by the temporal manipulation of feeding schedule, but the rhythms of toxicity, clearance and volume of distribution were not. The manipulation of the feeding schedule and the choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of some drugs including VPA in certain experimental and clinical situations.

Animals↗
PubMed1995

Circadian rhythm of embryotoxicity induced by sodium valproate in mice.

The influence of dosing time on embryotoxicity of valproate was investigated in ICR (Institute of Cancer Research, USA) mice under light-dark (12:12) cycle. A significant circadian rhythm was shown for embryotoxicity, with the highest value at 17:00 and the lowest at 01:00. No significant difference between injection at 17:00 and 01:00 was demonstrated for valproate concentrations in the embryo. The rhythm in the embryotoxicity seems to be related to the rhythm in the sensitivity to the drug. Embryotoxicity and valproate concentrations were significantly higher on gestational day 13 than day 7. The timing of drug administration (i.e., gestational stage and circadian phase) appears to be essential in the study of embryotoxicity of valproate in mice.

Animals↗