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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 235 records · Page 13Linked to original sources
PubMed1997

Pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male subjects.

AIMS: To study the pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male volunteers following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODS: RhIL-11 was infused intravenously at 10-50 micrograms kg-1 for 1 or 3 h, or administered subcutaneously at 3-50 micrograms kg-1 to volunteers. RhIL-11 was also administered at 3 micrograms kg-1 s.c. once daily for 7 days. Plasma and urinary concentrations were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: RhIL-11 showed linear pharmacokinetics after both intravenous infusion and s.c. administration. Comparison of t1/2 and MRT values after i.v. administration with those after s.c. administration indicated that rhIL-11 pharmacokinetics after s.c. administration were absorption rate-limited. Bioavailability after s.c. administration was about 65%. Since RhIL-11 was not detected in urine after a single 50 micrograms kg-1 s.c. dose, rhIL-11 was considered to be eliminated by metabolism. There was no significant change in the pharmacokinetic profile of rhIL-11 following repeated s.c. administration. CONCLUSIONS: RhIL-11 demonstrated linear pharmacokinetics at these dose ranges after single and repeated s.c. administration or constant-rate i.v. infusion in healthy volunteers.

Adolescent↗
PubMed1997

An updated report of a case of lung cancer resected using cardiopulmonary bypass.

Although surgical intervention for advanced lung cancer invading the aortic wall is challenging, we successfully carried out such radical surgery under cardiopulmonary bypass as previously reported in this journal. One patient has now been followed for more than 5 years after the operation, so that we conclude if there is no evidence of metastatic cancer in selected patients then complete resection should be attempted using circulatory support, with the hope of an occasional cure.

Aorta, Thoracic↗
PubMed1997

Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker.

1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N-debenzylated product (M-1), a hydrolyzed product of the benzyl-pyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. Involvement of CYP3A in the three primary metabolic pathways was revealed by the following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies. The secondary metabolites, M-2 and M-4 (pyridine forms of M-1 and M-3), were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 microM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC50 for the latter drugs was estimated to be > 200, 200 and 20 microM respectively, which was roughly > 200, 6000 and 50 times higher than their respective therapeutic plasma levels, suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance.

Calcium Channel Blockers↗
PubMed1997

Drug disposition of incadronate, a new bisphosphonate, in rats with bone metastases.

1. Drug disposition of incadronate in the nude rat with bone metastases induced by A375 human melanoma cells was studied after intravenous administration. 2. The pharmacokinetics of incadronate (plasma concentration, urinary excretion and bone uptake) in rat with bone metastases was not markedly different from that in the control rat. This compound, however, was selectively taken up in the bone region around metastatic tumour nests. 3. Drug concentrations in the bone region around tumour nests were 3-10 micrograms/g, these levels being higher than the IC50 (0.35 microgram/ml) for the inhibitory effect of this drug on osteoclasts in vitro. 4. In contrast, concentrations in the tumour nest itself was < 0.7 microgram/g, being markedly lower than the IC50 (35 micrograms/ml) for the inhibitory effect on the proliferation of tumour cells in vitro. 5. These results strongly suggest that pharmacological action of incadronate in mouse with bone metastases (inhibitory effect on the growth of metastatic tumour in bone) is caused not by the direct action on the tumour cells but by the distribution of the drug in the perifocal bone region followed by inhibition of the activity of osteoclasts, resulting in inhibition of the osteolytic process, which is necessary for the progress of metastatic tumour.

Animals↗
PubMed1997

Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation.

1. The metabolism and pharmacokinetics of barnidipine hydrochloride, a 1, 4-dihydropyridine calcium antagonist were evaluated following single oral administration of a sustained release formulation (SR) capsule comprising of quick and slow release pellets to healthy male volunteers. 2. Various metabolites were identified and quantitated by newly established GC-MS analytical methods. Major metabolites were the hydrolyzed product of the benzyl-pyrrolidinyl ester (M-3) in plasma and its oxidized pyridine product (M-4) in plasma and urine. The pyridine form of unchanged barnidipine and the N-debenzylated product were observed as minor metabolites. Therefore, the primary metabolic pathways in man are (a) hydrolysis of the benzylpyrrolidine ester, (b) N-debenzylation, and (c) oxidation of the dihydropyridine ring. 3. When the SR and normal capsules were administered at a dose of 10 mg to six subjects in a crossover design, AUC 0-infinity of unchanged drug, M-3 and 4 in each subject receiving the SR were 97 +/- 15, 85 +/- 31 and 76 +/- 21% respectively of those subjects receiving the normal formulation. The sum of the excretion of urinary metabolites for the SR formulation was 65 +/- 6% of that for the normal formulation. These data suggest that the absorption of the SR formulation is slightly reduced but that its bioavailability is comparable to that of the normal formulation.

Administration, Oral↗
PubMed1997

Effect of genetic risk factors and disease progression on the cerebrospinal fluid tau levels in Alzheimer's disease.

OBJECTIVE: This study was undertaken to gain insights into the clinical utility of measuring cerebrospinal fluid tau protein (CSF-tau) to aid in the diagnosis of Alzheimer's disease (AD). SETTING: AD patients from Tohoku University Hospital, Sendai Japan were sampled. SUBJECTS AND METHODS: CSF-tau levels were examined by sandwich enzyme-linked immunosorbent assay in a total of 62 patients carrying different alpha 1-antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphic alleles. Further, the CSF-tau levels were followed up on two occasions during the progression of the disease in 17 AD patients. RESULTS: There was no evident gradient for tau protein in CSF. Neither the ACT/A allele nor the PS-1/1 allele affected the CSF-tau levels. Although CSF-tau levels changed to a variable extent over time, the CSF-tau levels were significantly increased (P < .01) during the follow-up period. Three of the AD patients demonstrated decreasing values, whereas 14 patients showed increasing values. Finally, these temporal changes in CSF-tau levels were not influenced by the apolipoprotein E epsilon 4, ACT/A or PS-1/1 alleles during the progression of AD. CONCLUSION: Regardless of the mechanisms leading to the degeneration of neurons in AD, our findings provide further evidences that monitoring CSF-tau levels may provide useful information about AD irrespective of the background of genetic risks and disease progression.

Age of Onset↗
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

Apolipoprotein E genotyping and cerebrospinal fluid tau protein: implications for the clinical diagnosis of Alzheimer's disease.

Apolipoprotein E (ApoE) genotyping was conducted in sporadic Alzheimer's disease (AD, n = 91) as well as in other dementing disorders including Parkinson's disease (PD, n = 73), autopsy-confirmed diffuse Lewy body disease (DLBD, n = 16), progressive supranuclear palsy (n = 13), vascular dementia (n = 55), alcoholic dementia (n =25) and normal control subjects (n = 77). ApoE epsilon 4 allele frequency was significantly higher in AD (33.5%, p < 0.001), DLBD (40.6%, p < 0.001) and demented PD (29.4%, p < 0.05) compared to that in normal controls (11.7%). The association of the ApoE epsilon 4 allele with AD was more pronounced in early-onset AD (46.4%) than in late-onset AD (27.8%). 46% of the AD individuals developed AD without association to ApoE epsilon 4, and epsilon 4 homozygotes were found not only in AD, but also in many of other dementing disorders. These results suggest that ApoE genotyping cannot provide certainty about the presence of absence of AD, and that it should be used as an adjunct to other diagnostic tests for AD. On the other hand, cerebrospinal fluid (CSF) tau levels were significantly elevated (p < 0.0001) in AD (78.0 +/- 44.2 pg/ml) compared to those in normal controls (10.6 +/- 8.6 pg/ml). The specificity and the sensitivity of distinguishing AD from normal controls was 95.0 and 91.2%, respectively. Elevated CSF-tau levels were also detected in some patients with acute neurological diseases including meningoencephalitis, Creutzfeld-Jacob disease, normal pressure hydrocephalus and vitamin B12 deficiency encephalopathy. Increased CSF-tau levels in AD were found regardless of the age at onset, clinical stage, ApoE genotype, alpha 1-antichymotrypsin genotype, and presenilin-1 genotype. The CSF-tau levels continued to be abnormal during the progression of AD. These results suggest that CSF-tau serves as an unequivocal and reliable biological marker to aid in the clinical diagnosis of AD.

Aged↗
PubMed1997

Apolipoprotein E epsilon 4 allele and pupillary response to tropicamide.

OBJECTIVE: This study was designed to investigate in cognitively normal subjects the possible association between hypersensitive pupil dilation response to the cholinergic antagonist tropicamide and the presence of the apolipoprotein E epsilon 4 (APOE4) allele, a well-defined genetic risk factor for Alzheimer's disease. METHOD: The authors measured tropicamide-induced changes in pupil area in 44 cognitively normal Japanese subjects with and without the APOE4 allele. RESULTS: The subjects with the APOE4 allele had significantly greater increases in pupil area than the others. The significant correlation of changes in pupil area with age for the subjects with the APOE4 allele was lacking for those without this allele. CONCLUSIONS: The results suggest that a hypersensitive pupil dilation response to tropicamide is already present in cognitively normal individuals with the APOE4 allele. This association also suggests the potential involvement of APOE4 in the mechanism of pupil dilation.

Aging↗
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

Effects of reduction in arousal level caused by long-lasting task on CNV.

The present study aimed at investigating an inverted-U relationship between contingent negative variation (CNV) and arousal level by examining the effects on CNV of gradually reduced arousal level by long-lasting task. The subjects conducted a simple reaction time task consisting of warning stimuli (S1) and imperative stimuli (S2). This task consisted of 200 trials and lasted about 40 minutes. During this task, spontaneous EEG before S1 and SPL (skin potential level) were measured as indicators for arousal level. The 200 CNV, EEG and SPL data were classified into 5 blocks each of which included 40 trials of data. Analysis was made in seven subjects in whom reduction in the arousal level in long-lasting task was shown by increase in the relative power values of alpha waves before S1 and decrease in the SPL. As a result, the amplitude of early CNV at Fz was observed to increase from the earlier half phase (block 1) to the middle phase (block 3) and to decrease from the middle phase (block 3) to the latter half (block 5). In the middle phase, the amplitude was the greatest. The low amplitude of early CNV in the early half of the task (block 1) was inferred to have been induced by excessive arousal state because of the low relative power values of alpha waves and the high SPL at this time. On the other hand, the low amplitude in the later phase (block 5) was inferred to have been induced by reduction in arousal level because of the high relative power values of alpha waves and the low SPL. These results suggested that CNV amplitude and arousal level was in an inverted-U relationship.

Adult↗
PubMed1997

Effects of changes in arousal level by continuous light stimulus on contingent negative variation (CNV).

The purpose of the present study was to investigate an inverted-U relationship between contingent negative variation (CNV) and arousal level which was influenced by extraneous environment. As an extraneous stimulant, stimulation by light was adopted, and five levels of luminance conditions, 10 cd/m2, 100 cd/m2, 320 cd/ m2, 1,000 cd/m2, and 1,800 cd/m2 were provided randomly. Under five luminance conditions, seven subjects who had been accustomed a measurement of CNV executed simple reaction time tasks to evoke CNV. Outside CNV, spontaneous EEG prior to S1 was measured as an indicator for arousal level. As a result, a negative correlation existed between the logarithm of luminance and the relative power value of alpha waves at Fz. Otherwise, an increase in luminance caused an increase in CNV amplitude until the luminance level reached 320 cd/m2, beyond which however CNV amplitude was found to decrease. These tendencies were most remarkable in the phase of early CNV at Fz. The low amplitude of early CNV seen in the high luminance conditions was inferred to have been induced by excessive arousal state because of the low relative power value of alpha waves, while the low amplitude in the low luminance conditions was inferred to have been induced by low arousal state because of the high relative power value of alpha waves. However, changes in arousal level by light stimulus caused no effect on reaction time. From these findings, it was suggested that a definite "inverted-U" relationship existed between the change in arousal level by light stimulation and resultant CNV, and that it could be discriminated as to whether reduction in CNV is caused by excessive arousal effect of environment by analyzing spontaneous EEG preceding S1.

Adult↗
PubMed1997

Effect of GK-128 [2-[(2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one monohydrochloride hemihydrate], a selective 5-hydroxytryptamine3 receptor antagonist, on colonic function in rats.

We investigated the effects of various selective 5-hydroxytryptamine (5-HT)3 receptor antagonists, including GK-128 [2-[(2-methylimidazol-1-yl)methyl]benzo[f]thiochromen-1-one monohydrochloride hemihydrate], on colonic function. In conscious rats, 5-HT and a 5-HT3 receptor agonist, 2-methyl-5-HT, dose-dependently increased fecal pellet output, but another 5-HT3 receptor agonist, m-chlorophenylbiguanide, did not affect output. The selective 5-HT3 receptor antagonists GK-128, granisetron, ramosetron, azasetron and ondansetron depressed the increase in fecal pellet output caused by 2-methyl-5-HT and by wrap-restraint stress. However, the rank order of potency of antagonists in the two defecation models was not consistent with that for the von Bezold-Jarisch reflex. Although granisetron and ramosetron dose-dependently reduced the spontaneous excretion of fecal pellets, GK-128 did not affect it. These results suggest that GK-128 may be used for the treatment of stress-induced gastrointestinal dysfunction. Furthermore, the present results suggest that the 5-HT3 receptor involved in colonic motility may be different from the classically defined 5-HT3 receptor and/or that the regulation of colonic motility mediated by 5-HT3 receptors during stress may be different from normal physiological conditions.

Animals↗