Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 163 records · Page 9Linked to original sources

PubMed1998

Mutation in the alpha-synuclein gene and sporadic Parkinson's disease, Alzheimer's disease, and dementia with lewy bodies.

Recently, alpha-synuclein attracted attention when Polymeropoulos and colleagues identified a missense mutation of this gene (Science 276:2045-2047, 1997), which is responsible for a form of early-onset familial Parkinson's disease (PD). Immunohistochemically, alpha-synuclein is localized in Lewy bodies, characteristic brain pathology of PD, dementia with Lewy bodies (DLB), and Alzheimer's disease (AD), suggesting that this protein may link these common neurological diseases. Exploration of the possibility that the same mutation of the alpha-synuclein gene as that in familial PD (Ala53Thr) may also confer susceptibility to sporadic PD, DLB, and AD revealed the mutation in none of the samples of 329 cases and 230 controls examined, suggesting that this mutation is not involved in these neurological diseases.

Aged↗

PubMed1998

[Initial clinical experiences of the ABIOMED BVS SYSTEM 5000 in Japan].

The initial clinical experience of the ABIOMED BVS SYSTEM 5000 in Japan is reported. The system is a paracorporeal pulsatile assist device intended for temporary ventricular support. It consists of a pneumatic drive console, a blood pump, and the atrial and arterial cannulas. The pump is of a dual chamber design, with the upper chamber as a passive, gravity filled resevoir and the lower chamber as a pumping chamber. Since the system is designed to be simple, safe and automatically controlled, no additional personnel is required to control perfusion. This report describes our initial clinical experiences with the ABIOMED BVS SYSTEM 5000 in Japan. This device was used in three patients with post cardiotomy cardiogenic shock and fulminant myocarditis. The first patient developed acute occlusion of left main coronary artery who required emergent surgical revascularization following PTCA and stent implantation. He couldn't wean from CPB and required the insertion of an LVAD. The second case suffered from a cardiac arrest after CABG and could not be resuscitated. The ABIOMED BVS 5000 was inserted and the patient successfully weaned from support. The third patient developed fulminant myocarditis and was supported with the system for 269 hours and was successfully weaned after near complete myocardial recovery. Our initial experience with the ABIOMED BVS SYSTEM 5000 indicates that the system can provide complete cardiac support allowing full recovery from a cardiac variety of causes of dysfunction. The device has the potential to improve the survival rate of patients with severe acute recoverable myocardial damage. It is expected that this device can be a viable tool for treatment of intractable heart diseases.

Adult↗

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

The ratio of neutrophils to lymphocytes and the phenotypes of neutrophils in patients with early gastric cancer.

We examined 55 patients (40 male, 15 female) who were diagnosed from 1987 to 1991 as having early gastric cancer (EGC) stage I according to the general rules of classification of the Japanese Research Society for Gastric Cancer. Of the 55 patients, 42 (30 male, 12 female) were alive in April 1992. The prognosis correlated well with the ratio of neutrophils to lymphocytes (N/L ratio) but not with the total number of white blood cells in the peripheral blood. The patients were divided into two groups according to their N/L ratio. Of the 29 patients with an N/L ratio less than 2, 27 were alive in 1992, whereas only 15 of the 26 patients with an N/L ratio of 2 or more were alive (chi2 analysis, P=0.0022). We further examined the phenotypes of neutrophils from 29 other patients with EGC at the time of diagnosis before surgical operation. These patients were divided into two groups: 17 patients with a low N/L ratio (less than 2) and 12 patients with a high N/L ratio (2 or more). CD10 and CD35 expressions on neutrophils from the patients with a low N/L ratio were lower than those from the patients with a high N/L ratio. The N/L ratio correlated well with both CD10 and CD35 expression, whereas no correlation was observed between the numbers of neutrophils and the expression of these phenotypes. The respiratory burst of neutrophils from the patients with a high N/L ratio was higher than that of neutrophils from the patients with a low N/L ratio, though there was no correlation in the phagocytic activity between both groups. It was thus suggested that the heterogeneity of neutrophils is, at least partly, related to the prognosis of patients with EGC.

Adult↗

PubMed1998

Body support effect on standing balance in the visually impaired elderly.

OBJECTIVE: To evaluate the effectiveness of body support in compensating for decreased standing balance stability in elderly persons with visual impairment. DESIGN: Standing balance was measured in a cross-section of elderly persons from two nursing homes--one for aged individuals with visual impairment, the other for aged individuals without visual impairment. PARTICIPANTS: The subjects were 44 visually impaired persons with a mean age of 79.0 yrs and 39 people without visual impairment, mean age 76.3 yrs. OUTCOME MEASURES: The area of gravity-center sway was measured with subjects standing on a gravicorder for 30sec in three positions: (1) without support, (2) with cane, (3) with light support by touching a wall. RESULTS: Both men and women in the visually impaired group swayed more than their sighted counterparts when standing without support, the only statistically significant difference between the two groups. For all subjects, the greatest degree of sway occurred when subjects stood unsupported, and the least sway occurred when subjects touched a wall for support. CONCLUSION: In visually impaired elderly persons, touching a wall for body support while standing is more effective than using a cane.

Aged↗

PubMed1998

Relationship between bioavailability and hypocholesterolemic activity of YM17E, an inhibitor of ACAT, in cholesterol-fed rats.

The relationship between bioavailability and the serum cholesterol-lowering effect of YM17E, an ACAT inhibitor was investigated. Serum cholesterol levels in cholesterol-fed rats decreased after both oral and intravenous administration of YM17E. Marked inhibition of cholesterol absorption was observed after oral administration, but not after intravenous administration. YM17E and its five active metabolites were primarily distributed in the liver after intravenous administration, but in small intestine and liver after oral administration. Hepatic ACAT activity in cholesterol-fed rats was inhibited by intravenous administration. Cholesteryl ester input into plasma by Triton WR-1339 treatment to the rats was inhibited by intravenous administration of YM17E. Plasma clearance of 125I-LDL in cholesterol-fed rats increased after YM17E treatment suggesting a decrease in LDL production. These results indicate that the hypocholesterolemic effect of intravenous YM17E was due to hepatic ACAT inhibition, not an inhibition of intestinal cholesterol absorption. The contribution of ACAT inhibition in small intestine and liver on the pharmacological effect could be explained by plasma inhibitor concentration after oral or intravenous administration of YM17E. From these results, it is concluded that the change in bioavailability of ACAT inhibitors change the mechanism of hypocholesterolemic effects, shifting the relative contributions of small intestinal and hepatic ACAT inhibition.

Animals↗

PubMed1998

Possible involvement of nitric oxide-cGMP pathway in the negative chronotropic effect of CD-832, a novel dihydropyridine derivative.

Effects of zaprinast, an inhibitor of guanosine 3', 5'-cyclic monophosphate (cGMP)-specific phosphodiesterase, and methylene blue, an inhibitor of soluble guanylate cyclase, on the negative chronotropic response to CD-832, a novel dihydropyridine derivative with a nitrate moiety, and nifedipine were examined with isolated guinea-pig right atria in the presence and absence of isoproterenol. CD-832 and nifedipine produced concentration-dependent negative chronotropic effects both in the absence and presence of isoproterenol. In the absence of isoproterenol, the concentration-response curves for CD-832 and nifedipine were neither potentiated by zaprinast nor inhibited by methylene blue. In the presence of isoproterenol (10[-8] M), zaprinast produced a three-fold leftward shift of the concentration-response curve for CD-832, while methylene blue produced a three-fold rightward shift. The concentration-response curve for nifedipine was not affected by these agents. SIN-1, a nitric oxide (NO) donor, had no chronotropic effect in the absence of isoproterenol, but had a concentration-dependent negative chronotropic effect in the presence of isoproterenol: the beating rate decreased to values close to that in the absence of isoproterenol. These findings suggest that NO-cGMP mediated pathway is involved in the negative chronotropic actions of CD-832 under beta-adrenergic stimulation.

Animals↗

PubMed1998

HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits.

HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine.

Acetanilides↗

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

Chronopharmacological study of KE-SI-TO components in mice.

Influence of dosing time on pharmacological effects and toxicity of KE-SI-TO (KST) components, as well as the role of each component in the circadian rhythms of KST, was investigated in ICR male mice under an LD (12:12) cycle. The mice given Cinnamomi Cortex (258 mg/kg, i.p.) or Paeoniae Radix (258 mg/kg, i.p.) showed a significant circadian rhythm in the time spent on the hot plate with the shortest latency at 0900 and the longest one at 0100 (p<0.01, respectively). The mice given Cinnamomi Cortex or Glycyrrhizae Radix (129 mg/kg, i.p.) showed a significant circadian rhythm with the lowest rectal temperature (RT) at 1700 and the highest one at 0500 (p<0.01, respectively). Cinnamomi Cortex (850 mg/kg, i.p.)- or Glycyrrhizae Radix (2500 mg/kg, i.p.)-induced toxicity showed a significant circadian rhythm with the highest mortality at 1700 and the lowest one at 0500 (p<0.05, respectively). The rhythmic patterns of the drug-induced analgesia, hypothermia and toxicity resembled the overall rhythms occurring after KST (1000 or 6000 mg/kg, i.p.) injection. These results suggest that the circadian rhythms in actions of Cinnamomi Cortex, Paeoniae Radix and Glycyrrhizae Radix are mainly responsible for the rhythm in the effects and toxicity of KST.

Analgesics↗

PubMed1998

Ex vivo occupancy by tamsulosin of alpha1-adrenoceptors in rat tissues in relation to the plasma concentration.

At 0.5-12 h after oral administration of tamsulosin (2.3 micromol/kg) in rats, there was a significant decrease in specific [3H]prazosin binding in the prostate as compared to the control value. The greater decrease occurred in the submaxillary gland. The effect of tamsulosin was mainly due to a marked reduction of [3H]prazosin binding sites (Bmax) rather than to an increase in the dissociation constant (Kd). In contrast, there was only a slight decrease or no change in the [3H]prazosin binding in the spleen, heart, and cerebral cortex of tamsulosin-administered rats at 0.5-12 h. Oral administration of terazosin (21.7 micromol/kg) significantly increased Kd values for [3H]prazosin binding with little effect on Bmax values in the rat prostate at 3 and 6 h. The greater increases in Kd values were observed in the submaxillary gland, spleen and heart at 0.5-12 h. Terazosin had a slight effect on Kd values for the cerebral cortical [3H]prazosin binding. Tamsulosin was absorbed rapidly after oral administration at a dose of 2.3 micromol/kg in rats, and at 6 h, plasma concentration decreased markedly to approximately one-twentieth of the 0.5 h peak level. alpha1-Adrenoceptor occupancy was estimated as a percentage of decrease in Bmax values for [3H]prazosin binding in tissues of tamsulosin-treated rats compared with control rats. The alpha1-adrenoceptor occupancy by tamsulosin in the prostate and submaxillary gland occurred rapidly in parallel with the rise in plasma concentration of tamsulosin, and lasted for over 12 h despite the marked decrease in plasma concentration. Consequently, it is suggested that tamsulosin produces more selective and sustained occupancy in vivo of alpha1-adrenoceptors in the submaxillary gland and prostate of rats than in other tissues.

Administration, Oral↗

PubMed1998

Role of nitric oxide and prostaglandin in the protective effect of pibutidine hydrochloride, a novel histamine H2-receptor antagonist, on the gastric mucosal lesions in rats.

1. The role of endogenous nitric oxide (NO) and prostaglandins (PGs) in the gastric mucosal protective action of pibutidine hydrochloride (IT-066), a novel histamine H2-receptor antagonist, was investigated in a 0.15 N hydrochloride (HCl) + 60% ethanol (EtOH)-induced gastric lesion model. 2. The 0.15 N HCl + 60% EtOH-induced lesion formation was reduced significantly by IT-066 (3 mg/kg, PO), NOR3 (spontaneous NO releaser; 0.03-0.1 mg/kg, SC) or PGE2 (0.01 mg/kg, PO) but was not reduced by famotidine (1-10 mg/kg, PO). 3. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) (3 mg/kg, IV), an inhibitor of NO synthase, inhibited the protective action of IT-066 (3 mg/kg, PO), and the inhibitory effect of L-NAME was reversed by L-arginine (300 mg/kg, IV). The protective effect of PGE2 (0.01 mg/kg, PO) was not affected by the pretreatment with L-NAME (3 mg/kg, IV). 4. Infusion of carboxy-PTIO (1 mg/kg/min), a direct NO scavenger, inhibited the protective effect of IT-066 (3 mg/kg, SC) or NOR3 (0.1 mg/kg, SC). Pretreatment with indomethacin (5 mg/kg, SC) markedly reduced the protective effect of IT-066 (3 mg/kg, PO) or NOR3 (0.1 mg/kg, SC). 5. These results suggest that endogenous NO and PGs may be implicated in the gastric mucosal protection induced by IT-066 and that the endogenous PGs may contribute to the protective effect of NO.

Animals↗

PubMed1998

The ACAT inhibitor HL-004 inhibits cholesterol absorption and lowers serum cholesterol in rats.

1. HL-004 decreased absorption of cholesteryl ester from the intestine into the lymph in a rat lymph-fistula model. 2. HL-004 reduced serum cholesterol level in acute cholesterol-fed rats. 3. HL-004 simultaneously decreased hepatic cholesteryl ester content and increased free cholesterol in cholesterol-fed rats. 4. These findings suggest that: (1) the hypocholesterolemic effect of HL-004 is principally due to inhibition of cholesterol absorption via inhibition of ACAT in the intestine; and (2) changes in hepatic cholesterol metabolism due to direct inhibition by HL-004 of hepatic ACAT may account in part for reduction of serum cholesterol level by HL-004.

Absorption↗

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

Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes.

1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1998

Cloning and expression analysis of a cDNA coding for a dexamethasone-inducible cytochrome P450 in Xenopus laevis liver.

We previously purified a cytochrome P450 (P450) from liver microsomes of adult female Xenopus laevis. In this study, we screened a cDNA library of Xenopus liver to isolate the cDNA clone coding for this P450. The 5'-end of the resultant cDNA was truncated at the N-terminal region and extended by method of rapid amplification of cDNA end to give the complete coding sequence. Amino acid sequence showed this clone to be 36% to 55% identical to members of the CYP2 family and less than 31% identical to members of other gene families, and to belong to the CYP2Q subfamily. This gene is expressed constitutively in the livers of adult male and female frogs, and is significantly induced by dexamethasone administration.

Amino Acid Sequence↗

PubMed1998

Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics.

Aldehyde dehydrogenase-2 (ALDH2) eliminates most of the acetaldehyde produced during alcohol metabolism. In some drinkers, a mutant ALDH2 allele contributes to diminished activity of the enzyme, dramatically increasing the risk for esophageal cancer. This study was designed to evaluate the ALDH2 gene polymorphism as a predictor of the development of cancers prevalent in Japanese alcoholics. We performed ALDH2 genotyping on lymphocyte DNA samples from Japanese alcoholic men (487 cancer-free; 237 with cancer, including 34 oropharyngolaryngeal, 87 esophageal, 58 stomach, 46 colon, 18 liver, 7 lung, 9 other sites, and 19 multiple primary cancers in two or three organs). The frequencies of the mutant ALDH2*2 allele were significantly higher in alcoholics with oropharyngolaryngeal (52.9%), esophageal (52.9%), stomach (22.4%), colon (21.7%) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (78.6%), than in cancer-free alcoholics (9.0%). After adjustment for age, daily alcohol consumption and amount of cigarette smoking, significantly increased risks (odds ratios) in the presence of the ALDH2 *2 allele were found for oropharyngolaryngeal (11.14), esophageal (12.50), stomach (3.49), colon (3.35), lung (8.20) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (54.20) but not for liver or other cancers. These results suggest a general role of acetaldehyde, a recognized animal carcinogen, in the development of human cancers.

Adult↗

PubMed1998

Alteration of circadian time structure of blood pressure caused by night shift schedule.

The effects of night shift schedules on circadian time structure of blood pressure were studied in seven healthy young subjects by continuous monitoring of blood pressure every 30 min for 72 h. In the control experiment, subjects were instructed to sleep at regular times with the light off at 00.00 h and the light on at 07.00 h. In the shift experiment, they were instructed to go to bed at 06.00 h and wake up at 11.00 h. The circadian rhythm of blood pressure rapidly phase delayed by 3.5 h in the second night shift day as a group phenomenon. Individual differences in changes in power spectral patterns of blood pressure were found in the night shift schedule. Ultradian rhythmicity of blood pressure was more pronounced in three subjects, whereas the circadian rhythmicity was maintained in four subjects. These findings held when the adaptation to shift work was taken into account.

Adult↗