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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 289 records · Page 16Linked to original sources
PubMed1996

Metabolism of barnidipine hydrochloride, a potent calcium antagonist, in rat and dog.

1. In vitro experiments in the rat indicated that barnidipine was metabolized extensively in the liver and was catalyzed by P450s. 2. After oral dosing, nine metabolites were identified in the urine and bile of rat and dog. No unchanged drug was detected in urine and bile. Ester hydrolysis and pyridine formation were the main metabolic pathways in urine in both species, whereas glucuronide conjugates of the debenzylated metabolite and the hydrolyzed pyrrolidine ester were noted in bile. 3. The metabolism of barnidipine in the rat and dog were qualitatively similar. Metabolites are generated by one or several of the following pathways: (a) N-debenzylation of the side chain, (b) hydrolysis of the pyrrolidine ester, (c) oxidation of the dihydropyridine ring to a pyridine ring, (d) hydrolysis of the methylester, (e) reduction of the nitro group to the amino group, and (f) conjugation of the generated metabolites with glucoronic acid.

Animals↗
PubMed1996

Metabolism of tamsulosin in rat and dog.

1. The metabolism of tamsulosin hydrochloride (TMS), a potent alpha 1-adrenoceptor blocking agent, was studied after a single oral administration to rat and dog. 2. Eleven metabolites (1, 2, 3, 4 and their glucuronides, sulphates of 1 and 3, and A-1) were identified from the urine and bile of rat and dog administered TMS. 3. Unchanged drug and metabolites in urine and bile were quantified in rat and dog dosed with 14C-TMS(1 mg/kg). In rat the main metabolic routes were de-ethylation of the o-ethoxyphenoxy moiety, demethylation of the methoxybenzenesulphonamide moiety, and conjugation of the resultant metabolites by glucuronic acid and sulphuric acid. In dog the main pathways were de-ethylation of the ethoxyphenoxy moiety, conjugation of the de-ethylated product by sulphuric acid, and oxidative deamination of the side chain. 4. The organ responsible for the metabolism of TMS in rat was estimated using 9000g supernatants of liver, kidney, small and large intestine homogenate and plasma. The drug was rapidly metabolized in liver but hardly metabolized in the other organs or plasma.

Adrenergic alpha-Antagonists↗
PubMed1996

Absorption, metabolism and excretion of tamsulosin hydrochloride in man.

1. The absorption, excretion and metabolism of tamsulosin hydrochloride (TMS), a potent alpha 1-adrenoceptor blocking agent, were studied in four healthy male subjects after a single oral administration of 14C-TMS at a dose of 0.2 mg. 2. Plasma and blood radioactivity concentrations attained peak levels (Cmax) within 1 h after dosing and then declined biphasically. Mean terminal elimination half-lives were 11.8 h for plasma and 9.1 h for blood. The respective mean area under the radioactivity concentration-time curves (AUC0-infinity) were 122.8 and 57.8 ng equivalents h/ml. 3. Mean plasma Cmax of unchanged TMS was 13.0 ng/ml. Plasma levels of TMS declined biphasically. Mean terminal elimination half-life and AUC0-infinity were 8.4 h and 90.3 ng h/ml. The percentage of unchanged TMS to total radioactivity was 91% for Cmax and 74% for AUC0-infinity indicating small amounts of metabolites in plasma. 4. By 1 week post-dosing, 76.4% of the administered radioactivity was recovered in urine and 21.4% in faeces. The major part of radioactivity excreted in urine was recovered within the first 24 h (62.2% of the dose). 5. Unchanged TMS and 11 metabolites in 0-24-h urine samples were quantified. TMS accounted for 8.7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15.7 and 7.5% of the dose respectively.

Absorption↗
PubMed1996

[Experimental study on directional asymmetry of vertical OKN and OKAN].

We studied the directional asymmetry of human vertical optokinetic nystagmus (OKN) and optokinetic after nystagmus (OKAN) based on two experiments conducted in 22 normal subjects. The results of the first experiment indicated that, during upward optokinetic stimulation OKN is produced by the pursuit system and the velocity storage system while during downward optokinetic stimulation the velocity storage system plays no significant role. Up-down asymmetry in vertical OKN seemed to be caused mainly by directional asymmetry of the velocity storage system. Furthermore, as the velocity storage function is very important for producing OKN at a higher stimulation velocity, domination of upward slow phase velocity becomes more apparent with a high stimulation velocity. In our second experiment the subjects were exposed to optokinetic stimulation with or without a stable fixation point. When subjects were exposed to optokinetic stimulation with fixation, they felt a rotating sensation within themselves or a moving sensation of the fixation point. When the stimulation disappeared, most experienced an illusion of small dots moving in the direction opposite the stimulation. In this condition some of the subjects showed after-nystagmus the slow phase of which was in the opposite direction. Subsequently the after-nystagmus became more distinct, with pursuit of the moving dot illusion. This result shows the existence of a mechanism which produces reverse after-nystagmus by mean of a retinal error input. We speculate that these phenomena play causative roles in reverse after-nystagmus (RAN), pursuit reverse after nystagmus (pRAN), and the RAN system.

Adult↗
PubMed1996

[Squamous cell carcinoma of the parotid gland in children].

A five-year-old boy with squamous cell carcinoma of the parotid gland is presented. The patient had a painless mass in his left parotid region with left facial palsy. Squamous cell carcinoma of the parotid gland shows high grade malignancy and is extremely rare in children, especially under five years old. After neo-adjuvant chemotherapy, he was given a total parotidectomy and radical neck dissection. The left facial nerve could not be preserved. Radiotherapy was also administered postoperatively. There was no evidence of local recurrence or distant metastasis 18 months after the surgery. Careful long-term follow-up is mandatory for this patient.

Carcinoma, Squamous Cell↗
PubMed1996

Evaluation of the therapeutic range of whole blood cyclosporin concentration in the treatment of psoriasis.

Cyclosporin (CyA) trough levels in whole blood in 17 patients receiving CyA for the treatment of severe psoriasis were measured by fluorescence polarization immunoassay (FPIA) employing a specific monoclonal antibody. Clinical success was defined as a PASI score reduction greater than or equal to 75% (group A), partial success by a PASI score reduction of 60%-74% (group B), and insufficient efficacy by a PASI score reduction of less than 60% (group C). Nine of the 17 patients given CyA (53%) exhibited an improvement rate of > or = 75% in the PASI score within 8 weeks of the initiation of treatment. At 8 weeks of treatment the values for the daily dose and whole blood trough CyA concentration were both significantly higher in group A than in group C, daily dose (3.6 +/- 1.0 vs. 2.3 +/- 0.4 mg/kg/day, respectively) and whole blood concentration (141.3 +/- 46.0 vs. 79.7 +/- 19.0 ng/ml). Throughout the study period, during an average observation period of 30 weeks, 13 of the 17 patients (76%) achieved a reduction rate of > or = 75% in the PASI score. In these 13 patients in whom psoriasis lesions cleared satisfactorily the values for the mean daily CyA dose, and whole blood trough levels were 2.4 mg/kg/day and 94.8 ng/ml, respectively. The improvement rate was significantly higher when the CyA trough level was above, rather than below, 100-140 ng/ml within the first 8 weeks, although a lower CyA dose and/or whole blood level was effective in maintaining the reduced PASI score in the subsequent phase. The most important side-effect was mild hypertension in 7 of the 17 patients (41%), however, the onset of hypertension in these patients varied from 30-100 days after the initiation of treatment. Antihypertensive drug therapy and/or dose reduction resulted in a significant decrease, from 166 +/- 17/100 +/- 7-140 +/- 6/84 +/- 10 mmHg, of the CyA-induced hypertension. The relationship between the time course of the duration of improved PASI score and the whole blood concentration of CyA was observed, which suggests that the changes in drug effects were correlated with changes in whole blood levels. During the study period we experienced recurrences in 2 patients after the tapering or withdrawal of CyA treatment. In these 2 patients the relapse may have been due, in part, to the sharp decrease in whole blood concentration secondary to partial noncompliance. Measurement of whole blood CyA trough level is the only method for assessing the patient's noncompliance. Contrary to previous reports we confirmed that the measurement of CyA concentration in whole blood was useful for monitoring the effects in patients with psoriasis.

Cyclosporine↗
PubMed1996

[An aortic valve-sparing operation (David's operation) for a patient with annulo-aortic ectasia (AAE) and aortic regurgitation (AR)--evaluation by intraoperative endoscopy].

Now, the standard operation for a case with AAE and AR is the composite graft replacement. In this case, an aortic valve sparing aortic root reconstruction, the so-called David's operation, and the intraoperative endoscopic study were performed. In the case of 68-year-old male with AAE and AR, the aortic valve was reimplanted in a tubular Dacron graft and coronary arteries were reconstructed with the Carrel patch technique. After the completion of the aortic root reconstruction, intraoperative endoscopic study revealed the disappearance of AR. Postoperative aortography revealed trivial AR and at present, seven months postoperatively, this patient have been uneventful. In this paper, we discuss the merits and demerits of the David's operation and the effectiveness of intraoperative endoscopic study for the aortic valve sparing operation.

Aged↗
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↗
PubMed1996

Effects of a new calcium antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial coronary stenosis.

Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of coronary artery stenosis, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with stenosis was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with stenosis. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with stenosis. These data show that CD-832 improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832.

Angina Pectoris↗
PubMed1996

Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese males.

Although drinking alcohol is an established esophageal cancer risk factor, the mechanisms by which alcohol induces this high-mortality rate cancer are not clear. To help elucidate this problem and develop an implementable preventive strategy, this genetic epidemiological study focused on aldehyde dehydrogenase 2 (ALDH2), the key enzyme for elimination of acetaldehyde generated by alcohol consumption. This enzyme is polymorphic; its mutant allele, ALDH2*2, which leads to the enzyme inactivity, is prevalent in Orientals. This Japanese case-control study of ALDH2-related risk for esophageal squamous cell carcinoma included alcoholics (40 cases and 55 controls) and nonalcoholic drinkers (29 cases and 28 controls). The analysis of the results of genotyping these subjects showed that the increased risk for esophageal cancer in those with one ALDH2*2 allele was substantially higher in both alcoholics (odds ratio = 7.6; 95% confidence interval = 2.8-20.7) and nonalcoholic drinkers (odds ratio = 12.1; 95% confidence interval = 3.4-42.8). The results strongly suggest that because persons who have this mutant ALDH2*2 allele have a high concentration of blood acetaldehyde after drinking alcohol, acetaldehyde (a recognized animal carcinogen) plays a pivotal role in the pathogenesis of alcohol-related esophageal cancer in humans. These results suggest that to help lower their risk for esophageal cancer, persons with the ALDH2*2 allele should be encouraged to reduce their consumption of alcoholic beverages.

Acetaldehyde↗
PubMed1996

Genotypes of alcohol-metabolizing enzymes and the risk for alcoholic chronic pancreatitis in Japanese alcoholics.

Genetic predisposition to alcoholism and alcoholic liver disease has been reported. However, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine it, we examined genotype patterns of aldehyde dehydrogenase (ALDH2), alcohol dehydrogenase (ADH2 and ADH3), and cytochrome P-4502E1 (CYP2E1) in alcoholic pancreatitis patients. In 296 alcoholic patients, 52 cases showed findings of chronic pancreatitis by ultrasonography and x-ray computed tomography and/or had a history of pancreatitis (P+). The remaining 244 patients had neither abnormal findings of the image examinations nor a history of pancreatitis (P-). As for the ADH2 genotype, distribution of 2(1)/2(1), 2(1)/2(2), and 2(2)/2(2) was 22, 37, and 42% in P+ patients, whereas 34, 35, and 30% in P- patients, respectively. The frequency of ADH2(2)/2(2) genotype was significantly higher in P+ patients, compared with that in P- patients. There were no significant differences in the distribution of ADH3, ALDH2, and CYP2E1 genotypes between P+ and P- patients. In 14 alcoholic patients who showed low contents of fecal chymotrypsin, which suggests dysfunction of pancreatic exocrine, the rate of ADH2(2)/2(2) genotype also tended to be higher (50%) than in 74 controls who showed normal contents of the fecal chymotrypsin (28%). No differences were observed in genotypes of ADH3, ALDH2, and CYP2E1. Moreover, the frequency of ADH2(2)/2(2) genotype was significantly higher in autopsy cases with interlobular fibrosis in the pancreas, which suggests alcoholic pancreatic damage, than in cases with only intralobular pancreatic fibrosis. These data suggest that the risk of alcoholic pancreatitis seems to be associated with the presence of ADH2(2)/2(2) genotype.

Adult↗
PubMed1995

The relation of emotional behavior to plasma catecholamines, cortisol and ventricular arrhythmia.

Hypothalamic stimulation applied through chronically implanted electrodes elicits several kinds of emotional behavior in conscious cats. We chose 3 kinds of emotional behavior, i.e., restlessness, threat and searching-biting. Under lightly anesthetized condition, we examined the changes of E, NE, DA and cortisol levels in arterial plasma and the cardiovascular responses (changes of systolic and diastolic blood pressure, heart rate and the occurrence of poststimulus ventricular arrhythmia) associated with electrical stimulation of specific sites within the hypothalamus. Both in restlessness and threat groups, elevation in systolic blood pressure was significantly greater and also the occurrence of ventricular arrhythmia and elevation in diastolic blood pressure tended to be greater than in the searching-biting group. Plasma E, NE, DA and cortisol increased significantly in restlessness and threat groups but remained unchanged in searching-biting and control groups. The ratios of changed values in catecholamines: delta E/delta NE, delta E/delta DA or delta NE/delta DA were not significantly different between any groups of emotional behavior. Furthermore, in the restlessness group, delta E, delta NE and delta DA all showed significant correlation with both the number of ventricular arrhythmia and changes of diastolic blood pressure; and the number of ventricular arrhythmia showed significant correlation with both the changes of diastolic blood pressure and heart rate. None of these correlations was observed in the threat or searching-biting group. These results suggested that restlessness and threat behaviors were more closely related to stress response than searching-biting behavior in cats. The differences in the endocrine and cardiovascular responses between restlessness and threat behavior were also discussed in the paper.

Animals↗
PubMed1995

The anti-emetic activity of GK-128 in Suncus murinus.

In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.

Animals↗
PubMed1995

Dopamine transporter gene polymorphism and alcoholism.

In this search for a possible association between the dopamine transporter gene (DAT1) polymorphism and alcoholism, 655 Japanese alcoholics were grouped according to their aldehyde dehydrogenase-2 (ALDH2) genotypes. Because inactive ALDH2 is an established negative risk factor for alcoholism, alcoholics with the mutant allele, ALDH2*2, were considered a relatively homogeneous group. The frequency of the 7-repeat allele of the DAT1 variable number of tandem repeat was significantly higher in alcoholics with ALDH2*2 than in control subjects. These results are consistent with the hypothesis that alteration in the dopaminergic system plays some role in the development of alcoholism.

Alcoholism↗
PubMed1995

Establishment of a T cell-dependent nude mouse liver injury model induced by Propionibacterium acnes and LPS.

Normal ICR mice developed severe liver injury when they were given intravenous injections of Propionibacterium acnes and lipopolysaccharide (LPS) with a 7 day interval. In contrast, T cell-deficient ICR nude mice were resistant to P. acnes and LPS-induced liver injury. However, athymic ICR nude mice, which were treated with cell transfer of normal ICR mouse spleen cells (10(8) cells) or ICR mouse nylon-wool passed splenic T-enriched cells (over 10(7) cells), showed severe liver injury as assessed by elevation of serum transaminase activities. Histological analyses also demonstrated that the transferred cells migrated into the liver of nude mice to induce liver injury. However, depletion of both CD4+ T cells and CD8+ T cells from transferred cell populations caused a marked decrease in the elevation of serum transaminase, indicating the actual involvement of T cells in liver injury. Moreover, in vivo administration of anti-LFA-1 mAb blocked P. acnes and LPS-induced liver injury in nude mice following T cell transfer. Thus, this model will provide a new strategy to investigate T cell-dependent cell-cell interaction during the induction of liver damage.

Animals↗
PubMed1995

Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's disease.

Cerebrospinal fluid from 70 patients with Alzheimer's disease (AD) and 96 patients with non-AD neurological diseases as well as 19 normal control subjects was surveyed by sandwich enzyme-linked immunosorbent assay to quantitate levels of the microtubule-associated protein tau in cerebrospinal fluid. The tau level was significantly increased in AD patients as compared with that in patients with non-AD neurological diseases and control subjects. Increased tau levels were found irrespective of age at onset, apolipoprotein E genotype, and clinical stage. Western blots of AD cerebrospinal fluid proteins revealed two to three tau-immunoreactive bands with an apparent molecular mass between 50 and 65 kd consistent with phosphorylated cerebrospinal fluid tau. Taken together, our results suggest that cerebrospinal fluid tau might reflect the progressive accumulation of altered tau due to the progressive death of neurons in the AD brain, and that the enzyme-linked immunosorbent assay of cerebrospinal fluid tau may prove to be a reliable and early diagnostic test for AD.

Adult↗
PubMed1995

Prolonged inhibition of an antigen-specific IgE response in vivo by monoclonal antibody against lymphocyte function-associated antigen-1.

Intraperitoneal injection of ovalbumin (OVA) into BALB/c mice caused the induction of OVA-specific IgE production in vivo. However, administration of monoclonal antibody against lymphocyte function-associated antigen-1 (anti-LFA-1 mAb) at days 0 and 1 after OVA immunization resulted in an inhibition of OVA-specific primary and secondary IgE production in a dose-dependent manner. The inhibition of the antigen-specific IgE response due to anti-LFA-1 mAb was seen up to 8 weeks after anti-LFA-1 mAb administration. The OVA-specific IgG1 response was also blocked by anti-LFA-1 mAb. The spleen cells obtained from OVA-immunized mice showed enhanced proliferation against secondary stimulation with OVA in vitro. However, the spleen cells obtained from the mice treated with both OVA and anti-LFA-1 mAb revealed a markedly decreased proliferative responses to OVA, while they showed no reduced responses against keyhole limpet hemocyanin stimulation, indicating that anti-LFA-1 mAb might induce antigen-specific anergy in vivo. It was also demonstrated that treatment of the mice with anti-LFA-1 mAb significantly inhibited the interleukin-4-producing ability of OVA-immunized mouse spleen cells. These results demonstrated that LFA-1-dependent cell-cell interaction is essential for the production of IgE in vivo and may be important in IgE-dependent allergic disease.

Animals↗