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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 253 records · Page 14Linked to original sources
PubMed1997

[An approach to lobectomy under a thoracoscopic surgery].

Lobectomy under a thoracoscope is a minimally invasive surgery and full consideration must also be given to the length of access thoracotomy and the number of access ports inserted. On the other hand, securing a full visual field within a limited access and treating the pulmonary artery/vein and bronchus safely and for sure are needed. However, it would not be too much to say that the easiness of lobectomy under a thoracoscope depends on the length of access thoracotomy and the number of access ports inserted. In the experiment this time we discussed an approach to the access area in lobectomy under a thoracoscope in our cases.

Aged↗
PubMed1997

Pharmacokinetics of incadronate, a new bisphosphonate, in healthy volunteers and patients with malignancy-associated hypercalcemia.

We investigated the pharmacokinetics of incadronate, a new bisphosphonate, after a 2-hour intravenous infusion to healthy volunteers and patients with malignancy-associated hypercalcemia. Following administration at 0.025-1.6 mg to healthy volunteers, peak plasma concentration of incadronate increased in a dose-proportional manner. Plasma concentration thereafter declined biexponentially with a half-life of 0.26-0.40 h (t1/2 alpha) and 1.58-1.98 h (t1/2 beta). AUC increased dose-proportionally, whereas distribution volume (Vdss), total body clearance (CLt), renal clearance (CLr) and nonrenal clearance (CLnr), corresponding to bone uptake clearance, changed little among doses, indicating the linear pharmacokinetics of the drug after intravenous administration. Within 24 h, 55.1-69.5% of the dose was excreted into urine as the unchanged drug, most in the first 6 h. CLr and CLnr accounted for about 60% and 40% of the CLt, respectively, suggesting that the pharmacokinetics of incadronate are affected by changes in these clearances. In patients, plasma concentration at 2 h increased dose-proportionally in the range of 2.5-10.0 mg. Urinary excretion of YM175 up to 24 h after dosing was as low as 10.5% of the dose, being 1/6 of those in volunteers. A positive correlation (r > 0.89) was observed between creatinine clearance and urinary incadronate excretion in all volunteers and patients, indicating that the reduction of urinary excretion in patients is due to the decrease in renal function accompanying hypercalcemia. Based on comparison of the dose-normalized plasma concentration, the plasma level at 2 h in patients was comparable with that in volunteers, whereas the level at 8 h was 3 times higher in patients, suggesting that elimination from plasma in patients is delayed due to decreased renal function. Nevertheless, the plasma concentration profile in patients was lower than that predicted from the decrease in CLr. This finding suggests that the increase in plasma concentration with decreasing renal excretion in hypercalcemic patients was compensated for by enhanced bone uptake of the drug.

Adult↗
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↗
PubMed1997

Reliability of a flushing questionnaire and the ethanol patch test in screening for inactive aldehyde dehydrogenase-2 and alcohol-related cancer risk.

Molecular epidemiology of esophageal and upper aerodigestive tract cancers revealed that alcohol is more carcinogenic in persons with inactive aldehyde dehydrogenase-2 (ALDH2) than in those with active ALDH2. A simple questionnaire has been developed to screen for the facial flushing that occurs in persons with inactive ALDH2 when they drink even a single glass of beer. In this study, 266 of 284 consecutive male Japanese clinic patients (age > or = 50 years) completed the flushing questionnaire, and 239 underwent the ethanol patch test (a cutaneous model for the flushing response). Blinded genotyping showed inactive ALDH2 for 94.4% (102 of 108) of subjects who reported always flushing (early in their drinking history or currently) and for 47.7% (21 of 44) of those who reported sometimes flushing, whereas 95.6% (109 of 114) of subjects reporting that they never exhibited facial flushing had active ALDH2. When all three categories of flushing (current always, former always, and sometimes) were collapsed into one, the questionnaire's sensitivity and specificity for identifying inactive ALDH2 were 96.1 and 79.0%, respectively, compared with 72.4 and 71.4% for the ethanol patch test. The results suggest the utility of this simple flushing questionnaire in daily practice, as well as large-scale studies to assess cancer risks associated with drinking and ALDH2 and for activities aimed at preventing alcohol-related cancer.

Aged↗
PubMed1997

Effect of cold-stress and indomethacin on the biosynthesis of gastric sulfated mucin in rats.

The biosynthesis of sulfated mucin in gastric tissue was investigated in cold-stress and indomethacin (CSI)-induced gastric ulcer models. To examine the synthesis of gastric sulfated mucin, [35S]H2SO4 (sulfate) incorporation into gastric mucin was measured. The treatment of CSI inhibited the incorporation of [35S]sulfate after 2 hr. The gastric acid hypersecretion or the formation of severe ulcer was observed at 1 or 4 hr after the CSI-treatment, respectively. Pibutidine hydrochloride (IT-066), a novel H2-receptor antagonist, (0.3 mg/kg, s.c.) inhibited the formation of ulcer and reversed the inhibition of mucin sulfation by the CSI-treatment, whereas atropine sulfate, a muscarinic receptor antagonist, (1.0 mg/kg, s.c.) did not inhibit the development of ulcer nor decrease in the mucin sulfation at 6 hr after the CSI-treatment. IT-066 inhibited the total acid output (T.A.O.) due to the reduction of the acidity in the gastric juice, whereas atropine inhibited the T.A.O. due to that of the volume. These results indicated that a different mode of action between IT-066 and atropine on gastric acid secretion influences their actions in the incorporation of [35S]sulfate and the formation of ulcer in the CSI-treated rat. Therefore, it is considered that the reduction of biosynthesis of gastric sulfated mucin following acid hypersecretion may be responsible for the formation of gastric ulcer.

Animals↗
PubMed1997

Comparative effects of gallopamil and verapamil on the mechanical and electrophysiological parameters of isolated guinea-pig myocardium.

The effects of gallopamil, D600, a methoxy derivative of verapamil, on the mechanical and electrophysiological parameters of isolated guinea-pig myocardial preparations were compared with those of verapamil. Both gallopamil and verapamil produced concentration-dependent negative chronotropic and negative inotropic effects in isolated right atrial and right ventricular papillary muscles, respectively. The negative chronotropic and negative inotropic potencies of gallopamil were 7.2 and 4.3 times higher than those of verapamil, respectively. Gallopamil decreased the action potential duration of isolated papillary muscles without substantially affecting other action potential parameters, while verapamil decreased not only the action potential duration but also the maximum rate of rise and amplitude. In voltage-clamped single ventricular myocytes, gallopamil as well as verapamil decreased the L-type Ca2+ current amplitude. The potency orders for the shortening of the action potential duration and inhibitory effects of the L-type Ca2+ current amplitudes were verapamil > gallopamil. These results indicate that gallopamil has higher negative chronotropic and inotropic potency than verapamil as a result of factors other than L-type Ca2+ current inhibition.

Animals↗
PubMed1996

Cancer screening of upper aerodigestive tract in Japanese alcoholics with reference to drinking and smoking habits and aldehyde dehydrogenase-2 genotype.

In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper-aerodigestive-tract cancer in Japanese alcoholics. For these high-risk drinkers, regimented screening appears to be indicated.

Adult↗
PubMed1996

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders.

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.

Adult↗
PubMed1996

Expression of apolipoprotein E in normal and diverse neurodegenerative disease brain.

Brains from 21 patients with Alzheimer's disease (AD), nine with diffuse Lewy body disease (DLBD), six with progressive supranuclear palsy (PSP) and five with Parkinson's disease (PD) as well as 20 normal subjects were examined to detect apolipoprotein E (ApoE) by immunohistochemistry and immunoblotting. ApoE antigenicity was optimally preserved in Bouin-fixed tissues compared with those fixed in neutral-buffered formalin, 70% ethanol or denatured by microwave energy. ApoE immunoreactivity was prominent in senile plaques and in intra- and extra-neuronal tangles, as well as in a diverse neurones and their processes and astroglial cells. Notably, tangles in PSP and Lewy bodies in PD and DLBD were both devoid of ApoE immunoreactivity. Western blots of cerebral cortex revealed an immunoreactive ApoE band with mol. wt of 34 kDa. Our results suggest that ApoE is not a crucial factor in the development of neuronal inclusions in DLBD, PSP and PD.

Aged↗
PubMed1996

No evidence of association between structural polymorphism at the dopamine D3 receptor locus and alcoholism in the Japanese.

Dopaminergic systems mediate reward mechanisms and are involved in reinforcing self-administration of dependence-forming substances, including alcohol. Studies have reported that polymorphisms of the dopamine D2 receptor, whose structure and function are similar to those of the dopamine D3 receptor, increase the susceptibility to alcoholism. These observations led to the examination of the possible association between a structural polymorphism of the D3 receptor gene and alcoholism. Genotyping results, employing a PCR-RFLP method, showed no difference in allele and genotype frequencies of the D3 BalI polymorphism (Ser9/Gly9) between Japanese alcoholics and controls. Moreover, these frequencies were not altered in alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), a well-defined negative risk factor for alcoholism. These results strongly suggest that the dopamine D3 receptor is not associated with alcoholism.

Adult↗
PubMed1996

Relative selectivity for negative chronotropic and inotropic effects of a novel dihydropyridine derivative CD-832.

The effects of CD-832 [(4R)-(-)-2-(nicotinoyl-amino) ethyl 3-nitroxypropyl 1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate], a novel dihydropyridine derivative, on various guinea-pig myocardial preparations were compared with those of nifedipine, verapamil and diltiazem. CD-832 decreased the action potential duration of isolated papillary muscles without substantially affecting other parameters. In voltage-clamped single ventricular myocytes, CD-832 decreased the L-type Ca2+ current amplitude while having little effect on outward currents. CD-832 and other Ca2+ channel antagonists produced negative chronotropic effects in isolated right atrial preparations and negative inotropic effects in right ventricular papillary muscles, respectively, in a concentration-dependent manner. The potency order for the negative chronotropic effect was CD-832 > nifedipine > verapamil > diltiazem, while that for the negative inotropic effect was nifedipine > verapamil > or = CD-832 > diltiazem. The ratio, EC20 for negative inotropic effect divided by EC20 for negative chronotropic effect, which was considered to be an index of selectivity for negative chronotropic effect was highest for CD-832, the ratio for CD-832, nifedipine, verapamil and diltiazem being 5.4, 0.11, 0.25 and 0.37, respectively. These results indicate that CD-832 is an L-type Ca2+ channel antagonist with relative selectivity for a negative chronotropic effect rather than for a negative inotropic effect. This 'chrono-selective' cardiosuppressive effect of CD-832 could be of value in the treatment of cardiovascular diseases such as angina pectoris.

Action Potentials↗
PubMed1996

Multiple primary esophageal and concurrent upper aerodigestive tract cancer and the aldehyde dehydrogenase-2 genotype of Japanese alcoholics.

BACKGROUND: Multiple intraesophageal primary cancer and upper aerodigestive tract (UADT) cancer associated with esophageal cancer are common diseases, especially in heavy drinkers. They are often explained by the concept of field cancerization, which suggests a similar etiology. However, little is known about the nature of the hypothesized etiology. METHODS: Among 901 Japanese male alcoholics systematically screened by upper gastrointestinal endoscopy (with esophageal iodine staining), 33 had squamous cell carcinoma of the esophagus. The multiplicity of their esophageal carcinoma and their concurrent UADT cancer was compared with their genotype for aldehyde dehydrogenase-2 (ALDH2), the major determinant of blood acetaldehyde concentration after drinking. RESULTS: Of 17 patients with inactive ALDH2, 13 (76.5%) had multiple primary carcinoma of the esophagus, whereas 5 of 16 (31.3%) with active ALDH2 had multiple carcinomas (P < 0.01). The prevalence of concurrent UADT cancer was 29.4% in those patients with inactive ALDH2, compared with 6.3% in those patients with active ALDH2. CONCLUSIONS: Inactive ALDH2 is a risk factor for multiple carcinoma of the esophagus in alcoholics. Acetaldehyde, a recognized animal carcinogen, appears to play a critical role in field cancerization.

Alcoholism↗
PubMed1996

Pupil dilatation assay by tropicamide is modulated by apolipoprotein E epsilon 4 allele dosage in Alzheimer's disease.

The mydriatic response to dilute tropicamide was studied in 25 Japanese patients with Alzheimer's disease (AD), 13 patients with non-AD neurological diseases (non-AD) and 11 normal elderly subjects (control). Although the changes in resting pupil diameter and area over baseline were significantly greater (p < 0.05) in AD patients than in non-AD patients and controls, there was considerable overlap between the three groups. The change in resting pupil area was significantly greater (p < 0.05) in AD patients homozygous for ApoE epsilon 4 than in AD patients heterozygous for or without this allele. Despite a limited sample size in the present study, our results indicate that the pupil dilation assay by tropicamide is not an effective diagnostic tool for AD, and it may be modulated by different gene dosage of ApoE epsilon 4.

Aged↗
PubMed1996

Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions.

Functional roles of the cortical backward signal in long-term memory formation were studied in monkeys performing a visual pair-association task. Before the monkeys learned the task, the anterior commissure was transected, disconnecting the anterior temporal cortex of each hemisphere. After training with 12 pairs of pictures, single units were recorded from the inferotemporal cortex of the monkeys as the control. By injecting a grid of ibotenic acid, we unilaterally lesioned the entorhinal and perirhinal cortex, which provides massive direct and indirect backward projections ipsilaterally to the inferotemporal cortex. After the lesion, the monkeys fixated the cue stimulus normally, relearned the preoperatively learned set (set A), and learned a new set (set B) of paired associates. Then, single units were recorded from the same area as for the prelesion control. We found that (i) in spite of the lesion, the sampled neurons responded strongly and selectively to both the set A and set B patterns and (ii) the paired associates elicited significantly correlated responses in the control neurons before the lesion but not in the cells tested after the lesion, either for set A or set B stimuli. We conclude that the ability of inferotemporal neurons to represent association between picture pairs was lost after the lesion of entorhinal and perirhinal cortex, most likely through disruption of backward neural signals to the inferotemporal neurons, while the ability of the neurons to respond to a particular visual stimulus was left intact.

Animals↗