Biomedical subjects

Yuji Nakamura

Publications and source records attributed to Yuji Nakamura.

At least 19 recordsLinked to original sources

PubMed2006

Anti-inflammatory activities of the triterpene acids from the resin of Boswellia carteri.

Boswellic acids are the main well-known active components of the resin of Boswellia carteri (Burseraceae) and these are still dealing with the ethnomedicinal use for the treatment of rheumatoid arthritis and other inflammatory diseases. Although several studies have already been reported on the pharmacological properties, especially on the anti-inflammatory activity, of Boswellia carteri resin and boswellic acids, the ethnomedicinal importance of Boswellia carteri and its components, boswellic acids, prompted us to undertake detailed investigation on the constituents of the resin and their anti-inflammatory activity. Fifteen triterpene acids, viz., seven of the beta-boswellic acids (ursane-type) (1-7), two of the alpha-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12-14, 16), along with two cembrane-type diterpenes (17, 18), were isolated and identified from the methanol extract of the resin of Boswellia carteri. Upon evaluation of 17 compounds, 1-14 and 16-18, and compound 15, semi-synthesized from 14 by acetylation, for their inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 18, exhibited marked anti-inflammatory activity with a 50% inhibitory dose (ID(50)) of 0.05-0.49 mg/ear.

Animals↗

PubMed2006

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.

Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.

Animals↗

PubMed2005

Pancreatic volume associated with endocrine and exocrine function of the pancreas among Japanese alcoholics.

BACKGROUND/AIMS: The pancreas is often damaged by excessive alcohol consumption. Because alcohol-related problems and diabetes mellitus (DM) are increasing in Japan, this cross-sectional study was designed to investigate how pancreatic volume (PV, calculated using multi-slice helical computed tomography) represents alcohol consumption and both endocrine and exocrine pancreatic function among alcoholics. METHODS: Consenting male and female inpatients undergoing psychiatric therapy for alcoholism from June 2003 to May 2004 were subjected to four-slice MCT to determine PV. Fasting plasma glucose (FPG) and serum lipase levels were examined for endocrine and exocrine pancreatic functions, respectively. RESULTS: The average PVs of 535 male and 117 female patients (57.2 +/- 21.91 ml and 54.5 +/- 17.56 ml, respectively) were related to age and height (H) but not to body weight (W). Lipase values had a strong relationship with PV/W. Multiple regression analysis revealed weak associations between PV and both daily ethanol consumption and duration of habitual drinking. The diagnosis of DM in 109 of these alcoholics was more strongly associated with the PV/W value than with PV or PV/H. CONCLUSION: The association of PV with endocrine and exocrine functions suggests new markers, especially PV/W, for the assessment of DM among alcoholic patients.

Adult↗

PubMed2005

A simple in vivo atrial fibrillation model of rat induced by transesophageal atrial burst pacing.

A simple in vivo closed-chest atrial fibrillation (Af) model of rats was developed. Af was reproducibly induced by transesophageal atrial burst pacing for 30 s in each of the pentobarbital-anesthetized rats, whereas the cardiohemodynamic condition as well as the inducibility and duration of Af episode was stable over time. Moreover, the anti-Af effect of the class Ic drug pilsicainide was confirmed in this model, which was essentially the same as those reported previously in other Af animal models and clinical practice. Thus, this new model may become an alternative to current techniques.

Animals↗

PubMed2005

Comparison of the direct negative dromotropic effect of a new calcium channel blocker, cilnidipine, with that of nicardipine.

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.

Aged↗

PubMed2005

Certain background factors exhibit an association with an increased risk for pancreatic calcification among Japanese male alcoholics.

OBJECTIVE: This was a cross-sectional study conducted from April 2003 through March 2004 to investigate the background factors related to pancreatic calcification (PC) in male Japanese alcoholics. METHODS AND RESULTS: Helical computed tomography examination revealed PC in 44 of 263 alcoholics, and this group was further divisible into 3 subgroups: "scant" (n = 24), "moderate" (n = 6), and "extensive" PC subgroups (n = 14). The extensive subgroup was associated with larger daily ethanol consumption (P = 0.05) and high-alcohol beverages, such as whisky (P = 0.02). The moderate subgroup was associated with a longer duration of habitual drinking (P = 0.04), whereas the scant PC group was associated with never having smoked (P = 0.05) and with low-alcohol beverages, such as beer (P = 0.09). None of the 40 subjects with inactive mitochondrial aldehyde dehydrogenase (ALDH2*2 allele) exhibited PC (P = 0.004). Heterozygous alcohol dehydrogenase 2 genotype (ADH2*1/2*2) exhibited an association with the scant subgroup (P = 0.02). The TG12 repeats in the cystic fibrosis transmembrane conductance regulator (CFTR) gene tended to have a weak association with PC. CONCLUSION: Drinking behavior, smoking status, and genetic backgrounds are associated with PC and are likely to increase the risk for alcoholic chronic pancreatitis.

Adult↗

PubMed2005

A red wine vinegar beverage can inhibit the renin-angiotensin system: experimental evidence in vivo.

A new beverage made of red wine vinegar and grape juice (Budo-no-megumi) was developed for people who wish to take effective amount of both polyphenols and vinegar. Since the beverage was recently demonstrated to exert hypotensive effect in rats, we analyzed its underlying mechanisms in this study. Sprague-Dawley rats were anesthetized with pentobarbital, and the blood pressure and lead II ECG were continuously monitored (n=6). The effects of recommended volume of the beverage (3 ml/kg, p.o.) on the renin-angiotensin system were assessed in vivo. At the basal control state, the increase in the mean blood pressure induced by the angiotensin I (1 microg/kg, i.v.) and norepinephrine (0.3-3 microg/kg, i.v.) were +57+/-2 and +36+/-8 mmHg, respectively. Sixty minutes after the administration of the beverage, the angiotensin I-induced pressor response decreased to +45+/-7 mmHg at 60 min (p<0.05), whereas no significant change was detected in the norepinephrine-induced pressor response. In another parallel series of the experiment using Sprague-Dawley rats (n=6), the serum angiotensin-converting enzyme activity was 39.4+/-1.2 IU/l at basal control state, which was slightly but significantly decreased to 37.0+/-1.4 IU/l at 60 min after the administration of the beverage (p<0.01). These results suggest that previously described hypotensive action of the beverage may be partly induced by the inhibition of angiotensin-converting enzyme.

Acetic Acid↗

PubMed2005

The endothelium-dependent vasodilator action of a new beverage made of red wine vinegar and grape juice.

A new non-alcoholic beverage made of red wine vinegar and grape juice (Budo-no-megumi) has been recently demonstrated to lower the blood pressure of human as well as rats. In this study, we pharmacologically analyzed the mechanism of its hypotensive action. The thoracic aorta with intact endothelium was isolated from Sprague-Dawley rats, and incubated with a Tyrode's solution. The beverage in concentrations of 0.25 to 2% relaxed the pre-contracted aorta with an alpha-adrenoceptor agonist phenylephrine in a concentration-dependent manner, 2% of which induced 59% relaxation. In contrast, the vasodilator response disappeared in the aorta without endothelium. L-Nitro-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, significantly reduced the vasodilator effect of the beverage, whereas indomethacin, an inhibitor of cyclooxygenase, hardly affected it. These results suggest that the beverage can activate the nitric oxide synthase activity to exert vasodilation, which may partly explain its previously reported hypotensive action.

Acetic Acid↗

PubMed2004

Electropharmacological effects of a spironolactone derivative, potassium canrenoate, assessed in the halothane-anesthetized canine model.

While aldosterone receptor blockers improve survival of patients with congestive heart failure, spironolactone and its derivatives were recently shown to block ether-a-go-go-related gene (HERG) channels and native IKs and IKr currents in guinea pig ventricular myocytes. In this study, we examined in vivo electropharmacological effects of an active derivative of spironolactone, potassium canrenoate, using a halothane-anesthetized canine model. Potassium canrenoate was intravenously administered in three doses of 1, 10, and 100 mg/kg per 10 min with a pause of 20 min between doses (n = 5). The low dose hardly affected any of the cardiovascular parameters. The middle dose, a clinically recommended daily maximum i.v. dose, slightly inhibited the intraventricular conduction. The high dose decreased the heart rate, ventricular contraction and blood pressure, delayed the atrioventricular and intraventricular conduction, and prolonged the ventricular repolarization and refractory period. Increment in the refractoriness by the high dose was greater than that in the repolarization, resulting in the reduction of ventricular electrical vulnerability. This unique electrophysiological profile of potassium canrenoate may in part contribute to the favorable clinical results, whereas caution has to be paid on the cardiohemodynamic actions, particularly for patients with risk of elevated plasma drug concentration.

Action Potentials↗

PubMed2004

Cardiovascular effects of an L/N-type Ca2+ channel blocker cilnidipine assessed in the chronic atrioventricular conduction block dogs.

Cardiovascular effects of cilnidipine, a dual L/N-type Ca2+ channel blocker, were evaluated in the chronic atrioventricular block dogs, of which systemic blood pressure and plasma catecholamine levels significantly increased in the pre-drug control. Administration of antihypertensive doses of cilnidipine (1 and 3 microg/kg, i.v.) significantly decreased the total peripheral vascular resistance, mean blood pressure, and atrial rate and increased the cardiac output. These results suggest that cilnidipine not only decreases the blood pressure, but also decreases the sinus automaticity in the in vivo hypertensive condition with increased adrenergic tones.

Animals↗

PubMed2004

Acetaldehyde accumulation suppresses Kupffer cell release of TNF-Alpha and modifies acute hepatic inflammation in rats.

BACKGROUND: Alcohol-related diseases have multiple and varied associations with acetaldehyde, a highly toxic product of ethanol oxidation that accumulates in the absence of active aldehyde dehydrogenase (ALDH). This study was designed to clarify the role of acetaldehyde in liver injury, specifically in vivo and in vitro effects on Kupffer cell release of the inflammatory cytokine tumor necrosis factor-alpha (TNF-Alpha). METHODS: Rats pretreated overnight with the ALDH inhibitor disulfiram (or saline control) were ethanol loaded and challenged with lipopolysaccharide (LPS), and their blood and histological parameters were examined 3 h later. Similarly, isolated rat Kupffer cells were pretreated with disulfiram or cyanamide incubated in ethanol (1 h), then challenged with LPS and evaluated 2 h later for TNF-Alpha and acetaldehyde levels in the culture medium. TNF-Alpha release from Kupffer cells after LPS challenge was also evaluated following incubation in acetaldehyde and acetate for comparison with ethanol loading. RESULTS: Higher blood acetaldehyde concentration following disulfiram pretreatment significantly attenuated acute hepatic inflammation in the ethanol-loaded, LPS-challenged rat (18 +/- 2.9 vs 30 +/- 3.7 polymorphonuclear cells/portal area; P = 0.01). After LPS challenge, ALDH inhibitor pretreatment attenuated Kupffer cell release of TNF-Alpha in the presence of disulfiram at 5063 +/- 151 pg/ml and cyanamide at 4390 +/- 934 pg/ml, versus no inhibitor, 5869 +/- 265 pg/ml ( P < 0.01), but not in the absence of ethanol. Acetaldehyde significantly suppressed Kupffer cell TNF-Alpha release ( P < 0.05), but acetate treatment did not. CONCLUSIONS: Acetaldehyde accumulation suppresses macrophage function, at least suppressing TNF-Alpha release, which plays a role in modifying acute hepatic inflammation in rats.

Acetaldehyde↗

PubMed2004

Severe chronic pancreatitis and severe liver cirrhosis have different frequencies and are independent risk factors in male Japanese alcoholics.

BACKGROUND: Chronic pancreatitis and liver cirrhosis are major alcohol-related diseases in most countries. Neither their specific etiologies nor the relationship between them is fully understood. This study was designed to examine a possible association between alcoholic chronic pancreatitis (ACP) and alcoholic liver cirrhosis (ALC), and to identify factors relating to them. METHODS: The subjects were 141 consenting participants from 1087 male patients consecutively admitted to Kurihama National Hospital from July 2000 to November 2002. All were negative for major medical disorders (e.g., viral hepatitis, operative history, malignancy), except for ACP and ALC. Analysis of each subject included background information (collected by face-to-face interview, regarding quantity and duration of drinking, usual alcoholic drinks, smoking, education, employment, and marital status) and signs of ACP detected on endoscopic retrograde cholangiopancreatography (ERCP) and ALC indicated by Child-Pugh classification. Subjects consenting to genome analyses ( n = 83) were genotyped for two key alcohol-metabolizing enzymes: alcohol dehydrogenase-2 and aldehyde dehydrogenase-2. RESULTS: Grouping patients by ERCP grading and Child classification revealed a nonparallel relationship between the severities of the two diseases. This relationship held, even after controlling for several pertinent background variables (sociofamilial, drinking, clinical, and genetic factors) by logistic regression analysis. The drinking of spirits and a high daily consumption of alcohol were independent risk factors for ACP, while never-married status was the only risk factor identified with ALC among these male Japanese patients. CONCLUSIONS: Different risk factors may confer susceptibility to ACP versus ALC, which may explain the nonparallel relationship between the severities of the two diseases in Japanese alcoholics.

Adult↗

PubMed2004

Homozygous (TG)11 allele in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has a protective role against bicarbonate decrease in pure pancreatic juice among Japanese male alcoholics.

BACKGROUND: Heavy drinkers have a high incidence of chronic pancreatitis (CP), but the mechanism of alcohol-related CP is largely unknown. Exocrine pancreatic insufficiency exists in about 90% of the patients with cystic fibrosis (CF), which results from an abnormal cystic fibrosis transmembrane conductance regulator gene (CFTR). AIM: To investigate in Japanese alcoholics the association between bicarbonate concentration in pure pancreatic juice and one of the polymorphisms of the CFTR gene, the (TG)m Tn tract length in intron 8. METHODS: Fifty-six patients under treatment for alcohol dependence were stimulated by intravenous injection of secretin during endoscopic retrograde cholangiopancreatography to provide pancreatic juice specimens. Individual maximum bicarbonate concentrations (MBC) were compared with (TG)m Tn tract polymorphisms identified by directly sequencing lymphocyte DNA. RESULTS: Among the 41 patients able to provide adequate pancreatic juice specimens, 15 had low MBC and 26 had normal MBC. The frequencies of the six haplotypes identified in these patients were 17.1% (TG)11T7/(TG)llT7, 46.3% (TG)11T7/(TG)12T7, 29.3% (TG)12T7/(TG)12T7, 2.4% (TG)10T9/(TG)11T7, 2.4% (TG)12T5/(TG)11T7, and 2.4% (TG)12T6/(TG)12T7. Among the 92.7% of patients who had the common (TG) miT7/(TG)m2T7 haplotype, all of the 7 with homozygous (TG)11 alleles had normal MBC (p<0.05). CONCLUSION: Alcoholics with homozygous (TG)11 alleles in intron 8 of the CFTR gene appear to be protected against decreased MBC, compared with those who have the (TG)11/(TG)12 and (TG)12/(TG)12 genotypes, suggesting a role for CFTR gene polymorphism in the progression of alcohol-related pancreatic disease.

Adult↗

PubMed2003

Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems.

The effects of famotidine on the cardiac repolarization process were assessed using four different levels of test systems described in the draft stage guideline ICH S7B. A supratherapeutic concentration of famotidine (10(-5) M), which is >8 times higher than C(max) obtained after its therapeutic dose, neither inhibited human ether-a-go-go-related gene (HERG) K(+) current expressed in human embryonic kidney 293 (HEK293) cells nor affected any of the action potential parameters of guinea pig papillary muscles. Therapeutic (0.3 mg/kg, i.v.) to supratherapeutic doses (3-10 mg/kg, i.v.) of famotidine did not affect the repolarization process of the halothane-anesthetized canine model, while only supratherapeutic doses exerted the positive chronotropic, inotropic and dromotropic effects without affecting the mean blood pressure. Moreover, supratherapeutic doses of famotidine (1-10 mg/kg, i.v.) neither induced torsades de pointes nor prolonged QT interval in the canine chronic atrioventricular conduction block model. These results suggest that famotidine possesses no cardiovascular effects at a therapeutic dose, while it may exert cardiostimulatory actions after drug overdoses that might potentiate the proarrhythmic potential of co-administered cardiotonic agents by increasing the intracellular Ca(2+) concentration.

Action Potentials↗

PubMed2003

Benign type of central pontine myelinolysis in alcoholism--clinical, neuroradiological and electrophysiological findings.

Nine alcoholic patients with central pontine myelinolysis (CPM),who showed a favorable prognosis, are reported. The majority of them had taken part in binge drinking and had a subsequent consciousness disturbance for 18.1+/-10.9 (mean+/-SD) days. None of the patients had had acute correction of hyponatremia. Truncal ataxia and gait instability were present in most of the patients after recovery from the disturbance of consciousness. Most of them eventually gained independence, and magnetic resonance imaging showed that their pontine lesions tended to shrink. Electrophysiological studies detected prolonged latency between the I and III waves in auditory brainstem responses and between N11 and P13/14 onsets in the somatosensory evoked potentials. These clinical, radiological and electrophysiological findings should be of use in diagnosing CPM.

Adult↗

PubMed2003

Constitutional rho-kinase regulates atrioventricular nodal conduction and ventricular repolarization of the canine heart.

Given the limited information, physiological roles of Rho-kinase in the cardiac conduction system and ventricular repolarization process were assessed in comparison with those in the coronary vascular tone. A specific Rho-kinase inhibitor Y-27632 was administered to the nutrient coronary artery of the canine isolated, blood-perfused atrioventricular node preparation under the monitoring of the ventricular monophasic action potentials. Administration of Y-27632 moderately suppressed the atrioventricular nodal conduction, slightly but significantly accelerated the repolarization process, and potently increased the coronary blood flow, whereas it hardly affected the intraventricular conduction. The estimated concentrations of Y-27632 causing the currently observed effects were enough to inhibit Rho-kinase. These results suggest that constitutional Rho-kinase functions to moderately facilitate the atrioventricular nodal conduction, slightly delay ventricular repolarization process, and significantly increase the coronary vascular tone.

Action Potentials↗

PubMed2003

Spirits and gastrectomy increase risk for chronic pancreatitis in Japanese male alcoholics.

INTRODUCTION: Most cases of chronic pancreatitis are alcohol-related, but not all alcoholics develop pancreatitis. AIM: To elucidate historical and biologic risk factors for this disease. METHODOLOGY: Alcoholic Japanese men (n = 132) consecutively admitted to the National Alcoholism Center over 24 months, including 54 with chronic pancreatitis (diagnosed by endoscopic retrograde cholangiopancreatography) and 78 without, were surveyed about drinking history, smoking, education, and marital status, and tested for amylase, glycosylated hemoglobin, body mass, alcohol and aldehyde dehydrogenase genotypes, and K-ras gene mutations in pancreatic juice. RESULTS: Higher risk for chronic pancreatitis was associated with drinking spirits rather than lower-alcohol beverages (odds ratio [OR], 2.58; p= 0.01). Daily ethanol consumption by those who drank spirits was greater than that among those who drank lower-alcohol beverages; however, no differences in either daily ethanol consumption or duration of drinking were observed between alcoholics with and without chronic pancreatitis. Postgastrectomy patients were at higher risk for chronic pancreatitis than unoperated comparison subjects (OR, 4.35, P< 0.05). Elevated glycosylated hemoglobin (OR, 4.62, p< 0.01), decreased amylase (OR 4.20, P<0.02), and low body mass (OR 1.89, P<0.1) were more frequent in alcoholics with chronic pancreatitis. K- gene mutations existed in 18.8% of alcoholics with chronic pancreatitis but in only 11.4% of those without the disorder. The frequencies of alcohol and aldehyde dehydrogenase genotypes in alcoholics with and without pancreatitis did not differ significantly. CONCLUSION: Our study strongly suggested that spirits and partial gastrectomy increase the risk for chronic pancreatitis in male alcoholics.

Adult↗

PubMed2003

Low serum amylase levels in drinking alcoholics.

BACKGROUND: We have reported that the serum level of amylase, different from other pancreatic enzymes, increases temporarily after abstinence in alcoholics. To elucidate the mechanism of this phenomenon, pancreatic isoamylase, salivary isoamylase, and amylase in urine were measured together with total serum amylase. METHODS: Total serum amylase, pancreatic isoamylase, and salivary isoamylase values were measured in 38 male patients admitted to the National Alcoholism Center, Kurihama Hospital, for alcoholism after abstinence. In an investigation of amylase secretion, amylase in urine was measured in some patients after abstinence. RESULTS: In the group with abnormally high total serum amylase on admission, levels were found to decrease after abstinence. In patients with pancreatic disorders in this group, abstinence leads to a decrease in total serum amylase, but in patients with no such disorders, total serum amylase increases temporarily due to increases in salivary isoamylase. In the group with normal total serum amylase on admission, levels increased sharply after abstinence, and both pancreatic isoamylase and salivary isoamylase contributed to the gains. In the group with low total serum amylase, a sharp increase of 2-fold or more was noted after abstinence, and a major contributor was pancreatic isoamylase. The ratio of urine amylase to total serum amylase gradually declined, indicating clearly that abstinence led to a decrease in the excretion of amylase in urine. CONCLUSIONS: In cases of heavy alcohol consumption, a decrease in the production or secretion of pancreatic isoamylase and salivary isoamylase while drinking could happen. It was thus suggested that the increase in serum amylase might be due to the fact that this situation is improved by abstinence, plus the fact that excretion of amylase in urine increases during alcohol consumption, and abstinence brings about a decline in such excretion. Measurement of total serum amylase is not appropriate for diagnosing pancreatitis in alcoholic patients or those who consume large quantities of alcohol.

Adult↗