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Biomedical subjects

Y Sawada

Publications and source records attributed to Y Sawada.

At least 217 records · Page 12Linked to original sources
PubMed1997

Kinetics of respiratory depression in rats induced by buprenorphine and its metabolite, norbuprenorphine.

The respiratory depression induced by buprenorphine and its active metabolite, norbuprenorphine (NBN), was evaluated in rats by measurement of changes in respiratory rate and arterial pCO2 levels. After i.v. bolus administration of buprenorphine no effects were noted over the dose range 0.008 to 3 mg/kg; by contrast, the respiratory rate after rapid i.v. administration of NBN decreased in a dose-dependent fashion within the dose range of 1 to 3 mg/kg, and the arterial pCO2 levels also varied in relation to the change in respiratory rate. The minimum respiratory rate was observed 15 min after NBN administration. Judging by the respiratory depressive effect after i.v. infusion, NBN was approximately 10 times more potent than the parent drug. In spite of the similarity of NBN concentrations in the brain after i.a. and after i.v. administration of NBN (3 mg/kg), neither the respiratory rate nor the arterial pCO2 levels after i.a. administration changed compared with the control levels. Moreover, the NBN concentration in the lungs after i.v. administration was approximately 4-fold higher than that after i.a. administration. NBN-induced depression was rapidly reduced after i.v. administration of naloxone and beta-funaltrexamine, but ICI 174864 was without effect. These results suggest that the respiratory depression induced by NBN may be mediated by opioid mu receptors in the lung rather than in the brain.

Analgesics, Opioid↗
PubMed1997

[Critical review on the WHO/IARC report regarding carcinogenicity of Helicobacter pylori].

Helicobacter pylori has been defined as a "definite carcinogen" at the WHO/IARC meeting in 1994. H. pylori causes histological gastritis. Long-lasting infection may induce atrophic gastritis, which is considered to be the first step in the gastritis-metaplasia-carcinoma sequence of the stomach. In a pooled analysis of the three prospective epidemiological studies, the relative risk for developing gastric cancer with H. pylori infection was 3.8, which was statistically significant. Thus, it was concluded that there was sufficient evidence in humans for the carcinogenicity of infection with H. pylori. However, there was no evidence experimentally for the carcinogenicity of infection with H. pylori. Further study is necessary to elucidate the role of H. pylori in gastric carcinogenesis.

Animals↗
PubMed1997

Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies.

It is known that catalepsy serves as an experimental animal model of parkinsonism. In this study, the relationship between in vivo dopamine D1 and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs that bind to D1 and D2 receptors nonselectively. 3H-SCH23390 and 3H-raclopride were used for the labeling of D1 and D2 receptors, respectively. The ternary complex model consisting of agonist or antagonist, receptor, and transducer was developed, and the dynamic parameters were determined. After coadministration of SCH23390 and nemonapride, catalepsy was stronger than sum of the values predicted by single administration of each drug, and it was intensified synergistically. This finding suggested the existence of interaction between D1 and D2 receptors, and the necessity for constructing the model including this interaction. To examine the validity of this model, catalepsy and in vivo dopamine receptor occupancy were measured after administration of drugs that induce or have a possibility to induce parkinsonism (haloperidol, flunarizine, manidipine, oxatomide, hydroxyzine, meclizine, and homochlorcycilzine). All of the tested drugs blocked both dopamine D1 and D2 receptors. Intensity of catalepsy was predicted with this dynamic model and was compared with the observed values. In contrast with haloperidol, flunarizine, manidipine, and oxatomide (which induced catalepsy), hydroxyzine, meclizine, and homochlorcyclizine failed to induce catalepsy. Intensities of catalepsy predicted with this dynamic model considering the interaction between D1 and D2 receptors overestimated the observed values, suggesting that these drugs have catalepsy-reducing properties as well. Because muscarinic acetylcholine (mACh) receptor antagonists inhibit the induction of catalepsy, the anticholinergic activities of the drugs were investigated. After SCH23390, nemonapride and scopolamine were administered simultaneously; catalepsy and in vivo mACh receptor occupancy were measured to evaluate quantitatively the anticholinergic activity. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs. Measurement of in vivo mACh receptor occupancy revealed a significant blockade of mACh receptor by all of the tested drugs except for haloperidol. The predicted values of catalepsy, when corrected for the mACh receptor-related reduction, approached the observed values. This finding indicates the possibility that mACh receptor antagonism of drugs may contribute to the reduction of catalepsy. In conclusion, the dynamic model considering D1, D2, and mACh receptor occupancies and synergism between D1 and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.

Animals↗
PubMed1997

[Effect of aprotinin on bleeding during and graft patency after coronary artery bypass grafting].

The purpose of this study was to evaluate the effect of aprotinin on intraoperative bleeding and graft patency in 200 patients undergoing elective CABG. Patients were classified into three groups; patients receiving 1500000 KIU of aprotinin (group A), 300000 KIU of aprotinin (group B) and no aprotinin as the control (group C). The groups were almost the same as to age, sex, number of grafts and use of ITA. Intraoperative bleeding and reexploration were significantly decreased in group A compared with group B and C. All patients underwent coronary angiography between the 4th and 8th post-operative weeks. Graft patency was significantly decreased in group A (SVG: 90.4%, ITA: 91.1%) compared with group B (SVG: 95.3%, ITA: 100%) and C (SVG: 95.5%, ITA: 99.2%). Perioperative myocardial infarction increased in group A (3.7%). Aprotinin was effective in reducing intraoperative bleeding in CABG, but decreased early graft patency after CABG. It is suggested that aprotinin should not be used routinely in CABG unless a patient has bleeding tendency which is likely to be seen in emergency and redo surgery.

Aged↗
PubMed1997

[A case of mobile left atrial thrombus without mitral valve disease].

A 70-year-old woman who had a left atrial thrombus without mitral valve disease was reported. On admission her electrocardiogram showed atrial fibrillation, but there was no cardiac murmur. Transthoracic echocardiogram revealed a dilated left atrium and an intact mitral valve, but did not detect any thrombus. Transesophageal echocardiogram, however, demonstrated the thrombus attaching to the left atrial appendage. Removal of the thrombus and maze procedure were performed at the same time. Although a pacemaker (DDDR mode) was required postoperatively, she spends uneventful daily life at two years after the surgery.

Aged↗
PubMed1997

[A case report of emergency mitral valve replacement for infective endocarditis in pregnancy].

Infective endocarditis is extremely rare in early pregnancy. We report an emergency mitral valve replacement performed successfully on a 16 week pregnant woman for infective endocarditis without preexisting heart disease. On admission, the patient was in acute heart failure, and the fetus had been already dead. Induced abortion was performed uneventfully 6 days after the cardiac operation.

Adult↗
PubMed1997

[A case of Jehovah's Witness underwent double valves replacement in reoperation].

The patient was a sixty five-year-old woman and Jehovah's Witness who refused either homologous or autologous blood transfusion on the ground of her faith. At the age of 47, she had closed commissurotomy for mitral valve stenosis. This time, because mitral valve restenosis and tricuspid valve regurgitation were found, double valve replacement, mitral and tricuspid, was performed on her, with an excellent result. It is expected that, in the near future, the indication for open heart surgery without blood transfusion will be increased by means of the following considerations as to blood loss preservation; 1. to shorten the time necessitating for an operation and reduce preoperative blood loss, 2. to improve cardio-pulmonary bypass system (Heparin coating etc), and 3. to augment the erythropoiesis (administration of EPO at the patient's own expense, etc.) and so on.

Aged↗
PubMed1997

Tissue distribution kinetics of a new nonsteroidal 5 alpha-reductase [correction of 5 A-reductase] inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-YL ]-butyric acid, in rats.

The disposition of a new nonsteroidal 5alpha-reductase inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyric acid (FK143), was investigated in rats. After intravenous administration of FK143 at 1 and 5 mg/kg, total body clearance, elimination half-life, and volume of distribution at steady-state were, respectively, 6.96 and 8.76 ml/min/kg, 10.31 and 9.83 hr, and 4.11 and 3.33 liters/kg. There were no essential differences between the two doses in any parameters. The serum protein binding in vitro was very high (>99%). The unidirectional uptake clearance (CL1) to 13 tissues was determined by integration plot until 10 min after intravenous administration of 1 mg/kg. CL1 values were much smaller than blood flow rate in all tissues, including the prostate, the target organ, indicating that FK143 was transported from blood to tissues by a membrane-limited process. Since the elimination rates of FK143 from the liver, kidney, lung, epididymis, seminal vesicle, and prostate were slower than from the blood, the efflux rate constant (k2) and rate constants at a binding compartment (k3 and k4) were assumed in the pharmacokinetic model. A correlation was found between the binding potential of binding compartment (k3/k4) and V(max) of steroid 5alpha-reductase, the target enzyme, suggesting that the levels of 5alpha-reductase activity or that of associated substances are a primary determinant of the specific binding of FK143 in these tissues.

5-alpha Reductase Inhibitors↗
PubMed1997

[Open heart surgery in a Jehovah's Witness boy--a case report of successful management of aortic regurgatation and aneurysm of sinus Valsalva due to infective endocarditis].

Jehovah's Witness who require operation represent a challenge to the physician because of the patients' refusal to accept blood transfusion. We report an 8-year-old male of Jehovah's Witness who underwent a surgical treatment of infective endocarditis. He was transferred to our hospital because of high fever and heart murmur. Echocardiogram revealed a developing vegetation of aortic cusps and an aneurysmal change of the non-coronary sinus Valsalva. On admission he was complicated by anemia, purulent meningitis and suppurative arthritis of left knee. There were no signs of cardiac failure. Erythropoietin (6000 U thrice weekly) and iron (60 mg daily) were given for 11 weeks prior to surgery, raising the hemoglobin level from 9.2 g/dl to 18.4 g/dl. Aortic valve replacement and plasty of the sinus Valsalva were then performed. Intraoperatively hemoglobin concentration dropped to 10.3 g/dl and it raised to 15 g/dl postoperatively. We also used Cell-Saver to reduce blood loss. The patient made an uncomplicated recovery. Erythropoietin therapy contributed substantially to the successful outcome of this case.

Aortic Aneurysm↗
PubMed1997

Immunosuppressive drugs inhibit the production of interleukin-6 and interleukin-8 in cultured cardiac myxoma cells.

Cardiac myxoma cells produce large amounts of interleukin (IL)-6 and IL-8. To determine whether immunosuppressive agents could be used to treat cardiac myxoma, we tested the effects of dexamethasone and three of the newer second-generation immunosuppressive drugs, cyclosporin A, tacrolimus, and deoxyspergualin, on the production of IL-6 and IL-8 in these cells. Cultured cardiac myxoma cells were used as in vitro model of cardiac myxoma. Cells were tested for 24 hours with 10(-7) M dexamethasone, 10(-6) M cyclosporin A, 10(-8) M tacrolimus, and 10(-6) M 15-deoxyspergualin, with aliquots of conditioned medium being assayed for cytokine levels at 0, 6, 12, and 24 hours. Cardiac myxoma cells isolated from 4 patients all produced quantities of IL-6 and IL-8. The concentrations of IL-6 in the medium after 7 days in culture ranged from 79,000 to 2,740,000 pg/ml, and the concentrations of IL-8 ranged from 40,000 to 1,000,000 pg/ml. Exposure of cyclosporin A and dexamethasone almost completely inhibited the production of IL-6 and IL-8 after 24 hours of treatment. Tacrolimus inhibited the production of both cytokines by 55%, while 15-deoxyspergualin reduced IL-6 levels by 24% and IL-8 levels by 48% after separate 24 hour treatments. These results suggest that these newer immunosuppressive agents may be useful in reducing the production of IL-6 and IL-8 in patients with cardiac myxoma.

Aged↗
PubMed1996

Quantitative determination of epinastine in plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the quantitative determination of epinastine, a non-sedating histamine H1 receptor antagonist, in rat plasma, was developed. A 100-microliters volume of plasma sample was spiked with a solution of internal standard (diphenidol) and extracted with dichloromethane under alkaline conditions. The extract was applied onto the HPLC system and detected by ultraviolet absorption at a wavelength of 220 nm. The linearity of the calibration curve was preserved over the concentration range of 20-1000 ng/ml. Both intra-assay variation and relative error were less than 5% for the plasma containing 50 ng/ml or 1000 ng/ml of epinastine hydrochloride. The analytical method presented here should be useful for the investigation of the pharmacokinetic properties of epinastine, which is of clinical significance.

Animals↗
PubMed1996

Proprotein-processing endoprotease furin decreases regulated secretory pathway-specific proteins in the pancreatic beta cell line MIN6.

Prohormone convertases PC2 and PC3, yeast Kex2-family endoproteases specific to the regulated secretory pathway, cleave proinsulin to insulin in the secretory granules of pancreatic beta cells. The well-differentiated beta cell line MIN6 expresses PC2 and PC3 and another regulated secretory pathway-specific protein chromogranin A. Furin, another yeast Kex2 endoprotease, exists in the trans-Golgi networks of many cell types. The beta cell line RINm5F (a cell line that is less differentiated than the MIN6 cell line) does not express the regulated pathway-specific proteins, but strongly expresses furin. We suspected that furin expression may cause the decrement of regulated secretory pathway-specific proteins. To test this hypothesis, we expressed a furin cDNA with a metallothionein promoter in MIN6 cells. With Zn2+ stimulation of furin expression, the messages of PC2, PC3, and chromogranin A decreased, and the processing of proinsulin to mature insulin became less efficient. The furin-expressing MIN6 cells exhibited less insulin content and weakened insulin secretion in response to a high glucose concentration. The conditioned medium from furin-expressing MIN6 cells also exerted a decrease of PC2 and PC3 expression in unaltered MIN6 cells. Thus, proteins cleaved by furin inside the cells or by truncated furin shed into the culture medium appear to cause decreased PC2 and PC3 expression, insulin content, and glucose-responsive insulin secretion in MIN6 cells.

Amino Acid Sequence↗
PubMed1996

Three-year follow-up after implantation of metallic coronary-artery stents.

BACKGROUND: Coronary-artery stents are known to reduce rates of restenosis after coronary angioplasty, but it is uncertain how long this benefit is maintained. METHODS: We evaluated clinical and angiographic follow-up information for up to three years after the implantation of Palmaz-Schatz metallic coronary-artery stents in 143 patients with 147 lesions of native coronary arteries. RESULTS: The rate of survival free of myocardial infarction, bypass surgery, and repeated coronary angioplasty for stented lesions was 74.6 percent at three years. After 14 months, revascularization of the stented lesion was necessary in only three patients (2.1 percent). In contrast, coronary angioplasty for a new lesion was required in 11 patients (7.7 percent). Follow-up coronary angiography of 137 lesions at six months, 114 lesions at one year, and 72 lesions at three years revealed a decrease in minimal luminal diameter from 2.54 +/- 0.44 mm immediately after stent implantation to 1.87 +/- 0.56 mm at six months, but no further decrease in diameter at one year (in patients with paired angiograms, 1.95 +/- 0.49 mm at both six months and one year). Significant late improvement in luminal diameter was observed at three years (in patients with paired angiograms, 1.94 +/- 0.48 mm at six months and 2.09 +/- 0.48 mm at three years; P < 0.001). CONCLUSIONS: Clinical and angiographic outcomes up to three years after coronary-artery stenting were favorable, with a low rate of revascularization of the stented lesions. Late improvement in luminal diameter appears to occur between six months and three years.

Aged↗
PubMed1996

Neurotoxic convulsions induced by histamine H2 receptor antagonists in mice.

Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2 receptor antagonists (H2 blockers). Four H2 blockers, cimetidine (721-1236 nmol), ranitidine (477-954 nmol), famotidine (7.4-44 nmol), and nizatidine (226-603 nmol) were administered intracerebrally (i.c.) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (+/-)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after i.c. administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. Ed50 values for convulsive occurrence after i.c. administration of four H2 blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 microM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2 blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2 blockers may be associated with the blockade of H2 receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.

Animals↗
PubMed1996

Pharmacodynamic analysis of contractile potentiation by cholinesterase inhibitors in rats.

Pharmacological profiles of four cholinesterase (ChE) inhibitors: edrophonium, pyridostigmine, neostigmine, and ambenonium after to administration to rats were analyzed. A pharmacodynamic model was developed by considering acetylcholinesterase (AChE) inhibition, direct antagonism to the nicotinic receptor, and desensitization of the nicotinic receptor. Pharmacokinetics of these drugs are dose-independent and have similar volumes of distribution at steady state (0.4-0.6 L/kg various doses). The t1/2 increases in the order of neostigmine, edrophonium, pyridostigmine, and ambenonium. Inhibitory constants of ChE inhibitors to bovine erythrocyte AChE determined in vitro were 2019, 276, 26, and 3.7 nM for edrophonium, pyridostigmine, neostigmine, and ambenonium, respectively. The effect of ChE inhibitor was monitored as the increase of developed tension of triceps muscle induced by sciatic nerve stimulation. The maximum value of contractile tension after i.v. administration decreased at high doses of each drug and the dose-response curves were biphasic. Time courses of plasma concentration and contractile muscle tension were modeled to estimate the association/dissociation rate constants to AChE and the nicotinic receptor, desensitization rate constant of receptor and the dissociation constant of acetylcholine (ACh) to nicotinic receptor/basal acetylcholine level ratio (Kd/ACh0). The estimated Kd/ACh0 values were not dependent on the drug. A significant correlation between inhibitory constants of ChE inhibitors to AChE estimated by in vivo pharmacodynamic analysis and those determined by an in vitro enzyme kinetic study was shown, while the relationship between dissociation constants to nicotinic receptor estimated by in vivo pharmacodynamic analysis and those measured by an in vitro binding study was not clear. Other process such as desensitisization induced by endogenous ACh diffusion rate of drugs into the synaptic cleft, action of presynaptic receptors, etc., might contribute to the dose-effect relationship of ChE inhibitors.

Ambenonium Chloride↗
PubMed1996

Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats.

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2, 5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2-10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6-fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+/-)-MPD was greater than that (2.2-fold) of the same dose of (-)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (-)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (-)-isomer.

3,4-Dihydroxyphenylacetic Acid↗