[Disorders of tetrahydrobiopterin homeostasis].
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Amino Acid Metabolism, Inborn Errors↗
Biomedical subjects
Y Sawada
Publications and source records attributed to Y Sawada.
[Prognostic value of myocardial 123I-BMIPP imaging in patients with congestive heart failure without coronary artery disease].
We performed 123I-BMIPP (BMIPP) imaging in order to clarify the characteristics of fatty acid metabolism and its effect on prognosis in patients with congestive heart failure (CHF) without coronary artery disease. We studied 15 normal subjects and 42 patients with CHF (idiopathic dilated cardiomyopathy; 24, hypertensive heart disease; 12, valvular heart disease; 6). We obtained cardiac imaging with BMIPP and 201Tl at rest on separate days before discharge. Using whole body imaging, the ratio of cardiac uptake of the isotope to total injected dose was calculated (%Uptake). We calculated the cardiac uptake ratio of BMIPP (%Uptake of BMIPP divided by %Uptake of 201Tl), percent washout of BMIPP from the heart over 3 hours and unhomogeneity of myocardial distribution of BMIPP (coefficient of variation of BMIPP, CV) as scintigraphic parameters. Cardiac events were defined as cardiac death or deterioration of CHF which requiring readmission. Uptake ratio (CHF: 0.91 +/- 0.17, normal; 1.10 +/- 0.09, p = 0.0000) and CV (CHF; 20 +/- 5, normal; 16 +/- 5, p = 0.0385) were different significantly between CHF and normal subjects. During the follow-up period of 27.2 +/- 14.4 months (4.5-53.5 months) cardiac events developed in 15 patients (cardiac death; 8, deterioration of CHF; 7). In univariate analysis, %uptake of 201Tl, uptake ratio, % FS, serum norepinephrine level and serum renin activity were different significantly between event and event-free groups. Cox proportional hazard analysis showed that the uptake ratio (p = 0.0000) and age (p = 0.018) were independent predictors of cardiac events. In patients with uptake ratio less than 0.88, relative risks of cardiac events was 23.7 times greater than in patients with uptake ratio more than 0.89. These data suggested that in patients with CHF fatty acid metabolism was deteriorated and cardiac uptake of BMIPP was a strong and independent predictor of long-term prognosis in patients with heart failure.
Adult↗
A further application of buried chip skin grafting.
Buried chip skin grafting used to close a granulation wound, that cannot be kept at rest, or else is in some way irritated, is described. This requires an extremely small amount of skin. Although it takes a month to heal, irritation or contamination of the grafted area does not affect or have any influence on the take of graft survival. Therefore, the patient need not be kept at rest after surgery, and can continue with daily living or rehabilitation exercises.
Adult↗
Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain.
Recently, clinical cases of parkinsonism due to antiarrhythmics drugs amiodarone and aprindine and a local anesthetic drug procaine have been reported. We performed both in vivo and in vitro experiments to quantitatively predict the intensity of catalepsy by these drugs and haloperidol in mice. Haloperidol showed the most potent relative intensity of catalepsy, followed by aprindine, metoclopramide, tiapride, amiodarone and procaine, in that order. In vivo dopamine D1 and D2 receptor occupancies of the six drugs to the striatum were observed. In vitro binding affinity (Ki) of these drugs to the D1 and D2 receptors in the striatum synaptic membrane was within the range of 60 nM to 706 microM, 0.5 nM to 75 microM and 860 nM to 115 microM, respectively. A good correlation between the relative intensity of drug-induced catalepsy and the Ki values for the dopamine D1 and D2 receptors was obtained (r =.911 and r =.896, respectively; P <.05). The partial tertiary structure of the tested drugs was well superimposed on that of haloperidol. In conclusion, these drug-induced catalepsies were due to the blockade of the D1 and D2 receptors, which was related to the analogous tertiary structures (diethylaminoethyl side chain).
Amiodarone↗
Pathological changes in glandular stomach of Helicobacter pylori-infected Mongolian gerbil model.
We have established a Helicobacter pylori-infected Mongolian gerbil model, following Hirayama's method, to clarify gastric diseases associated with H. pylori infection. We administered the culture broth of H. pylori ATCC 43504 orally to 8-week-old male Mongolian gerbils. After H. pylori inoculation, the gerbils were fed in a vinyl isolator. Subsequently, over the course of 48 weeks, they were killed for histopathological examination, H. pylori culture, and serum antibody measurement. H. pylori colonization in the glandular stomach was seen in all the infected gerbils, but only a few H. pylori were detected histologically. The serum antibody titer in the H. pylori-inoculated group increased gradually in comparison with controls. Acute inflammation, immature epithelium, and erosion were observed 2 weeks after H. pylori infection. Chronic inflammation was noted from 4 weeks after H. pylori infection. We also found intestinal metaplasia and gastric ulcers from 12 and 24 weeks after inoculation, respectively. Some histological findings were similar to those in humans, but the chronic inflammation in the gerbils was present mainly in the deep mucosa and submucosa. This appears to be a good animal model for H. pylori-associated gastric diseases and it may be useful for investigating the pathogenesis of H. pylori infection.
Animals↗
[Evaluation of factors for stenosis of coronary artery bypass graft--their relationship with the vascular wall angiotensin II producing system].
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Angiotensin II↗
[Case of intractable ulcerative colitis resistant to steroid high-dose venous-infusion therapy treated by leukocytapheresis].
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Adult↗
Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344.
To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344, N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2, 4dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethyl aminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [3H]bradykinin binding to bradykinin B2 receptors present in guinea-pig ileum membrane with an IC50 value of 6.6 X 10(-10) M. In isolated guinea-pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [3H]bradykinin binding to human bradykinin B2 receptors with an IC50 value of 1.3 X 10(-8) M, but not [3H]des-Arg10-kallidin binding to human bradykinin B1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B2 receptor antagonist.
Animals↗
Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.
When hypertrophic growth is induced in neonatal rat cardiocytes by stretching, the cardiocytes express high levels of brain-type natriuretic peptide (BNP) and the proprotein-processing enzyme furin. A BNP precursor, gammaBNP, possesses a furin-cleavable Arg-X-X-Arg motif, which is cleaved when gammaBNP is processed to form BNP-45. The Arg-X-X-Arg motif is found in many precursors of growth factors and growth-related proteins. To determine if furin converts gammaBNP to BNP-45 as well as other unidentified growth-promoting protein precursors to their active form that may induce hypertrophic growth in cardiocytes, we used two protease inhibitor systems, synthetic peptidyl chloromethyl ketones (CMK) (dec-Arg-Val-Lys-Arg-CMK and dec-Phe-Ala-Lys-Arg-CMK; where dec is decanoyl) and vaccinia vector-integrated native and variant alpha1-antitrypsins. The furin-specific inhibitors, dec-Arg-Val-Lys-Arg-CMK and variant alpha1-antitrypsin with the inhibitory determinant Arg-X-X-Arg, suppressed the stretch-induced hypertrophic growth of cardiocytes as well as the processing of gammaBNP to BNP-45. The other serine protease inhibitors and variant alpha1-antitrypsin against elastase, or thrombin, however, neither suppressed the hypertrophic growth nor prevented the processing of gammaBNP to BNP-45. Thus, we suggest that furin catalyzes the conversion of gammaBNP to BNP-45 as well as growth-promoting proproteins to their active form, which might induce hypertrophic growth in cardiocytes.
Animals↗
Cloning and characterization of the rat p130, a member of the retinoblastoma gene family.
A cDNA clone encoding rat p130, a member of the retinoblastoma (Rb) gene family, was isolated based on the sequence homology of the E1A-binding domain. The 4.87 kb cDNA contained an 1135-amino acid open reading frame with high homologies to the human and mouse p130 and a partial homology to the pRb protein. p130 showed difference in distribution of potential phosphorylation sites from pRb in the N-terminal and the B pocket regions. p130 mRNA was detected in most rat tissues. The p130 gene was mapped to rat chromosome 19p11-13 by fluorescence in situ hybridization.
Amino Acid Sequence↗
Cloning and characterization of rat p27Kip1, a cyclin-dependent kinase inhibitor.
Cyclin-dependent kinase (Cdk) inhibitors play significant roles in the cell cycle control of various biological phenomena. To characterize the role of Cdk inhibitors in rat cells, we isolated a cDNA encoding rat p27Kip1, a 27-kDa Cdk inhibitor. The 1.04-kb cDNA of rat p27 contained an open reading frame of 197 amino acids that shared high homology with mammalian p27 and significant homology with mammalian p21Cip1 and p57Kip2. p27 mRNA was detected in most rat tissues and cell lines. The levels of p27 protein expression were similar in rat cell lines transformed by E1A and in normal cells. Rat p27 was able to interact with Cdk 2/4 and cyclin A/D in rat cells, but the amounts of rat p27 in Cdk2 complexes were different between transformed cells and normal cells. Thus, the formation of stable complexes of rat p27 may be modulated by E1A. Rat p27 protein could inhibit the increased Cdk2-associated kinase activity in transformed rat cells.
Adenovirus E1A Proteins↗
Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection.
A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 microl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 microg/ml for plasma and 0.5-100.0 microg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.
Animals↗
Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease furin after myocardial infarction in rats.
We investigated the expression of the yeast Kex2 family endoproteases furin and PACE4, and brain natriuretic peptide (BNP) in the atrium and ventricle after infarction as well as the conversion of the BNP precursor gammaBNP to BNP-45. In a rat heart failure model, plasma BNP rose in two phases--first at day 3, and again at day 14. BNP mRNA, as measured by Northern blot analysis, increased strongly at day 3, then at days 14 and 28 less strongly in the atrium, and in the ventricle it increased weakly at day 3, then strongly at days 14 and 28. Furin mRNA showed the same pattern of expression as that of BNP message, whereas PACE4 message stayed unchanged after the infarction. Both furin and BNP were immunostained in the myocardium adjacent to the infarcted tissue. We suggest that after myocardial infarction, furin is co-expressed with BNP in both the atrium and ventricle, and that furin may be responsible for the conversion of gammaBNP to BNP-45.
Animals↗
Prediction of the therapeutic dose for benzodiazepine anxiolytics based on receptor occupancy theory.
Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (Kd), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the Kd values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r < 0.77). In contrast, a good log-linearity (r = 0.96) was observed in the correlation between their Kd values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52.3 +/- 3.2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory.
Administration, Oral↗
The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats.
The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl4-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62.2 +/- 7.4 and 64.4 +/- 7.5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63.1 +/- 19.1 and 68.7 +/- 15.2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 micrograms mL-1. In rats, the total body clearance (Cltot) for glycrrhizin in the CCl4-treated rats after i.v. administration of glycyrrhizin (5 mg kg-1 dose) was three-tenths of that of the control, and the t1/2 for glycyrrhizin was 3.4-fold longer than that of the control. A good correlation was observed between Cltot and AST (r = -0.838) or ALT (r = -0.873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl4-treated rats showed a greater improvement than for a 10 mg kg-1 dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats.
Alanine Transaminase↗
Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.
Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.
Animals↗
Therapeutic effect of co-enzyme Q10 on idiopathic dilated cardiomyopathy: assessment by iodine-123 labelled 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid myocardial single-photon emission tomography.
It has been reported that myocardial mitochondrial function can be improved by the administration of co-enzyme Q10 (CoQ10). Recently, iodine-123 labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) was developed for metabolic imaging using single-photon emission tomography (SPET). This study was conducted to determine whether the therapeutic effects of CoQ10 on idiopathic dilated cardiomyopathy can be evaluated by BMIPP myocardial SPET. Fifteen patients, comprising 14 men and one woman (mean age: 64+/-12 years), were examined. CoQ10 was administered at 30 mg/day for a period of 35.7+/-12.4 days. BMIPP myocardial SPET was carried out before and after CoQ10 treatment. The count ratio of the heart (H) to the upper mediastinum (M) (H/M ratio) was calculated using a region of interest method with anterior planar imaging. Representative short-axis tomograms were divided into 27 segments (three slicesxnine segments). Each segmental score was analysed semiquantitatively using a four-point scoring system (normal=0, mild low uptake=1, severe low uptake=2, defect=3). The H/M ratio showed a significant improvement, from 2.39+/-0.39 to 2.54+/-0.47, after treatment (P<0.05). The BMIPP total defect score after CoQ10 treatment was significantly decreased to 10.1+/-4.3, compared to 13. 9+/-4.5 without CoQ10 treatment (P<0.001). However, the percent fractional shortening measured using echocardiography was not significantly different before and after CoQ treatment (19.2+/-8.1 vs 19.7+/-7.1). BMIPP myocardial SPET was confirmed to be sensitive in evaluating the therapeutic effects of CoQ10 in patients with idiopathic dilated cardiomyopathy. This method is unique, since the therapeutic effects can be estimated from the perspective of metabolic SPET imaging.
Cardiomyopathy, Dilated↗
Indications and problems of coronary artery bypass grafting without cardiopulmonary bypass.
As an alternative method of myocardial protection and to obviate the inherent risks of cardiopulmonary bypass (CPB), we have been performing coronary artery bypass grafting (CABG) without CPB in carefully selected patients. Since the first such operation was successfully performed in January 1995 on a patient with angina pectoris and lung cancer, four other patients have subsequently undergone this technique. This series of 5 patients, being 1 man and 4 women ranging in age from 68 to 80 years, is presented in this report. The reasons for the selection of this procedure were concomitant diseases including lung cancer, a calcified aorta, and myocardial infarction. The mean time of ischemia for each anastomosis was 15.3 +/- 5.3 min, and the maximum cardiac muscle creatine phosphokinase (CPK-MB) was less than 14 unit/l postoperatively. None of the patients required ventilatory support for longer than 24 h postoperatively, and oral intake was started within 24 h after extubation in all patients. Postoperative angiography confirmed graft patency and none of the patients developed any ischemic symptoms. All the patients were discharged between 1 and 2 months postoperatively. Thus, the off-pump technique is useful when concomitant diseases are present and will become an alternative method of treatment for coronary artery disease in selected patients.
Aged↗