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Biomedical subjects

Y Sawada

Publications and source records attributed to Y Sawada.

At least 199 records · Page 11Linked to original sources
PubMed1997

Right ventricular myxoma: report of a case.

We herein report a 36-year-old man who underwent surgical resection for myxoma. Preoperative two-dimensional echocardiography demonstrated a mass in the right ventricle. Intraoperatively, the tumor was found to derive from an anterior papillary muscle of the tricuspid valve. The tumor was successfully excised and the tricuspid valve was repaired with chordoplasty and annuloplasty. A histopathological examination revealed myxoma and a 2-year follow-up has shown no evidence of recurrence or tricuspid valve regurgitation.

Adult↗
PubMed1997

New technique for time series analysis combining the maximum entropy method and non-linear least squares method: its value in heart rate variability analysis.

A new technique for time series analysis, which is a combination of the maximum entropy method (MEM) for spectral analysis and the non-linear least squares method (LSM) for fitting analysis, is described. In this technique, the MEM power spectral density (MEMPSD) is calculated using a very large lag that could diminish the lag dependence of dominant periods estimated by the MEM analysis. The validity of this large lag is confirmed by the LSM, given that the ten dominant MEM periods are known quantities. To validate the MEM plus LSM technique, it is compared with autoregressive (AR) modelling, by analysing heart rate variability under pharmacological interventions (phenylephrine and trinitroglycerine), using 16 young males. The results indicate that the MEMPSD, when compared with the ARPSD, has numerous periods that could reproduce the original time series much more accurately, as revealed by the LSM analysis. However, both the low- and high-frequency powers with MEMPSD and ARPSDs shift in the expected directions in accordance with the pharmacological effects on the cardiovascular system. The implications of these results are discussed from the theoretical and practical standpoints of the MEM plus LSM technique, compared with AR modelling.

Adolescent↗
PubMed1997

Detection of impaired fatty acid metabolism in right ventricular hypertrophy: assessment by I-123 beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial single-photon emission computed tomography.

Fatty acid metabolism has been reported to be impaired earlier than myocardial blood flow in left ventricular hypertrophic myocardium, e.g., in hypertrophic cardiomyopathy or hypertensive heart disease. The purpose of this study was to determine whether impaired fatty acid metabolism also occurs in right ventricular (RV) hypertrophy. The subjects consisted of 6 patients with chronic obstructive pulmonary disease, 4 with primary pulmonary hypertension, 2 each with refractory pulmonary tuberculosis, tricuspid insufficiency, pulmonary embolism, 1 each with atrial septal defect, ventricular septal defect (Eisenmenger complex), Ebstein anomaly, and endocardial defect, and 7 healthy controls. SPECT imaging with Tl-201 (Tl) and I-123 beta-methyliodophenyl pentadecanoic acid (BMIPP), and Tc-99m RBC first pass and gated blood pool scintigraphy were performed. Based on Tl planar images, the subjects were classified into 3 groups: 7 patients with no RV visualization (Group A), 11 with moderate RV visualization (Group B) and 9 with marked RV visualization (Group C). As a semi-quantitative evaluation by Tl myocardial SPECT, 3 regions in 3 representative short axial images were divided into 9 segments, each of which was graded from 0 to +3, and their sum was calculated as the RV score. The right ventricular ejection fraction (RVEF) and the left ventricular ejection fraction were obtained by Tc-99m RBC cardiac scintigraphy. The groups with marked visualization of the right ventricle had lower RVEF (p < 0.01), and there was a good correlation between the RVEF and the RV score with both Tl and BMIPP (Tl: r = -0.79, BMIPP: r = -0.70). Although a good correlation was demonstrated between the RV score with Tl and BMIPP in Groups A and B (r = 0.86, p < 0.001), in Group C, in which there was marked RV T1 visualization, the RV score with BMIPP was significantly smaller than with Tl (BMIPP vs. Tl: 11.5 +/- 3.7 vs. 16.4 +/- 3.8, p < 0.01). These findings suggest that impaired fatty acid metabolism may exist in severely hypertrophic right ventricle due to RV overload.

Aged↗
PubMed1997

Basal cell carcinoma developing on a burn scar.

Basal cell carcinoma occurring on a burn scar is quite care. However, when it does occur, it is usually seen on sites exposed to the sun or on sites with embryological closure lines. A case of basal cell carcinoma which developed on a burn scar on the trunk is described. The injury was from a flame burn which occurred more than 50 years ago. No mechanical irritation had occurred on the lesion since then.

Aged↗
PubMed1997

Is prolonged and excessive cooling of a scalded wound effective?

An experimental study was carried out using rats to evaluate the effectiveness of prolonged and excessive cooling on the burned wound just immediately after injury. The wound was produced by applying a lint immersed in boiled water at 99 degrees C. The wound produced by applying a lint for 3 s, and then immediately soaking with tap water for 1 min, resulted in little damage. However, the wound produced by applying a lint for 10 s, and immediately after an ice cube applied for 10 min, resulted in the most severe damage. The wound produced by applying a lint for 10 s, and no treatment applied thereafter, and the wound produced by applying a lint for 10 s and immediately after soaked with tap water for 1 min, resulted in moderate damage. From this experiment, it is suggested excessive and prolonged cooling of the burn wound, such as using an ice cube immediately after injury, is harmful in some instances.

Animals↗
PubMed1997

Identification of specific amino acid residues of adenovirus 12 E1A involved in transformation and p300 binding.

The early region 1A (E1A) gene of highly oncogenic adenovirus type 12 (Ad12) was analyzed for transforming activity and protein binding using specific mutations. The Ad12 E1A proteins were found to bind p300 protein mainly within the CR1 region, although mutations that affect both p300 binding and transformation were identified in both the CR1 and the N-terminal region. The most critical mutation dlf89 located in the CR1 region was further dissected by point mutations and the results identified 68S as the most critical for transformation and 67E as the most critical for p300 binding. Specific mutations that retain p300 binding but impair transcriptional repression of a viral enhancer were also identified in both the N-terminal and CR1 regions.

Adenovirus E1A Proteins↗
PubMed1997

Pharmacodynamic modeling for change of locomotor activity by methylphenidate in rats.

PURPOSE: The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. METHODS: MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. RESULTS: The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 +/- 73.8 nM (mean +/- SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. CONCLUSIONS: The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may by useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.

Animals↗
PubMed1997

Pharmacokinetic analysis of benzodiazepine receptor binding of [123I]iomazenil in human brain.

PURPOSE: The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding. METHODS: BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric disease. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding. RESULTS: Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient. CONCLUSIONS: Our findings suggest the possibility of detecting the epileptic focus by using our method.

Blood-Brain Barrier↗
PubMed1997

The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657.

1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.

Administration, Oral↗
PubMed1997

A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats.

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with urethane and alpha-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner, its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

Animals↗
PubMed1997

Nonpeptide mimic of bradykinin with long-acting properties at the bradykinin B2 receptor.

Kinins, members of a family of peptides released from kininogens by the action of kallikreins, exhibit a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells, and activation of sensory neurons. However, investigation of the physiological actions of kinins has been greatly hampered because its effects are curtailed by rapid proteolysis in blood, lung, and liver. We describe the pharmacological characteristics of a novel nonpeptide bradykinin receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoli ne). FR190997 markedly stimulated phosphatidylinositol hydrolysis in Chinese hamster ovary cells permanently expressing the human bradykinin B2 receptor. The response of phosphatidylinositol hydrolysis was antagonized by the B2 receptor selective antagonist Hoe 140 (D-Arg-[hydroxyproline3,beta-thienylalanine4,D-Tic7,++ +Oic8]bradykinin). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the human bradykinin receptor subtypes, FR190997 showed a high affinity binding to the B2 receptor with IC50 value of 5.3 nM and no binding affinity for the B1 receptor. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity. This compound should represent a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.

Animals↗
PubMed1997

Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.

To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorded under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo.

Animals↗
PubMed1997

Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by recombinant granulocyte colony-stimulating factor (rhG-CSF): comparison between intravenous and subcutaneous administration.

Pharmacological effect after intravenous (i.v.) or subcutaneous (s.c.) administration of human recombinant granulocyte colony stimulating factor (rhG-CSF) was evaluated by using a physiologically based pharmacokinetic/pharmacodynamic model. The increase of neutrophil counts in blood after s.c. administration of rhG-CSF (0.5-1.0 microgram/kg) was larger than that after i.v. administration of the same dose, while area under the curves of plasma concentration of rhG-CSF after s.c. administration was smaller than that after i.v. administration (Azuma et al., J. Clin. Therap. Med., 5, 1579-1603, 1989). Based on the pharmacokinetic/pharmacodynamic model considering metabolic turnover of neutrophil in vivo, time course of absolute neutrophil counts in blood after either type of rhG-CSF administration to normal healthy volunteers was analyzed. The nonlinear relationship between the concentration of rhG-CSF and in vitro activity for proliferation of neutrophil could be explained by the drug-receptor-effector ternary complex model. These in vivo and in vitro models made it possible to understand the above-mentioned discrepancy of pharmacokinetic/pharmacodynamic behavior between i.v. and s.c. administration of rhG-CSF. Simulation of the neutrophil count-time profiles after repeated i.v. and s.c. dosing of rhG-CSF according to these models showed good agreement with the observed data. In order to obtain the rational dosage regimen of rhG-CSF from pharmacological and economical points of view, a slow constant infusion method may be more useful than rapid infusion.

Administration, Cutaneous↗
PubMed1997

Effect of acute renal failure on neurotoxicity of enoxacin in rats.

We investigated the effect of acute renal failure on the neurotoxicity of enoxacin (ENX) in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. ENX was intravenously infused to ureter ligated (UL) and control rats, and its concentration in plasma, brain and cerebrospinal fluid (CSF) was compared. Plasma concentration of ENX increased rapidly in UL rats as compared with control rats. Brain/plasma concentration ratio (Kp)-time profile of ENX was similar in UL and control rats. Brain concentration of ENX at the occurrence of convulsion did not depend on the infusion rate, suggesting that in the brain tissue it equilibrates rapidly with the site of action for clonic convulsion. Brain concentration of ENX in UL rats at the occurrence of clonic convulsion was lower than that in control rats. A similar tendency was also observed with CSF concentration. In conclusion, the potentiation of neurotoxicity of ENX with acute renal failure may be caused by not only decreased capability for renal elimination of ENX but also increased sensitivity to convulsant activity of ENX in the central nervous system.

Acute Kidney Injury↗
PubMed1997

Effect of acute renal failure on the distribution of iomeprol, a nonionic contrast agent, to cerebrospinal fluid in rats.

The effect of acute renal failure on the pharmacokinetics concerning the cerebrospinal fluid (CSF) distribution of iomeprol, a nonionic contrast agent, was studied. The concentrations of iomeprol in the plasma and CSF were measured after intravenous (i.v.) administration at the dose of 50 or 500 mg/kg body weight. The time courses of plasma and CSF concentration were linear within the dose studied. Influx and efflux clearances estimated by simultaneous fitting were 4.6 x 10(-5) ml/min and 8.8 x 10(-4) ml/min, respectively, which suggested that the distribution of iomeprol to CSF low and linear. The distribution volume at steady state was 300-500 ml/kg, suggesting that iomeprol was readily distributed to the extracellular space but hardly distributed to the intercellular space. Total body clearance (9-13 ml/min/kg) indicated that iomeprol was mainly excreted by glomerular filtration. In the rat with acute renal failure induced by ligating the binary ureters, the concentration of iomeprol in CSF after i.v. administration of 500 mg/kg dose was much higher than that in the intact rat according to the delay of elimination from plasma (CLtot = 0.07 ml/min/kg). However, the time course of iomeprol concentration in CSF was predictable using the values of the influx clearance to CSF and the efflux clearance from CSF determined by intact rats. In conclusion, renal failure is one risk factor for central nervous system toxicity because of decreased total body clearance, while acute renal failure may not affect the transport of iomeprol to CSF.

Acute Kidney Injury↗
PubMed1997

[Quantitative evaluation of pharmacological effects and adverse effects based on receptor occupancy theory].

For the quantitative assessment of therapeutic/pharmacologic effects and adverse/toxic effects of drugs which interact with several specific receptors, we developed an integrated pharmacokinetic analysis system by considering a receptor occupancy theory and a ternary complex model. The developed system has made it possible to predict the optimal dosage for the investigation of drugs using pre-clinical and clinical data (phase I study) under development, and to assess quantitatively the intensity of adverse/toxic effects of drugs which are not observed in the stage of clinical study. As for commercially available drugs, the developed system may be useful for planning the rational drug dosage regimen to obtain desired therapeutic effects with minimum adverse/toxic effects. Our new methodology for the rational dosage regimen of a new drug will be established based on the results of this study.

Animals↗
PubMed1997

Proprotein-processing endoprotease furin controls growth of pancreatic beta-cells.

We have previously reported that in the well-differentiated beta-cell line MIN6 cells, the beta-cell-specific differentiated characteristics, such as insulin content, expression of prohormone convertases PC2 and PC3, and glucose-regulated insulin secretion, diminished when the proprotein-processing endoprotease furin was highly expressed. Since furin converts many growth-related protein precursors to their bioactive forms, we compared the four pancreatic islet cell lines RINm5F, betaTC3, betaHC9, and MIN6 with respect to cell growth rate, furin expression, endoprotease activity, and insulin content. RINm5F cells exhibited the strongest furin expression, higher furin-type endoprotease activity, and the fastest cell growth, but had the least insulin content. In contrast, MIN6 cells exhibited only a weak furin expression, little furin-type endoprotease activity, and the slowest cell growth, but had the highest insulin content. To test whether furin-expressing cells secrete growth-promoting factors cleaved by furin, we prepared conditioned media from RINm5F and furin cDNA-introduced MIN6 (MIN6-F) cells. The conditioned media from RINm5F and MIN6-F induced increased DNA synthesis and promoted the growth of normal MIN6 cells, compared with the medium from the empty vector-introduced MIN6-0 cells. We then examined the effect of the protease inhibitors alpha1-antitrypsin and its variants by infecting their vaccinia recombinants to the four cell lines. All conditioned media from each cell line expressing the furin-specific alpha1-antitrypsin variant exhibited the least DNA synthetic capacity on normal MIN6 cells. Furthermore, all three sublines of MIN6-F grew faster than MIN6-0 and MIN6. Thus, we suggest that the islet cells with higher furin expression may induce increased production of growth factors, which result in an increase in cell growth, through an autocrine/paracrine mechanism.

Animals↗