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Biomedical subjects

Y Sawada

Publications and source records attributed to Y Sawada.

At least 289 records · Page 16Linked to original sources
PubMed1994

Identification of functional domains of adenovirus tumor-specific transplantation antigen in types 5 and 12 by viable viruses carrying chimeric E1A genes.

The adenovirus (Ad) E1A gene induces in immunized animals a strong tumor transplantation (TSTA) immunity against Ad tumors. Such immunity with group-A and group-C viruses is highly group-specific and no cross-protection is detected between serotypes 5 and 12. This fact was used to map the domains of the Ad5 and Ad12 E1A gene products, respectively, which control the TSTA. We constructed a library of 8 recombinant viruses (H5sub1101 through H5sub1108) which carry chimeric Ad5/Ad12 E1A genes in the background of Ad5. The chimeric genes are functional and these viruses are viable. Some of these constructs induce strong and highly specific tumor syngraft immunity in immunized rats. The viruses carrying the 5' terminus of the first E1A exon derived from Ad12 (viruses H5sub1101, H5sub1102 and H5sub1103) induce strong protection against Ad12 tumors irrespective of the rest of their E1A sequence. The viruses which carry the second exon of the Ad5 E1A gene (viruses H5sub1101, H5sub1102 and H5sub1106) protect against group-C tumors, regardless of the origin of the rest of their E1A gene. The 2 viruses that carry the 5' E1A terminus of the first exon of Ad12 and the second exon of Ad5 (H5sub1101 and H5sub1102) are thus effective in inducing immunity against Ad12 tumors as well as against Ad2 tumors. The viruses which carry the 5' terminus of the first exon derived from Ad5 and the second exon of Ad12 (H5sub1107 and H5sub 1108) fail to induce immunity against either tumor. Expression of only the truncated 5' terminus of the Ad12 E1A gene (viruses H5sub1104 and H5sub1105) is sufficient for induction of Ad12 TSTA. Our results provide direct and unequivocal in vivo evidence that TSTA activities of adenovirus groups A and C are controlled by different domains of their respective E1A genes. The Ad12 TSTA is a function of the 5' terminus of the first E1A exon, while the Ad5 TSTA is coded for by the 3' exon of its E1A gene.

Adenovirus E1A Proteins↗
PubMed1994

Effects of a benzothiazepine calcium blocker on electrolyte alteration in human ischemic and reperfused myocardium.

Intracellular electrolyte alterations of the myocardial cells from the patients pretreated and non-treated with diltiazem in coronary surgery were measured by means of X-ray microanalysis. Myocardial biopsy specimens were obtained at the right atrial wall at non-ischemia, ischemia and reperfusion periods. The ion concentrations at non-ischemia which is the condition of pre-open heart surgery in patients were: Ca 0.8 +/- 0.05, K 108 +/- 2.3, Na 10 +/- 1.9, Cl 30 +/- 1 (mean +/- S.E., mmol/kg wet weight, n = 100-130), and there were no significant differences for Ca, K, Na and Cl with diltiazem administration. The intracellular Ca increased without diltiazem in reperfusion after open heart surgery. However, there was no Ca increase in either the ischemia or reperfusion states with diltiazem. The K content was significantly lower, and the Na and Cl contents were higher than those of non-ischemia in both ischemia and reperfusion without diltiazem. The K loss, and Na and Cl increases in the reperfusion period were recovered to the levels in the non-ischemia state with diltiazem administration. This study showed that the use of calcium-free cardioplegic solution caused intracellular calcium accumulation in a hypothermic global ischemic and reperfused conditions during coronary surgery, whereas, diltiazem could suppress the calcium accumulation. The alterations of potassium, sodium and chlorine were also favourable in patients with diltiazem. The possible mechanism of the effects of diltiazem on the element alterations of myocardium are discussed.

Adult↗
PubMed1994

The effect of food on the interaction of ofloxacin with sucralfate in healthy volunteers.

We have studied the effect of food on the interaction of ofloxacin with sucralfate. Six healthy men took a single oral dose of ofloxacin (200 mg) on 4 occasions: alone after overnight fasting or after breakfast (non-fasting), and with sucralfate fasting or non-fasting. There were no significant differences in the plasma concentration-time profiles of ofloxacin after ofloxacin alone between fasting and non-fasting conditions. On the other hand, the peak plasma concentration and AUC of ofloxacin after co-administration with sucralfate while fasting fell by 70 and 61% compared with ofloxacin alone; the changes non-fasting were 39 and 31% respectively. The interaction of ofloxacin with sucralfate was markedly reduced by food, but still could not be disregarded.

Adult↗
PubMed1994

Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data.

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic parameters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82-0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by "diffusion and flow model" with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.

Animals↗
PubMed1994

A case of protein-losing enteropathy in idiopathic thrombocytopenic purpura with decreased IgA.

A young woman presented with high fever and edema in January, 1984, and was diagnosed as having systemic lupus erythematosus. Prednisolone administration failed to improve her symptoms. In May she was admitted to hospital because of elevated erythrocyte sedimentation rate (ESR), hypoproteinemia, hypogammaglobulinemia, hypocomplementemia, positive antinuclear antibody, elevated immune complex level, and diarrhea. Edema disappeared following administration of diuretics and albumin, although the pathogenesis was still undetermined. In September, she was referred to our institution because of severe watery diarrhea and hypoproteinemia. Endoscopic examination showed a diffuse inflammatory lesion in the duodenum and the colon. Radioisotopic 51Cr-albumin study results were compatible with protein-losing enteropathy. Hypoproteinemia and inflammatory changes of the intestine were improved by antibiotics, suggesting that the inflammatory lesion was caused by bacterial infection. Despite the improvements in clinical symptoms and laboratory findings, the serum IgA level was still low and the thrombocytopenia remained. The morphological characteristics of the megakaryocytes were consistent with idiopathic thrombocytopenic purpura. In May, 1986, the thrombocytopenia deteriorated, causing purpura. Prednisolone was administered again, and this resulted in normalization of the platelet count, although the IgA level remained low. Finally the prednisolone was stopped, and the IgA level gradually recovered, with the improvement of the enterocolitis. The exact pathogenesis of the whole picture in this case is unclear, but an 8-year-long clinical course suggests that the protein-losing was caused by an infectious enterocolitis superimposed on IgA deficiency.

Adult↗
PubMed1994

An evaluation of a new lactic acid polymer drug delivery system: a preliminary report.

A new drug delivery system, made of a mixture of DL-lactic acid polymer and a copoly (L-lactic acid/delta-valerolactone) polymer (LAP) containing varying concentrations of Ofloxacin, has been evaluated. Results revealed that a LAP drug delivery system containing 0.03% Ofloxacin inhibited the in vitro growth of clinically derived Staphylococcus aureus and Pseudomonas aeruginosa. Further, in an in vivo situation in rats, at 1 week after the wound was inflicted, no infection was macroscopically seen in split-thickness wounds that had been covered by LAP drug delivery system containing 0.5 or 0.03% Ofloxacin, and more than 80% of the wound area had epithelialised.

Animals↗
PubMed1994

A method of recording and objective assessment of hypertrophic burn scars.

A technique for recording the shape and size of hypertrophic burns scars during conservative treatment is described. This technique is extremely useful not only for an objective assessment of the healing process but also as an adjunctive research method for comparing two or more differing techniques of treatment. After taking a negative impression of the scar using dental impression material, a positive cast model of the scar is made, which is a three-dimensional copy of the scar. These cast models can be easily obtained and are very precise. They represent the height, size and general appearance of the scar, so that by taking positive impression models at regular intervals, and combining them with photographic and tonometric evaluations, they help in the evaluation of conservative treatment or in studying the mode of action of treatment.

Burns↗
PubMed1994

Effect of perfusate pH on the influx of 5-5'-dimethyl-oxazolidine-2,4-dione and dissociation of epidermal growth factor from the cell-surface receptor: the existence of the proton diffusion barrier in the Disse space.

The influx clearance (PSinf.MID) of the weak acid 5,5'-dimethyl-oxazolidine-2,4-dione (DMO) was determined by the multiple indicator dilution method with the isolated perfused rat liver under various perfusate pH conditions, ranging from 6.4 to 7.6. Although the pH partition theory predicted an increase in influx clearance of ten times in proportion to the change in the unionized fraction of DMO, there was no measurable change in this value. The effect of medium pH on the steady-state cell/medium concentration ratio (C/M) ratio of DMO was also investigated using isolated hepatocytes. The C/M ratio increased while medium pH decreased, but this change was less marked than predicted by the pH partition theory. Finally the pH dependency of the dissociation rate constant (koff) of epidermal growth factor from its receptor was also investigated using both isolated rat hepatocytes and the perfused rat liver. When the extracellular pH was changed from 6.4 to 5.6, the koff value of isolated hepatocytes increased 44 times, while that of the perfused rat liver increased only 9 times. Therefore, the effect of changing the extracellular pH on pH-dependent dissociation of epidermal growth factor from its cell-surface receptor was less in the perfused liver than in isolated hepatocytes. These findings, in addition to the well-known existence of the Na(+)-H+ exchanger on the sinusoidal membrane and the possible existence of the unstirred water layer in the Disse space, seem to suggest the existence of the proton diffusion barrier in the rat liver, which remains stronger in the perfused liver than in isolated hepatocytes.

Animals↗
PubMed1994

Stereospecific distribution of methylphenidate enantiomers in rat brain: specific binding to dopamine reuptake sites.

To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from Kpapp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean Kpapp values for (+)-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the Kpapp values (7.5 and 7.0, respectively) for the (-)-isomer (P < 0.01). The Kpapp value for (+)-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that (+)-MPD was bound specifically to the dopamine reuptake site in the striatum.

Animals↗
PubMed1994

Effect of renal or hepatic dysfunction on neurotoxic convulsion induced by ranitidine in mice.

We investigated the effect of acute renal and hepatic dysfunction on the neurotoxicity of ranitidine, a histamine H2 receptor antagonist. Experimental acute hepatic and renal dysfunction in mice were produced by i.p. injection of uranyl nitrate (UN) and carbon tetrachloride (CT), respectively. Ranitidine was then constantly infused into the tail vein until the onset of clonic convulsion. When compared to control mice, UN treated mice had a significantly shorter onset time to clonic convulsion, lower total dose and higher plasma concentration at initiation of clonic convulsion. In contrast, the convulsive threshold concentration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic and pharmacodynamic data described above were not significantly different from those of the control mice. No significant difference in the brain/plasma concentration ratio was observed between both disease models and the corresponding control mice. Finally, the effect of UN and CT treatment on the convulsive potency after intracerebral (i.c.) administration of ranitidine was investigated in mice. Potentiation of the intrinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we conclude that renal dysfunction is a risk factor for ranitidine neurotoxicity, and this increased risk results from increase in the drug concentration in plasma and brain as a result of impaired renal excretion. No apparent effect of acute hepatic dysfunction was observed on both the pharmacokinetic and pharmacodynamic behavior of the drug.

Acute Disease↗
PubMed1994

Pharmacokinetics and pharmacodynamics of (+)-threo-methylphenidate enantiomer in patients with hypersomnia.

The pharmacokinetics of (+)-methylphenidate after oral administration of 20 mg racemic methylphenidate hydrochloride and the relationship between clinical effects of plasma (+)-methylphenidate concentration were investigated in 15 patients with hypersomnia and four healthy volunteers. The elimination half-life of (+)-methylphenidate in patients was within the range of 2.6 to 3 hours, and the time to reach the peak concentration ranged from 1 to 3 hours. The values of half-life and time to reach the peak concentration in the patients were almost the same as the values in healthy subjects. The plasma (+)-methylphenidate concentration profiles after repeated administration of racemic methylphenidate were similar to those after single administration. No correlation was observed between the plasma (+)-methylphenidate concentration and the subjective sleepiness as measured by Stanford Sleepiness Scale. On the other hand, a significant correlation was found between the sleep latency as measured by the multiple sleep latency test and the plasma concentrations of (+)-methylphenidate (r = 0.850). The time course of the sleep latency after repeated administration was similar to that after single administration. The sleep latency of more than 10 minutes was achieved by maintaining the plasma (+)-methylphenidate concentrations above 3 ng/ml.

Administration, Oral↗
PubMed1994

Pseudopregnancy-dependent accumulation of cholesterol sulfate due to up-regulation of cholesterol sulfotransferase and concurrent down-regulation of cholesterol sulfate sulfatase in the uterine endometria of rabbits.

The uterine endometria of rabbits induced into pseudopregnancy by intramuscular injection of 17 beta-estradiol, followed by intravenous injection of human chorionic gonadotropin, expressed cholesterol sulfate at a significantly high concentration. The highest concentration of cholesterol sulfate was observed 4 days after the injection of gonadotropin for formation of the corpus luteum, being 10 times higher than that in nonpregnant endometria, and 15.2% of the total cholesterol in the endometrium was converted to the sulfated form, whose percentage in nonpregnant endometrium was 3.2%. However, no significant change in the concentration of gangliosides was observed during the period of pseudopregnancy. In the pseudopregnant endometria, the activity of cholesterol sulfotransferase, a cytosolic thiol enzyme, was increased thirtyfold over that in the nonpregnant endometria, whereas cholesterol sulfate sulfatase, a microsomal enzyme, exhibited approximately one-tenth of the activity in nonpregnant endometria. Arylsulfatase C, but not arylsulfatases A and B, exhibited the same change in activity as cholesterol sulfate sulfatase. Thus, the striking increase in cholesterol sulfate after induction of pseudopregnancy was found to be due to the activation of cholesterol sulfotransferase and the simultaneous inhibition of cholesterol sulfate sulfatase.

Animals↗
PubMed1994

The determination of ofloxacin in human skin tissue by high-performance liquid chromatography and correlation between skin tissue concentration and serum level of ofloxacin.

A simple high-performance liquid chromatographic (HPLC) assay was developed for the measurement of ofloxacin in skin tissue, and the correlation between serum levels and skin tissue levels of ofloxacin was determined. The homogenized skin samples were directly introduced into an HPLC system after filtering through a Molcut II membrane filter to remove proteins. The filtrate was concentration on a pre-column using a phenyl-stationary phase and was then introduced to an analytical column using an ODS-stationary phase by column-switching techniques. Ofloxacin and lomefloxacin as an internal standard were detected by UV absorbance at 300 nm. Determination was possible for ofloxacin over the concentrated range 250-3000 ng (g skin tissue)-1; the limit of detection was 100 ng g-1. The absolute recovery of ofloxacin added to skin tissue homogenate was over 72% with a coefficient of variation of less than 4.1%. This method is applied to determination of skin tissue level of ofloxacin in patients after treatment with ofloxacin. The correlation between serum levels and skin tissue levels of ofloxacin was determined for 30 patients after oral administration of ofloxacin. Good correlation was obtained and the coefficient of correlation was 0.84.

Administration, Oral↗
PubMed1994

Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats.

Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression.

Analysis of Variance↗
PubMed1994

Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation.

To examine the role of the choroid plexus in eliminating organic anions from the cerebrospinal fluid (CSF), a kinetic study was performed both in in vivo and in vitro experiments using [3H]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [3H]PCG was eliminated from the CSF much more rapidly than [14C]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [3H]PCG can be accounted for by convective loss at a rate equivalent to CSF turnover, and by diffusional loss across the ependymal surface into the brain extracellular space, respectively. Approximately two-thirds of [3H]PCG elimination was due to a saturable process [Michaelis constant (Km) = 43.0 +/- 17.8 microM, maximum velocity (Vmax) = 619 +/- 286 pmol.min-1 x rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [3H]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (Km = 58 microM, Vmax = 504 pmol.min-1 x rat-1; H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Exp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [3H]PCG in a dose-dependent manner both in vivo and in vitro. A good correlation was observed between the log inhibition constant (Ki) values obtained for these ligands in vivo and in vitro (r = 0.94, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Appearance of tolerance in the increase of contractile muscle tension by ambenonium in rats.

The relationship between the concentration of ambenonium (AMB), a selective and reversible acetylcholinesterase (AChE) inhibitor, in plasma and the potentiation of contractile muscle tension was investigated using a sciatic nerve-muscle preparation of rat. The developed isometric contraction was enhanced dose-dependently after i.v. administration of low doses (5-20 nmol/kg) of AMB, but the contraction was weakened when AMB was administered at high doses (100-1000 nmol/kg), and the concentration-effect relationship was bell-shaped. The muscle contraction profile after 50 nmol/kg administration without previous administration, with 20 nmol/kg and with 50 nmol/kg administered previously were quite different from each other. These findings suggest that the potentiation of contractile muscle tension by AMB may be acutely tolerated and the concentration-effect relationship may change time-dependently.

Ambenonium Chloride↗