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Biomedical subjects

M Otsuka

Publications and source records attributed to M Otsuka.

At least 307 records · Page 17Linked to original sources
PubMed1992

Amorphism and physicochemical stability of spray-dried frusemide.

The physicochemical properties of amorphous forms of frusemide, prepared by spray-drying at 50 or 150 degrees C, and their hygroscopic stability at temperatures of 25 and 40 degrees C, and at 0 and 75% relative humidity were investigated. The glass transition temperature of the amorphous form A was 44.2 degrees C as measured by differential scanning calorimetry, while that of the amorphous form B was 54.4 degrees C. The activation energies for glass transition and crystallization processes were calculated from the differential scanning calorimetry thermograms of amorphous forms A and B, respectively. Stability determined by X-ray diffraction at 0% relative humidity, 25 and 40 degrees C suggested that form B was more stable than form A. However, the stability of form A at 75% relative humidity and 25 and 40 degrees C was similar to that of form B.

Drug Stability↗
PubMed1992

CBF and oxygen metabolism in hemodialysis patients: effects of anemia correction with recombinant human EPO.

To investigate the effects of anemia correction with recombinant human erythropoietin (rhEPO) on both cerebral blood flow and oxygen metabolism in hemodialysis (HD) patients, the regional cerebral blood flow (rCBF), oxygen extraction (rOEF), and metabolic rate for oxygen (rCMRO2) were measured by positron emission tomography in five HD patients, and the data were compared with eight nondemented controls who had neither anemia nor uremia. In the HD patients, 1,500 U of rhEPO were administered intravenously three times a week to achieve a 10% increase in hematocrit (Hct) as an absolute value. Before rhEPO administration, the hemispheric rCMRO2 in HD patients was 1.48 +/- 0.09 (SE) ml.min-1.100 ml-1, which was significantly lower than that of 2.18 +/- 0.10 in the controls (P less than 0.01). In contrast, both rCBF and rOEF were significantly greater in the HD patients than the control, being 40 +/- 3 vs. 32 +/- 3 ml.min-1.100 ml-1 for rCBF (P less than 0.02) and 49 +/- 1 vs. 38 +/- 1% for rOEF (P less than 0.001). After treatment with rhEPO, Hct rose significantly from 21 +/- 1 to 31 +/- 1% in HD patients (P less than 0.001). There were significant reductions in both the hemispheric rCBF to 32 +/- 1 ml.min-1.100 ml-1 (P less than 0.01) and rOEF to 42 +/- 1% (P less than 0.01). However, the hemispheric rCMRO2 remained low at 1.58 +/- 0.06 ml.min-1.100 ml-1 even after rhEPO treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Combined effects of laser irradiation and chemical inhibitors on the dissolution of dental enamel.

It has previously been shown that the susceptibility of human teeth to acid dissolution can be reduced by the presence of various chemical agents in the dissolution medium or by pretreatment of the teeth with laser irradiation. Now synergism between these two approaches to improving acid resistance has been demonstrated. Extracted human teeth were irradiated with a continuous-wave carbon dioxide laser at a wavelength of 10.6 microns. Energy doses of either 65 or 130 J/cm2 given over periods of 2 or 4 s, respectively, were applied and the teeth subjected to a severe acid challenge (0.1 M acetate buffer, pH 4.5, no calcium or phosphate common ion present) for 24 h. Mineral loss was assessed by measurement of mineral density profiles with quantitative microradiography. Experiments were carried out in the presence or absence of three chemical inhibitors with distinctly different mechanisms of action: ethane-1-hydroxy-1, 1-diphosphonic acid, fluoride, and dodecylamine HCl. Laser irradiation alone was found to lead to increased resistance of the teeth to acid challenge, with the higher energy dose being more effective than the lower dose. Each of the chemical inhibitors was effective on both lased and unlased teeth, with the percent reduction of dissolution greater when the inhibitors were applied to teeth lased with an energy dose of 130 J/cm2 which were already more resistant to acid challenge than were unlased teeth or teeth lased with a dose of 65 J/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1992

Cerebrovascular responsiveness to hypercapnia in Alzheimer's dementia and vascular dementia of the Binswanger type.

BACKGROUND AND PURPOSE: Alzheimer's dementia is thought to be a primary degenerative dementia, whereas vascular dementia of the Binswanger type is an entity of vascular dementia. We evaluated the cerebrovascular responsiveness to hypercapnia to clarify the differences in the cerebral hemodynamics between two groups of patients. The subjects were eight younger control subjects, five age-matched control subjects, five Alzheimer's patients, and five patients with vascular dementia of the Binswanger type. SUMMARY OF REPORT: In the resting state, the regional cerebral blood flow was low in both Alzheimer's dementia and vascular dementia of the Binswanger type. The responsiveness to hypercapnia was preserved in Alzheimer's dementia, whereas it was impaired in vascular dementia of the Binswanger type in the cerebral cortices and in the deep white matter. CONCLUSIONS: These results suggest that small vascular lesions exist in vascular dementia of the Binswanger type but not in Alzheimer's dementia, even though regional cerebral blood flow was thought to decrease by hypometabolism in both types of dementia.

Adult↗
PubMed1992

Initial dissolution rate studies on dental enamel after CO2 laser irradiation.

The influence of CO2 laser irradiation on the dissolution behavior of human dental enamel has been investigated. Human enamel was irradiated by a continuous-wave CO2 laser at 10.6 microns and initial dissolution rates (IDRs) were measured in 0.1 mol/L acetate buffer, pH = 4.5, both with and without calcium and/or phosphate common ion, by means of a rotating disk assembly. The effects of (1-hydroxyethylidene) bisphosphonic acid (EHDP), fluoride (F), and dodecylamine HCl (DAC) at various levels upon the IDR were also determined. All of the findings were consistent with the hypothesis that CO2 laser irradiation converts dental enamel to hydroxyapatite (HAP) possessing site #2 character (Yamamoto et al., 1986). The dissolution driving force function, KHAP = aCa10aPO4(6)aOH2, was found to have a value of 10(-129.9) after being lased, as compared with 10(-121.4) before being lased. The IDR values for EHDP (3 mmol/L) and DAC (3 mmol/L) were essentially zero as expected for site #2 HAP. For solution F, the deduced dissolution driving force function, KFAP = aCa10aPO4(6)aF2 was 10(-128.6) after being lased as compared with 10(-116.3) before being lased. These results all support the hypotheses (1) that laser irradiation may convert the surface of human dental enamel to an apatite of significantly lower effective solubility (i.e., site #2 HAP) than that of unlased enamel; and (2) that there is significant synergism between laser treatment and these chemical dissolution rate inhibitors (again consistent with site #2 HAP). Simple model calculations indicate that, in both the presence and absence of fluoride, these laser-induced changes in the driving force for dissolution should dramatically lessen the susceptibility of enamel to the types of acid challenge that might be encountered in the mouth.

Amines↗
PubMed1992

[Mutagenicity studies of prednisolone farnesylate (PNF)].

Prednisolone farnesylate (PNF) was tested for mutagenicity by Ames test using Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), for clastogenic activity in vitro by the chromosomal aberration test in a Chinese hamster fibroblast cell line (CHL), and for induction of micronuclei by the micronucleus test in male ICR mice. 1) In Ames test, PNF with and without metabolic activation showed no mutagenicity in any strains at any dose levels (312-5,000 micrograms/plate). 2) In the chromosomal aberration test, PNF with metabolic activation produced a slight increase in the incidence of structural chromosomal aberrations in CHL cells at 1,500 micrograms/ml. 3) In the micronucleus test, a single administration of PNF caused no significant increase of micronucleated polychromatic erythrocytes at any doses (250-2,000 mg/kg).

Animals↗
PubMed1992

Vitamin C activity of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid in guinea pigs.

The vitamin C activity of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), which is one of chemically stable derivatives of L-ascorbic acid (AsA), in guinea pigs was investigated. Male guinea pigs were divided into 9 groups and fed AsA-deficient diet for 24 days with the following supplement: AA-2G- or AsA-supplemented groups were orally supplemented with 0.96, 1.92, 9.6 and 192 AA-2G mg/animal/day or equimolar amounts of AsA (0.5, 1, 5 and 100 mg/animal/day, respectively); AsA-deficient group received neither of them. The body weight gain, serum alkaline phosphatase activity, and the concentration of AsA and AA-2G in the liver, adrenals and urine of the guinea pigs were measured at the end of the experimental period. The AA-2G-supplemented guinea pigs showed similar body weight gain to the animals supplemented with equimolar amount of AsA. Serum alkaline phosphatase activity in both AA-2G- and AsA-supplemented groups was significantly higher than that of AsA-deficient group. But there was no significant difference between the groups supplemented with AA-2G and the equimolar amount of AsA. AA-2G-supplemented guinea pigs showed no apparent symptoms of scurvy. In AA-2G-supplemented groups, AA-2G was not detected in the liver, adrenals and urine, but AsA was found and the AsA concentration increased with increasing AA-2G dosage. The AsA concentration in the tissues of each AA-2G-supplemented groups was higher than that of AsA-deficient group, which was similar to that of the groups supplemented with equimolar amount of AsA. These results showed that AA-2G has the same vitamin C activity as AsA on a molar basis for the orally supplemented guinea pigs.

Adrenal Glands↗
PubMed1992

An improved high-performance liquid chromatographic assay for the determination of pyridinoline in connective tissues.

A high-performance liquid chromatographic (HPLC) method for determination of pyridinoline and its application to connective tissues are described. The chromatographic separation was accomplished by using Inertsil ODS-2 column and a mixture of 0.1 M sodium phosphate and acetonitrile (75:25, v/v) containing sodium dodecyl sulfate (SDS) and ethylenediamine tetraacetic acid (EDTA) as eluent. The chromatogram was developed isocratically and the eluted components were monitored with excitation at 295 nm and emission at 395 nm. The pyridinoline in crude hydrolysate of connective tissues can be determined in 5 min, with as little as 1 pmol of sample. The present method is rapid, simple and can be used for the routine analysis of connective tissues such as cartilage, bone, Achilles tendon and aorta.

Amino Acids↗
PubMed1992

Origin of sequence specific cleavage of DNA by bleomycins.

A new DNA photocleaving agent which contains bleomycin A2's DNA binding portion and its mono- and terthiazole analogues have been designed and synthesized, and their DNA binding mode and cleavage base specificity have been studied. The photoactive p-nitrobenzoyl group attached at the end of molecules cleaves DNA on UV irradiation. All the oligo-thiazole compounds exhibited high sequence specificity in DNA scission. The bithiazole derivative did not cleave DNA at or near 5'-GpT-3' or 5'-GpC-3' as expected from widely believed DNA binding mechanism of the antibiotics.

Bleomycin↗
PubMed1992

[Endoscopic analysis of gastric mucosal lesions in patients with adult T-cell leukemia during chemotherapy].

Gastric mucosal lesions in 13 patients with adult T-cell leukemia (ATL) were endoscopically studied at least at 2 occasions during chemotherapy for these patients. X-ray examinations by using barium meal showed deformities in 10 patients and abnormal mucosal pattern in 11 out of 13 patients with ATL. The endoscopic examinations revealed gastric ulcers in 5 patients, erosion in 8, diffuse bleeding in 2, tumorous mucosal folds in one, and submucosal tumor in one patient. In 9 out of 12 ATL patients, pathological study revealed that ATL cells had invaded the mucosal area of the stomach. The ulcers and erosions were improved by chemotherapy in 3 out of 5 and 5 out of 8 patients, respectively, whereas the erosion was not reduced in 2 and even aggravated in one patient. Interestingly, the gastric lesions formed by ATL cell invasion were improved by the administration of anticancer agents in 5 out of 9 patients. However, these lesions reappeared together with systemic lesions of ATL.

Adult↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 2nd communication: tissue distribution and whole-body autoradiography of imidapril in rats.

Tissue distribution, whole-body autoradiography and metabolic profiles in selected tissues of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) were studied in male and female rats after oral and intravenous administration of [N-methyl-14C]-imidapril (1 and 5 mg/kg) or [alanine-3-14C]-imidapril (1 mg/kg). After oral administration of [N-methyl-14C]-imidapril, radioactivity was distributed relatively rapidly to all tissues, except for the central nervous system. Maximum concentrations in most tissues were observed at 30 min to 1 h after dosing. Concentrations greater than those in the plasma were found in the liver, kidney and particularly in the lung except for the gastrointestinal contents. The elimination from the lung was relatively slow (t1/2: ca. 28 h). At 96 h after dosing, there was no evidence of remaining radioactivity in any tissues, except for the lung and kidney. No gender-related differences in the tissue distribution profile of radioactivity were observed in the whole-body autoradiogram. After intravenous administration, the distribution pattern of radioactivity was similar to the results of oral administration, except for the gastrointestinal contents. There was no specific binding of drug-related compounds to melanin-containing tissues such as the hair follicles and the uveal tract of the eye in the pigmented rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 3rd communication: tissue accumulation after consecutive oral administration of [N-methyl-14C]-imidapril in rats.

Accumulation characteristics of radioactivity in the organs and tissues, metabolism, and excretion of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), an oral angiotensin-converting enzyme inhibitor, were investigated after consecutive oral administration of [N-methyl-14C]-imidapril at a once-daily dose of 1 mg/kg to male rats for 14 days. During the consecutive oral administration, the plasma radioactivity levels at 1 h after each dose reached steady-state following the 3rd to 4th administered dose; this was about 1.4 times higher than the corresponding plasma levels of the first dose. At 24 h after each administration, the plasma levels attained a steady-state at 3-4 days after the beginning of the consecutive dosing. Examination of the time course of plasma radioactivity after the single and multiple (7 and 14 times) oral administration revealed that the Cmax and AUCO-24 h values slightly, but significantly, increased according to repeated dosing and the beta-phase of the t1/2 of disappearance became longer after consecutive dosing. However, these values were not markedly different among consecutive dosing groups. The extent and rate of excretion of radioactivity in the urine and feces were nearly constant during the periods of consecutive oral administration, and were also similar to those after the single oral administration. Total recovery of radioactivity from urine and feces within 96 h after the final dosing was more than 98% of the total dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 4th communication: placental transfer and secretion into milk in rats.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylproply]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-car box ylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) labeled with 14C was administered orally or intravenously to pregnant rats on the 13th or 19th day of pregnancy, and lactating rats on the 7th or 13th day after delivery at a dose of 1 or 5 mg/kg. The placental transfer and the secretion into milk were studied using whole-body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy. Irrespective of the stages of pregnancy, the placental transfer of imidapril was low in the rats after oral administration. The transfer of total radioactivity per fetus on the 13th and 19th day of pregnancy was below 0.001 and 0.07%, respectively, of the dose to their dams during the observation periods. This indicates that the substance-associated radioactivity penetrates the placental barrier to a low extent. After oral administration of [N-methyl-14C]-imidapril to lactating rats on the 7th day after delivery, the concentration of radioactivity in the milk attained a peak at 4 h after administration (0.05 microgram equivalents of imidapril/g), which was about 1/3 of Cmax in the blood. The transfer of imidapril and/or its radioactive metabolites to each suckling via milk after oral dosing was only below 0.03% of the dose to the dams on the 13th day after delivery during the observation periods. The present autoradiographic findings confirmed the above results of tissue distribution studies.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 5th communication: isolation and identification of metabolites of imidapril in rats, dogs, and monkeys.

The metabolism of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino] propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) was studied in rats and dogs after oral or intravenous administration of [N-methyl-14C]-imidapril or [alanine-3-14C]-imidapril, and in monkeys after oral administration of [alanine-3-14C]-imidapril. Radio-chromatographic analysis of the metabolites of imidapril from the plasma, urine, and bile of rats, dogs, or monkeys resulted in the detection of at least four metabolites. These four metabolites were isolated and characterized by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry(GC-MS). Of these metabolites, M1 (6366 A, CAS 89371-44-8) was pharmacologically active; however, M2, M3, and M4 were inactive. There was no evidence of any glucuronides or sulfates of drug-related compounds, or of the piperazine-dione lactam type metabolites of imidapril or 6366 A in the urine of the animals used. Imidapril was metabolized by hydrolysis at the carboxylic ethyl ester side-chain to give M1, and by cleavage of the amide bond to form M2 and M3. M4 was formed by hydrolysis of M3 and/or cleavage of the amide bond of M1. Qualitatively, the same metabolites were found in all animal species tested; however, quantitatively, there were differences in the amounts of metabolites formed depending on the species.

Administration, Oral↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 6th communication: interspecies comparison of pharmacokinetics and excretion of imidapril metabolites in rats, dogs, and monkeys.

The pharmacokinetics and excretion of the main metabolites of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) were investigated in rats, dogs, and monkeys after oral or intravenous administration of [N-methyl-14C]-imidapril and [alanine-3-14C]-imidapril. After oral administration of 14C-labeled imidapril to rats and dogs, the plasma concentrations of the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), reached a peak at 1-2 h in rats and at 2-6 h in dogs. The disappearance half-lives of M1 from plasma were much longer in dogs (6.3-9.3 h) than in rats (0.9-2.3 h). At the point of peak plasma radioactivity, the major radioactive metabolites in the plasma were M2, followed by M3, M4 greater than M1 in rats; in dogs, M2 and M3 followed by M1 greater than M4. After intravenous administration of [N-methyl-14C]-imidapril to rats and dogs, plasma levels of M1 reached a peak at the first measuring time of 5 min in rats and at about 2 h in dogs. The half-lives of plasma M1 levels were similar to those after oral dosing. At 1 h after dosing, the major metabolites in plasma were M1 followed by M2 in both rats and dogs. Irrespective of the route of administration, unchanged imidapril disappeared more rapidly from the plasma in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 7th communication: in vitro metabolism.

In order to clarify the sites of metabolism and the metabolizing enzymes of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), metabolism studies were carried out using rat, dog, monkey, and human plasma and rat tissue homogenates. After incubating with the various plasma samples, imidapril was mainly metabolized to the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), in rat plasma; on the other hand, the ester bond of imidapril was not hydrolyzed in dog, monkey, and human plasma. Imidapril was metabolized to M1, M2, M3, and M4 in all rat tissue homogenates tested. Aside from the above metabolites, no other metabolites were detected. The metabolic activity of imidapril to M1 was the highest in the liver, followed by the kidney and lung; however, it was low in other tissue homogenates. From the results of experiments using certain esterase inhibitors, it has been concluded that the metabolic conversion of imidapril to M1 is mainly due to a carboxylesterase (B-esterase). In contrast, the metabolic activity of imidapril to M2 and M3 (or M4) was highest in the kidney and small intestine while low in other tissues. From the experiments using certain enzyme inhibitors, it has been found that an acetylesterase (C-esterase) is largely involved in the metabolism of imidapril into M2 and M3.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗