Biomedical subjects

M Shibasaki

Publications and source records attributed to M Shibasaki.

At least 145 records · Page 8Linked to original sources

PubMed1995

Interindividual variations of desmethylation and hydroxylation of amitriptyline in a Japanese psychiatric population.

We measured the concentrations in plasma of amitriptyline and its metabolites, nortriptyline and geometric isomers of 10-hydroxynortriptyline and 10-hydroxyamitriptyline, in 73 Japanese psychiatric patients receiving amitriptyline hydrochloride (Tryptanol; Banyu Pharmaceutical Co. Ltd., Tokyo, Japan) by high-performance liquid chromatography. Although there were large interindividual variations of total drug concentrations and concentrations of parent or intermediate metabolic compounds in plasma, significant positive correlations were observed between these drug concentrations and daily doses of amitriptyline hydrochloride (milligrams per kilogram of body weight). The metabolic ratios for both hydroxylation and desmethylation varied substantially with approximately 8- to 19-fold interindividual variations. Frequency distribution histograms and probit analyses of these parameters identified neither definite poor hydroxylators nor poor desmethylators of amitriptyline.

Adult↗

PubMed1994

Pharmacological properties of YM-26365, a low molecular weight, orally active renin inhibitor.

This report describes the pharmacological properties of a novel renin inhibitor (YM-26365: (3R)-3-[3-[(1S)-1-cyclohexylmethyl-2-hydroxy-3- [(1-methyl-5-tetrazolyl)thio]propyl]ureido]-1-methyl-5-phenyl- 2,3-dihydro-1H-1,4-benzodiazepin-2-one) with molecular weight 577 and no peptide bonds. YM-26365 inhibited human plasma renin with an IC50 value of 2.9 x 10(-6) M, but did not affect plasma renin from dogs, rabbits, and rats at 10(-4) M. YM-26365 inhibited not only human renin, but also cathepsin D with an IC50 value of 1.7 x 10(-5) M. This compound competitively inhibited the reaction between recombinant human renin and N-acetyl tetradecapeptide with a Ki value of 1.1 x 10(-6) M. In pithed spontaneously hypertensive rats, YM-26365 at 10 mg/kg i.v. significantly antagonized the pressor response to recombinant human renin, but did not affect responses to angiotensin II, angiotensin I, norepinephrine, or arginine vasopressin. Similarly, oral administration of YM-26365 (10 and 30 mg/kg) to pithed spontaneously hypertensive rats caused a shift to the right of the recombinant human renin dose-pressor response curve. Systemic bioavailability as determined on the basis of the ratio of the total area under the plasma concentration-time curve after 3 mg/kg i.v. and 30 mg/kg orally to rats was 9.6%. These results demonstrate that YM-26365 is a weak but orally absorbed, low molecular weight renin inhibitor.

Administration, Oral↗

PubMed1994

Specific immunotherapy reduces the antigen-dependent production of eosinophil chemotactic activity from mononuclear cells in patients with atopic asthma.

BACKGROUND: The efficacy of specific immunotherapy has been verified. There is accumulating evidence focusing on the T lymphocyte-eosinophil interaction in the pathogenesis of asthma. The aim of this study was to clarify whether immunotherapy affects the production of eosinophil chemotactic activity (ECA) from peripheral blood mononuclear cells (PBMC). METHODS: PBMC obtained from persons with bronchial asthma who were sensitive to Dermatophagoides farinae (Df) or from healthy volunteers were cultured for 96 hours in the presence or absence of Df. ECA in culture supernatants was assayed by means of the modified Boyden's chamber method. RESULTS: There was no significant difference in the baseline levels of ECA between asthmatic persons treated with immunotherapy and those without immunotherapy. The addition of Df (10 to 10(4) ng/ml) enhanced the ECA production in a dose-dependent fashion in asthmatic persons without immunotherapy, and there was a statistically significant correlation between the concentrations of Df and the levels of ECA (rk = 0.34; p < 0.05). In contrast, Df-dependent ECA production was suppressed in asthmatic persons with immunotherapy, and the suppressive effect was observed from 4 weeks after rush immunotherapy. CONCLUSIONS: These results indicate that immunotherapy induces the suppression of antigen-dependent production of ECA from PBMC. This may contribute to the attenuation of eosinophil infiltration into the airways in asthma patients.

Adolescent↗

PubMed1994

Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys.

1. The effects of barnidipine, a new dihydropyridine Ca2+ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys. 2. Barnidipine (0.3-3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr. 3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph. 4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration. 5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

Animals↗

PubMed1994

Characterization of the adrenoceptor antagonistic and antihypertensive activity of oral amosulalol, a combined alpha- and beta-adrenoceptor antagonist, in hypertensive rats.

The adrenoceptor antagonistic and antihypertensive effects of amosulalol, 5-[1-hydroxy-2-[[2-(o- methoxy)ethyl]-2-ethylbenzenesulfonamide HCl, a combined alpha- and beta-adrenoceptor antagonist, were examined in hypertensive rats. Oral administration of amosulalol (1-30 mg/kg) produced a dose-dependent antihypertensive effect without reflex tachycardia in conscious spontaneously hypertensive rats (SHR) with a duration > 10 h after the higher doses (10 and 30 mg/kg). Amosulalol was approximately threefold more potent than labetalol and arotinolol in decreasing blood pressure (BP) in conscious SHR. Oral (p.o.) administration of amosulalol 10 mg/kg produced equally potent reductions in mean arterial BP (MBP) without reflex tachycardia in deoxycorticosterone acetate-salt rats (DHR) and renal hypertensive rats (RHR) as it did in SHR. Repeated oral administration (1, 4, 8, or 12 weeks) of amosulalol 10 mg/kg elicited an antihypertensive effect without evidence of tolerance in conscious SHR and produced a rightward shift in phenylephrine (PE)-induced vasopressor and isoproterenol (ISO)-induced positive chronotropic responses with dose ratios of 3.3-12.5 and 3.7-6.4, respectively, in pithed SHR. In addition, single p.o. administration of amosulalol 10 mg/kg produced a rightward shift in these responses with dose ratios of 12.1 and 3.5, respectively, in pithed SHR. Amosulalol exerted antihypertensive activity without tachycardia through blockade of vascular alpha- and cardiac beta-adrenoceptors, and its activities were constant even after repeated p.o. administration.

Administration, Oral↗

PubMed1994

Serum levels of major basic protein in patients with or without eosinophilia: measurement by enzyme-linked immunosorbent assay.

A bone marrow proteoglycan (BMPG) has been purified which consists of the same amino acid sequence as that of pro-MBP, and produced two anti-BMPG mAbs. Serum levels of major basic protein (MBP), a cationic protein rich in the eosinophil granule, were measured in patients with eosinophilia or allergic diseases by an enzyme-linked immunosorbent assay (ELISA) using these mAbs. The serum levels of MBP in patients with eosinophilia (n = 64) and in those with allergic diseases without eosinophilia (n = 32) were elevated significantly (P < 0.001 and P = 0.038, respectively). There was a weak positive correlation between the serum levels of MBP and the eosinophil counts in the patients with eosinophilia (r = 0.38). Among these patients, extremely high serum levels of MBP were found in those with hypereosinophilic syndrome (HES) and Kimura's disease. Serum levels of MBP decreased more slowly than the eosinophil counts in patients with eosinophilia when treated by glucocorticoids. We conclude that measurement of serum levels of MBP is useful in evaluating the total-body proliferation and infiltration of eosinophils more accurately than following-up the eosinophil counts alone.

Aged↗

PubMed1994

Crossreactivity of IgE antibody against Dermatophagoides farinae with Limulus polyphemus agglutinin.

Crossreactivity of IgE antibody against Dermatophagoides farinae (Der f) with Limulus polyphemus agglutinin (LPA) was examined using RAST and immunoblot analysis. Of 40 Der f-sensitive asthmatic patients, 28 revealed a positive RAST reaction to LPA, while none of 20 Der f-insensitive hay fever patients showed this reaction. LPA-specific RAST levels of the 40 asthmatic patients correlated with their Der f-specific levels. The RAST reactivity to LPA was competitively inhibited by the addition of either soluble Der f or LPA, but not by the specific inhibitory sugar of sialic acid. LPA could also induce histamine release from leucocytes of Der f-sensitive asthmatic patients. IgE immunoblot analyses showed that the positive RAST sera for LPA had a strong IgE binding activity to the 30 kDa and 80 kDa components of Der f body extract, whereas gel filtration studies showed that the high molecular weight fractions above 150 kDa retained antigenic constituents associated with IgE reactivity to LPA. These results suggest that the antigenic materials of Dermatophagoides mites share some determinants with the haemagglutinin of horseshoe crabs.

Adolescent↗

PubMed1994

Pharmacokinetics and cardiovascular effects of YM-21095, a novel renin inhibitor, in dogs and monkeys.

The pharmacokinetics and cardiovascular effects of YM-21095 ((2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)- butyl]-L-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thi o]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg-1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t1/2 alpha = 4.9 +/- 0.2 min, t1/2 beta = 2.76 +/- 0.79 h, Vdss = 3.86 +/- 1.04 L kg-1, plasma clearance = 2.22 +/- 0.39 L kg-1, and AUC = 1445 +/- 266 ng h mL-1. After 30 mg kg-1 oral dose, maximum plasma concentration, tmax and AUC of YM-21095 were 28.8 +/- 9.6 ng mL-1, 0.25 h and 23.6 +/- 7.7 ng h mL-1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0.16 +/- 0.04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg-1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg-1 oral dose to monkeys was 71.8 +/- 41.5 ng mL-1, which was reached 0.5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1994

Influence of age on IgE responsiveness to Dermatophagoides farinae: an immunoblot study.

IgE responsiveness to Dermatophagoides farinae body extract was compared by immunoblotting among four groups of mite-sensitive asthmatic children: group I aged 0-3, group II aged 4-7, group III aged 8-11 and group IV aged 12-15. In the group I subjects, the 15-kD component was bound by 88% of sera and strongly by 56% of sera. The 25-kD component was bound by 40% of sera, but most of the binding reactions were faint. IgE binding to other components was generally low. In the group II subjects, 15- and 25-kD components were bound by 96% and 56% of sera, 30-kD and 110-kD components by 76% and 60% of sera, respectively. In addition, 18-, 40-, 59- and 80-kD components were bound by more than 30% of sera. In group III and IV subjects, the frequencies of IgE binding to these components were not significantly changed as compared with those of group II subjects. The rabbit antisera against Der f I and Der f II specifically reacted with 25- and 15-kD components, respectively. These results suggest that the 15-kD Der f II allergen is the most important antigenic constituent associated with the early IgE response to house dust-mites in mite-reactive asthmatic children.

Adolescent↗

PubMed1994

Effect of electric heating carpet on house dust mites.

An electric heating carpet (EHC) that had been especially modified to produce a steady surface temperature of 45 to 50 degrees C was set up in the bedroom of an asthmatic patient, and the density of floor dust mites in this room was compared monthly for 2 years with that in two non-EHC control rooms. When the EHC was used during the mite-growing summer season, the monthly variation in mite density in the EHC room was almost parallel to that in the non-EHC rooms, with a preponderance of floor mites in the non-EHC rooms. In contrast, when the EHC was used during the winter season, the density of floor mites in the EHC room increased as compared with that in the non-EHC rooms, and the ratio of mite density in the EHC room to that in the non-EHC rooms was transiently reversed during this period.

Animals↗

PubMed1993

Relation of plasma and red blood cells reduced haloperidol concentrations to haloperidol reductase activity assayed in red blood cells in psychiatric population.

1. Haloperidol (HAL) reductase activity in red blood cells (RBC) was determined by a newly developed assay method in 120 blood samples from 75 Japanese psychiatric patients receiving HAL. 2. Plasma concentrations of HAL and reduced haloperidol (RHAL), a reductive metabolite of haloperidol, were also measured in these samples. 3. RBC concentrations of HAL and RHAL were measured in 62 of these samples. 4. No significant correlations were found between HAL reductase activity in RBC vs plasma or RBC RHAL/HAL ratios, which may represent activity of the enzyme metabolizing HAL into RHAL. 5. RHAL concentrations were three times higher in RBC than in plasma, though HAL concentrations were at the same level in both tissues. This may reflect accumulation of RHAL in RBC.

Adolescent↗

PubMed1993

Regional cerebral blood flow in catatonic schizophrenia.

Single photon emission computed tomography (SPECT) with 123I-iodoamphetamine (IMP) as tracer was used to study regional cerebral blood flow (rCBF) distribution in six patients with the catatonic subtype of schizophrenia (DSM-III-R). IMP-SPECT imaging revealed a significant reduction of rCBF in the parietal lobes of both hemispheres. Three-dimensional reconstruction of the SPECT images identified the superior region of the frontoparietal lobe as the most severely affected region. The pattern of rCBF deficits observed in catatonic schizophrenia differs markedly from that seen in 13 patients with other subtypes of schizophrenia and 7 normal control subjects. These observations indicate that parietal lobe dysfunction may be an important component in the pathology of the catatonic subtype of schizophrenia.

Adolescent↗

PubMed1993

Syntheses and biological activities of chemically stable prostacyclin mimics with cis-bicyclo[4.3.0]nonene ring system: the novel homoisocarbacyclin analogues.

The synthetic studies concerning a series of homoisocarbacyclin analogues, which are homologous compounds of isocarbacyclin, with cis-bicyclo[4.3.0]non-2-ene or cis-bicyclo[4.3.0]non-3-ene as a nucleus have been carried out. The general synthetic methods of homoisocarbacyclin analogues have been accomplished starting with the versatile Corey lactone. Among the analogues synthesized in the present studies, a promising compound (TY-11223) exhibiting a good selectivity in biological actions was found to be studied further.

Animals↗

PubMed1993

Relation between bronchial responsiveness to methacholine and levels of IgE antibody against Dermatophagoides farinae and serum IgE in asthmatic children.

The relation between non-specific bronchial responsiveness and allergic sensitivity was evaluated in children with asthma. Bronchial responsiveness was determined by methacholine inhalation challenge test, and was expressed as a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20). RAST titre for Dermatophagoides farinae and serum IgE level were evaluated as parameters of allergic sensitivity. When the PC20 values, RAST titres for D. farinae, and serum IgE levels of 47 asthmatic children and 16 normal controls were compared, the asthmatic children had significantly lower PC20 values and higher D. farinae-RAST titres and serum IgE levels than the normal controls. The correlation analyses in 47 asthmatic children have shown that there is no significant correlation between PC20 values and RAST titres for D. farinae (r = 0.04, P > 0.1) or between PC20 values and serum IgE levels (r = 0.03, P > 0.1). These results suggest that although both bronchial hyperresponsiveness and allergic sensitization may be in some way related to one another in children with asthma, the magnitude of allergic sensitization does not influence the degree of the non-specific bronchial responsiveness.

Adolescent↗

PubMed1993

[Bronchial asthma pediatric field].

The role of eosinophils and their activation products in the development of asthma in children has been reviewed, based on the recent data from our laboratory. The levels of the peripheral blood eosinophils and eosinophil cationic protein (ECP), and bronchial sensitivity to methacholine (PC20) were compared among three groups: Group A, mite-sensitive asthmatic children, Group B, mite-sensitive non-asthmatic children having the same level of IgE antibody against mite(Df) as Group A, and Group C, mite-insensitive normal control children. Group A had significantly higher eosinophil and ECP levels than Group B, and Group B had also higher levels than Group C. The PC20 values in Group A were significantly lower than those in Group B, and the values in Group B were also significantly lower than those in Group C. These results have suggested that activation of eosinophil is an important contributing factor for the development of asthma in children in addition to allergic sensitization.

Age Factors↗

PubMed1993

[The influence of rush immunotherapy on the production of interleukin-5 from mononuclear cells].

We investigated the influence of rush immunotherapy (RI) on the production of interleukin (IL)-5 from peripheral blood mononuclear cells (PBMC) in asthmatics sensitive to Dermatophagoides farinae (Df). The levels of IL-5 produced varied among the subjects, and these levels were not affected by the addition of Df, regardless of RI. When IL5 levels were individually compared before and after RI, some cases demonstrated an apparent decrease in production at 16 weeks after RI. It is considered that further study will be needed to confirm whether or not immunotherapy can truly suppress the production of IL-5.

Adolescent↗

PubMed1992

The effect of intravenous recombinant human renin on blood pressure in pithed spontaneously hypertensive rats.

The effect of highly purified recombinant human renin (rh-renin), expressed in Chinese hamster ovary cells, on mean blood pressure (MBP) was evaluated in pithed spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous bolus injection of rh-renin produced dose-dependent increases in MBP in pithed SHR and WKY. The pressor response to rh-renin in pithed SHR was about 3 times as potent as that in pithed WKY. Intravenous infusion of rh-renin produced dose-dependent progressive increases in MBP during the first 40 min, reaching plateaus and thereafter MBP was maintained up to 120 min. This hypertensive response to rh-renin was antagonized by renin inhibitors, YM-21095 and KRI-1314, which inhibited the reaction between rh-renin and tetradecapeptide competitively, with Ki values of 5.1 x 10(-10) and 4.3 x 10(-9) M, respectively. In rh-renin-infused pithed SHR, the hypotensive effect of YM-21095 was 37 times as potent as that of KRI-1314. These results suggest that rh-renin can stimulate the rat renin-angiotensin system, thereby producing hypertension. Moreover, the rh-renin-infused rat model could be useful to evaluate the effect of renin inhibitor.

Animals↗

PubMed1992

Effect of the optical isomers of YM-12617 on increased intra-urethral pressure induced by phenylephrine in anaesthetized dogs.

1. Effects of the individual optical isomers of YM-12617 (R, S 5-[2-[[2-(o-ethoxyphenoxy)ethyl]-amino]propyl]-2- methoxybenzenesulphonamide HCl, (+/-)-YM), a potent selective alpha 1-adrenoceptor antagonist, on the increase in intraurethral pressure (IUP) and diastolic blood pressure (DBP) induced by phenylephrine were evaluated in pentobarbital-anaesthetized female dogs. 2. Phenylephrine (0.1-30 micrograms kg-1 i.v.), an alpha 1-adrenoceptor agonist, dose-dependently increased IUP and DBP. 3. alpha-adrenoceptor antagonists (i.v.) dose-dependently antagonized the increase in IUP and DBP induced by phenylephrine, with a potency ranking of R(-)-YM greater than (+/-)-YM greater than prazosin greater than phentolamine greater than S(+)-YM greater than yohimbine. 4. These results suggest that the alpha 1-adrenoceptor mediates the increase in IUP as well as DBP in anaesthetized dogs, and that alpha 1-adrenoceptors in the urethra and arteries show a stereochemical preference for R(-)-YM.

Adrenergic alpha-Agonists↗