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Biomedical subjects

M Nakashima

Publications and source records attributed to M Nakashima.

At least 307 records · Page 17Linked to original sources
PubMed1994

Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors.

The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram (26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Induction of dentin formation on canine amputated pulp by recombinant human bone morphogenetic proteins (BMP)-2 and -4.

Dental pulp cells have the potential to differentiate into odontoblasts. The molecular mechanisms underlying differentiation are not clear. Demineralized dentin matrix is osteoinductive and contains bone morphogenetic protein (BMP) activity. BMPs have been implicated in embryonic odontogenic differentiation and hence may play a role in the differentiation of adult pulp cells into odontoblasts during pulpal healing. This study examined the hypothesis that BMPs induce dentin formation on amputated canine pulp. Recombinant human BMP-2 and BMP-4 were capped with inactivated dentin matrix on amputated pulp. At two months, the amputated pulp was filled with tubular dentin in the lower part and osteodentin in the upper part. The amount of dentin formed was markedly diminished when dentin matrix alone was implanted. These findings imply that recombinant human BMP-2 and BMP-4 induce differentiation of adult pulp cells into odontoblasts. Thus, BMPs may have a role in dentistry as a bioactive pulp-capping agent to induce dentin formation.

Animals↗
PubMed1994

Expression of parathyroid hormone-related peptide in relation to perturbations of gastric motility in the rat.

We studied the expression of PTH-related peptide (PTHrP) and its mRNA in rat gastric smooth muscle in relation to various gastric motility states. Male rats were divided into groups subjected to fasting, feeding ad libitum, cold restraint stress, pyloric ligation, and carbachol stimulation. Cold restraint stress induced abnormal contractions. Rhythmic and moderate contractions were produced by carbachol administration, and marked distension was induced by pyloric ligation. PTHrP mRNA expression was weak in the physiological fasting and feeding states, but was markedly increased by pyloric ligation and carbachol stimulation. PTHrP and its mRNA were localized to the proper muscle layer and muscularis mucosa, but not in the mucosa by immunohistochemistry and in situ hybridization. The gene expression of PTHrP receptor in the gastric tissue was confirmed by reverse transcription-polymerase chain reaction, but serum PTHrP levels did not increase in all groups. These findings suggest that PTHrP acts as an autocrine or paracrine factor in gastric smooth muscle that responds to muscle activity caused by distension and cholinergic stimulation. However, PTHrP gene expression was decreased by stress despite the presence of strong contractions, and the sufficient relaxation did not occur. PTHrP suppression by stress is caused by the increase in corticosterone, as pretreatment of metyrapone, an inhibitor of 11 beta-hydroxylation, enhanced PTHrP gene expression in association with serum corticosterone suppression. In conclusion, PTHrP might be an important gastrointestinal peptide that regulates gastric contractile activity and is influenced by the serum corticosterone level.

Animals↗
PubMed1994

In vivo microdialysis for the transdermal absorption of valproate in rats.

The suitability of sampling via microdialysis for a lipophilic drug, valproate (VPA), was evaluated by the elimination rate constant of VPA solution in an in vitro experimental first-order elimination system. The elimination rate constant of VPA in dialysate was found to be 0.43 +/- 0.05h-1, which was in good agreement with the real elimination rate constant (0.46 +/- 0.02h-1). A change in VPA concentration in the solution surrounding a microdialysis probe was well maintained by the microdialysis method, suggesting no adsorption between the membrane of the microdialysis probe and VPA. On the basis of the in vitro experiment, the effect of a penetration enhancer, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101), on the transdermal absorption of VPA was examined in rats by the use of microdialysis in vivo. An intradermal microdialysis was performed at a flow rate of 1.0 microliter/min for 7h after the dermal application of 50 mM VPA solution with or without 3% (w/v) HPE-101. HPE-101 increased the transdermal absorption rate of VPA by 80 times compared with the control. The microdialysis system was found to be quite useful for assessing the in vivo transdermal absorption of a lipophilic VPA.

Animals↗
PubMed1994

In vivo microdialysis for pharmacokinetic investigations: a plasma protein binding study of valproate in rabbits.

The use of microdialysis to study the binding of valproate (VPA) to plasma proteins was evaluated in rabbits. Prior to an in vivo microdialysis, in vitro relative recovery of VPA respectively from Ringer's solution, 5% (w/v) of albumin solution and plasma sample via a microdialysis probe was examined. The in vitro relative recovery was defined as a ratio of the VPA concentration determined in the dialysate to the free VPA concentration in the sample solution surrounding the membrane of the microdialysis probe. When the sample solution was well stirred at 700 rpm and maintained at 37 degrees C, the in vitro relative recovery of VPA was significantly different among them. It increased in the order of Ringer's solution (34.3 +/- 2.6%) > 5% (w/v) of albumin solution (25.7 +/- 4.6%) > rabbit plasma sample (15.8 +/- 1.2%). Thereafter, pharmacokinetics of VPA was determined using both microdialysis sampling via the rabbit femoral vein and collection of whole blood via the rabbit ear vein after intravenous administration of VPA at a dose of 43 mg/kg. Free concentrations of VPA in plasma were determined by ultrafiltration method as opposed to microdialysis method. There was no difference in the elimination half-life of VPA determined by microdialysis, 1.09 +/- 0.22 h, or ultrafiltration, 1.22 +/- 0.21 h. The AUC of VPA in dialysate was 15 +/- 4 micrograms.h/ml, which corresponded to 15% of that in ultrafiltrate (103 +/- 17 micrograms.h/ml). The value was in good agreement with the in vitro relative recovery of VPA from plasma sample (15.8 +/- 1.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Analysis of the transport of valproic acid into saliva from serum.

A study was conducted to explore whether a positive correlation between serum and salivary concentrations of the well-known antiepileptic drug, valproic acid (VPA), in epileptic patients could be explained by facilitated diffusion. The total concentration in saliva (Cs) would be related to the apparent ratio (R(app)++ = 100.Cs/Ct) of Cs to the total concentration in serum (Ct) as follows: Cs = A.R(app)B. This equation can be illustrated with microcomputer-simulated figures by assuming a process of facilitated diffusion for the transport of VPA into saliva from blood by the mechanism of monocarboxylic acid absorption through the intestinal brush-border membrane vesicles. The above equation has been proved to be valid when applied to the data reported separately by Gugler and coworkers and by Nitsche and Mascher, who evaluated the pharmacokinetics of VPA. Moreover, we can estimate the serum concentration with the salivary concentration using the above equation.

Adolescent↗
PubMed1994

Synergistic interaction between class I antiarrhythmic drugs and halothane in depressant effects on ventricular activation in a canine myocardial infarction model.

Previous studies have showed that halothane has depressed ventricular activation in a canine myocardial infarction model. It is also well known that class I antiarrhythmic drugs depress ventricular activation in the infarcted myocardium. In the present study, we examined whether some electrophysiologic interactions between halothane and two class I antiarrhythmic drugs, lidocaine and procainamide, occur in a canine myocardial infarction model. Halothane, lidocaine and procainamide prolonged the activation time in the infarcted zone, and the combination of halothane and either lidocaine or procainamide markedly prolonged the activation time or blocked the delayed activation in the infarcted zone. Although the mechanism of the interaction is not clear, the present results suggest a synergistic interaction between halothane and class I antiarrhythmic drugs. Therefore, care should be taken that doses of class I antiarrhythmic drugs during halothane anesthesia will not be an overdose.

Animals↗
PubMed1994

Comparison of electrophysiologic and hemodynamic effects of SD-3212, a new antiarrhythmic drug, and flecainide in a canine myocardial infarction model.

Electrophysiologic and hemodynamic effects of SD-3212, a new antiarrhythmic drug, were examined and compared with those of flecainide, a class Ic antiarrhythmic drug, in a canine myocardial infarction model. The doses of SD-3212 were 1 mg/kg bolus injection followed by 0.1 mg/kg/min infusion and 3 mg/kg bolus injection followed by 0.3 mg/kg/min infusion, while those of flecainide were 0.3 mg/kg bolus injection followed by 0.03 mg/kg/min infusion and 1 mg/kg bolus injection followed by 0.1 mg/kg/min infusion. SD-3212 at the high dose prolonged the effective refractory period and QT interval, and depressed ventricular delayed conduction. Flecainide at the high dose also prolonged the effective refractory period and depressed ventricular delayed conduction. Flecainide reduced a maximal rate of rise of left ventricular pressure at the high dose, while SD-3212 did not significantly change it. Neither of the drugs significantly affected mean arterial blood pressure or cardiac output. Thus, SD-3212 may produce antiarrhythmic effects with less cardiac depressant effect than flecainide.

Animals↗
PubMed1994

Electrophysiologic interaction between class I antiarrhythmic drugs and volatile anesthetics in depressant effects on ventricular activation in a canine myocardial infarction model.

Previous studies showed that volatile anesthetics depressed ventricular delayed activation in a canine myocardial infarction model. It is well known that class I antiarrhythmic drugs depress the ventricular activation in the infarcted myocardium. In the present study, we examined the electrophysiologic interaction between volatile anesthetics (sevoflurane, isoflurane) and class I antiarrhythmic drugs (lidocaine, procainamide) in effects on the ventricular delayed activation in a canine myocardial infarction model. The conduction time of the premature stimulation-induced ventricular excitation was measured in both normal and infarcted zones of the ventricle. An interval from the premature stimulus artifact to the epicardial activation was measured on bipolar electrograms as an index of conduction time, i.e., activation time. In the infarcted zone, the volatile anesthetics and class I antiarrhythmic drugs prolonged the activation time in the infarcted zone, and the combination of the volatile anesthetics and the class I antiarrhythmic drugs markedly prolonged the activation time or blocked the delayed activation. In the normal zone, a similar synergistic interaction was observed, but the effect of these drugs was less compared with that in the infarcted zone. From these results, possible mechanisms to explain the synergistic interaction were discussed.

Anesthetics↗
PubMed1994

Angiotensin I-converting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle.

The ACE inhibitory activity of an alkaline protease hydrolyzate from sardine muscle did not change after being treated by gastrointestinal proteases (IC50 = 0.082 mg protein/ml). Eleven new ACE inhibitory peptides, constructed with 2 to 4 amino acid residues, were isolated from the hydrolyzate. The ACE inhibitory activity of each was mostly below 100 microM of IC50 value; the maximal inhibitory activity was observed for Lys-Trp (IC50 = 1.63 microM). The isolated peptides inhibited ACE competitively, except for Met-Tyr with non-competitive inhibition. As the result of sequence homology, Arg-Val-Tyr isolated from the hydrolyzate was found in the primary structure of angiotensins I, II, and III, and of des As[1]-angiotensin I.

Amino Acid Sequence↗
PubMed1994

Gastric mucosal blood flow in relation to stress-induced hypercontraction in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a widely used animal model for essential hypertension, and is less susceptible to cold restraint stress in gastric ulcer formation. We previously reported that acid secretion is low in SHR due to sympathetic facilitation compared with normotensive Wistar-Kyoto rats (WKY). The purpose of this study was to evaluate the autonomic nervous function and the gastric mucosal blood flow related to gastric motility during cold restraint stress in SHR. Male SHR and WKY, 24-28 weeks old, were used in this study. Noradrenergic innervation, noradrenaline and dopamine contents in the muscle layer were significantly greater in SHR than in WKY, and tissue choline acetyltransferase activity was significantly lower in SHR. Gastric motility was markedly enhanced by cold restraint stress in WKY. By contrast, SHR maintained the rhythmic and low amplitude contractions regardless of hypothermia. Mucosal blood flow decreased markedly during hypothermia in WKY but was well sustained in SHR. In conclusion, the increase in gastric motility associated with cold restraint stress was suppressed in SHR by sympathetic facilitation in the muscle layer, and this may have contributed to the prevention of ulcer formation by maintaining mucosal blood flow in SHR.

Animals↗
PubMed1994

Pharmacokinetics and safety of intravenous recombinant human superoxide dismutase (NK341) in healthy subjects.

Recombinant human superoxide dismutase (rhSOD), NK341, was intravenously administered to healthy male volunteers at doses of 1750-35000 U/kg, and the safety and pharmacokinetic properties were evaluated. There were no abnormal findings attributable to the test drug throughout the study, showing that NK341 was well tolerated in healthy subjects. Tri-exponential elimination of the drug from blood was observed with half-lives of about 20 minutes (alpha phase), 80 minutes (beta phase), and 6 hours (gamma phase). The values of the maximal plasma concentration and the areas under the plasma concentration curves linearly increased with the doses given. On the other hand, the urinary recovery of the drug also increased with the dose, ranging approximately from 3%-45% of the dose. The plasma concentration of the drug measured by an enzyme immunoassay was quite comparable to SOD activity measured by electron spin resonance, suggesting that NK341 was present in blood as the active form of SOD.

Adult↗
PubMed1994

Pharmacokinetics of the H1-receptor antagonist ebastine and its active metabolite carebastine in healthy subjects.

Pharmacokinetics of ebastine (CAS 90729-43-4), a histamine H1-receptor antagonist, was evaluated in healthy male volunteers. The subjects were given single oral doses of 5, 10, 20 and 40 mg of ebastine (5 or 6 subjects) and repeated oral doses of 20 mg once daily for 7 days (6 subjects). Administration of ebastine resulted in a negligible level of the unchanged drug in plasma and urine. Mean plasma concentration of carebastine (CAS 90729-42-3), an active carboxylated metabolite, reached maximum levels of 40, 112, 195 and 388 ng/ml at 4-6 h after single oral administration of ebastine at doses of 5, 10, 20 and 40 mg, respectively. Plasma levels of carebastine showed a first-order decrease with apparent half-lives of 13.8 to 15.3 h. The Cmax and AUC of carebastine increased in proportion to the dose. Urinary excretion of carebastine during 72 h after single administration accounted for 1.3-1.8% of the dose. Food intake did not affect the pharmacokinetics and gastrointestinal absorption of ebastine. Repeated administrations of ebastine once daily for 7 days did not cause any change in the pharmacokinetics of ebastine and carebastine. Plasma concentration of carebastine reached the steady state on day 4. The Cmax (360-396 ng/ml) was 1.6- to 1.7-fold greater than that after the first administration (229 ng/ml). These results strongly suggest that carebastine is responsible for the antihistamine activity after administration of ebastine.

Adult↗
PubMed1994

Increase in adhesion molecules on CD4+ cells and CD4+ cell subsets in synovial fluid from patients with rheumatoid arthritis.

OBJECTIVE: To elucidate the role of adhesion molecules in the pathogenesis of rheumatoid arthritis (RA). METHODS: We evaluated their expression and that of an activation marker on CD4+ cell populations and CD4+ cell subsets in specimens of peripheral blood (PB) and synovial fluid (SF) obtained from 10 patients with RA and 7 with osteoarthritis (OA). A 2 or 3-color immunofluorescent method was used for analysis. RESULTS: The SF from both groups of patients showed a greater density of adhesion molecules including LFA-1 alpha, LFA-1 beta, CD2, VLA-4 alpha and VLA-5 alpha on CD4+ cells, and a higher percentage of CD4+HLA-DR+ cells compared with their PB. IN PB-CD4+ cell subsets from the arthritic and healthy subjects, the CD4+CD45RO+ cell population showed an increased expression of adhesion molecules compared with CD4+CD45RA+ cell population. The expression of adhesion molecules on circulating CD4+ cell population and CD4+ cell subsets from the patients with RA and OA was comparable to that from healthy subjects. SF from both groups of patients showed a higher percentage of CD4+CD45RO+ cells and a lower percentage of CD4+CD45RA+ cells. In SF-CD4+ cell subsets from patients with RA, the CD4+CD45RO+ cell population had an increased expression of VLA-4 alpha compared to the CD4+CD45RA+ cell population; however, there was no significant difference in other adhesion molecule expression and the percentage of HLA-DR+ cells between the 2 cell subsets. Furthermore, the expression of VLA-4 alpha on the CD4+CD45RO+ cell population in SF from patients with RA was significantly higher than that in matched PB. In CD4+CD45RA+ cell population from both groups of patients, SF showed an enhanced expression of adhesion molecules and an increased percentage of HLA-DR+ cells compared with matched PB. CONCLUSION: Our results suggest that increased expression of adhesion molecules and increased percentage of HLA-DR+ cells on CD4+ cells in SF may be responsible for cellular interactions between these cells and synovial cells or extracellular matrix.

Adult↗
PubMed1994

Pharmacokinetic and pharmacodynamic properties of a novel xanthine oxidase inhibitor, BOF-4272, in healthy volunteers.

A novel pyrazolotriazine derivative [BOF-4272, sodium-(+-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1 ,3,5-triazine-4-olate monohydrate], which inhibits biosynthesis of uric acid (UA) by interfering with xanthine oxidase/xanthine dehydrogenase, was administered p.o. to healthy male volunteers to evaluate its pharmacokinetic and pharmacodynamic properties. In the single-dose study, three doses of BOF-4272 (100, 200 and 400 mg) and a placebo were allocated to eight subjects on three occasions at more than 1-week intervals in a single-blind and balanced incomplete block design. In the multiple-dose study, 200 mg of BOF-4272 and a placebo were administered to six and four subjects, respectively, twice daily for 6.5 days (13 total doses) in a single-blind design. Throughout the whole study period BOF-4272 was well tolerated in healthy subjects. In the single-dose study, the maximal plasma concentrations of BOF-4272 and its major metabolite (M-4) and their areas under the plasma concentration-time curve increased in proportion to the given dose. Both substances were eliminated from plasma with half-lives of 1.7 to 1.9 and 4.8 to 6.9 hr irrespective of the dose. BOF-4272 was recovered in the urine at about 1% as unchanged drug and 15% as M-4. In the single-dose study, serum UA concentration was decreased dose-dependently to about 80% of the predose value. In the multiple-dose study, serum UA concentration, which was measured before each morning dose, was decreased to about 72% on day 3 and maintained thereafter at almost the same level until 24 hr after the last administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Collagen diseases complicated with myelodysplastic syndrome (MDS)--report of three cases].

We presented three cases of collagen diseases complicated with myelodysplastic syndrome (MDS). To our knowledge, MDS following collagen disease is very rare, and only seven cases have been reported previously. First case (a 40-years old woman) had suffered from rheumatoid arthritis, systemic lupus erythematosus and Sjögren's syndrome for 16 years. Second case (a 65-years old woman) had suffered from rheumatoid arthritis for 15-years. Third case (a 63-years old woman) had suffered from progressive systemic sclerosis for 16 years. These patients developed MDS. After onset of MDS, cytopenia progressed rapidly within half a year. In the types of MDS, case 1 and case 2 had refractory anemia and case 3 had refractory anemia with excess of blasts and a preleukemic state. Case 2 had a clonal abnormality of haemopoietic stem cells. It is unlikely that MDS in our cases are caused by mutant agents or irradiation. These results suggest MDS may be contributed to long-term immunodysfunction found in these collagen diseases.

Adult↗