Biomedical subjects

M Nakashima

Publications and source records attributed to M Nakashima.

At least 361 records · Page 20Linked to original sources

PubMed1993

[A new model of middle cerebral artery thrombosis in rats].

We have established a new model of middle cerebral artery (MCA) occlusion in rats due to photochemically induced thrombosis (PIT). This thrombosis is caused by photochemical reaction between green light and systemic injection of Rose Bengal (RB). Under anesthesia, the left MCA was observed without cutting the dura mater via a subtemporal craniotomy under an operation microscope. Photoillumination (wavelength, 540 nm; L4887, Hamamatsu Photonics, Japan) was applied to the MCA and then RB (20 mg/kg) was administered intravenously. The MCA was completely occluded by thrombus about 6 min after the administration of RB with an operation microscope. Effects of antithrombotic agents can be evaluated in this model, since this thrombus is a typical arterial one caused by the injury of the endothelium, and this method is easy and the location and volume of cerebral infarction are reproducible, since thrombus is induced at the same portion of the MCA. Additionally the damage to animals is little, since thrombosis in the MCA is induced without cutting the dura mater; furthermore, it is possible to do chronic experiments. In conclusion, this model is a useful one for investigation of thrombolytic therapy in cerebral thrombosis.

Animals↗

PubMed1993

Immunological differentiation between novel monomeric and classic tetrameric rat liver glutathione peroxidases.

Difference between a novel monomeric enzyme and the classic tetrameric enzyme of glutathione peroxidase in rat liver was examined immunologically. The polyclonal antibody raised against the novel enzyme reacted with the novel enzyme, but not with the classic enzyme. Likewise the anti-classic enzyme antibody reacted with the classic enzyme, but not with the novel one. The activity of the novel enzyme was decreased by the treatment with the anti-novel enzyme antibody, but not with the anti-classic enzyme antibody, and vice versa for the classic enzyme. Thus the novel monomeric glutathione peroxidase is a protein immunologically distinct from the classic enzyme.

Animals↗

PubMed1993

Phase 1 study of L-627, biapenem, a new parenteral carbapenem antibiotic.

The safety and pharmacokinetics of L-627, a new injectable carbapenem antibiotic, were evaluated in healthy volunteers. In single-dose studies, 20, 40, 80, 150, 300 and 600 mg of L-627 were administered by i.v. infusions over 1 hour. Plasma concentration-time profiles were well described with a two-compartment open model. The half-life of elimination from plasma was 1.3 +/- 0.8 (mean +/- SD) hour, and the Cmax and AUC paralleled the doses given. The mean urinary recovery of unchanged L-627 within the first 12 hours was 63.1 +/- 2.7% of the dose. In the multiple-dose studies, 300 mg of L-627 (i.v. over 1 hour) was administered every 12 hours, 11 times in total and 600 mg of L-627 was administered every 12 hours, 9 times in total. No discernible accumulation of the drug in plasma was observed. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject in one of the multiple-dose regimens (300 mg b.i.d.) showed only a slight elevation of transaminase value, although the elevated value promptly recovered after completion of dosing. No abnormality was observed in the other multiple-dose regimen (600 mg b.i.d.). From these results, L-627 was concluded to be safe and well tolerated.

Adult↗

PubMed1992

Comparison of the inhibitory effects of the TXA2 receptor antagonist, vapiprost, and other antiplatelet drugs on arterial thrombosis in rats: possible role of TXA2.

The antithrombotic effect of the thromboxane A2 receptor antagonist, vapiprost, was compared with those of other antiplatelet drugs using an arterial thrombosis model which utilized photochemical reaction in the rat femoral artery. Vapiprost prolonged the time required to occlude the artery with thrombus and inhibited collagen-induced rat platelet aggregation in whole blood ex vivo, in a dose-dependent manner. The potency ranking of antithrombotic effect was vapiprost > ketanserin (serotonin 5-HT2 receptor antagonist) >> ticlopidine (inhibitor of ADP-induced platelet aggregation) = dipyridamole (adenosine uptake inhibitor) > aspirin (cyclooxygenase inhibitor). On the other hand, the ranking of antiplatelet effect was ticlopidine > or = vapiprost > or = aspirin. Ketanserin and dipyridamole were ineffective. Relative to their antiplatelet effect, vapiprost and ketanserin had powerful antithrombotic effects. It is possible that the potent antithrombotic effects of vapiprost and ketanserin in vivo reflect the ability of these drugs to inhibit mediator-induced vascular contractions in addition to platelet aggregation. The results of the present study also suggest that TXA2 may play an important role in thrombogenesis in rats.

Animals↗

PubMed1992

Arterial thrombosis model with photochemical reaction in guinea-pig and its property.

We have already developed an arterial thrombosis model in the rat femoral artery which utilized photochemical reaction between systemically injected rose bengal and transillumination of a green light with 540 nm wave length from the outside of the vessel. In the present study, we applied this model to guinea-pigs in order to produce a more suitable thrombus model for evaluation of antithrombotic drugs which act on the prostaglandin cascade. In the guinea-pigs, the irradiated femoral artery was completely occluded in 7 min after the injection of rose bengal (10 mg/kg) in a similar manner to the rats. The processes of primary endothelial injury and the subsequent formation of thrombus during this manipulation were observed by the electron microscopy. Pretreatment with aspirin and Y-20811, a thromboxane synthetase inhibitor, significantly prolonged the time required for occlusion in the guinea-pigs, while these drugs were ineffective in the rats. The antithrombotic effect of vapiprost, a thromboxane A2 receptor antagonist, was more pronounced in the guinea-pigs than the rats. In conclusion, this model in guinea-pigs is more suitable for evaluating antithrombotic drugs, particularly, the action of which is exerted involving the prostaglandin cascade.

Animals↗

PubMed1992

Effect of aldose reductase inhibitor on the inhibition of platelet aggregation induced by diabetic rat plasma.

Plasma isolated from streptozotocin-induced diabetic rats inhibited platelet aggregation. Treatment of diabetic rats with an aldose reductase inhibitor, ONO-2235, which did not improve hyperglycemia, prevented the antiaggregating activity of plasma as did insulin treatment. Both treatments reduced the elevated sorbitol concentrations in erythrocytes. Although the factor(s) accounting for the antiaggregatory effect of diabetic plasma has not yet been characterized, it is possible that the accumulation of sorbitol in erythrocytes is related to the generation of the factor(s).

Aldehyde Reductase↗

PubMed1992

How secure are laparoscopically placed clips? An in vitro and in vivo study.

We tested the security of laparoscopic, hemostatic clips in vitro and in vivo. In vitro, the force needed to transversely dislodge clips that were applied to silicone (Silastic) tubing ranged from a mean +/- SEM of 1.81 +/- 0.07 N (Endo Clip) to 2.68 +/- 0.04 N (Ligaclip). The force needed to axially dislodge clips that were applied to silicone tubing ranged from 4.08 +/- 0.20 N (Endo Clip) to 4.78 +/- 0.18 N (Ligaclip). In vivo, on mesenteric vessels in anesthetized pigs, 34 of 100 clips that were applied laparoscopically with the Endo Clip were moved or dislodged compared with 11 of 100 of those applied with the Ligaclip. We conclude that laparoscopically placed vascular clips applied with the Ligaclip are more secure than those applied with the Endo Clip. The laparoscopic surgeon should be aware of the relative ease with which clips may be dislodged.

Animals↗

PubMed1992

Possible effect of pigment on the pharmacokinetics of ofloxacin and its excretion in hair.

The mechanism of excretion of the antimicrobial ofloxacin in human scalp hair was investigated. When black and white hairs were taken from a patient with grizzled hair, who had been treated with ofloxacin, a much larger quantity of the drug was detected in the black hair. To study this difference and to elucidate the cause, ofloxacin (6, 20, and 60 mg/kg/day, b.i.d.) was administered ip for 5 weeks to albino and pigmented rats, whose backs had been depilated beforehand. In the last week of administration, the time-plasma concentration profile of ofloxacin was determined. One week after the last dosing, the newly grown hair on the depilated area was collected, and the drug concentration in hair was measured. The concentration in hair of the pigmented rats correlated significantly with the daily dose, area under the plasma concentration curve (AUC), and maximum plasma concentration (Cmax) at steady state, whereas that in the albino rats correlated with the dose and Cmax only, because AUC did not increase linearly with the dose in the albino rats. Moreover, the drug concentration in the hair of the pigmented rats was always much larger than that in the hair of the albino ones, although AUC and Cmax did not differ greatly between both rat groups. The findings suggest that ofloxacin is excreted in the hair in relation to the dose administered, and that the mechanism of the excretion is closely linked with the presence of melanin.

Animals↗

PubMed1992

Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair.

Profiles of the steady-state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4-30 mg/day, three times a day) for greater than 4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high-performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax, respectively) varied widely among patients: 3.0-22.9 and 6.2-32.7 ng/mL for HL and 2.8-21.4 and 5.7-33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration-time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 +/- 0.48, mean +/- standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax, or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.

Administration, Oral↗

PubMed1992

Antiarrhythmic and electrophysiological effects of SD-3212, a novel Na+ and Ca++ channel blocker, in anaesthetized dogs with myocardial infarction in comparison with its stereoisomer (SD-3211) and bepridil.

Antiarrhythmic and electrophysiological effects of SD-3212, a novel antiarrhythmic agent, which has both Na+ channel and Ca++ channel blocking activities, were compared with those of its (+)-stereoisomer, SD-3211, which has only a Ca++ channel blocking activity, and bepridil, a known Ca++ channel blocker with additional Na+ channel blocking activity, using the two-stage coronary ligation induced arrhythmia (24 h after the ligation of the left anterior descending coronary artery) and 7 day-old myocardial infarcted hearts in anaesthetized dogs. SD-3212 showed a dose-dependent antiarrhythmic effect on the two-stage coronary ligation induced arrhythmia. SD-3212 at a dose of 3 mg/kg reduced the arrhythmic ratio, i.e. ectopic beats per min divided by the sum of ectopic beats and sinus beats per min, significantly from 1 up to 12 min after the administration. Neither bepridil (1-6 mg/kg) nor SD-3211 (1 mg/kg) had an antiarrhythmic effect. SD-3212 (0.3-3 mg/kg) prolonged both the conduction time in the normal myocardium and the delayed potential in the infarcted myocardium in the 7 day-old myocardial infarcted hearts in anaesthetized dogs in a dose-dependent manner. This effect of SD-3212 was shown at coupling intervals of 150-1000 ms increasing with decreasing interval. In this respect, SD-3212 is similar to drugs which show fast recovery of Vmax from use-dependent block such as lidocaine. Bepidril (1-6 mg/kg) also prolonged these parameters in a dose-dependent manner, however, the prolongation induced by bedripil was limited to shorter coupling intervals as compared with that induced by SD-3212. SD-3212 (0.1-1 mg/kg) did not show this prolonging effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Photochemically induced thrombosis of the rat coronary artery and functional evaluation of thrombus formation by occurrence of ventricular arrhythmias. Effects of acetylsalicylic acid and a thromboxane A2 synthetase inhibitor of thrombus formation.

During i.v. infusion of rose bengal (48 mg/kg/h), the proximal portion of the rat left coronary artery was illuminated from the outside of the myocardium by green light (540 nm) to produce a transluminal thrombus subsequent to endothelial damages. The primary endothelial damages within the illuminated vascular portion, which resulted from the photochemical reaction between the dye and green light, and the subsequent formation of transluminal platelet-rich thrombus, were easily revealed by both light and electron microscopy. The establishment of the thrombus was accompanied in all cases by the occurrence of ventricular arrhythmias due to myocardial ischaemia. The times required to initiate ventricular premature beats (VPBs) and ventricular tachycardia (VT) were 381 +/- 96 s and 444 +/- 114 s (mean +/- SEM, n = 10), respectively. Pretreatment of the rat with acetylsalicylic acid (3 and 10 mg/kg, i.v.) before the initiation of illumination had no effect on the times required to exhibit the first VPBs and VT, the incidences of both types of arrhythmias were not reduced, and the thrombus was finally formed. On the other hand, pretreatment with Y-20811, a novel thromboxane A2 synthetase inhibitor (0.3, 1 and 3 mg/kg, i.v.), delayed the onset of both VPB and VT in a dose-dependent manner. The incidences of VPBs and VT were significantly reduced at 1 and 3 mg/kg, and the thrombus formation was prevented. The formation of a transluminal thrombus in the left coronary artery by the present technique was highly reproducible and could be functionally evaluated by the occurrence of ventricular arrhythmias.

Animals↗

PubMed1992

Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects.

The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n = 6), or 100 mg (n = 6) or placebo (n = 3) once daily for 7 consecutive days. In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg.dl-1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged. In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg.dl-1) and last administrations (4.42 mg.dl-1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576). The findings suggest that DuP-753 possesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.

Adult↗

PubMed1992

A new model of equilibrium dysfunction in the rat induced by photochemical damage to the inner ear's microcirculation.

A new photochemical method was employed to damage the inner ear microcirculation in the rat. Under pentobarbital anesthesia, the middle ear was exposed by a ventral approach and the tympanic membrane and the malleus and incus were removed. The vestibule was then illuminated by a filtered xenon light (wave length: 540 nm) while rose bengal was infused intravenously. Microscopic examination revealed disintegration of the hair cells in the vestibule. Changes could be prevented by pretreatment with intravenous acetylsalicylic acid (ASA) or heparin. Twenty-four hours after the completion of photo-illumination the rats exhibited nystagmus toward the intact ear and showed rolling during the swimming test, both signs of equilibrium dysfunction. These findings were inhibited by ASA or heparin pretreatment. Our present results indicate that our method causes a photochemically induced occlusion in the rat's inner ear microcirculation and may be useful for evaluating the various effects of drugs on the inner ear.

Animals↗

PubMed1992

Pharmacokinetics of temocapril hydrochloride, a novel angiotensin converting enzyme inhibitor, in renal insufficiency.

The pharmacokinetics of temocapril hydrochloride, a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, has been studied in patients with mild (Group II) to severe (Group III) renal insufficiency in comparison with subjects with normal renal function (Group I). The pharmacokinetic parameters of the active diacid metabolite, including Cmax, AUC and half-life (t1/2), showed only slight changes between the three groups: AUC (0-inaffinity) was significantly larger in Group III than Group I, and t1/2 tended to be prolonged in Group III, but the change was not significant. The urinary recovery of the diacid was significantly decreased in Group III. (Group I, 28.1%, Group II, 21.6%, Group III, 12.8%). Compared with other ACE inhibitors, which are mainly excreted through the kidney, the plasma concentration of the active diacid metabolite was hardly influenced by renal function. It was speculated that lowering of the dose of temocapril might be recommended only in patients with severe renal insufficiency.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

The effects of growth factors on DNA synthesis, proteoglycan synthesis and alkaline phosphatase activity in bovine dental pulp cells.

Platelet-derived growth factor (PDGF), insulin-like growth factor-I and -II (IGF-I and -II), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) stimulated [125I]-deoxyuridine incorporation about 13, 6.2-, 4.6-, 3.8-, 3.1- and 1.2-fold, respectively, above control values at a concentration of 50 ng/ml. Transforming growth factor-beta (TGF-beta) decreased incorporation about 30% at the same dose. aFGF, IGF-I, IGF-II, bFGF and TGF-beta increased [35S]-sulphate incorporation 231, 71, 64, 42 and 39%, respectively, in proliferating cells, while EGF, IGF-I, TGF-beta and PDGF decreased incorporation about 30%, and aFGF increased incorporation 80% in stationary-stage culture. TGF-beta, PDGF, aFGF and bFGF caused 65-40% inhibition of alkaline phosphatase activity in proliferating and stationary cultures. These findings suggest that the proliferation of pulp cells may be stimulated mainly by PDGF and IGF-I, and the production of extracellular matrix proteoglycan may be enhanced by aFGF, IGF-I and IGF-II. Furthermore, TGF-beta, PDGF, aFGF and bFGF may regulate the differentiation of pulp cells into odontoblasts.

Alkaline Phosphatase↗

PubMed1992

Effect of opioids on delayed neuronal death in the gerbil hippocampus.

The effect of opioids on delayed neuronal death was evaluated in the gerbil hippocampus. Male Mongolian gerbils were subjected to transient forebrain ischemia and neuronal density was evaluated in the hippocampus 7 days following ischemia. When hypothermia during and after ischemia was prevented, treatment with morphine, U-50488H, or naloxone provided no significant protection. In contrast, a spontaneous drop in rectal temperature to 32 degrees C at the end of ischemia produced near-complete protection of CA1 pyramidal neurons. No opioids modulate the protective effect of hypothermia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1992

Mitogenic and dentin-inductive effects of crude bone morphogenetic protein from bone and dentin in primary adult pulp cell culture.

The effects of crude bone morphogenetic protein (BMP) derived from bone and dentin matrix on proliferation, production of extracellular matrix, and biologic function of the pulp cell were examined in the primary cell culture from permanent dental pulp. BMP from bone and from dentin matrix stimulated iodine 125-deoxyuridine incorporation in the absence of 10% calf serum. They increased sulfur 35-sulfate incorporation in proliferating stage and had no effects in stationary stage of culture. Alkaline phosphatase activities were inhibited in proliferating, stationary, and multilayered stages of culture. Osteocalcin synthesis was increased in culture treated with BMP from day 2 to day 10. These findings suggest that crude BMP might have mitogenic activity and some role in regulation of differentiation of pulp cells into odontoblasts.

Alkaline Phosphatase↗

PubMed1992

Data processing for multi-channel optical recording: action potential detection by neural network.

Using a neural network, we have developed a program for fast and precise detection of action potentials (AP) in raw multi-channel optical recording data. The AP detection was performed in two steps: first, peaks were detected in raw optical data, and, second, the peaks were classified by the neural network into APs, noise and undecided peaks. The network was optimized and trained by the backpropagation learning algorithm, employing some thousands of manually classified peaks. The performance of the optimized network was found to be not completely satisfactory, although it was better than the classification by template matching and nearest-neighbor rules. The addition of a signal-to-noise ratio (SNR) of a peak to the network classification improved the classification performance: in comparison with the manual classification results, 96% of manually classified APs were detected. The causes of classification errors were discussed. In spite of the fact that the program required a slight amount of human intervention for undecided peaks, the program could allow mostly automatic AP detection.

Action Potentials↗