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T Sakurama

Publications and source records attributed to T Sakurama.

14 recordsLinked to original sources
PubMed2001

Protective effects of SM-20302, an orally active GPIIb/IIIa antagonist, in an ADP/epinephrine-induced guinea pig model of transient cerebral ischemia.

The potential benefits of SM-20302, (2S)-3-(3-(4-amidinobenzoylamino)propanoylamino)-2-(4-ethyl)benzensulfonylaminopropionic acid hydrochloride, a nonpeptide GPIIb/IIIa receptor antagonist, were compared with those of aspirin and ticlopidine in a transient cerebral ischemia model in guinea pigs. Transient cerebral ischemia was induced in guinea pigs by an infusion of ADP/epinephrine into the left internal carotid artery. Each compound was orally administered 1 h (SM-20302 and aspirin) or 3 h (ticlopidine) before the ADP/epinephrine infusion. The ischemic area in coronal brain slices was assessed 1 min after the cessation of ADP/epinephrine infusion by a carbon black perfusion method. In a separate experiment, neurological deficits and lactate contents of ipsilateral hemispheres were evaluated 60 min after the cessation of ADP/epinephrine infusion by neurological scores and the standard enzymatic method, respectively. SM-20302 (0.3 and 1 mg/kg p.o.) significantly reduced the ischemic area, neurological deficits and lactate contents in comparison with the vehicle control. Aspirin (100 mg/kg po) had no significant effect on either parameter. Ticlopidine (300 mg/kg p.o.) reduced the lactate content. Although a combination of aspirin (100 mg/kg p.o.) and ticlopidine (300 mg/kg po) also reduced the lactate content, no additive effect was observed. These results suggest that SM-20302 is of potential clinical benefit in the treatment of thromboembolic diseases.

Administration, Oral↗
PubMed1999

Antithrombotic effect of SM-20302, a nonpeptide GPIIb/IIIa antagonist, in a photochemically induced thrombosis model in guinea pigs.

SM-20302, a synthetic inhibitor of the fibrinogen receptor of platelets, has been shown to inhibit the platelet aggregation induced by various stimuli. In the present study, we performed ex vivo platelet aggregation studies by using heparinized platelet-rich plasma (PRP) as well as citrated PRP and compared the antiaggregatory activity with the in vivo antithrombotic efficacy of SM-20302. The oral administration of SM-20302 (0.3-10 mg/kg) to guinea pigs completely inhibited the ADP-induced ex vivo platelet aggregation in citrated PRP. In heparinized PRP, SM-20302 (1-10 mg/kg) showed a dose-dependent inhibition of ex vivo platelet aggregation, and it exhibited complete inhibition at a dose of 3 and 10 mg/kg, respectively. The concentration of ionized calcium in the citrated samples was approximately 35 times lower than that in heparinized samples. Chelation of ionized calcium caused an enhancement of the antiaggregatory activity of SM-20302 in guinea pig heparinized PRP in vitro. And addition of CaCl2 to citrated PRP reversed the enhancement. Citrate therefore appeared to enhance the inhibitory activity of SM-20302 by lowering the ionized calcium levels. We also examined the in vivo efficacy of SM-20302 in a photochemically induced femoral artery thrombosis model in guinea pigs. The photochemical injury of the endothelium of femoral artery resulted in a progressive decline in the blood flow. The oral administration of SM-20302 (0.1-3 mg/kg) produced a dose-dependent maintenance of the femoral artery patency and significantly prolonged the time to occlusive thrombus formation at a dose of 1 and 3 mg/kg, respectively. These results suggest that SM-20302 may be an orally active antithrombotic agent, and its in vivo antithrombotic efficacy appeared to correlate well with the ex vivo platelet inhibition in PRP prepared from heparinized blood but not in PRP anticoagulated with citrate.

Adenosine Diphosphate↗
PubMed1999

Temporary and partial inhibition of platelets by SM-20302 prevents coronary artery thrombosis in a chronic canine model.

We proposed that temporary and partial platelet inhibition by a GPIIb/IIIa receptor antagonist, SM-20302, would provide sustained antithrombotic efficacy in a chronic model of coronary artery thrombosis. Instrumented, conscious dogs received vehicle (Group I, n = 7), low dose SM-20302 (30 microg/kg bolus + 1 microg/kg/min infusion for 6 h) (Group II, n = 7), or high dose SM-20302 (100 microg/kg bolus + 1 microg/kg/min infusion for 6 h) (Group III, n = 7). Thrombosis was initiated by electrolytic injury to the circumflex coronary artery. Coronary blood flow was monitored for 6 h on day 1 and days 2-6. Platelet aggregation was performed in platelet-rich plasma prepared from citrated or heparinized blood. At 6 h, both doses of SM-20302 inhibited adenosine diphosphate-induced platelet aggregation completely (> 90%) in citrated platelet-rich plasma, but incompletely (57-59%) in heparinized platelet-rich plasma. Platelet reactivity returned to baseline values at 24 h. Control animals developed thrombotic occlusion on Day 1. Both doses of SM-20302 maintained vessel patency during the infusion period (Day 1) and the subsequent 5 days. Myocardial infarct size and mortality in the drug treated groups were reduced compared to the vehicle group. Thus, temporary inhibition of platelet reactivity by SM-20302 is associated with sustained prevention of primary thrombus formation, and reduction in infarct size and mortality.

Animals↗
PubMed1999

SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist, exhibits a wide therapeutic window in a newly developed hemorrhage model in mice.

We have developed a gastrointestinal hemorrhage model in mice and thereby assessed the potential risk of bleeding following administration of SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist. First, SM-20302 selectively inhibited the interaction between human platelets and fibrinogen in vitro. Second, SM-20302 dose-dependently inhibited ADP-induced ex vivo platelet aggregation in mice and produced an ED50 value of 0.02 mg/kg. ED50 values of cyclo(RGDT)2, aspirin and ticlopidine were 0.48, 0.74 and 13.3 mg/kg, respectively. Finally, the bleeding risk of SM-20302 was examined in our newly developed hemorrhage model. Gastrointestinal hemorrhage was assessed 24 h later when the antiplatelet agents tested were administered to mice prior to the oral dosing of 0.1 N hydrochloric acid in 90% ethanol. The resulting hemorrhage was classified into three grades, major, minor or no bleeding, primarily based on the criteria used in the TIMI trial. All compounds tested induced gastrointestinal hemorrhage in a dose-dependent manner. Minimum hemorrhagic doses, MHDs, of SM-20302, cyclo (RGDT)2, aspirin and ticlopidine were 3, 3, 1 and 100 mg/kg, respectively. The potential risk of bleeding was assessed by the ratio of MHD to ED50 value. MHD/ED50 values of SM-20302, cyclo(RGDT)2, aspirin and ticlopidine were calculated to be 150, 6.3, 1.4 and 7.5, respectively. These results suggest that this experimental hemorrhage model may be useful for the evaluation of the bleeding complications of antiplatelet agents and that SM-20302 may have a wider therapeutic window than nonspecific integrin inhibitor and conventional antiplatelet agents.

Administration, Oral↗
PubMed1998

Novel indole S,O-bisdesmoside, calanthoside, the precursor glycoside of tryptanthrin, indirubin, and isatin, with increasing skin blood flow promoting effects, from two Calanthe species (Orchidaceae).

The methanolic extracts from Calanthe discolor LINDL. and C. liukiuensis SCHLTR. were found to exhibit hair restoring and skin blood flow promoting activities. Through bioassay-guided separation using the skin blood flow increasing effect, a novel indole S,O-bisdesmoside, calanthoside, was isolated together with three new components, glucoindican, calaliukiuenoside, and calaphenanthrenol, and known compounds such as tryptanthrin, indirubin, isatin, and indican. The structures of the new compounds were determined on the basis of physicochemical and chemical evidence and they showed an activating effect on skin blood flow. In addition, it was found that enzymatic hydrolysis of calanthoside with beta-glucosidase furnished tryptanthrin together with a small amount of indirubin and isatin, whereas indirubin and isatin were obtained from calanthoside by acid hydrolysis. Based on their contents in the fresh and dried plant, calanthoside may be a common genuine glycoside of tryptanthrin, indirubin, and isatin in the plant.

Animals↗
PubMed1997

Separation of Bombyxin from a neuropeptide of Bombyx mori showing Summer-morph-producing Hormone (SMPH) activity in the Asian Comma Butterfly, Polygonia c-aureum L.

A neuropeptide from brain-suboesophageal ganglion (Br-SG) complexes of the silkmoth, Bombyx mori, shows summer-morph-producing hormone (SMPH) activity in the Asian comma butterfly, P. c-aureum. The SMPH-active peptide was extracted and demonstrated to be almost the same molecular size as bombyxin (4-5kD), a nueropeptide which shows prothoracicotropic hormone (PTTH) activity when assayed in vitro with prothoracic glands (PGs) of 4th-instar B. mori larvae in vitro. A Sephadex G-50 fraction of 3-8kD molecules prepared from Br-SG complexes of B. mori adults was applied to CM-, SP-, DEAE- or QAE- Toyoperal columns at pH 5.6 (or pH 6.9). The SMPH-activity could be separated from the PTTH-activity (or bombyxin) by subjecting a SMPH- and PTTH-active preparation of B. mori to anion-exchange chromatography at pH 6.9. By reversed-phase HPLC following an anion-exchange chromatography, SMPH-activity was recovered in two fractions of 40-45% acetonitril. Results demonstrate that the B. mori peptide showing the SMPH-activity in P. c-aureum is a different molecule than bombyxin.

Journal Article↗
PubMed1997

Medicinal foodstuffs. VI. 1) Histamine release inhibitors from kidney bean, the seeds of Phaseolus vulgaris L.: chemical structures of sandosaponins A and B.

Two new olean-12-ene-type triterpene oligoglycosides, named sandosaponins A and B, were isolated from kidney bean, the seed of Phaseolus vulgaris L., together with three known saponins, soyasaponins I and V and dehydrosoyasaponin 1. The structures of sandosaponins A and B were determined on the basis of chemical and physicochemical evidence, which included the chemical derivation of sandosapogenol from a known sapogenol, soyasapogenol B. Five saponins obtained from kidney bean were found to inhibit histamine release from rat exudate cells induced by an antigen-antibody reaction and, among them, sandosaponins A and B showed the most potent inhibitory activity.

Animals↗
PubMed1996

Comparative studies of thrombolysis with single-chain and two-chain recombinant tissue-type plasminogen activators in canine coronary thrombosis.

Tissue-type plasminogen activator (t-PA) can occur in two different forms, single- and two-chain t-PA. Such a difference in structure of the t-PA molecule may induce different biological functions. We compared the thrombolytic efficacy of single-chain t-PA with that of two-chain t-PA and urokinase in a canine thrombosis model. The thrombolytic properties of single- and two-chain recombinant t-PA and urokinase with equivalent activity in vitro after intravenous infusion were examined in 24 anesthetized, open-chest dogs with intracoronary thrombi. Repeated coronary angiography showed that the time to reperfusion was 29.0 +/- 4.8, 32.5 +/- 6.3, and 39.2 +/- 6.8 min, respectively. One dog in the single-chain t-PA group and all dogs in the vehicle group showed no recanalization. Plasma t-PA antigen reached similar plateau levels within 15. min in both the single- and two-chain t-PA groups. The infusion of single- and two-chain t-PA was not associated with systemic fibrinolytic activation, except for a decrease in alpha 2-plasmin inhibitor in single-chain t-PA. However, the infusion of urokinase was associated with significant depletion of fibrinogen. These findings suggest that single-chain t-PA has potent thrombolytic effect without systemic fibrinolytic activity similar to that of two-chain t-PA in a canine coronary artery thrombosis model.

Animals↗
PubMed1995

Intermittent cyclical etidronate treatment maintains the mass, structure and the mechanical property of bone in ovariectomized rats.

We examined the mechanical properties of rat bones treated with etidronate intermittent cyclic treatment (etidronate-ICT). Fifty Fisher rats, 7 months of age, underwent ovariectomy (OVX; n = 40) or sham operation (n = 10). The OVX rats were assigned to 4 groups injected with etidronate at the respective dose of 0, 2, 4, or 8 mg/kg of body weight (bw) 5 days each week for 2 weeks, followed by a 10-week period of no treatment. This regimen was repeated for 48 weeks. At the end of the treatment period, the ultimate bending strength and structural stiffness of the femoral midshaft in the OVX-alone group were not reduced compared with the values of the sham group, while those in the etidronate-treated groups were significantly larger than the values of the OVX group. The compressive stiffness and strength of the vertebral bodies specimens prepared from L3 and L5 vertebrae were markedly decreased in the OVX group compared with those in the sham group, but the values in the etidronate-treated groups were maintained at the same levels as those in the sham group. Mechanical properties at the tissue level, such as elastic modulus and material strength of the femoral cortex, were increased in etidronate-treated groups compared with the OVX group. The flexural modulus was also increased. The compressive elastic modulus of vertebral body in treated groups was preserved at the same level as that in the sham group. These results clearly demonstrate that in ovariectomized rats long-term etidronate intermittent cyclic treatment preserves the mechanical properties both at the whole bone and the tissue level.

Absorptiometry, Photon↗
PubMed1994

Tissue-type plasminogen activator improves neurological functions in a rat model of thromboembolic stroke.

BACKGROUND AND PURPOSE: The capacity of an intravenous infusion of double-stranded tissue-type plasminogen activator to salvage neurological functions in a rat model of thromboembolic stroke was studied. METHODS: The model of thromboembolic stroke was induced by the intracarotid injection of 2-hour-old homologous blood clots to rats. Neurological functions were scored on a 5-point scale 48 hours after the injection of the clots. Infarction size was determined by triphenyltetrazolium chloride staining, and cerebral hemorrhage was examined macroscopically. RESULTS: Intravenous infusion of tissue-type plasminogen activator (1 or 5 x 10(5) IU/kg) within 3 hours after embolization significantly improved neurological functions (P < .01) and reduced infarction size (P < .05). Tissue-type plasminogen activator treatment 6 hours after embolization failed to attenuate the neurological status score. Treatment with tissue-type plasminogen activator did not increase the incidence of intracerebral hemorrhage and was not associated with a systemic fibrinolytic state. In comparison with tissue-type plasminogen activator treatment, although urokinase treatment (5 x 10(5) IU/kg) improved neurological functions, it was associated with a systemic fibrinolytic state and a tendency to increase the incidence of intracerebral hemorrhage. CONCLUSIONS: These findings in this model suggest that tissue-type plasminogen activator should be given early after the onset of ischemic symptoms to effectively prevent or limit pathological infarction and improve neurological functions without an increase in the incidence of cerebral hemorrhage.

Animals↗
PubMed1975

Intradermal catabolism of rabbit IgG and its fragments.

Disappearance of rabbit EgG and its Fc fragment from the injected sites in skin and also the relationship to reverse passive cutaneous anaphylaxis (RPCA) were studied using guinea pigs. Rabbit IgG and its Fc fragment, trace labelled with -125-I, disappeared from the injected sites with half-lives of 12--14 and 6--7 hr, respectively. The shorter half-life of the Fc fragment explained why its activity to provoke RPCA disappeared more rapidly than that of intact IgG as the sensitization period was prolonged. The ability to provoke RPCA did not seem to influence the persistence of Fc fragment in the sites, since F(ab')2 as well as Fab fragments had the same half-life as Fc fragment.

Animals↗