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PubMed1977

Controlled trial of the effect of cycloalliin on the fibrinolytic activity of venous blood.

Cycloalliin is a natural constituent of onion, sulphur-containing but odourless. It was synthesised for this randomised double-blind study; its effect on fibribolytic activity and platelet aggregability was tested in venous blood from 18 male volunteers. It increased the former to a highly significant degree but had no effect on the latter. It was well tolerated and harmless in the single oral dosage used.

Adult↗
PubMed1994

Characterization of platelet activity in neuroblastoma.

A study was conducted to characterize the platelet aggregation induced by neuroblastoma tissue to investigate the mechanism of hypercoagulability in patients with neuroblastoma. The patients whose tumor tissues were examined had been shown clinically to have enhanced platelet activity. Platelet aggregation induced by neuroblastoma tissue extract was compared with that of other pediatric tumors. The effects of pretreatment with an antithrombin agent and prostacyclin (PGI2) on the platelet aggregation induced by tumor tissue extracts were also evaluated. Tissue extracts of 12 of 15 neuroblastomas, 3 of 3 Wilms' tumors, and 1 pheochromocytoma were demonstrated to have an activity that potentiated platelet aggregation in vitro. The platelet aggregation induced by tissue extracts of neuroblastomas and other tumor tissues was suppressed almost completely by pretreatment with a PGI2 analogue. The aggregation induced by neuroblastomas and the pheochromocytoma was also suppressed by pretreatment with an antithrombin agent, argatroban, whereas the aggregation induced by Wilms' tumors was not suppressed by this agent. These results suggest that (1) malignant tumors in children also have some chemical substances that sensitize platelet activity, such as those in adult cancers, and (2) thrombin is one of the mediators stimulating platelet aggregation in cases of neuroblastoma, although it is unlikely to be a contributing factor in other pediatric malignancies such as Wilms' tumor.

Antithrombins↗
PubMed1984

The behavioural effects of an N-methylaspartate receptor antagonist following application to the lumbar spinal cord of conscious rats.

The selective N-methylaspartate (NMA) receptor antagonist 2-amino-5-phosphonopentanoate (AP5) has been applied to the lumbar region of the spinal cord in conscious rats through chronically implanted intrathecal cannulae. Administration of AP5 was compared with administration of 2-amino-4-phosphonobutyrate (AP4), morphine and control injections. Intrathecal injection of AP5 (250 nmol) produced extensor paralysis in the hindquarters and depression of aversive responses to tail heat (54 degrees C), paw heat (hotplate 56.5 degrees C) and paw pressure. Depression of AP5 of the vocal response to aversive electrical stimuli, applied to the tail, suggested that AP5 produced analgesia independently of locomotor paralysis. Intrathecal injection of morphine (20-30 nmol) produced no observed locomotor effects, but depressed responses to all the aversive stimuli. Intrathecal injection of AP4 had no significant effects. When tritiated AP5 was administered intrathecally, the proportion of radioactivity recovered from the lumbar spinal cord suggested that the concentration of AP5, which produced locomotor depression and analgesia, was likely to have been in the range (15-75 microM) known to depress excitatory transmission in isolated spinal cord preparations. It is concluded that synaptic activation of n-methylaspartate receptors is important in spinal pathways which control locomotion, posture and central transmission of nociceptive information.

2-Amino-5-phosphonovalerate↗
PubMed1992

Pharmacological study of the chicken's monocular optokinetic nystagmus: involvement of the ON retinal channel evidenced by the glutamatergic separation of ON and OFF pathways.

The chicken's monocular optokinetic nystagmus (OKN), recorded by the magnetic search coil technique, displays a directional asymmetry, the temporal-nasal (T-N) stimulation being more efficient than the nasal-temporal (N-T) one to evoke the reflex. The intravitreal administration of APB, a glutamate agonist which selectively blocks the ON retinal channel strongly reduced the eye monocular OKN; it also induced spontaneous eye movements in the T-N direction. The intravitreal injection of PDA another glutamate analog, which reduces the OFF channel, while increasing the activity of the ON channel, induced a large increase in OKN velocity gain, especially for a N-T stimulation at the lowest drum speeds. These results indicate the main involvement of the ON retinal channel in the OKN genesis and the inhibitory effect of the OFF channel upon this oculomotor reflex.

Aminobutyrates↗
PubMed1987

Similarity and dissimilarity in the stereogeometry of the active sites of thrombin, trypsin, plasmin and glandular kallikrein.

The relationship between chemical modifications of arginine derivatives and inhibitory activity to trypsin, plasmin and glandular kallikrein was investigated comparing with that of thrombin and concluded as follows: The hydrophobic binding pocket, which has been reported previously to be stereogeometrically very similar in trypsin and thrombin, corresponded to the length of ethylpiperidine. Concerning the site (termed the P site) next to the hydrophobic binding pocket, there were large differences in stereogeometry between trypsin and thrombin; the binding site of trypsin extended further to allow propyl and phenyl group attached to piperidine, while that of thrombin would be much narrower and unable to allow them. The P sites of plasmin and glandular kallikrein resembled that of trypsin in being able to allow phenyl group. To substantialize the hydrophobic binding pocket and the P site, a (2R, 4R)-MQPA-trypsin complex model was generated using the results of X-ray crystallography of (2R, 4R)-MQPA and BPTI-trypsin complex by calculation to minimize van der Waals contacts, and it was of great use for understanding the geometry of the active sites of trypsin, thrombin, plasmin and glandular kallikrein.

Animals↗
PubMed1989

Effects of an antithrombotic agent (MD-805) on progressing cerebral thrombosis.

The effects of the newly developed synthetic selective antithrombin agent MD-805 were examined in 11 patients with progressing cerebral thrombosis, as an open trial. Nine (82%) of 11 patients improved after 1 week of intravenous drip infusion. No hemorrhagic complications were observed during the therapy. These results suggest that MD-805 is a safe and effective agent for treatment of progressing cerebral thrombosis.

Aged↗
PubMed1990

A new method for the determination of prothrombin in human plasma.

A two stage method for the determination of prothrombin is described in which the potent synthetic thrombin-inhibitor MD805 is used to suppress the inactivation process of thrombin by antithrombins in plasma. In the activation stage, prothrombin was activated almost instantaneously after the addition of tissue thromboplastin in 20-times diluted plasma and then the generated thrombin was inactivated progressively. Addition of MD805 suppressed the inactivation process of thrombin in a dose-dependent manner, while it hardly affected the complete activation of prothrombin. Thus, the generated thrombin was maintained stable in the presence of 50 microM MD805, and was measured by using 0.5 mM S-2238 as substrate. The method exhibited a linear relationship to the dilution of plasma. The decreased level of the other extrinsic coagulation factors such as FVII, FV, FX and tissue thromboplastin did not cause any significant changes until their activities were decreased to 3, 12, 12 and 20% of their controls. In addition, the method is very simple and easy for standardization.

Arginine↗
PubMed1990

The effect of heparin on multiple organ failure and disseminated intravascular coagulation in a sepsis model.

In order to elucidate a possible role of hypercoagulability leading to disseminated intravascular coagulation (DIC) in the pathogenesis of multiple organ failure (MOF), unfractionated heparin and the related agents were administered to septic rabbits which manifest DIC and MOF. Administration of heparin resulted in prevention of thrombocytopenia, leukopenia and elevation of plasma bilirubin and creatinine. The morphological hepatic damage was also ameliorated by heparin. Similar favorable effects were obtained by the administration of low molecular weight heparin. Dextran sulfate prevented the hepatic damage to some extent without improvement on other parameters. No significant effect was observed by the administration of a synthetic thrombin inhibitor (MD805). These results indicate that the favorable effect of heparin is due to its anticoagulant property, especially anti-Xa activity. Thereby, it is concluded that the hypercoagulable state leading to DIC is a prerequisite for the occurrence of MOF in sepsis.

Animals↗
PubMed1990

Effect of a synthetic thrombin-inhibitor MD805 on the reaction between thrombin and plasma antithrombin-III.

MD805, a synthetic thrombin-inhibitor, effectively retarded the time-dependent inactivation of thrombin which was generated endogeneously or added exogeneously in human plasma. The kinetical study of the time-dependent inactivation indicated that the type of inhibition was competitive and the obtained Ki of MD805 for thrombin was 3 x 10(-8)M. MD805 also inhibited the formation of thrombin-ATIII complex. These results indicated that the active site of thrombin was involved in the reaction between thrombin and ATIII, and that MD805 competed with ATIII for thrombin in exactly the same manner as it competed with fibrinogen or synthetic peptide substrates. As a result, MD805 would serve as a protective agent for ATIII from being consumed, in addition to its potent thrombin-inhibitory activity without the aid of ATIII. By contrast, heparin accelerated the time-dependent inactivation rate of thrombin and the formation of thrombin-ATIII complex, which indicates that heparin accelerates the consumption of ATIII.

Antithrombin III↗
PubMed1991

Heparin and the thrombin inhibitor argatroban enhance fibrinolysis by infused or bolus-injected saruplase (r-scu-PA) in rabbit femoral artery thrombosis.

Enhancement by anticoagulation of thrombolysis with infused or bolus-injected saruplase (r-scu-PA) has been studied using heparin and the thrombin inhibitor argatroban. In a rabbit femoral artery thrombosis model infusion of saruplase (3 - 12 mg/kg, 60 min) caused a dose-dependent thrombolysis. Reperfusion rate after infusion of 3 mg/kg saruplase alone was 3/6, reperfusion time 42 +/- 3 min and reocclusion rate 2/3; final patency rate at 120 min was 17%. Combination of 3 mg/kg saruplase with heparin (150 U/kg + 100 U/kg.hr i.v.; 5.3-fold PTT-prolongation) resulted in a reperfusion rate of 6/6 after a reperfusion time of 39 +/- 7 min; reocclusion rate was 3/6 and final patency rate was 50%. Argatroban (1 mg/kg + 3 mg/kg.hr i.v.; 2.3-fold PTT prolongation) in combination with saruplase resulted in a reperfusion rate of 6/6 after 26 +/- 5 min; no reocclusion occured and final patency rate was 100% (p less than 0.05 vs saruplase alone). Bolus injection of 6 mg/kg saruplase achieved reperfusion in 5/6 arteries after 15 +/- 3 min, but reocclusion rate was 4/5; final patency rate was 17%. Combination of bolus-injected saruplase with heparin resulted in a reperfusion rate of 4/6 after 8 +/- 3 min and no reocclusion occured; patency rate was 67%. With combination of argatroban and bolus-injected saruplase 6/6 arteries were reperfused after 8 +/- 3 min; reocclusion was prevented and final patency rate was 100% (p less than 0.05 vs saruplase-bolus alone). Systemic fibrinogenolysis was more pronounced with bolus injection than infusion of saruplase. The results indicate that arterial thrombolysis with saruplase can be enhanced by heparin and the thrombin inhibitor argatroban. The bolus injection of saruplase resulted in persistent reperfusion when simultaneous anticoagulation was performed. Despite less PTT prolongation, enhancement of saruplase-induced thrombolysis was more effective with argatroban than with heparin in rabbit femoral artery thrombosis.

Animals↗