Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defibrotide, a polydeoxyribonucleotide, has been found to modulate endothelial cell function, causing an increase in tissue plasminogen activator (t-PA) levels, a decrease in plasminogen activator inhibitor (PAI) levels, and an increase in prostaglandin I2 (PGI2) formation in humans. Defibrotide has no direct anticoagulant effect but has a synergistic action with heparin. A strong antithrombotic effect has been observed in animal models. Thus, defibrotide has a beneficial effect in cases of deep venous thrombosis (DVT), peripheral obliterative vascular disorder (POVD), stroke, vasculitis, and thromboembolism. Defibrotide also inhibits platelet function and activation. A significant decrease in platelet aggregate formation on the suture line in microarterial anastomosis in rats is one way defibrotide can inhibit platelet function and activation. In humans, a slight prolongation' of the lag period in collagen-induced aggregation has been observed. In addition, a slight decrease in the maximum amplitude of the secondary wave of ADP and adrenalin-induced aggregations was also found. Platelet adhesion is diminished, the platelet differential count on formvar membrane is altered, and platelet aggregate formation is significantly inhibited. With an increase in platelet cyclic AMP (cAMP) content and a decrease in malonyl dialdehyde (MDA) and thromboxane B2 (TXB2) formation, the levels of platelet secretion products such as PF-4 and beta-thromboglobulin (beta-TG) in plasma decreased progressively. It was also demonstrated that the 14C-glucose transport defect of the platelet membrane of atherosclerotic patients was partially corrected with defibrotide treatment.
 ...
PMID:Effect of defibrotide on platelet function. 880 24

Thirteen patients with mild hypertension (untreated diastolic blood pressure of 95 to 114 mmHg) received, in random order, three successive treatments of four weeks with placebo, spirapril (6 mg daily), or hydrochlorothiazide (HCT2) (24 mg daily). At the end of each treatment, blood samples for assessment of platelet aggregation and platelet release of platelet factor 4 (PF4) and for assessment of fibrinolysis, estimated by tissue plasminogen activator (t-PA), plasminogen activator inhibitor-type 1 (PAI-1), and euglobulin clot lysis time (ECLT), were taken, first at rest, then immediately after five to ten minutes of vigorous exercise, and finally after the subsequent hour of recovery rest. Platelet aggregation induced in vitro by adrenaline significantly decreased during treatment with HCT2, the threshold rising to 10 microM as compared with 1.0 with placebo (P < 0.05) at rest, and the threshold for adenosine diphosphate (ADP) aggregation also rose, from 2 microM to 4 (NS). The resting plasma PF4 value fell, although not significantly, during HCT2 treatment from the placebo value of 3.28 to 2.56 ng/mL. During spirapril treatment there was no change in the threshold of either adrenaline or ADP for aggregation of platelets sampled at rest, and the PF4 plasma levels showed no significant reductions at rest. However, during exercise PF4 showed an approximate doubling of the resting value irrespective of therapy. This exercise-induced increase in PF4 was significantly reduced by spirapril as compared with placebo (P < 0.05). ECLT and t-PA did not shift significantly from the placebo level during either therapy. PAI-1 did not change during spirapril therapy, but during HCT2 treatment it fell, although not significantly, to 9.36 IU/mL from 15.91 with placebo (NS). Spirapril and HCT2 did not produce any unwanted side effect on platelet function or fibrinolysis. HCT2 seems to decrease platelet activity at rest, whereas spirapril seems to some extent to decrease platelet activity at exercise.
 ...
PMID:Effect of spirapril and hydrochlorothiazide on platelet function and euglobulin clot lysis time in patients with mild hypertension. 887 80

The thrombin inhibitor inogatran is a synthetic peptidomimetic with a molecular weight of 439 dalton. In vitro studies have shown that inogatran is a classical competitive inhibitor of the active site of thrombin with a Ki of 15 x 10(-9) mol/l. Inogatran doubles the thrombin clotting time in human plasma at 20 x 10(-9) mol/l, APTT at 1.2 x 10(-6) mol/l, and prothrombin time at 4 x 10(-6) mol/l. The effects on rat and dog plasma are similar although slightly weaker. IC50 for inhibition of thrombin-induced aggregation of human platelets is 17 x 10(-9) mol/l. Inogatran has no effect on platelet aggregation induced by ADP or collagen. Up to a concentration of 10 x 10(-6) mol/l inogatran does not inhibit t-PA-induced fibrinolysis as seen in an ECLT system. Inogatran has good selectivity for thrombin as compared to several other serine proteases occurring in the blood. It is concluded that the properties of inogatran in vitro make the compound suitable for further studies in animals and man.
 ...
PMID:In vitro effects of inogatran, a selective low molecular weight thrombin inhibitor. 905 87

We have established a novel thrombosis model of the middle cerebral artery (MCA). The thrombotic occlusion of the MCA was induced by the photochemical reaction between Rose Bengal and green light, which causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of the photochemical reaction. With this model, we have investigated the effects of anti-thrombotic agents, thrombolytic agents and neuroprotective agents. In our model, ADP, thromboxane A2 (TXA2) and thrombin play a key role in thrombus formation of the MCA. Tissue-type plasminogen activator (tPA) could cause an opening of the thrombotic MCA occlusion and reduced the size of the cerebral infarction. Furthermore, a TXA2 antagonist enhanced the thrombolytic efficacy of tPA. MS-153 ((R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline), a glutamate release inhibitor and YM90K [6-(1 H-imidazol-1-yl)-7-nitro-2,3(1H, 4H)-qunoxalinedione monohydrochloride, an alpha-amino-3hydroxy-5methyl-4-isoxazole (AMPA) antagonist reduced the cerebral infarction 24 hr after the MCA occlusion. This model is very useful for investigating the mechanisms of anti-thrombotic and neuroprotective agents and evaluating the effects of these agents.
 ...
PMID:[A novel photochemical model of the middle cerebral artery for thrombosis research and evaluation of anti-thrombotic agents]. 916 Mar 47

Daily oral 6-week administration of epaden in a dose containing 0.3 g eucosopentanoic acid and 0.05 g docosahexaenoic acid caused decrease in collagen-induced platelet aggregation in rabbits in vivo and in the activity of the tissue type plasminogen activator, as well as reduction in the level of antithrombin III cofactor activity. No changes were encountered in ADP-induced aggregation, in the platelet count, in platelet adhesion to collagen, and in activated partial thromboplastin time.
 ...
PMID:[The effect of the chronic internal administration of the new Russian n-3 polyunsaturated fatty acid concentrate--epaden--on blood coagulation system indices in rabbits]. 920 67

Previous in vitro studies have suggested that nitric oxide-releasing agents can increase the fibrinolytic capacity while platelet aggregability is decreased. We have therefore directly compared the influence of organic nitrates on ex vivo platelet aggregation and the fibrinolytic system in 16 healthy volunteers. Each subject received glyceryl trinitrate (GTN, 2 x 32 mg patches), isosorbide-dinitrate (ISDN, 120 mg p.o.), isosorbide-5-mononitrate (ISMN, 50 mg p.o.), and placebo in a randomized double-blind manner. Ex vivo platelet aggregation, activities and concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured before, 90 and 150 minutes after drug intake. GTN, ISDN, and ISMN were equipotent in respect to their hemodynamic responses. Platelet aggregation induced with a low (1 microM) but not with a high (4 microM) agonist concentration (adenosine diphosphate, ADP) was reduced after GTN and ISDN. ISMN had no influence on aggregation. An increase of t-PA activity was significantly reduced after GTN and ISDN (p<0.05), whereas t-PA concentrations were not affected by the nitrates. A decrease of PAI-1 activity after ISMN and placebo was not apparent after GTN and ISDN. In the case of GTN, the decrease of PAI-1 concentration was delayed. In conclusion, GTN and ISDN did not increase the fibrinolytic capacity but decreased the reversible phase of ADP-induced platelet aggregation, while ISMN had neither an effect on the fibrinolytic system nor on platelet aggregation.
 ...
PMID:Effect of organic nitrates on ex vivo platelet aggregation and fibrinolysis in man. 936 42

Misoprostol, the oral analogue of alprostadil was used for the treatment of 20 patients (aged 40-60) with peripheral arterial disease according to Fontaine's classification at stages IIa and IIb (PAD). All patients received 200 micrograms of misoprostol 3 times a day during a month. The therapy with misoprostol resulted in a clinical improvement in all patients. Elongation of pain free (before treatment 129 m +/- 78 m, after treatment 214 m +/- 109 m) and maximum walking distance (before treatment 304 m +/- 169 m, after treatment 471 m +/- 264 m) was observed. At the same time a shortening of the pain duration was noted (before treatment 100 sec +/- 37 sec, after treatment 71 sec +/- 23 sec). The ankle/arm pressure ratio (AAPR) and arterial blood flow increased in both limbs after 4 weeks of the treatment. Activation of the fibrinolytic system was seen in the course of the therapy (shortening of euglobulin clot lysis time-ECLT and increase in t-PA activity). The platelets became less sensitive to ADP and collagen after intake of misoprostol. The results justify administration of misoprostol as a new therapeutic agent for the treatment of patients with PAD.
 ...
PMID:[Misoprostol--oral prostanoid--the first clinical trial for use in patients with peripheral vascular disease]. 948 Apr 58

We examined the effect of a humanized anti-glycoprotein IIb/IIIa monoclonal antibody, YM337, on thrombolysis with tissue-type plasminogen activator in a copper coil-induced coronary thrombosis model in rhesus monkeys. Fifty minutes after the formation of an occlusive thrombus, a test drug was administered by either i.v. bolus injection followed by continuous infusion (YM337, 0.25 mg/kg + 1.5 microg/kg/min) or i.v. bolus injection (aspirin, 17 mg/kg). Sixty minutes after induction of the occlusive thrombus, thrombolysis was initiated with tPA at a total dose of 0.5 mg/kg intravenously administered over 60 min, with 10% given as an initial bolus. The median time to reperfusion was significantly shortened by YM337 [saline, 60 min (n = 5); aspirin, 45 min (n = 5); YM337, 30 min (n = 5)]. The incidence of reocclusion was significantly decreased by YM337 (saline, 4/4; aspirin, 5/5; YM337, 1/5), and the median time to reocclusion was significantly prolonged by YM337 [saline, 30 min (n = 4); aspirin, 30 min (n = 5); YM337, 180 min (n = 5)]. YM337 significantly reduced the thrombus protein content at the end of experiment. ADP-induced platelet aggregation was completely inhibited by YM337. These results suggest that YM337 may be of clinical value as an adjunctive agent in thrombolytic therapy for patients with acute myocardial infarction.
 ...
PMID:Enhancement of tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by combination with a humanized anti-glycoprotein IIb/IIIa monoclonal antibody, YM337, in a rhesus monkey model of coronary thrombosis. 953 Oct 59

RGD-containing peptides and other antagonists of the platelet glycoprotein (GP) IIb/IIIa may induce a high-affinity binding site for fibrinogen and the expression of novel epitopes, called ligand-induced binding sites (LIBS). The functional relevance of LIBS expression in a canine model of coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was examined. Ro43-5054 (N-[N-[N-(p-amidinobenzoyl)-b-alanyl]-l-a-aspartyl]-3-phenyl-l- alanine) and Ro44-9883 ([1-(N-(p-amidinobenzoyl)-l-tyrosyl)-4-piperidinyl)oxy]acetic acid), antagonists of the GP IIb/IIIa receptor, were administered in increasing doses of 2 to 10 microg/kg/min, beginning 30 min before the infusion of t-PA. LIBS expression was determined by the binding of the monoclonal antibody, D3GP3, to platelets on exposure to Ro43-5054, Ro44-9883 and t-PA. Ro43-5054 was shown to induce LIBS, whereas Ro44-9883 and t-PA did not. Both drugs abolished platelet aggregation in response to U46619 and ADP ex vivo. Reocclusion was prevented with both Ro43-5054 and Ro44-9883, but neither drug altered reperfusion times (49 +/- 8 and 55 +/- 39 min). Both drugs increased the rate of bleeding compared with t-PA alone, but there was no difference in hemostasis between the two drugs. To determine whether the drugs differed in their effect on platelet activation in vivo, urinary 2,3-dinor-thromboxane (TX) B2, a major metabolite of TXB2, was determined by gas chromatography-mass spectrometry. After reperfusion, the urinary 2,3-dinor-TXB2 increased in the Ro43-5054-treated group, similar to control groups (32 +/- 8 and 37 +/- 9 ng/mg creatinine). This increase was blunted in the Ro44-9883-treated group (9 +/- 3 ng/mg creatinine). GP IIb/IIIa antagonists that do not induce LIBS result in a greater suppression of platelet activity but not in any discernible functional benefit in vivo.
 ...
PMID:Functional relevance of the expression of ligand-induced binding sites in the response to platelet GP IIb/IIIa antagonists in vivo. 969 54

The antithrombotic effect of GR144053, which inhibits platelet aggregation by binding to the fibrinogen receptor (glycoprotein IIb/IIIa), was investigated in vitro and in vivo by using hamsters. This compound inhibited the platelet aggregation induced by adenosine diphosphate (ADP; 2.5 microM) with a mean inhibitory concentration (IC50) value of 2.2 +/- 0.4 x 10(-5) M. Vascular injury was inflicted in one carotid artery by using a modified catheter to produce endothelial denudation. In the control group, arterial blood flow was interrupted 4.4 +/- 2.3 min (n = 12) after the injury. When GR144053 continuously infused intravenously at doses of 0 (saline) 0.1, 0.3, and 1.0 mg/kg/h (n = 8, each), the time that elapsed before the vessel became completely obstructed was prolonged in a dose-dependent manner. In separate experiments, reperfusion could be obtained by continuous infusion of tissue-type plasminogen activator (tPA; 0.52 mg/kg) starting 30 min after the initiation of thrombus formation. When GR144053 (0.3 and 1.0 mg/kg/h) was infused in addition to tPA, the incidence of reperfusion and the later patency of the reperfused artery were much improved as compared with tPA alone. The bleeding time at the end of tPA infusion was significantly prolonged in the presence of the highest dose of GR144053. Next, neointima formation was evaluated 2 weeks after the vascular injury. When GR144053 (0.3 mg/kg/h) was continuously infused i.v. by an implanted osmotic pump for 14 days, the neointimal area was significantly reduced. In separate hamsters, the proliferating index of smooth muscle cells (SMCs) by using bromodeoxyuridine (BrdU) was investigated, and treatment with both tPA and GR144053 significantly decreased the SMC proliferation index in vivo. However, in the in vitro experiments using a hamster SMC line, GR144053 did not have an inhibitory effect on SMC proliferation. These findings suggest that GR144053 inhibits platelet activation on the injured artery and improves vascular patency after thrombolysis with tPA, which furthermore results in suppression of neointima formation.
 ...
PMID:Effect of GR144053, a fibrinogen-receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tPA in the injured carotid artery of the hamster. 970 Sep 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>