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M Verstraete

Publications and source records attributed to M Verstraete.

At least 37 records · Page 2Linked to original sources
PubMed1995

Benefit of thrombolytic therapy is sustained throughout five years and is related to TIMI perfusion grade 3 but not grade 2 flow at discharge. The European Cooperative Study Group.

BACKGROUND: Long-term follow-up in patients treated with thrombolysis for acute myocardial infarction thus far has been reported in a few studies only, and no long-term follow-up is available for patients who underwent additional percutaneous transluminal coronary angioplasty (PTCA). This report describes 5-year survival as collected in patients who received placebo, recombinant tissue plasminogen activator (rTPA), or rTPA with additional immediate PTCA in two European Cooperative Study Group trials. Determinants for long-term survival were assessed in 1043 patients discharged alive. METHODS AND RESULTS: Five-year follow-up information on mortality was collected. Hospital mortality was lower after rTPA than placebo (2.5% versus 5.7%, P = .04) and higher after rTPA with immediate PTCA compared with rTPA without additional intervention (6.0% versus 2.2%, P = .07). Of the 1043 hospital survivors, data were available for 923 patients, of whom 109 died. In the placebo group, mortality after hospital discharge was 10.7% versus 11.0% in the comparative rTPA group. The patients treated with rTPA and immediate PTCA had a mortality rate of 10.5% versus 8.9% in the rTPA group without PTCA (all P = NS). Significant determinants of mortality in multivariate proportional hazards analysis were enzymatic infarct size, indicators of residual left ventricular function, number of diseased vessels and TIMI perfusion grade at discharge. Patients with TIMI grade 2 flow had mortality rates similar to those with TIMI flow grades 0 and 1, while prognosis was better in patients with TIMI flow grade 3. CONCLUSIONS: The initial in-hospital benefit of thrombolysis with intravenous rTPA is maintained throughout 5 years, with no early or late beneficial effect of systematic immediate PTCA. Enzymatic infarct size, left ventricular function, and extent of coronary artery disease are predictors for long-term survival. TIMI perfusion grade 2 at discharge should be considered as an inadequate result of therapy.

Angioplasty, Balloon, Coronary↗
PubMed1995

Thrombolytic therapy of non-cardiac disorders.

Patients with a recent (less than 10 days) proximal deep vein thrombosis of the leg or pelvis are candidates for thrombolysis as the major benefit over heparin seems to be the prevention of the postphlebitic limb, an aim which is still not proven in a satisfactory manner. Nonocclusive thrombi appear to lyse more readily than occlusive thrombi. For this indication the optimal dose regimens for the three thrombolytic drugs (streptokinase, urokinase, alteplase) are not established. Acute massive pulmonary embolism with hypotension or shock should be treated with thrombolytic drugs and, pending the outcome in the first hour, be considered for pulmonary embolectomy. Major acute pulmonary embolism with haemodynamic instability responds well to thrombolysis. Whether thrombolysis is superior to heparin in subacute intermediate pulmonary embolism has not been proven unequivocally in terms of mortality or clinically important endpoints. Systemic administration of thrombolytic drugs for peripheral arterial occlusion has been abandoned for catheter-directed and intraoperative intra-arterial repeated bolus or short-term infusions. The efficacy and safety of intravenous thrombolytic treatment following a major ischaemic stroke is presently being tested in large scale trials; its use must be restricted to experimental protocols.

Arterial Occlusive Diseases↗
PubMed1995

New developments in antiplatelet and antithrombotic therapy.

Several agents which inhibit platelet aggregation (aspirin, ticlopidine, dipyridamole), and anticoagulants (vitamin K antagonists, unfractionated heparin, low molecular weight heparins and heparinoids) are in clinical use. The search for more effective antiaggregating agents has resulted in the development of clopidogrel, a chemical analogue of ticlopidine with minimal bone-marrow suppressing effects, thromboxane synthase inhibitors and receptor blockers, and antagonists of platelet receptor glycoproteins Ib and IIb/IIIa. In addition there is increasing therapeutic experience with chimeric monoclonal antibodies against the platelet receptors, glycoprotein IIb/IIIa, and, to a minor extent, with synthetic peptides or non-peptide inhibitors against the same receptors. Although new anticoagulants have become available, their efficacy has only been tested in animal models of thrombosis: tissue factor pathway inhibitor, factor Xa inhibitors (recombinant tick anticoagulant peptide, antistasin, natural pentasaccharide and DX-9065), recombinant thrombomodulin and recombinant protein C have been tested in this manner. Considerable clinical progress has been made with direct thrombin inhibitors, such as recombinant hirudin and hirulog which appear to be effective antithrombotic agents in patients. There is also clinical experience with argatroban, an arginine derivative which is a competitive antagonist to thrombin. However, PPACK, a tripeptide synthetic compound which irreversibly blocks the active catalytic site of thrombin, has not been investigated in the clinical setting.

Cardiology↗
PubMed1995

Novel antithrombotic drugs in development.

Platelet activation plays a critical role in thromboembolic disorders, and aspirin remains a keystone in preventive strategies. This remarkable efficacy is rather unexpected, as aspirin selectively inhibits platelet aggregation mediated through activation of the arachidonic-thromboxane pathway, but not platelet aggregation induced by adenosine diphosphate (ADP), collagen and low levels of thrombin. This apparent paradox has stimulated investigations on the effect of aspirin on eicosanoid-independent effects of aspirin on cellular signalling. It has also fostered the search for antiplatelet drugs inhibiting platelet aggregation at other levels than the acetylation of platelet cyclo-oxygenase, such as thromboxane synthase inhibitors and thromboxane receptor antagonists. The final step of all platelet agonists is the functional expression of glycoprotein (GP) IIb/IIIa on the platelet surface, which ligates fibrinogen to link platelets together as part of the aggregation process. Agents that interact between GPIIb/IIIa and fibrinogen have been developed, which block GPIIb/IIIa, such as monoclonal antibodies to GPIIb/IIIa, and natural and synthetic peptides (disintegrins) containing the Arg-Gly-Asp (RGD) recognition sequence in fibrinogen and other adhesion macromolecules. Also, some non-peptide RGD mimetics have been developed which are orally active prodrugs. Stable analogues of prostacyclin, some of which are orally active, are also available. Thrombin has a pivotal role in both platelet activation and fibrin generation. In addition to natural and recombinant human antithrombin III, direct antithrombin III-independent thrombin inhibitors have been developed as recombinant hirudin, hirulog, argatroban, boroarginine derivatives and single stranded DNA oligonucleotides (aptanes). Direct thrombin inhibitors do not affect thrombin generation and may leave some 'escaping' thrombin molecules unaffected. Inhibition of factor Xa can prevent thrombin generation and disrupt the thrombin feedback loop that amplifies thrombin production.

Amino Acid Sequence↗
PubMed1995

Thrombolytic agents in development.

The quest continues for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin selectivity. Several lines of research towards improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators (PAs), chimaeric PAs, conjugates of PAs with monoclonal antibodies, and PAs from animal or bacterial origin. Some of these new thrombolytic agents have shown promise in animal models of venous or arterial thrombosis and in pilot clinical studies. Such molecules include numerous mutants of tissue-type PA (t-PA) with prolonged in vivo half-life and/or resistance to protease inhibitors, and chimaeric PAs consisting of different regions of t-PA and of urokinase-type PA (u-PA). Several molecular forms of the thrombolytic substance in the saliva of the vampire bat have been characterised and cloned. Vampire bat PA exhibits 85% homology to human t-PA but lacks kringle 2 and the plasmin-sensitive cleavage site. A thrombolytic enzyme of 203 amino acids is present in the venom of a southern copperhead snake. This polypeptide, termed fibrolase, is now produced by recombinant technology. Fibrolase does not activate plasminogen or protein C, but directly degrades the alpha and beta chains of fibrin and fibrinogen. Recombinant staphylokinase is not an enzyme, but it forms a 1:1 stoichiometric complex with plasminogen, which becomes active after conversion of plasminogen to plasmin. It is a potent and highly fibrin specific thrombolytic agent in animals and patients.

Amino Acid Sequence↗
PubMed1995

[Prevention of deep venous thrombosis].

The positive and negative clinical symptoms and signs of deep venous thrombosis are both insensitive and non-specific. Venography is the reference investigation: Duplex ultrasonography is the usual diagnostic procedure for distal deep venous thrombosis but it is less reliable in proximal lesions. The sensitivity of plethysmography in proximal deep venous thrombosis is high but the diagnosis of isolated calf vein thrombosis and non-obstructive proximal thrombosis escape diagnosis in this technique. Most cases of deep venous thrombosis occur after major surgery, during pregnancy, in the post-partum period, after prolonged immobilisation and in obese patients or those with varicose veins. Congenital and acquired causes should also be investigated when spontaneous deep venous thrombosis occurs or when the condition complicates minor surgical trauma in a young patient. The incidence of deep venous thrombosis varies with the type of surgical procedure: 25% in general surgery, 50% after hip or knee arthroplasty, 43% after fracture of femur, 24% after neurosurgery. Graduated pressure stockings should be used for the prevention of deep venous thrombosis. Other measures include aspirin, dextran, oral and subcutaneous anticoagulants, non-fractionated and low molecular weight heparins. The relative efficacy of these different measures is discussed with respect to each type of surgical procedure.

Humans↗
PubMed1995

[Thrombolytic therapy of acute myocardial infarction].

Thrombolytic therapy has reduced the mortality of acute myocardial infarction when administered in the first 12 hours after its onset. The author reviews the evidence concerning the more difficult aspects of this treatment: do all patients derive the same benefits? How to administer the treatment as early as possible? What is the value of late thrombolytic therapy? What is the best agent and the optimal mode of administration? This article describes the state of the art at the beginning of 1995 in a rapidly evolving field of therapeutics.

Aged↗
PubMed1994

Novel thrombolytic agents.

The fibrinolytic system comprises an inactive pro-enzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin-selectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, or plasminogen activators from animal or bacterial origin.

Amino Acid Sequence↗
PubMed1994

Primary and secondary prevention of arterial thromboembolism.

Aspirin in doses of approximately 300 mg/day may be recommended for the primary prevention of myocardial infarction in males and probably also in females, but only in those individuals with a moderate to high risk of cardiovascular disease. In patients with stable angina, aspirin decreases the risk for a first myocardial infarction. Aspirin or ticlopidine should be given to patients with unstable angina, in conjunction with heparin in the most severe cases. Long-term oral anticoagulant treatment after myocardial infarction in low risk patients has a limited effect on mortality but reduces the incidence of non-fatal recurrent myocardial infarction and stroke. Daily aspirin is more convenient and simple, and is at least as effective, but associated with a lower risk of bleeding. The concurrent use of aspirin and low intensity anticoagulation in the secondary prevention of myocardial infarction has, however, not been investigated. Various antiplatelet agents, including aspirin (alone or combined with dipyridamole) and ticlopidine, have, in contrast to oral anticoagulants, proved useful in the prevention of early thrombosis in aorto-coronary grafts, provided treatment begins at the latest 6 h after surgery. The usefulness of antiplatelet drugs has been well established in the prevention of immediate reocclusion following coronary angioplasty, but so far no drugs can prevent late restenosis. In patients with a synthetic cardiac valve prosthesis, lifelong treatment with coumarins is still indispensable, but their antithrombotic effect can be reinforced by dipyridamole or aspirin which also allows to reduce the intensity of anticoagulation. In uncomplicated bioprosthetic valve replacement, low intensity anticoagulation during the first 3 months suffices. Diuretics probably provide the best primary protection against cerebrovascular accidents in moderate hypertensives, although medium doses of aspirin may be considered in elderly people at high risk of such accidents. Aspirin (alone or combined with dipyridamole) and ticlopidine may be recommended for the secondary prevention of cerebral ischaemic accidents. Aspirin and ticlopidine, but not oral anticoagulants, reinforce the treatment of obliterative arterial disease in the lower limbs.

Angina Pectoris↗
PubMed1994

Ridogrel does not increase the speed and rate of coronary recanalization in patients with myocardial infarction treated with alteplase and heparin.

Ridogrel, a compound with the dual property of inhibiting the synthesis of thromboxane and blocking the receptors of thromboxane/prostaglandin/endoperoxides, has been shown to accelerate the speed of recanalization and to delay or prevent reocclusion during systemic thrombolysis with tissue plasminogen activator in experimental animals. Ninety patients who had not taken any antiplatelet drugs within the last 10 days were randomized to either intravenous ASA 250 mg immediately before the thrombolytic treatment and 100 mg once a day orally thereafter or ridogrel 300 mg i.v. before thrombolytic treatment and 300 mg b.i.d. orally thereafter. All patients were given intravenous heparin concomitantly with alteplase. The patency of the infarct-related artery was determined by coronary angiography before the administration of the thrombolytic agent and by repeated coronary angiography every 15 min until the end of the administration of alteplase. A final angiogram was obtained 48 to 72 h later. At 90 min, the recanalization and patency rates were the same in the two treatment groups with no intergroup difference in the speed of recanalization.

Aspirin↗
PubMed1994

Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group).

BACKGROUND: As a result of their polypeptidic nature, hirudins could theoretically elicit an immunologic response in humans. METHODS: The present open survey evaluates the allergenic potential of recombinant hirudin CGP 39393 (REVASC) after repeated intravenous or subcutaneous exposures in immunocompetent volunteers with no known previous exposure to hirudins. Clinical signs and symptoms of allergic manifestations and surrogate markers of allergy (i.e. response to skin tests) were collected before and after each administration of CGP 39393. Hirudin-specific immunoglobulin (Ig)G or IgE antibodies were measured. RESULTS: Two hundred and sixty-three healthy volunteers were eligible, of whom 12.2% had a history of allergy and 18.3% had a high level of total IgE. No signs or symptoms of allergy directly attributable to CGP 39393 were reported, either during or immediately after a first challenge. Irritative skin reactions, to either the prick or the intradermal skin test, were observed in eight volunteers 28-56 days after the challenge. Three out of 200 volunteers exposed to a second course of CGP 39393 showed signs and symptoms of an allergic reaction. In all but one subject with a pruritic erythema it was possible to rule out a causative role for CGP 39393 (0.50%, 95% confidence limits [CL] 0.01-2.75). Three other volunteers displayed a suspect or a positive immediate-type skin reaction to the follow-up intradermal skin test without any signs or symptoms of allergy. Another asymptomatic volunteer (0.80%, 95% CL: 0.02-4.41) developed a low [i.e. 1+ on the radio-allergosorbent test (RAST) scale] but measurable titre of hirudin-specific IgE antibodies after the second exposure to CGP 39393. A third exposure in five volunteers was clinically uneventful. A positive reaction to the prick test and to the intradermal skin test was observed in one individual. CONCLUSIONS: Recombinant hirudin CGP 39393 appears to be a weak allergen. Repeated exposures are safe in fully immunocompetent subjects, including those with a history of previous allergies and high levels of total IgE. Type I allergic reactions are rare (i.e. less than 1%) after a second exposure and are limited to the skin. Routine skin tests are not needed to identify patients at risk of developing type I allergic reactions. Hirudin-specific IgE antibodies are rarely seen and then at very low titres.

Adult↗