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

Desmoteplase, developed by Paion, Forest and Lundbeck, is a novel plasminogen activator that selectively activates fibrin-bound plasminogen and is currently being investigated for the treatment of acute ischemic stroke within the time window of 3-9 h after symptom onset. Desmoteplase is believed to offer pharmacologic advantages over currently approved treatment options. To date, two published Phase II perfusion imaging-based clinical trials have reported the safety and potential efficacy of desmoteplase in ischemic stroke. Results from a recently completed Phase III trial in Europe, Asia and the USA are awaited. This article reviews the available data on desmoteplase, including discussion of its favorable features and potential benefit beyond the 3-h time window in the treatment of ischemic stroke.
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PMID:Desmoteplase in the treatment of acute ischemic stroke. 1742 87

Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDP-choline) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their pleiotropic nature and the likelihood of either beneficial or detrimental effects that might depend on the timing of the treatment in relation to the stage of brain injury.
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PMID:Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. 1867 9

After ischaemic stroke onset, potentially viable (ie, penumbral) tissue might be salvageble for as long as 48 h. By increasing the therapeutic time window for treatment of stroke with intravenous alteplase from 3-4.5 h to 9 h, many more patients could be treated. Use of a combination of diffusion-weighted and perfusion-weighted MRI or perfusion CT might improve selection of patients with penumbral tissue. Several phase II trials of alteplase lend strong biological support to the use of this strategy for up to 6 h after stroke. However, the negative results of the phase III Desmoteplase In Acute ischaemic Stroke trial (DIAS-2) with desmoteplase given up to 9 h after stroke suggest that some refinements are needed. For trials of neuroprotection, the concept of freezing the penumbra (ie, preventing further deterioration of the vulnerable tissue) might be a more realistic expectation. Recent advances in penumbral imaging technology should enable a phase III alteplase trial to be done beyond 4.5 h by use of techniques to select patients with penumbral tissue.
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PMID:Penumbral selection of patients for trials of acute stroke therapy. 1923 36

The high fibrin specificity of Desmodus rotundus salivary plasminogen activator alpha1 (desmoteplase) renders it a promising candidate for the treatment of acute ischemic stroke. In the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) Phase II studies, doses of 90 microg/kg and 125 microg/kg desmoteplase were reported to have acceptable safety profiles, leading to potentially superior reperfusion compared with placebo, with possible clinical efficacy for up to 9 h after the onset of symptoms in patients with a significant ischemic penumbra selected from magnetic resonance perfusion-diffusion weighted mismatches imaging. However, a Phase III clinical trial (DIAS-2) was unable to detect any benefit from desmoteplase when given 3 - 9 h after stroke onset. In this study with a modest sample size, certain methodological factors may have reduced its potential to detect a desmoteplase effect, as only 30% of these patients had a visible occlusion at presentation, with only small core and mismatched lesion volumes. Indeed, it is surprising that a study testing an occluded vessel 'reopener' was conducted in a cohort of stroke patients, the majority of whom was known not to have a detected vessel occlusion. It has also been claimed that the DIAS-2 patients selection using core/penumbra mismatch calculation may not have followed an appropriate mismatch threshold. However, the corrective value of changing the mismatch threshold remains unclear, because the relative mismatch volumes were in fact higher in the 'negative' DIAS-2 than in the 'positive' DIAS and DEDAS. Two Phase II randomized trials with tPA, Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) provided strong biological support for the relation between infarct growth, reperfusion and clinical outcome in the 3 - 6 h time window after onset of stroke using penumbral imaging. In this frame, why exactly desmoteplase should have specific advantages over tPA, is not clear. Taken together, these findings may also lead to the disappointing conclusion that vessel recanalization after 4.5 - 5 h from stroke onset may generally be inefficacious for tissue salvage. Nevertheless, other randomized Phase III clinical trials (DIAS-3 and DIAS-4) are currently under way with a planned sample size of 320 patients having vessel occlusion or high-grade stenosis on MRI or CT-angiography in the proximal cerebral arteries.
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PMID:Desmoteplase. 1945 11

The discovery of thrombolytic agents goes back to the 1930s, when it was shown that substances derived from bacteria (streptokinase, staphylokinase), tissue (fibrinokinase), urine (urokinase) or bat saliva could activate the fibrinolytic system. The potential to treat arterial thrombosis with plasmin was recognized, but it was not until 1958 that its first use in acute ischaemic stroke (AIS) was described. However, since computer tomography (CT) was not available until the mid 1970s, optimal selection of patients was not possible. Early studies with streptokinase in AIS showed an increased risk of intracranial haemorrhage and lack of efficacy, which was associated with low fibrin specificity. The search for new agents with a better risk-benefit profile continued until 1979 when tissue plasminogen activator (t-PA) was discovered. In 1983 it became possible to produce recombinant t-PA (rt-PA) by expression of a cloned gene which enabled clinical trials to be started, mainly for coronary thrombolysis. In 1995, the National Institute of Neurological Disorders and Stroke study showed that rt-PA was an effective treatment for AIS, nowadays for use up to 4.5 h after onset. However, rt-PA still often fails in achieving rapid reperfusion, has relatively low recanalization rates and is associated with an increased bleeding risk. Several attempts have been made to develop thrombolytics with a better risk-benefit profile than rt-PA, but no real impact on clinical practice was observed. In 1994, it was shown that tenecteplase (rt-PA-TNK) had a higher fibrin specificity than rt-PA, but its clinical use in AIS was described only in 2005. The recently reported results of a small phase 2B trial showed significantly better reperfusion and clinical outcome with rt-PA-TNK compared to rt-PA; patients were selected by CT perfusion and angiography, and treated within 6 h after stroke onset. Currently, a phase 3 trial of rt-PA-TNK versus rt-PA is being planned in patients at an onset up to 4.5 h. The most fibrin-specific recombinant plasminogen activator desmoteplase originates from 1991, and its clinical development in AIS started in 2005. Desmoteplase is in phase 3 development for the treatment of AIS between 3 and 9 h after onset in AIS patients presenting with occlusion or high-grade stenosis.
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PMID:Thrombolytics in acute ischaemic stroke: historical perspective and future opportunities. 2361 79

The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).
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PMID:Review of stroke thrombolytics. 2432 44

Tissue-type plasminogen activator (t-PA) is the only thrombolytic treatment available for patients with acute ischaemic stroke. However, t-PA can increase permeability of the blood-brain barrier (BBB). Desmoteplase is a plasminogen activator derived from the common vampire bat, currently under clinical development for ischaemic stroke. We compared how t-PA and desmoteplase influenced BBB permeability using a human in vitro model where primary brain endothelial cells (BEC) and astrocytes are co-cultured on the opposite sides of a porous membrane. Permeability changes were evaluated 6 or 24h post-stimulation by passage of fluorescent albumin across the membrane. Under normoxic conditions, t-PA, but not desmoteplase, increased BBB permeability. Surprisingly, the ability of t-PA to affect the barrier was lost under conditions of oxygen-glucose deprivation (OGD). Addition of plasminogen re-sensitised the BBB to the action of t-PA under both normoxia and OGD, but did not affect the inert behaviour of desmoteplase, even when digested fibrinogen was added to ensure optimal plasmin generation. These observations coincided with plasmin-dependent changes in astrocyte and BEC morphology and disruption of tight junction proteins in BECs, specifically initiated by t-PA but not by desmoteplase. Finally, inhibition of plasmin post-stimulation with t-PA and plasminogen, especially within 2h, protected the BBB against t-PA-mediated barrier opening. Hence t-PA, but not desmoteplase, increases BBB permeability under both normoxic and OGD conditions in a reversible, plasmin-dependent process. The inability of desmoteplase to increase permeability despite its capacity to generate plasmin provides further support for its use as thrombolytic in patients with ischaemic stroke.
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PMID:t-PA, but not desmoteplase, induces plasmin-dependent opening of a blood-brain barrier model under normoxic and ischaemic conditions. 2467 27