Stroke - desmoteplase
Stroke is a major cause of death and disability, and results from the blood supply to the brain being interrupted. An ischaemic stroke is caused by a thrombosis or embolism, and if the clot can be broken up before it does too much damage then there is a good chance that disability can be minimised.
Stroke is a major cause of death and disability, and results from the blood supply to the brain being interrupted. An ischaemic stroke is caused by a thrombosis or embolism, and if the clot can be broken up before it does too much damage then there is a good chance that disability can be minimised.
Several thrombolytic agents are available, but they present problems with safety, as well as pharmacokinetics and pharmacodynamics. Fibrinolytic agents have potential as clot-busting drugs. In the fibrinolysis process, a key step is the conversion of the inactive proenzyme plasminogen to the active plasmin by a protease enzyme catalysed peptide bond cleavage. A plasminogen activator could have applications in other conditions caused by clots, such as acute myocardial infarction (AMI) or pulmonary embolism.
Desmoteplase is being developed by German company Paion, and is a plasminogen activator that has been isolated from the common vampire bat.1 Because it has developed naturally for the rapid lysis of fresh blood clots, it is more effective at dissolving clots than human t-PA, which is the agent used most frequently as a clot-busting medicine.
Several clinical trials have been carried out in clot-based conditions. For example, a prospective non-randomised open label dose finding Phase II study took place in 26 patients with AMI.1 Patients were given 0.5 or 0.75mg/kg of the drug as an intravenous bolus over one to two minutes, followed by intravenous heparin. Patency was achieved in a total of 17 patients within 90 minutes, and late patency in 21.
Two double-blind placebo controlled dose finding Phase II trials have been carried out in acute ischaemic stroke. In one, the first 47 out of a total of 104 patients were randomised to fixed doses of 23, 37.5 or 50mg desmoteplase three to nine hours after the stroke.2 Because of an excessive rate of symptomatic intercranial haemorrhage (sICH), lower weight-adjusted doses escalating through 62.5, 90 and 125µg/kg were given to the remaining 57. The rate of sICH in the first part was 26.7% and the second 2.2%, with no sICH observed in those given placebo. Reperfusion rates of more than 70% were seen in those given 125µg/kg desmoteplase, compared with 19% of those given placebo. Early reperfusion correlated favourably with clinical outcome.
In the second such trial, 37 patients were given 90 or 125µg/kg desmoteplase, or placebo three to nine hours after the onset of an acute ischaemic stroke. This time, no sICH was seen, and reperfusion was achieved in 37.5% of patients given placebo, 28.6% of those given the lower dose of desmoteplase, and 53.3% of the group given the higher dose. A good clinical outcome after 90 days was seen in 25.0, 28.6 and 60.0% of patients respectively, and trials continue.