Alteplase

Abstract

Alteplase (recombinant tissue-type plasminogen activator) stimulates the fibrinolysis of blood clots by converting plasminogen to plasmin. The efficacy of intravenous alteplase in the early treatment of patients with acute myocardial infarction has been unequivocally proven, and recent results from the GUSTO trial indicate a significant advantage in 30-day survival for alteplase in an accelerated dosage regimen (< or = 100mg infused over 90 minutes rather than 3 hours) over streptokinase. The advantage of the accelerated alteplase dosage regimen seems to be maintained for at least 1 year. The role of heparin as adjunctive therapy to thrombolysis remains to be fully defined but heparin administration appears to be more important in conjunction with alteplase than with streptokinase. Ideally, patients should receive alteplase as soon as possible after the onset of symptoms of acute myocardial infarction and, while therapy is most beneficial when administered early, survival is improved when the drug is administered up to 12 hours after symptom onset. The accelerated regimen of alteplase used in the GUSTO trial demonstrated a survival advantage in patients < or = 75 as well as those > 75 years of age which was at least as great as that seen with streptokinase. Similarly, alteplase reduces mortality in patients with both anterior and inferior infarctions; however, those with anterior wall infarctions show an improved outcome over those with inferior infarcts. On the basis of pharmacoeconomic analysis of GUSTO data, the accelerated alteplase regimen cost an estimated additional $US32,678 per year of life saved compared with a conventional streptokinase regimen. Cumulative 1-year costs were greater in patients who received the accelerated alteplase regimen but survival was significantly greater than in patients who received streptokinase. No difference in quality of life was evident in patients who received either treatment. The incidence of major haemorrhage associated with alteplase therapy appears to be similar to that seen with other fibrinolytic agents, increasing with increasing dose; however, the risk of stroke, particularly haemorrhagic stroke, is higher with alteplase than with streptokinase. Thus, alteplase has become firmly established as a first-line option in the management of acute myocardial infarction. On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.

Pharmacokinetics and thrombolytic effects of the recombinant tissue-type plasminogen activator in horses

“…The mechanism of action of plasminogen activator alteplase is advantageous in that it activates the thrombus associated plasminogen to plasmin leading to a direct induction of the fibrinolytic system [9]. With these properties rt-PA is an agent that is suitable for an initial thrombolytic therapy that is indicated in early phases of thrombosis, and should be combined or followed by a heparin therapy to be most effective [7,8]. Due to the initial thrombolytic effect it could be expected that a similar therapeutic regimen in horses is superior to commonly performed anticoagulative therapies.…”

“…Alteplase is a recombinant human tissue-type plasminogen activator. It is frequently used as a thrombolytic agent in human patients with cardiac infarction or stroke [7,8]. In veterinary medicine, experience with rt-PA is limited [9] and derive mainly from experiences with cats suffering from aortic thromboembolism and case reports in dogs [9,10].…”

Biopharmaceutical Products from Animal Cell Culture

“…The past and current cell lines utilized as a main platform for mammalian biopharmaceutical culture are murine myeloma lymphoblastoid type cells such as NS0 (Bebbington et al 1992;Barnes et al 2001) and Sp2/0-Ag14 (Shulman et al 1978), Chinese Hamster Ovary (CHO) (Cockett et al 1990;Milbrandt et al 1983), baby hamster kidney (BHK-21) (Carvalhal et al 2001;Christie and Butler 1999;Geserick et al 2000;Kirchhoff et al 1996), and human embryonic kidney epithelial cells (HEK-293) (Baldi et al 2005;Schlaeger and Christensen 1999). From these cell types, CHO cell lines were the host that dominated the first round of commercial mammalian cell culture produced drugs, with the first recombinant therapeutic protein produced from animal cell culture being a tissue plasminogen factor marketed in 1987, by Genentech, under the trade name Activase® (alteplase), FDA-approved for the treatment of myocardial infarctions (Walsh 2004;Cannon et al 1998;Gillis et al 1995;Kunadian and Gibson 2012). With CHO based biopharmaceuticals gaining regulatory approval, most manufacturers considered CHO an acceptable host system for intravenous drug production and naturally the popularity of CHO cells as hosts increased.…”

Dissolution of Urinary Bladder Clots in a Dog with Alteplase

“…Alteplase (recombinant type plasminogen activator [r‐TPA]) is a serine protease produced mainly by endothelial cells that is involved in the fibrinolysis of blood clots by converting inactive endogenous plasminogen to plasmin 5. Alteplase is more fibrin‐specific than streptokinase or urokinase, resulting in less depletion of plasma fibrinogen and in fewer degradation products 5. Because of the lack of established dosing guidelines for intravesical alteplase in small animals, we used the dose previously reported in neonatal human medicine 1.…”