Under the brand name Arwin, ancrod was marketed in Germany and Austria, where it was withdrawn in the 1980s after it was used for some decades. Arwin was a brand name of Knoll Pharma. Neurobiological Technologies, Inc., currently holds the worldwide rights to ancrod under the brand name Viprinex. Previously, the rights to Viprinex were respectively held by Empire Pharmaceuticals, Inc., Abbott Laboratories, and Knoll AG, developers of this investigational drug.
Neurobiological Technologies, Inc. (NTI) has signed agreements with Nordmark Arzneimittel GmbH & Co KG (Nordmark) and Baxter Pharmaceutical Solutions, LLC (Baxter) to manufacture, fill and package Viprinex for NTI's Phase III clinical trials in acute ischemic stroke. Nordmark will manufacture the biological active ingredient, ancrod. Date of this agreement was 1st. August 2005.
Ancrod has a triple mode of action. The exact structure and chemical data such as molecular weight are unknown, but it has been elaborated that the glycosylation of the molecule is an important factor. Glycosylation is remarkably homogenous with the major oligosaccharide accounting for approximately 90% of the total sugar content. Some in vitro reactions have been explored in very detail (see ref. #2, www.blckwell-synergy). Experimentally it was found that ancrod's actions are FAD dependent and that the substance has interesting apoptotic properties (causing programmed cell death), which still remain to be elaborated. Ancrod is prepared from the crude venom of the Malayan pit viper (Agkistrodon rhodostoma, also termed Calloselasma rhodostoma) and belongs to the group of proteolytic enzymes. Ancrod may also be found in the venoms of many poisonous snakes (crotalids, elapids and viperids) in general, but the Malayan pit viper is most suitable due to a high concentration of ancrod in its venom. For its preparation a snake farm, very skilled and well trained staff (for milking the highly poisonous snakes), and special production facilities are required to purify the enzyme.
The halflife of ancrod is 3 to 5 hours and the drug is cleared from plasma, mainly renally.
Due to its special mode of action (see below) and its price, Arwin was never been used as 'normal' anticoagulant such as heparin, but only for the symptomatic treatment of moderate to severe forms of peripheral arterial circulatory disorders such as those resulting from years of heavy smoking and/or arteriosclerosis.
The substance is intended for parenteral, namely subcutaneous (s.c.) injection and intravenous (i.v.) infusion, and indirectly inhibits aggregation, adhesion, and release of thrombocytes mediated through the action of a fibrinogen degradation product (FDP). It also cleaves and therefore inactivates a significant part of circulating plasma fibrinogen. Fibrinogen is often found in increased concentrations in arteriae with impaired circulation. This leads to a pathologically increased blood viscosity and thereby to a worsening of symptoms of the circulation disorder (more intense pain, decreased mobility of the limb and decreased temperature, need for partial or even total limb amputation). The blood viscosity in patients receiving ancrod is progressively reduced by 30 to 40% of the pretreatment levels. The decreased viscosity is directly attributable to lowered fibrinogen levels and leads to important improvements in blood flow and perfusion of the microcirculation. Erythrocyte flexibility is not affected by normal doses of ancrod. The rheological changes are readily maintained and the viscosity approaches pretreatment values very slowly (within about 10 days) after stopping ancrod. One of the cleavage fibrinogen products, termed 'desAA-Fibrin', acts as cofactor for the tPA-induced plasminogen activation and an increased fibrinolysis results in return (profibrinolytic activity of ancrod).
Ancrod decreases the blood viscosity in affected arteries, leads to less intense pain, improves physical limb mobility, and facilitates physical and ergo therapy. Finally, ancrod decreases the likelihood of local thrombotic events.
The above mentioned mechanisms also account for ancrod's activity in other diseases.
Effects on other clotting factors: Unlike thrombin, ancrod does not directly activate Factor XIII, nor does it produce platelet aggregation nor cause the release of ADP, ATP, potassium, nor serotonin from platelets. Platelet counts and survival time remain normal during ancord therapy.
For the treatment of moderate and severe chronic circulatory disorders of peripheral arteries (e.g., arteriosclerosis obliterans, thromboangiitis obliterans, diabetic microangiopathy and Raynaud's phenomenon).
Ancrod has been shown to be useful for maintaining anticoagulation in the presence of Heparin-induced thrombocytopenia (HIT) and thrombosis.
Currently, this drug is not approved nor available. It is being investigated in clinical trials for stroke.
In a multicenter, parallel, group sequential, randomized, double-blind, placebo-controlled German study of efficacy and safety of i.v. ancrod given within 6 hours after the onset of acute, ischemic stroke and continued for 5 days (called ESTAT study), the early findings for 800 patients were positive, but as the study was expanded to 1,600 patients, placebo was found to be more effective than ancrod and the study was abruptly terminated, mainly because the mortality in the ancrod group was higher. The smaller American study 'Stroke Treatment with Ancrod Trial (STAT)' confirmed the negative outcome for ischemic stroke. In these studies, patients received a multi-day infusion of Viprinex designed to maintain patients’ fibrinogen level within a targeted range. Currently, a new dosing strategy is being investigated in two international phase III trials as part of the 'Ancrod Stroke Program (ASP).' Each of these studies will enroll 650 patients and assess whether a brief, relatively rapid ancrod infusion with no maintenance dosing will be both effective and safe.
Thrombocytopenia as side-effect has never been noticed with ancrod in contrast to heparin.
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