Ancrod

Ancrod (current brand name: Viprinex) is a defibrinogenating agent derived from the venom of the Malayan pit viper. The defribrinogenation of blood results in an anticoagulant effect. Currently, Viprinex®/ancrod is not approved or marketed in any country, but is being investigated as a stroke treatment in worldwide clinical trials. In January 2005, the U.S. FDA granted a 'fast-track status' for investigation of ancrod use in patients suffering from acute ischemic stroke, a life threatening condition caused by the blockage of blood vessels supplying blood and oxygen to portions of the brain, for which phase III trials are currently being conducted.

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Marketing history

Under the brand name Arwin®, ancrod was marketed in Germany and Austria, where it was withdrawn in the 1980s after it was used for some decades.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.

Chemistry and pharmacology

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.

Indications

Historical

For the treatment of established deep vein thrombosis; central retinal and branch vein thrombosis; priapism; pulmonary hypertension of embolic origin; embolism after insertion of prosthetic cardiac valves; rethrombosis after thrombolytic therapy and rethrombosis after vascular surgery. It is also indicated for the prevention of deep venous thrombosis after repair of the fractured neck of a femur.

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.

Studies in early ischemic 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.

Contraindications and precautions

• Known bleeding disorders of any origin or any unexplained excessive bleedings in the past.
• Platelet counts of less than 100,000 (even if asymptomatic), exemption : HIT (Heparin- induced thrombocytopenia).
• Planned surgery or short before delivery.
• Active ulcerations of the GIT.
• Any kind of malignant disease.
• Renal stones (increased likelihood of significant urological bleeding).
• Severe and uncontrolled arterial hypertension.
• Active pulmonary tuberculosis.
• Impaired fibrinolysis.
• Severe liver disease.
• Manifest or impending shock.
• I.M.-Injection : Ancrod should not be injected i.m., because of rapid induction of neutralizing antibodies and therefore drug resistance.

Pregnancy

Category X : Ancrod was not found to be teratogenic in animal studies, but some fetal deaths occurred as a result of placental hemorrhages in animals given high doses; therefore, it should not be used during pregnancy as the defibrinogenation mechanism of ancrod might be expected to interfere with the normal implantation of the fertilized egg.

Side effects

• Hypersensitivity reactions : Local or generalized skin reactions (rash and urticaria); appearance of neutralizing antibodies to ancrod with partial or total loss of ancrod activity (drug resistance).
• Sometimes pain at injection site (normally mild). This side-effect may be, if necessary, treated with local or oral antihistaminic drugs (e.g., clemastine, or diphenhydramine). Bleeding at injection site, thrombophlebitis at local veins, and (paradoxical) arterial thrombotic events.
• Occasionally deposition of cleaved fibrinogen derivates in the splen resulting in splenomegaly; rupture is possible, if the spleen is palpated too strongly (life-threatening bleeding and need of splenectomy may result).
• Specific side-effects are local and systemic bleeding events. Local bleeding events may be treated with local pressure or surgical dressings, if necessary. Compared with other anticoagulants the risk of systemic bleeding is relatively low. If systemic bleeding is severe enough to warrant fast reversal of ancrod action, fibrinogen should be substituted (please refer to section 'special antidotes').
• Occasionally, increased headache has been found in patients with known migraine.
• Also, chills and fever may occur infrequently.

Thrombocytopenia as side-effect has never been noticed with ancrod in contrast to heparin.

Availablility

Viprinex® is not currently approved or available.

References

• H. P. T. Ammon (Editor) : Arzneimittelneben- und -wechselwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart (4th. ed.), 2001, ISBN 3-8047-1717-9, in German

• Geyer A, Fitzpatrick TB, Pawelek PD, et al (2001). "Structure and characterization of the glycan moiety of L-amino-acid oxidase from the Malayan pit viper Calloselasma rhodostoma". Eur. J. Biochem. 268 (14): 4044-53. PMID 11453999.

• http://archiv.ub.uni-heidelberg.de/volltextserver/volltexte/2003/3368/pdf/diss03-20.pdf (Some results of clinical research) - in German

• http://www.uni-leipzig.de/forsch00/49000/49219.htm (negative study results in ischemic strike), in German

• http://www.ntii.com/products/viprinex.shtml (phase III studies in the USA regarding ischemic stroke)

• http://www.prohostonline.com/ImpactingNews/IN%201%2028%2005.pdf (FDA grants fast-track status for indication ischemic stroke)

• http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20V)/VIPRINEX.html (scientific information on Viprinex®)

• http://www.findarticles.com/p/articles/mi_m0DHC/is_8_17/ai_n14792504 (marketing agreement Neurobiological - Nordmark - Baxter)

• Sherman DG, Atkinson RP, Chippendale T, et al (2000). "Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial". JAMA 283 (18): 2395-403. PMID 10815082.

• (1994) "Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators". Stroke 25 (9): 1755-9. PMID 8073455.

• Hennerici MG, Kay R, Bogousslavsky J, Lenzi GL, Verstraete M, Orgogozo JM (2006). "Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial". Lancet 368 (9550): 1871-8. doi:10.1016/S0140-6736(06)69776-6. PMID 17126719.