Ancrod

From Wikipedia, the free encyclopedia

You have new messages (last change).

Ancrod (also known under its former brand name Arwin® and recently Viprinex®) is an anticoagulant.

Image:Ancrod.png
Ancrod
Systematic (IUPAC) name
Ancrod, Ophidian l-amino-acid oxidase (l-amino-acid oxygen:oxidoreductase, deaminating)
Identifiers
CAS number 3.4.2&rn=1 EC 3.4.2
ATC code  ?
PubChem  ?
Chemical data
Formula  ?
Mol. weight  ?
Pharmacokinetic data
Bioavailability 100% after i.v. dosing
Protein binding 95% bound to erythrocytes
Metabolism mainly renal
Half life 3 to 5 hours
Excretion  ?
Therapeutic considerations
Pregnancy cat.

X (contraindicated)
Legal status

Rx only, where available
Routes s.c. injection or i.v. infusion

Contents

[edit] Basic Chemical, Pharmacological, and Marketing Information

Arwin® was marketed in Germany and Austria, where it was withdrawn in the 1980's after it was used for some decades. Arwin® and Viprinex® are brand names of Knoll Pharma and Nordmark, respectively (both belonging to BASF Group). Currently, Viprinex® is approved in a variety of countries, but not in the USA. However, the FDA has granted a 'fast-track status' for the indication ischemic stroke, for which phase III studies have been conducted in 2005 and 2006, as stated below.

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 must be 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 nursing the highly poisonous snakes), and special production facilities are required. This explains the high price of ancrod, because only the ultrapurified enzyme can be used clinically. Therapy with ancrod has to be started in a clinic and, if a response is seen and the drug is well tolerated, it is probably possible to continue drug therapy on an outpatient basis later.

The halflife of ancrod is 3 to 5 hours and the drug is cleared from plasma mainly renal.

Due to its special mode of action (see below) and its price Arwin® has 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. However, Viprinex® has been found to be indicated for the treatment or prophylaxis of a variety of many other coagulation related disorders (please refer to section 'current indications of Viprinex®').

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).

So ancrod decreases as well the blood viscosity in affected arteries, leads to less intense pain, improves physical limb mobility, and faciliates physical and ergo therapy. Finally, ancrod decreases the likelihood of local thrombotic events.

The above mentioned mechanisms also account for the activity of Viprinex® angainst 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.

[edit] Current Indications for Viprinex®

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.

Physicians should have at any time access to fibrinogen enriched cryoprecipitate.

[edit] Study Results in Patients with 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. However, in the USA ancrod progressed to phase III studies involving approximately 2,000 patients, because some limited beneficial effects may nevertheless be likely.

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.

[edit] Contraindications and Precautions

[edit] 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.

[edit] 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.

[edit] Interactions

The risk of bleeding events is increased, if other anticoagulants (e.g., coumarines such as warfarin), inhibitors of thrombocytic aggregation such as aspirin, or fibrinolytics such as urokinase are used concomitantly or within a period of 10 days after discontinuation of ancrod.

Plasma expanders: Artificial plasma expanders (e.g. dextran) may cause severe bleeding in defibrinated patients and should not be administered during or within 10 days of ancrod therapy.

Severe GIT-bleedings may result from the concomitant use of NSAIDs, glucocorticosteroids, nicotinic acid derivates, or other drugs with ulcerogenic potential.

The danger of thromboembolic events is considerably increased, if ancrod is given immediately after systemic fibrinolytics.

[edit] Necessary Laboratory Examinations

Pretreatment investigations: A complete blood cell count, including platelet count, and fibrinogen determination should be obtained before treatment.

In case of significant bleeding events : Hemoglobin, hematocrit, and a complete red cell status should be obtained. Blood pressure values should be monitored to exclude the development of an impending hemorrhagic shock.

Laboratory Control during Induction Dose Infusion: The fibrinogen concentration should be measured at six hours intervals during, and at the end of the infusion of the induction dose.

Fibrinogen should also be measured at regular intervals, at the same time of the day, during the maintenance dose infusions or injections.

[edit] Dosage Regime

Usually, a (high) induction dose is given as i.v. infusion for 12 hours to reach the desired decreased level of fibrinogen quickly, followed by regular lower dose infusions or s.c.-injections. In any case, the exact dosage is determined by an experienced clinician treating the condition for which ancrod is given. He or she will determine also the duration of treatment.

[edit] Special Antidotes

In case that quick reversal of Arwin® action was required, a special antidote was available from Knoll at no cost; it was a serum from the goat containing a high concentration of antibodies to ancrod, with which ancrod could be neutralized rapidly. Nonetheless, it was often necessary to restore normal fibrinogen activity with cryoprecipitate after use of the antidot, because the body needs some time to restore fibrinogen levels on its own. The aforementioned antidot is not obtainable any longer. Now, cryoprecipitate should be administered alone to raise the plasma fibrinogen concentrations to safe levels. Whole blood transfusions are also suitable, particular where cryoprecipitate is not available. Anemia related to severe bleeding events can be corrected with packed red blood cells or whole blood.

[edit] Drug Availablility

Viprinex® is delivered in vials containing 70 Biological Units each.

[edit] External References

Retrieved from "http://en.wikipedia.org../../../a/n/c/Ancrod.html"