In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ...

Basic Chemical, Pharmacological, and Marketing Information

Ancrod (also known under its former brand name Arwin® and recently Viprinex®) is an anticoagulant with a triple mode of action. Arwin® was marketed in Germany and Austria, where it was withdrawn in the 1980's after it was used for some decades.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 (the FDA has granted a 'fast-track status' for the indication ischemic stroke). An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ... The United States Food and Drug Administration is the government agency responsible for regulating food, dietary supplements, drugs, cosmetics, medical devices, biologics and blood products in the United States. ... This article is about stroke as medical term. ...

Ancrod must be prepared from the crude venom of the Malayan pit viper (Agkistrodon rhodostoma) and belongs to the group of proteolytic enzymes. 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. Wasp stinger, with droplet of venom Venom or zootoxin (literally, animal poison) is any of a variety of poisons used by several groups of animal species, for the purpose of defence and hunting prey. ... Genera Adenorhinos Atheris Azemiops Bitis Cerastes Daboia Echis Eristicophis Macrovipera Montatheris Proatheris Pseudocerastes Vipera This page is about Viper snakes. ... Ribbon diagram of the enzyme TIM. TIM is catalytically perfect, meaning its conversion rate is limited, or nearly limited to its substrate diffusion rate. ...

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®'). Heparin as a drug is used as an injectable anticoagulant. ... The coagulation of blood is a complex process during which blood forms solid clots. ...

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). Look up Aggregation in Wiktionary, the free dictionary The term aggregation may refer to— in economics, combining entities into a single entity which represent them, like aggregation of individual demand to total, or market, demand. ... Dew drops adhering to a spider web Water droplets adhering on a hibiscus petal Adhesion is the molecular attraction exerted between bodies in contact. ... Release may refer to multiple things: in marketing: issuing a product for sale or public showing (especially a music release or a film release). ... ... Fibrin is a protein involved in the clotting of blood. ... The pitch drop experiment at the University of Queensland. ... Amputation is the removal of a body extremity by trauma or surgery. ... TPA may refer to: Tampa International Airport (IATA code) Tissue plasminogen activator This is a disambiguation page — a navigational aid which lists other pages that might otherwise share the same title. ... Plasmin is an important degrading enzyme (EC 3. ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ...

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. Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Factor XIII or fibrin stabilizing factor is an enzyme (EC 2. ... ADP is a three-letter abbreviation with multiple meanings, as described below: Association for the Development of Pakistan, a Boston-based non-profit organization Access database project, a file format of the Microsoft Access database program Adenosine diphosphate, a nucleotide Aéroports de Paris (see Air travel in France), airport... Adenosine triphosphate (ATP) Adenosine triphosphate (ATP) is the nucleotide known in biochemistry as the molecular currency of intracellular energy transfer; that is, ATP is able to store and transport chemical energy within cells. ... General Name, Symbol, Number potassium, K, 19 Chemical series alkali metals Group, Period, Block 1, 4, s Appearance silvery white Atomic mass 39. ... Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ...

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. This article is about Deep-vein thrombosis. ... Bronze sculpture depicting Priapus. ... In medicine, pulmonary hypertension (PH) is an increase in blood pressure in the pulmonary artery or lung vasculature. ... In medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the body (through circulation) and cause(s) a blockage (occlusion) of a blood vessel in another part of the body. ...

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). // Introduction Arteriosclerosis means the hardening of the arteries in Greek. ... Buergers disease (also known as thromboangiitis obliterans) was first reported by physician Leo Buerger in 1908, who described a disease which had the characteristic pathologic findings of acute inflammation and thrombosis (clotting) of arteries and veins of the hands and feet (the lower limbs being more common). ... In medicine, Raynauds phenomenon is discoloration of the fingers or toes due to emotion or cold in a characteristic pattern in time: white, blue and red. ...

Ancrod has been shown to be useful for maintaining anticoagulation in the presence of Heparin-induced thrombocytopenia (HIT) and thrombosis. Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. ...

Physicians should have at any time access to fibrinogen enriched cryoprecipitate. Cryoprecipitate is a blood product manufactured by warming frozen plasma. ...

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.

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.

Haemophilia or hemophilia is the name of any of several hereditary genetic illnesses that impair the bodys ability to control bleeding. ... A thoracic surgeon performs a mitral valve replacement at the Fitzsimons Army Medical Center, November 1990. ... Childbirth in a hospital. ... An ulcer (from Latin ulcus) is an open sore of the skin, eyes or mucous membrane, often caused by an initial abrasion and generally maintained by an inflammation and/or an infection. ... In medicine, malignant is a clinical term that is used to describe a clinical course that progresses rapidly to death. ... Kidney stones, also known as nephrolithiases, urolithiases or renal calculi, are solid accretions (crystals) of dissolved minerals in urine found inside the kidneys or ureters. ... Arterial hypertension, or high blood pressure is a medical condition where the blood pressure is chronically elevated. ... Tuberculous lungs show up on an X-ray image Tuberculosis is an infection with the bacterium Mycobacterium tuberculosis, which most commonly affects the lungs (pulmonary TB) but can also affect the central nervous system (meningitis), lymphatic system, circulatory system (miliary TB), genitourinary system, bones and joints. ... Fibrinolysis is the process where a fibrin clot, the product of coagulation, is broken down. ... The liver is an organ in vertebrates including humans. ... Shock is a serious medical condition where the tissue perfusion is insufficient to meet the required supply of oxygen and nutrients. ... Wikipedia does not yet have an article with this exact name. ... Organisms are said to be drug-resistant when they are no longer affected by drugs that are meant to neutralize them. ...

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. Teratogenesis is a medical term from the Greek, literally meaning monster making. ...

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 splen is palpated to 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 beend 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. A typical rash A rash is a change in the skin which affects its appearance or texture. ... Clemastine is an over-the-counter antihistamine sold in the United States under the name Tavist. ... Diphenhydramine hydrochloride (trade name Benadryl®, as produced by Pfizer or Dimedrol outside the US) is an over-the-counter (OTC) antihistamine and sedative. ... It has been suggested that this article or section be merged into deep vein thrombosis. ... Splenomegaly is an enlargement of the spleen. ... The procedure of splenectomy involves removal of the spleen by operative means. ... This article does not cite its references or sources. ... A medical/clinical thermometer showing the temperature of 38. ...

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. Warfarin (also known under the brand names of Coumadin®, Jantoven®, Marevan®, and Waran®) is an anticoagulant medication that is administered orally or, very rarely, by injection. ... Aspirin or acetylsalicylic acid (acetosal) is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. ... Thrombolytic drugs are used in medicine to dissolve blood clots in a procedure termed thrombolysis. ... Urokinase, also called urokinase-type Plasminogen Activator (uPA) is an enzyme (EC 3. ...

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. Dextran is a complex branched polysaccharide made of many glucose molecules joined into chains of varying lengths. ...

Severe GIT-bleedings may result from the concomitant use of NSAIDs, glucocorticosteroids, nicotinic acid derivates, or other drugs with ulcerogenic potential. Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects. ... Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin whose derivatives such as NADH play essential roles in energy metabolism in the living cell. ...

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

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. 3-dimensional structure of hemoglobin. ... The hematocrit (Ht or HCT) and packed cell volume (PCV) are measures of the proportion of blood volume that is occupied by red blood cells. ...

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.

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.

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. An antidote is a substance which can counteract a form of poisoning. ... Blood plasma is a component of blood. ... Species See Species and subspecies The goat is a mammal in the genus Capra, which consists of nine species: the Ibex, the West Caucasian Tur, the East Caucasian Tur, the Markhor, and the Wild Goat. ... Blood transfusion is the taking of blood or blood-based products from one individual and inserting them into the circulatory system of another. ...

External References

• H. P. T. Ammon (Editor) : Arzneimittelneben- und -wechselwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart (4th. ed.), 2001, ISBN: 3-8047-1717-9, in German
• 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 Vipinex®)
• http://www.findarticles.com/p/articles/mi_m0DHC/is_8_17/ai_n14792504 (marketing agreement Neurobiological - Nordmark - Baxter)