Ancrod

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Ancrod
Clinical data
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Thrombin-like enzyme ancrod
Identifiers
OrganismCalloselasma rhodostoma
Symbol?
UniProtP26324
Thrombin-like enzyme ancrod-2
Identifiers
OrganismCalloselasma rhodostoma
Symbol?
UniProtP47797

Ancrod (current brand name: Viprinex) is a defibrinogenating agent derived from the venom of the Malayan pit viper. Defibrinogenating blood produces an anticoagulant effect. Ancrod is not approved or marketed in any country. It is a thrombin-like serine protease.[1]

Medical use[edit]

As of 2017 ancrod was not marketed for any medical use.[2]

Pregnancy[edit]

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.

Contraindications and precautions[edit]

Side effects[edit]

In clinical trials for ischemic stroke, ancrod increased the risk of intracebrral hemorrhage.[3]

  • 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 spleen 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.

It was not found to be of much use in the clinical trials. In vitro expermiments show that it may actually clot blood.[4]

Pharmacology[edit]

Ancrod has a triple mode of action. It was found that ancrod's actions are FAD dependent and that the substance has interesting apoptotic properties (causing programmed cell death), which remain to be explored.

The half-life of ancrod is 3 to 5 hours and the drug is cleared from blood plasma, mainly renally.

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.

The substance is intended for subcutaneous injection and intravenous 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. These 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, or serotonin from platelets. Platelet counts and survival time remain normal during ancrod therapy.

Chemistry[edit]

Ancrod was originally isolated from the venom of the Malayan pit viper (Calloselasma rhodostoma, formerly Agkistrodon rhodostoma) and is a serine protease.[5] It is one of the Venombin A enzymes. Two genes encoding for such enzymes have been found in the viper genome.[6][7]

The form used in clinical trials was not made recombinantly, but was purified from harvested venom.[8][9]

History[edit]

Under the brand name Arwin, ancrod was marketed for several decades in Germany and Austria, until it was withdrawn in the 1980s. Arwin was a brand name of Knoll Pharma.

In 2001 Knoll was acquired by Abbott Laboratories, and in 2002 Abbott licensed the rights to ancrod to Empire Pharmaceuticals, a startup that included a Knoll employee who had worked on ancrod.[10][11] :5 In 2004 Empire was acquired by Neurobiological Technologies.[12] NTI also acquired a lot of unpurified venom in the acquisition, and had that purified for use in its clinical trials.[8][9]

The failure of ancrod in the 6-hour window for ischemic stroke trial in 2008 led to cuts in staff, an effort to sell off the company's assets, and finally to the dissolution of NTI in August 2009.[13][14]

Society and culture[edit]

Viprinex is not currently approved or available.

Research[edit]

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.

A small study compared to ancrod to heparin in preventing thrombosis when given to people undergoing arterial graft surgery to treat peripheral arterial disease and found little difference between the two agents.[15]

Ancrod was intensively studied in ischemic stroke, starting at least by the early 1990s.[16] An RCT called "STAT" was published in 2000; it included 500 subjects and ancrod or placebo was administered within three hours of the stroke. Ancrod showed modest benefits but a trend toward increased intracranial haemorrhage.[5][17] A clinical trial published in 2006 found no benefit if ancrod was given within a wider 6 hour treatment window.[18] Another trial was launched to explore the 6 hour window, but it was halted early in 2008 when an independent review committee looked at the interim data and found no signal of benefit.[5][3][13]

References[edit]

  1. ^ Macheroux P, Seth O, Bollschweiler C, Schwarz M, Kurfürst M, Au LC, Ghisla S (March 2001). "L-amino-acid oxidase from the Malayan pit viper Calloselasma rhodostoma. Comparative sequence analysis and characterization of active and inactive forms of the enzyme". European Journal of Biochemistry. 268 (6): 1679–86. doi:10.1046/j.1432-1327.2001.02042.x. PMID 11248687.
  2. ^ "Ancrod". AdisInsight. Retrieved 5 February 2017.
  3. ^ a b Hao Z, Liu M, Counsell C, Wardlaw JM, Lin S, Zhao X (March 2012). "Fibrinogen depleting agents for acute ischaemic stroke". The Cochrane Database of Systematic Reviews (3): CD000091. doi:10.1002/14651858.CD000091.pub2. PMID 22419274.
  4. ^ Nielsen VG (August 2016). "Ancrod revisited: viscoelastic analyses of the effects of Calloselasma rhodostoma venom on plasma coagulation and fibrinolysis". Journal of Thrombosis and Thrombolysis. 42 (2): 288–93. doi:10.1007/s11239-016-1343-6. PMID 26905070.
  5. ^ a b c Asadi H, Yan B, Dowling R, Wong S, Mitchell P (2014). "Advances in medical revascularisation treatments in acute ischemic stroke". Thrombosis. 2014: 714218. doi:10.1155/2014/714218. PMC 4293866. PMID 25610642.
  6. ^ Burkhart W, Smith GF, Su JL, Parikh I, LeVine H (February 1992). "Amino acid sequence determination of ancrod, the thrombin-like alpha-fibrinogenase from the venom of Akistrodon rhodostoma". FEBS Letters. 297 (3): 297–301. doi:10.1016/0014-5793(92)80559-Y. PMID 1544412.
  7. ^ Au LC, Lin SB, Chou JS, Teh GW, Chang KJ, Shih CM (September 1993). "Molecular cloning and sequence analysis of the cDNA for ancrod, a thrombin-like enzyme from the venom of Calloselasma rhodostoma". The Biochemical Journal. 294 ( Pt 2) (2): 387–90. doi:10.1042/bj2940387. PMC 1134466. PMID 8373353.
  8. ^ a b Smith A (February 24, 2006). "California biotech looking in snakes' mouths for stroke drug - Feb. 24, 2006". CNN Money.
  9. ^ a b "Exhibit 10.1: Cooperation and Supply Agreement". NTI via SEC Edgar. Retrieved 5 February 2017.
  10. ^ "Form 10-K For the fiscal year ended June 30, 2007". NTI via SEC Edgar. September 13, 2007.
  11. ^ "Exhibit 10.18 License Agreement between Empire and Abbott, March 29, 2002". Law Insider.
  12. ^ "Neurobiological Tech buys Empire Pharma". The Pharma Letter. July 26, 2004.
  13. ^ a b Carroll J (December 17, 2008). "Neurobiological Tech halts enrollment, prepares cuts". FierceBiotech.
  14. ^ Brown SE, Leuty R (August 31, 2009). "Neurobiological Technologies to dissolve". San Francisco Business Times.
  15. ^ Geraghty AJ, Welch K (June 2011). "Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery". The Cochrane Database of Systematic Reviews (6): CD000536. doi:10.1002/14651858.CD000536.pub2. PMID 21678330.
  16. ^ "Ancrod for the treatment of acute ischemic brain infarction. The Ancrod Stroke Study Investigators". Stroke. 25 (9): 1755–9. September 1994. doi:10.1161/01.STR.25.9.1755. PMID 8073455.
  17. ^ Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng K, Futrell N, Hsu CY, Levy DE (May 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. doi:10.1001/jama.283.18.2395. PMID 10815082.
  18. ^ Hennerici MG, Kay R, Bogousslavsky J, Lenzi GL, Verstraete M, Orgogozo JM (November 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.

See also[edit]

  • Batroxobin, another medical snake venom serine protease

External links[edit]