Defibrotide is a deoxyribonucleic acid derivative (single stranded) derived from cow lung or porcine mucosa. It is an anticoagulant with a multiple mode of action (see below). 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. ... DNA replication Deoxyribonucleic acid (DNA) is a nucleic acid which carries genetic instructions for the biological development of all cellular forms of life and many viruses. ... The lungs flank the heart and great vessels in the chest cavity. ... The mucous membranes (or mucosa) are linings of ectodermic origin, covered in epithelium, that line various body cavities and internal organs. ... An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. ...

Pharmacokinetics

Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailability is in the range of 58-70% of the parenteral forms. T1/2 alpha is in the range of minutes while T1/2 beta is in the range of hours in studies with oral radiolabelled defibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug's short have-life, it is necessary to give the daily dose divided in 2 to 4 doses (see below).

Mode of Action

The drug appears to prevent the formation of blood clots and to help dissolve blood clots by increasing levels of prostaglandin I2, E2, and prostacyclin, altering platelet activity, increasing tissue plasminogen activator (tPA-)function, and decreasing activity of tissue plasminogen activator inhibitor. Prostaglandin I2 relaxes the smooth muscle of blood vessels and prevents platelets from adhering to each other. Prostaglandin E2 at certain concentrations also inhibits platelet aggregation. Moreover, the drug provides additional beneficial anti-inflammatory and antiischemic activities as recent sudies have shown. It is yet unclear, if the latter effects can be utilized clinically (e.g., treatment of ischemic stroke). A thrombus is the final product of blood coagulation, through the aggregation of platelets and the activation of the humoral coagulation system. ... Chemical structure of prostaglandin E1 (PGE1). ... Prostacyclin is a member of the family of lipid molecules known as eicosanoids. ... 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. ...

Unlike heparin and warfarin, defibrotide appears to have a relatively mild anticoagulant activity, which may be beneficial in the treatment of patients at high risk of bleeding complications. Nevertheless, patients with known bleeding disorders (e.g. hemophilia A) or recent abnormal bleedings should be treated cautiously and under close medical supervision.

The drug is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries, but is currently not approved in the USA. The manufacturer is Gentium.

Usual Indications

Defibrotide is used to treat or prevent a failure of normal blood flow (occlusive venous disease, OVD) in the liver of patients who have had bone marrow transplants or received certain drugs such as oral estrogens, mercaptopurine, and many others. Without intensive treatment OVD is often a fatal condition, leading to multiorgan failure. It has repeatedly been reported that defibrotide was able to resolve the condition completely and was well tolerated. Veno-occlusive disease (VOD) is a disease affecting the liver. ... Estriol. ... Mercaptopurine: chemical structure Mercaptopurine (also called 6-MP or by its brand name Purinethol®) is an immunosuppressive drug used to treat leukemia. ...

Other indications are: peripheral obliterative arterial disease, thrombophlebitis, and Raynaud's phenomenon. In very high doses defibrotide is useful as treatment of acute myocardial infarction. The drug may also be used for the pre- and postoperative prophylaxis of deep venous thrombosis and can replace the heparin use during hemodialytic treatments.

Potential Indications in the Future

Other recent preclinical studies have demonstrated that defibrotide used in conjunction with Granulocyte Colony-Stimulating Factor (rhG-CSF) significantly increases the number of Peripheral Blood Progenitor Cells (Stem cells). The benefit of this increase in stem cells may be crucial for a variety of clinical indications, including graft engineering procedures and gene therapy programs. This would expand the clinical usefulness of defibrotide to a complete distinct area.

Very recently (since early 2006) combination therapy trials (phase I/II) with defibrotide plus melphalan, prednisone, and thalidomide in patients with multiple myeloma have been conducted. The addition of defibrotide is expected to decrease the myelosuppresive toxicity of melphalan. However, is too early for any definitive results at that stage. Melphalan hydrochloride ( Alkeran®) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents. ... Prednisone is a synthetic corticosteroid drug which is usually taken orally and can be used for a large number of different conditions. ... // Thalidomide is a sedative, hypnotic, and anti-inflammatory medication. ... Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahlers disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. ...

Cautions and Contraindications

• The efficacy of the drug has been reported to be poorer in patients with diabetes mellitus.
• Pregnancy : The drug should not be used during pregnancy, because adequate and well controlled human studies do not exist.
• Lactation : No human data is available. In order to avoid damage to the newborn, the nursing mother should either discontinue the drug or breastfeeding, taking into account the importance of treatment to the mother.
• Known Bleeding Disorders or Bleeding Tendencies having occurred recently : Defibrotide should be used cautiously. Before initiation of treatment, the usual coagulation values should be obtained as baseline and regularly controlled under treatment. The patient should be observed regularly regarding local or systemic bleeding events.

Side effects

Increased bleeding and bruising tendency, irritation at the injection site, nausea, vomiting, heartburn, low blood pressure. Serious allergic reactions have not been observed so far.

Drug Interactions

Use of heparin with defibrotide may increase the aPTT, reflecting reduced ability of the body to form a clot. Nothing is known about the concomitant application of other anticoagulants than heparin and dextran containing plasma-expanders, but it can be anticipated that the risk of seriuos bleeding will be increased considerably. Heparin is a highly sulfated glycosaminoglycan widely used as an injectable anticoagulant. ...

Usual Doses

Doses of up to 5.6 grams per day have been used for the treatment of acute myocardial infarction. A daily dose of 800 mg intravenously or intramuscularly for 7-8 days starting 1 day preoperatively is usual given for the prevention of deep venous thrombosis. Doses of 400 to 1200 mg/day have been used for the treatment of peripheral obliterative arterial disease, thrombophlebitis, and Raynaud's phenomenon. The daily dose is divided into 2-4 doses.

A bolus of 100 mg to 400 mg intravenously given every hour or a continuous intravenous infusion to a total dose of 800 mg has been used during renal hemodialysis.

External References

Palmer KJ, Goa KL. Defibrotide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993;45:259-94.

• http://www.globalrx.com/medinfo/Defibrotide.htm
• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8747520&dopt=Abstract (Pharmacokinetic Aspects)
• http://www.gentium.it/Defibrotide.aspx (information provided by manufacturer)
• http://rx.onconews.org/news/Melphalan.html (on cytostatic combination therapy)
• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16252186&query_hl=3&itool=pubmed_docsum (Report from University of Istanbul regarding healing of VOC)