Defibrotide
Encyclopedia
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).
It has been used with antithrombin III.
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 half-life
, it is necessary to give the daily dose divided in 2 to 4 doses (see below).
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).
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 was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It is currently not approved in the USA. The manufacturer is Gentium.
s, mercaptopurine
, and many others. Without intensive treatment, VOD 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.
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.
It has been investigated for use in treatment of chronic venous insufficiency
.
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 myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.
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 serious bleeding will be increased considerably.
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
or porcine mucosa. It is an anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
with a multiple mode of action (see below).
It has been used with antithrombin III.
Pharmacokinetics
Defibrotide is available as an oral, intravenous, and intramuscular formulation. Its oral bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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
Isotopic labeling
Isotopic labeling is a technique for tracking the passage of a sample of substance through a system. The substance is 'labeled' by including unusual isotopes in its chemical composition...
defibrotide. These data suggest that defibrotide, in spite of its macromolecular nature, is absorbed well after oral administration. Due to the drug's short half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
, 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 prostaglandinProstaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
I2, E2, and prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
, altering platelet activity, increasing tissue plasminogen activator (tPA
TPA
TPA may refer to:* Third-Party Audit, an Audit performed by a specialized & independent Organization* TaxPayers' Alliance, a British free-market lobby group* Tempe Preparatory Academy, a preparatory secondary school in Arizona, USA...
-)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).
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 was marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. It 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 (Veno-occlusive disease, VOD) in the liver of patients having had bone marrow transplants or received certain drugs such as oral estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s, mercaptopurine
Mercaptopurine
Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...
, and many others. Without intensive treatment, VOD 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.
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.
It has been investigated for use in treatment of chronic venous insufficiency
Chronic venous insufficiency
Chronic venous insufficiency or CVI is a medical condition where the veins cannot pump enough oxygen-poor blood back to the heart. It is sometimes referred to as an "impaired musculovenous pump", this is due to damaged or "incompetent" valves as may occur after deep vein thrombosis or phlebitis...
.
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
Melphalan
Melphalan hydrochloride is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.An alkylating agent adds an alkyl group to DNA...
, prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, and thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
in patients with multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
have been conducted. The addition of defibrotide is expected to decrease the myelosuppressive toxicity of melphalan. However, is too early for any definitive results at that stage.
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 discontinue either 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 heparinHeparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
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 serious bleeding will be increased considerably.
External links
- 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.gentium.it/Defibrotide.aspx (information provided by manufacturer) (on cytostatic combination therapy)