Defibrotide

Identification

Name
Defibrotide
Accession Number
DB04932
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Nucleic Acid Based Therapies
Oligonucleotides
Description

Defibrotide is the sodium salt of a mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA. It has been shown to have antithrombotic, anti-inflammatory and anti-ischemic properties (but without associated significant systemic anticoagulant effects). It is marketed under the brand names Dasovas (FM), Noravid, and Prociclide in a variety of countries. In the USA it is was approved in March, 2016 as Defitelio.

Synonyms
  • Defibrotide free acid
  • Defibrotide free acid (porcine mucosa)
  • Defibrotide free acid (porcine)
Product Ingredients
IngredientUNIICASInChI Key
Defibrotide sodiumL7CHH2B2J0Not AvailableNot applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DefitelioSolution80 mgIntravenousJazz Pharmaceuticals Ireland Limited2017-09-06Not applicableCanada
DefitelioInjection, solution80 mg/1mLIntravenousJazz Pharmaceuticals2016-03-30Not applicableUs
International/Other Brands
Dasovas / Noravid / Prociclide
Categories
UNII
568FY5I1YI
CAS number
83712-60-1

Pharmacology

Indication

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.

Associated Conditions
Pharmacodynamics

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use.

Mechanism 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 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).

TargetActionsOrganism
UAdenosine receptor A1Not AvailableHuman
UAdenosine receptor A2aNot AvailableHuman
UAdenosine receptor A2bNot AvailableHuman
Absorption

Bioavailability is 58-70% following oral administration, compared to parenteral forms (i.v. and i.m. = 100%).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

t1/2-alpha = minutes (10-20 minutes in rat); t1/2-beta = a few hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of bleeding can be increased when Defibrotide is combined with Abciximab.
AcenocoumarolThe risk or severity of bleeding can be increased when Defibrotide is combined with Acenocoumarol.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Defibrotide.
AloxiprinThe risk or severity of adverse effects can be increased when Defibrotide is combined with Aloxiprin.
AlprostadilAlprostadil may increase the anticoagulant activities of Defibrotide.
AlteplaseThe risk or severity of bleeding can be increased when Alteplase is combined with Defibrotide.
Aminosalicylic AcidThe risk or severity of bleeding can be increased when Aminosalicylic Acid is combined with Defibrotide.
AnagrelideThe risk or severity of bleeding can be increased when Defibrotide is combined with Anagrelide.
AndrographolideAndrographolide may increase the anticoagulant activities of Defibrotide.
AnistreplaseDefibrotide may increase the anticoagulant activities of Anistreplase.
Food Interactions
Not Available

References

General References
  1. Noseda G, Fragiacomo C, Ferrari D: Pharmacokinetics of defibrotide in healthy volunteers. Haemostasis. 1986;16 Suppl 1:26-30. [PubMed:3754833]
  2. Palmer KJ, Goa KL: Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs. 1993 Feb;45(2):259-94. [PubMed:7681375]
  3. Fisher J, Johnston AM, Holland TK, McCallum J, Pescador R, Mantovani M, Prino G: Pharmacokinetics, absorption, distribution and disposition of [125I]-defibrotide following intravenous or oral administration in the rat. Thromb Res. 1993 Apr 1;70(1):77-90. [PubMed:8511753]
  4. Koehl GE, Geissler EK, Iacobelli M, Frei C, Burger V, Haffner S, Holler E, Andreesen R, Schlitt HJ, Eissner G: Defibrotide: an endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo. Cancer Biol Ther. 2007 May;6(5):686-90. Epub 2007 Feb 3. [PubMed:17495522]
  5. Kornblum N, Ayyanar K, Benimetskaya L, Richardson P, Iacobelli M, Stein CA: Defibrotide, a polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action. Oligonucleotides. 2006 Spring;16(1):105-14. [PubMed:16584299]
  6. Pescador R, Porta R, Ferro L: An integrated view of the activities of defibrotide. Semin Thromb Hemost. 1996;22 Suppl 1:71-5. [PubMed:8807733]
External Links
PubChem Substance
46508192
ChEMBL
CHEMBL2108396
PharmGKB
PA164749105
Wikipedia
Defibrotide
ATC Codes
B01AX01 — Defibrotide
AHFS Codes
  • 20:12.20 — Thrombolytic Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentMultiple Myeloma (MM)1
2CompletedTreatmentVeno-Occlusive Disease1
2RecruitingPreventionThrombotic Microangiopathies1
2RecruitingTreatmentAcute-graft-versus-host Disease / Graft Versus Host Disease (GVHD)1
2RecruitingTreatmentSickle Cell Disorders1
2, 3CompletedPreventionHepatic Veno-Occlusive Disease1
3CompletedTreatmentHepatic Veno-Occlusive Disease1
3CompletedTreatmentSevere Hepatic Veno Occlusive Disease / Severe Hepatic Veno-Occlusive Disease1
3RecruitingPreventionVeno-Occlusive Disease1
4RecruitingBasic ScienceEndotoxaemia / Healthy Volunteers1
Not AvailableNo Longer AvailableNot AvailableHepatic Veno-Occlusive Disease1
Not AvailableNo Longer AvailableNot AvailableLiver Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous80 mg/1mL
SolutionIntravenous80 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Purine nucleoside binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [PubMed:8405101]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Identical protein binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
ADORA2A
Uniprot ID
P29274
Uniprot Name
Adenosine receptor A2a
Molecular Weight
44706.925 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [PubMed:8405101]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
G-protein coupled adenosine receptor activity
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
ADORA2B
Uniprot ID
P29275
Uniprot Name
Adenosine receptor A2b
Molecular Weight
36332.655 Da
References
  1. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D, Cedro A, Salvetti L, Mantovani M, Prino G: Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol. 1993 Jul 20;238(2-3):327-34. [PubMed:8405101]

Drug created on October 21, 2007 16:23 / Updated on September 25, 2018 03:15