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Defibrotide, sold under the brand name Defitelio, is a mixture of single-stranded
oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, Recombinant DNA, research, and Forensic DNA, forensics. Commonly made in the laboratory by Oligonucleotide synthesis, solid-phase ...
s that is purified from the
intestinal mucosa The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are the mucosa, the submucosa, the muscular layer and the serosa or adventitia. ...
of pigs. It is used to treat veno-occlusive disease of the liver of people having had a
bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...
, with different limitations in the US and the European Union. It works by protecting the cells lining blood vessels in the liver and preventing
blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
; the way it does this is not well understood. The most common side effects include abnormally low blood pressure (hypotension), diarrhea, vomiting, nausea and nosebleeds (epistaxis). Serious potential side effects that were identified include bleeding (hemorrhage) and allergic reactions. Defibrotide should not be used in people who are having bleeding complications or who are taking blood thinners or other medicines that reduce the body's ability to form clots. Use of the drug is generally limited by a strong risk of life-threatening bleeding in the brain, eyes, lungs, gastrointestinal tract, urinary tract, and nose. Some people have hypersensitivity reactions. Defibrotide was approved for medical use in the European Union in October 2013, in the United States in March 2016, and in Australia in July 2020. Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition.


Medical uses

In the European Union defibrotide is indicated for the treatment of severe hepatic veno-occlusive disease (VOD) also known as sinusoidal obstructive syndrome (SOS) in hematopoietic stem-cell transplantation (HSCT) therapy for adults, adolescents, children, and infants over one month of age. Defibrotide is used to treat veno-occlusive disease of the liver of people having had a
bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...
, with different limitations in the US and the European Union. As of 2016, however, randomized placebo controlled trials have not been done. Hematopoietic stem cell transplantation (HSCT) is a procedure performed in some people to treat certain blood or bone marrow cancers. Immediately before an HSCT procedure, a patient receives chemotherapy. Hepatic VOD can occur in people who receive chemotherapy and HSCT. Hepatic VOD is a condition in which some of the veins in the liver become blocked, causing swelling and a decrease in blood flow inside the liver, which may lead to liver damage. In the most severe form of hepatic VOD, the patient may also develop failure of the kidneys and lungs. Fewer than two percent of people develop severe hepatic VOD after HSCT, but as many as 80 percent of people who develop severe hepatic VOD do not survive. It is administered by intravenous infusion in a doctor's office or clinic.


Contraindications

Use of defibrotide for people who are already taking
anticoagulants An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which h ...
is dangerous and use of other drugs that affect platelet aggregation, like
NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s, should be done with care. Defibrotide should not be given to people who have a difficult time maintaining a steady
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
.


Adverse effects

There is a high risk of bleeding and some people have had
hypersensitivity reaction Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes im ...
s to defibrotide. Common adverse effects, occurring in between 1 and 10% of people, included impaired blood clotting, vomiting,
low blood pressure Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
, bleeding in the brain, eyes, lungs, stomach or intestines, in the urine, and at catheterization sites. Other side effects have included
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
, nosebleeds,
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, graft vs host disease, and pneumonia.
Pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
women should not take defibrotide and women should not become pregnant while taking it; it has not been tested in pregnant women but at normal doses it caused hemolytic abortion in rats.


Pharmacology

Defibrotide's mechanism of action is poorly understood. ''In vitro'' studies have shown that it protects the
endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
lining blood vessels from damage by
fludarabine Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatm ...
, a
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
drug, and from a few other insults like serum starvation. It also appears to increase t-PA function and decrease
plasminogen activator inhibitor-1 Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor (serpin E1) is a protein that in humans is encoded by the ''SERPINE1'' gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis. ...
activity.


Chemistry

Defibrotide is a mixture of single-stranded
oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, Recombinant DNA, research, and Forensic DNA, forensics. Commonly made in the laboratory by Oligonucleotide synthesis, solid-phase ...
s. The chemical name is polydeoxyribonucleotide, sodium salt. It is purified from the
intestinal mucosa The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are the mucosa, the submucosa, the muscular layer and the serosa or adventitia. ...
of pigs.


History

The efficacy of defibrotide was investigated in 528 participants treated in three studies: two prospective clinical trials and an expanded access study. The participants enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after hematopoietic stem cell transplantation (HSCT). The studies measured the percentage of participants who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of participants treated with defibrotide were alive 100 days after HSCT. Based on published reports and analyses of participant-level data, the expected survival rates 100 days after HSCT would be 21 to 31 percent for participants with severe hepatic VOD who received only supportive care or interventions other than defibrotide.


Society and culture


Legal status

Defibrotide was approved in the European Union for use in treating veno-occlusive disease of the liver of people having had a bone marrow transplant in 2013; Gentium had developed it. At the end of that year, Jazz Pharmaceuticals acquired Gentium. In March 2016, the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) approved it for a similar use. Defibrotide is the first FDA-approved therapy for treatment of severe hepatic VOD, a rare and life-threatening liver condition. The FDA granted the application for defibrotide
priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
status and
orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...
designation. The FDA granted approval of Defitelio to Jazz Pharmaceuticals. Defibrotide was approved for medical use in Japan in June 2019. Defibrotide was approved for medical use in Australia in July 2020.


References


Further reading

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