去纤苷(Defibrotide)的适应症,用法用量,功效作用及药物相互作用？

Defibrotide is a new polydeoxyribonucleotide that has fibrinolytic properties but does not carry the risk of major bleeding. Numerous studies, including phase II/III trials, have demonstrated clinical benefit in pediatric patients with treatment and prophylaxis with defibrotide.

About Defibrotide

Defibrotide is a polydisperse mixture mainly composed of single-stranded polydeoxyribonucleotides. It is currently the only therapy approved in the United States for the treatment of liver VOD/SOS associated with lung/renal dysfunction (i.e., multiple organ dysfunction/multiple organ failure [MOD/MOF]) after HSCT, and in the EU for the treatment of severe liver VOD/SOS after HSCT.

China listing information

As of December 22, 2023, Defibrotide has not yet been launched in China. Countries where Defibrotide has been marketed include Germany, Canada, the United States, South Korea, France, etc.

Indications

Defibrotide was approved for medical use in the United States in March 2016 and in the European Union in October 2013. It is suitable for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD) and renal or pulmonary dysfunction after hematopoietic stem cell transplantation (HSCT).

Usage and Dosage

The recommended dose of Defibrotide for adult and pediatric patients is 6.25g/kg every 6 hours as a 2-hour intravenous infusion. This dose should be determined based on the patient's basal body weight.

Defibrotide should be used for at least 21 days. If signs and symptoms of hepatic VOD have not resolved after 21 days, continue defibrillation until VOD resolves or for up to 60 days.

Efficacy

Defibrotide is the only drug approved in the United States and Europe for the treatment of VOD/SOS after HCT. It is designated by the European Commission as an orphan drug for the prevention of graft-versus-host disease (GvHD) related to endothelial dysfunction.

This endothelial cell protector and stabilizer restores the thrombo-fibrinolytic balance and maintains endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, antioxidant and anti-adhesion activities. Defibrotide also protects endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulation of p38 mitogen-activated protein kinase (MAPK) and histone deacetylase (HDACs) is key to the endothelial protection of defibrotide.

In preclinical and human studies, defibrotide has been shown to have fibrinolytic, antithrombotic, anti-inflammatory and vasoprotective effects, thereby promoting the anticoagulant phenotype of the endothelium and protecting and stabilizing the function of endothelial cells.

Drug interactions

Antithrombotic agents: Defibrotide can enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Therefore, defibrotide is prohibited from being used simultaneously with antithrombotic or fibrinolytic drugs to avoid an increased risk of bleeding.

Side effects

The most common side effects of defibrotide treatment are nausea, vomiting, hypotension, diarrhea, and nosebleeds. In addition, patients may also experience adverse reactions such as alveolar hemorrhage, gastrointestinal bleeding, sepsis, graft-versus-host disease, pneumonia, pulmonary hemorrhage, intracranial hemorrhage, excess uric acid, and cerebral hemorrhage.

Methods for dealing with side effects

1. Nosebleeds: Patients with nosebleeds should avoid bad habits such as nose picking and nose picking. After nosebleeds, the bleeding can be stopped by packing and pressing.

2. Hypotension: Patients with hypotension can drink tea in moderation, and should usually supplement protein-rich foods, such as lean meat, eggs, and milk. Sympathomimetic drugs, anticholinesterase drugs and other drugs can be used when necessary.

3. Diarrhea: Patients with diarrhea should avoid catching cold in the abdomen, and can receive antidiarrheal treatment under the guidance of a doctor.

4. Nausea: It is recommended that patients avoid eating greasy and spicy foods, and can also use symptomatic drug treatment.

Efficacy of defibrotide treatment

Prophylactic use to prevent veno-occlusive disease (VOD), a relatively common and high-risk complication of hematopoietic stem cell transplantation (HSCT), may be an encouraging approach to reducing VOD morbidity and mortality. A systematic review was conducted to summarize the state of knowledge and identified one randomized controlled trial (RCT), four cohort studies and eight case series including a total of 1230 patients. The overall mean incidence of VOD in patients using defibrotide was 4.7%, which was significantly lower than the 13.7% data in 135 studies that did not use VOD prevention.

A meta-analysis of the incidence of VOD in controlled trials showed that the incidence of VOD in the defibrotide group was statistically reduced (RR=0.47). The overall average incidence of severe VOD was 0.8%, and the relative risk was 0.31.

In addition, defibrotide was found in one trial to reduce the incidence of VOD/SOS in children and reduce the incidence of graft-versus-host disease.

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