去纤苷酸 Noravid Defibrotide

【作用与用途】 抗血凝药。本品系由猪、牛、羊等哺乳动物的肺中提取而得，是一种部分解聚的脱氧核  糖核酸（DNA）。本品具有明显的纤溶作用。用于预防深部静脉血栓形成及血栓性静脉炎的治疗。

 經幹細胞移植的病患有5%到60%會罹患從輕微可逆到嚴重近乎經常致命不等的肝臟靜脈閉塞症(veno-occlusive disease:VOD)。而同種異體的移植受贈人比自體受贈人冒有更高罹患VOD的風險。VOD是種會源於移植前所施予之高化學劑量，潛在上致命的肝臟損傷。化療藥物會損及於肝臟微血管作為襯裡的細胞及肝臟細胞，擾亂肝臟的血液循環而導致肝臟腫脹。罹患VOD的病人通常會出現類似黃疸及浮腫的症狀，且冒有諸如腎臟及肺臟等其他器官衰竭的風險。

最近一項由Dana-Farber癌症研究所，就一種由豬腸內部組織所萃取之實驗性藥物`defibrotide`的研究顯示，於經歷嚴重且致命之幹細胞移植併發症VOD的病患中降低了死亡風險。該涉及多所中心的研究領導人，Dana-Farber癌症研究所的血液腫瘤學家Paul G.Richardson醫學博士宣稱，罹患嚴重VOD的幹細胞移植病患冒有極高的死亡風險，其死亡率超出90% 。

Defibrotide在一項令其得以於緊急狀態使用的研究方案下，被施予了88名罹患嚴重VOD且多重組織器官衰竭的移植病人。該藥物於32名(36%)病患中完全逆轉了VOD，且31名(35%)病患移植後至少存活100天。這可說是移植成功的里程碑，移植前這類病患被預期存活100天的通常不及10%。

先前醫師們施予像t-PA及肝制凝素(heparin)等分解血液凝塊的藥物來治療VOD，不過此些藥物會引發嚴重出血且對具多重組織器官衰竭的病患無效。此研究中，由單股組成之DNA片段的defibrotide，有選擇性地對微血管表面具活性及修復血管損傷，不會造成任何嚴重的出血，且諸如體熱感等的副作用極為輕微。
目前Richardson及其同僚正著手一項攸關defibrotide進一步隨機化的試驗，以證實此研究發現及確認最適宜的劑量。也是哈佛醫學院講師的Richardson表示，已知該藥物良好的安全紀錄及大有可為的活性，他們計劃完成當前就其在已診斷之VOD中的效用實驗，而後進行此藥物在經歷移植之病患中作為預防製劑的研究。於未來，這可能使我們得以治療其他方面因高風險的VOD而可能遭拒絕進行移植的病患。

另外：预防血栓形成是降低手术及术后死亡率的有效方法。Defibrotide是从动物组织中提取的多聚脱氧核糖酸，这种化合物具有抗血栓形成的活性，它能增加组织中游离纤维蛋白原活性，而不改变凝血参数，不增加术中出血。术前1日到术后数日内，给400mg，2次/d。但Defibrotide还没有在临床上广泛应用。Will，Jorgensen等研究，用小剂量肝素和加压橡皮袜能有效防止血栓形成。对有高危因素的患者，特别是恶性肿瘤患者，术前应完善各项检查，及时补充液体，纠正因禁食、灌肠等引起的脱水，术后及早下床活动，以减少血栓性静脉炎的发生。
NORAVID
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).
Contents
  1 Pharmacokinetics
  2 Mode of Action
  3 Usual Indications
  4 Potential Indications in the Future
  5 Cautions and Contraindications
  6 Side effects
  7 Drug Interactions
  8 Usual Doses
  9 External References

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 levelsofprostaglandin 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 thetreatment 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 name Noravid in a variety of countries, but is currently not approved in the USA.
                                
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.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 FutureOther 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.
                                
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.
                                
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.