重組人類凝血酶是一個耐受良好的局部止血劑


  【24drs.com】February 5, 2010 — 根據發表於2月美國外科學院期刊(Journal of the American College of Surgeons)的一篇新研究,8篇臨床試驗結果顯示,重組人類凝血酶(商品名rThrombin;Recothrom, ZymoGenetics公司)在多種手術對象的局部止血上耐受良好,形成抗體的比率低,再者,抗體並不會中和原本的人類凝血酶。
  
  加州橘郡、橘郡血管與介入專家公司的Jeffrey L. Ballard醫師等人寫道,重組凝血酶被發展作為人類和牛血漿衍生凝血酶產品的替代品,使用人類血漿衍生之凝血酶可能會有傳染感染症的風險,對於牛凝血酶產品的免疫反應也曾有報導;包括形成對牛凝血酶以及產品中不純物的抗體,這些可能會和原本的凝血蛋白質產生交叉反應,引起某些病患的凝血酶血液凝固疾病和形成血栓。
  
  研究目標是描述使用rThrombin治療後的副作用與免疫抗原性報告。
  
  這8篇臨床試驗包括1篇第一期試驗;5篇第二期試驗;1篇隨機雙盲第三期試驗;以及1篇開放標籤第3b其試驗。研究者研究了583名12-89歲的病患,年齡中位數為59歲,54%為男性,病患都未曾對凝血酶或其他凝血因素有過敏。
  
  這些試驗包括了多種手術,有脊椎手術、大範圍肝切除、週邊動脈繞道、建立進行血液透析的人工血管、燒傷傷口切除之後的皮膚移植等。
  
  在手術過程中使用凝膠棉(Gelatin sponge)或噴灑給藥器給予rThrombin,監測副作用與實驗室參數直到第29天研究結束時。在583名病患中,有552人在開始時與完成研究後第29天時被蒐集血漿樣本進行免疫抗原分析。
  
  研究者報告指出,在治療後將近1個月時,不到1%的病患(5/552)產生對於rThrombin的抗體(0.9%;95%信心區間為0.3 - 2.1),而這些抗體並不會中和原本的人類凝血酶的活性,作者們也指出,相較於其他治療用的蛋白質,這個抗體的發生率相對較低。
  
  根據作者們表示,開始時,552名病患中有12人發現原本有可以辨識rThrombin的抗體,這些病患以前未曾以rThrombin治療過,他們的抗體效價在29天時並未增加超過1.0單位以上(即≧10倍-fold)。
  
  整體而言,多數報告的副作用是切除部位疼痛、手術疼痛與噁心,作者們指出,病患發生對於rThrombin的抗體數量很少,少到無法進行抗體與副作用之關聯的分析。
  
  賓州匹茲堡大學醫學院的Rabih A. Chaer醫師為Medscape General Surgery對此報告發表評論時表示,凝血酶一般常被使用,這些資訊對於安全性相當重要。
  
  他表示,人類配方的凝血酶可能會引起來自捐贈者的傳染病,牛配方則可能會引起免疫反應,因此,不會引起免疫反應的中和型衍生物對於病患安全來說的確是一個好消息。
  
  他接著表示,市面上的其他產品可能可以達到同樣目標,必須探討的是,某種製劑是否比較有效,如果都一樣,那就會偏好比較安全以及比較有成本效益的產品。
  
  Chaer醫師也指出,還不知道rThrombin是否可以安全用於以前使用其他類型凝血酶如牛凝血酶的病患。
  
  有一些證據認為,牛凝血酶的抗體可能會和重組凝血酶有交叉反應,這一點需要進一步研究。
  
  ZymoGenetics公司支持本研究。Ballard醫師與 Chaer醫師皆宣告沒有相關財務關係。

Recombinant Human Thrombin Is a Well-Tolerated Topical Hemostatic Agent

By Fran Lowry
Medscape Medical News

February 5, 2010 — Results from 8 clinical trials show that recombinant human thrombin (rThrombin; Recothrom, ZymoGenetics, Inc) is well tolerated in several surgical settings for topical hemostasis with a low rate of antibody formation. Moreover, the antibodies do not neutralize native human thrombin, according to a new study published in the February issue of the Journal of the American College of Surgeons.

"Recombinant thrombin was developed as an alternative to human and bovine plasma-derived thrombin products," write Jeffrey L. Ballard, MD, from the Vascular and Interventional Specialists of Orange County, Inc, Orange, California, and colleagues. "The use of human plasma-derived thrombin may carry a risk of transmitting infectious agents. Immunologic responses to bovine thrombin products have been reported; these include the formation of antibodies to bovine thrombin and to impurities found in the products, which may cross-react with native coagulation proteins and cause coagulopathies and thrombosis in some patients."

The aim of this study was to describe the adverse events and immunogenicity reported after treatment with rThrombin.

The 8 clinical trials include data from one phase 1 trial; 5 phase 2 trials; 1 randomized, double-blind phase 3 trial; and 1 open-label phase 3b trial. The researchers studied 583 patients ranging in age from 12 to 89 years. The median age was 59 years, and 54% were men. The patients had no documented hypersensitivity to thrombin or other coagulation factors.

The trials encompassed a variety of surgical procedures, including spinal surgery, major hepatic resection, peripheral arterial bypass, arteriovenous graft formation for hemodialysis access, and skin grafts after burn wound excision.

rThrombin was applied with an absorbable gelatin sponge or spray applicator during the surgical procedure, and adverse events and laboratory parameters were monitored until the end of the study on day 29. Immunogenicity was evaluated on plasma samples that were collected at baseline and on day 29 after completion of the study in 552 of the 583 patients.

The investigators report that less than 1% of patients (5/552) developed antibodies to rThrombin approximately 1 month after treatment (0.9%; 95% confidence interval, 0.3 - 2.1) and that these antibodies did not neutralize the activity of native human thrombin. The authors also note that this incidence of antibody formation is low compared with those reported for other therapeutic proteins.

Preexisting antibodies that recognized rThrombin were found in 12 of the 552 patients at baseline. These patients had not been previously treated with rThrombin, and their antibody titer did not increase by 1.0 unit or more (?10-fold) at day 29, according to the authors.

Overall, the most commonly reported adverse events were incision site pain, procedural pain, and nausea. The authors add that the number of patients developing antibodies to rThrombin was too small for detailed analyses of the relationship between antibodies and adverse events.

Commenting on this paper for Medscape General Surgery, Rabih A. Chaer, MD, from the University of Pittsburgh School of Medicine in Pennsylvania, said that thrombin is very commonly used, and having this information on safety is important.

"The human formulation of thrombin can potentially cause transmission of disease from the donor, and the bovine formulation could potentially cause an immune response. Having a neutral type of derivative which does not cause an immune response on the part of the patient is a good safety profile to have," he said.

Other products on the market can achieve the same goal, he continued. "Clearly one would have to see if one agent is more efficacious, and all things being equal, the preferred product would be the safer and more cost-effective product."

Dr. Chaer also pointed out that it is not known whether rThrombin would be safe to use in patients who have received other forms of thrombin, such as bovine thrombin, in the past.

"There is some evidence to suggest that the antibodies to the bovine thrombin may cross-react with the recombinant thrombin. This is something that needs to be studied."

The study was supported by ZymoGenetics. Dr. Ballard and Dr. Chaer have disclosed no relevant financial relationships.

J Am Coll Surg. 2010;210:199-204.

    
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