Heffernan Jane K, Ponce Rafael A, Zuckerman Linda A, Volpone John P, Visich Jennifer, Giste Erika E, Jenkins Nancy, Boster Dan, Pederson Susan, Knitter Glenn, Palmer Thomas, Wills Margaret, Early Richard J, Rogge Mark C
ZymoGenetics Inc, Seattle, WA 98102, USA.
Regul Toxicol Pharmacol. 2007 Feb;47(1):48-58. doi: 10.1016/j.yrtph.2006.07.006. Epub 2006 Sep 12.
Recombinant human thrombin (rhThrombin) is being developed as an alternative to thrombin products purified from pooled human or bovine plasma, which are currently marketed for topical hemostasis. Preclinical studies of rhThrombin were conducted prior to its evaluation as a topical adjunct to surgical hemostasis in clinical trials. No overt clinical pathology or signs were observed in cynomolgus monkeys following implantation of a gelatin sponge containing either rhThrombin or bovine thrombin to a surgical liver wound, and similar gross and microscopic wound healing characteristics were observed over an eight-week recovery period with either compound. Repeated subcutaneous injections of rhThrombin or bovine thrombin to cynomolgus monkeys produced no treatment-related effects. Whereas no monkeys demonstrated anti-rhThrombin antibody seroconversion, specific anti-bovine antibodies were detected in all tested monkeys exposed to bovine thrombin. Addition of rhThrombin or bovine thrombin to mouse fibroblast cells resulted in expected detachment and shape change. Topical application of rhThrombin to rabbits did not cause irritation to the eye, normal skin, or abraded skin. These studies showed that topical, subcutaneous, or implanted rhThrombin was minimally immunogenic, safe, and well tolerated in nonclinical models, and supported the clinical evaluation of rhThrombin in a variety of surgical settings.
重组人凝血酶（rhThrombin）正在被开发，以替代从混合人血浆或牛血浆中纯化的凝血酶产品，目前这些产品已上市用于局部止血。在将rhThrombin作为手术止血的局部辅助药物进行临床试验评估之前，已对其进行了临床前研究。将含有rhThrombin或牛凝血酶的明胶海绵植入食蟹猴的手术肝伤口后，未观察到明显的临床病理学变化或体征，并且在八周的恢复期内，两种化合物的伤口愈合的大体和微观特征相似。对食蟹猴重复皮下注射rhThrombin或牛凝血酶未产生与治疗相关的影响。虽然没有猴子出现抗rhThrombin抗体血清转化，但在所有接触牛凝血酶的受试猴子中均检测到特异性抗牛抗体。向小鼠成纤维细胞中添加rhThrombin或牛凝血酶会导致预期的细胞脱离和形态变化。将rhThrombin局部应用于兔子的眼睛、正常皮肤或擦伤皮肤均未引起刺激。这些研究表明，在非临床模型中，局部、皮下或植入rhThrombin的免疫原性极低、安全且耐受性良好，并支持在各种手术环境中对rhThrombin进行临床评估。
