Schulman S, Bech Jensen M, Varon D, Keller N, Gitel S, Horoszowski H, Heim M, Martinowitz U
National Hemophilia Center, Chilm Sheba Medical Center, Tel-Hashomer, Israel.
Thromb Haemost. 1996 Mar;75(3):432-6.
Recombinant factor VIIa (rFVIIa; NovoSeven) is a recent addition to the hemostatic alternatives for the treatment of hemophiliacs with inhibitors. A drawback in the use of rFVIIa has been its half-life of only about 2 h, which necessitates very frequent and punctual injections. We evaluated the stability of reconstituted, but not further diluted, rFVIIa in 3 infusion systems (WalkMed 350 and CADD-Plus minipumps and Meddex 2001 syringe pump). The factor VII (F VII) activity was maintained for at least 3 days at room temperature with only a minor and clinically insignificant increase in oxidized forms of rFVIIa and minimal leaching of the plastic softeners dibutylphthalate and di-octylphthalate after 24-48 h. Addition of heparin, 5-10 U/ml, to reconstituted rFVIIa caused a loss of about 50% of the activity within 4 h of storage in the infusion system, whereas low molecular weight heparin had no such effect. Repeated samples showed that the infusion systems maintained sterility. Reconstituted rFVIIa did not support bacterial growth when inoculated with Staphylococcus aureus or Escherichia coli to any greater extent than did reconstituted factor VIII, lidocaine in saline or heparin in saline. Two patients were treated with continuous infusion of rFVIIa on 4 occasions (total knee arthroplasty, wound revision, and twice straightening of a 90 degrees contracture of the knee under general anaesthesia). A preoperative pharmacokinetic evaluation was performed, and the clearance was used to calculate the maintenance dose, aiming at a FVII level of 10 U/ml, which proved to be a hemostatic level. The first patient had no change in the clearance during the two treatment episodes. He suffered from repeated thrombophlebitis at the infusion site. The second patient had a progressive decrease of the clearance from 86.4 to 24.7 ml/h/kg. He received during the first treatment a parallel infusion with heparin (approximately 250 U/24 h) to the same venous access and did not develop thrombophlebitis during 3.5 days of therapy. For the second episode low molecular weight heparin was added directly to the infusion bag, and no adverse effects were observed. Continuous infusion with rFVIIa is thus feasible with the minipumps used by us, eliminates the need for 2 h injections and reduces the total dose of rFVIIa by 50-75%, depending on the behaviour of the clearance.
重组凝血因子VIIa（rFVIIa；诺其）是治疗有抑制剂的血友病患者的最新止血替代药物。使用rFVIIa的一个缺点是其半衰期仅约2小时，这需要非常频繁且准时的注射。我们评估了在3种输注系统（WalkMed 350和CADD-Plus微型泵以及Meddex 2001注射泵）中复溶但未进一步稀释的rFVIIa的稳定性。在室温下，凝血因子VII（F VII）活性至少维持3天，rFVIIa氧化形式仅有轻微且临床上无显著意义的增加，24 - 48小时后塑料软化剂邻苯二甲酸二丁酯和邻苯二甲酸二辛酯的浸出量极少。向复溶的rFVIIa中添加5 - 10 U/ml的肝素，在输注系统中储存4小时内会导致约50%的活性丧失，而低分子量肝素则无此作用。重复取样显示输注系统保持无菌状态。与复溶的凝血因子VIII、盐水中的利多卡因或盐水中的肝素相比，用金黄色葡萄球菌或大肠杆菌接种时，复溶的rFVIIa在支持细菌生长方面并无更大程度的差异。两名患者在4种情况下接受了rFVIIa持续输注治疗（全膝关节置换术、伤口修复以及在全身麻醉下两次矫正膝关节90度挛缩）。进行了术前药代动力学评估，并根据清除率计算维持剂量，目标是使FVII水平达到10 U/ml，这被证明是一个止血水平。第一名患者在两次治疗期间清除率无变化。他在输注部位反复发生血栓性静脉炎。第二名患者的清除率从86.4逐渐降至24.7 ml/h/kg。在第一次治疗期间，他通过同一静脉通路同时输注肝素（约250 U/24小时），在3.5天的治疗期间未发生血栓性静脉炎。在第二次治疗时，直接在输液袋中添加了低分子量肝素，未观察到不良反应。因此，使用我们的微型泵进行rFVIIa持续输注是可行的，无需2小时注射一次，并且根据清除率的情况，可将rFVIIa的总剂量减少50 - 75%。
