Reinhart Konrad, Glück Thomas, Ligtenberg Jack, Tschaikowsky Klaus, Bruining Albert, Bakker Jan, Opal Steven, Moldawer Lyle L, Axtelle Tim, Turner Terence, Souza Sonia, Pribble John
Department of Anesthesia and Critical Care, University Medical Center, University of Jena, Germany.
Crit Care Med. 2004 May;32(5):1100-8. doi: 10.1097/01.ccm.0000124870.42312.c4.
Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis.
Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial.
Six medical and surgical intensive care units located in Germany and The Netherlands.
Forty patients with severe sepsis.
IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included.
The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group.
Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.
细菌细胞壁成分与髓样细胞上的CD14及共受体结合会导致细胞活化并产生促炎介质。一种重组抗CD14单克隆抗体（IC14）已被证明可降低内毒素血症动物和人类模型中脂多糖诱导的反应。本研究旨在评估IC14在严重脓毒症患者中的安全性、药代动力学、药效学和临床药理学。
随机、双盲、安慰剂对照、剂量范围、多中心试验。
位于德国和荷兰的六个内科和外科重症监护病房。
40例严重脓毒症患者。
将IC14静脉注射给每个队列中的8名患者，采用单次剂量（1mg/kg或4mg/kg）或多次剂量（4mg/kg每日一次，共4天，或第1天4mg/kg，随后3天每日2mg/kg）。还包括一个安慰剂组（每个队列2名患者）。
各治疗组不良事件的总体发生率和类型相似。在接受每日4mg/kg多次剂量IC14共4天的组中，有1名患者在接受第一剂研究药物后发生过敏反应。IC14未诱导抗体形成或增加继发细菌感染的发生率。外周血单核细胞上最大膜结合CD14受体占有率达到50%时，所需的IC14血清平均浓度约为1μg/mL。患者和IC14治疗组对治疗反应的促炎和抗炎细胞因子、趋化因子、可溶性受体、可溶性E选择素和急性期蛋白模式变化很大。
单剂量和多剂量的IC14一般耐受性良好，未诱导抗体形成或增加继发细菌感染的发生率。结果表明，用IC14阻断CD14值得进一步进行临床研究，以确定其减轻感染引起的促炎反应的能力。
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