Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.
Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.
复制标题
DOI：
10.1186/1479-5876-9-55
复制
发表时间：
2011-05-08
影响因子：
7.4
通讯作者：
Tsubouchi H
中科院分区：
文献类型：
--
作者：
Ido A;Moriuchi A;Numata M;Murayama T;Teramukai S;Marusawa H;Yamaji N;Setoyama H;Kim ID;Chiba T;Higuchi S;Yokode M;Fukushima M;Shimizu A;Tsubouchi H
肝细胞生长因子（HGF）刺激肝细胞增殖，同时也是一种抗凋亡因子。因此，HGF是一种潜在的治疗致命性肝病的药物。我们使用重组人HGF （rh-HGF）进行了一项转化医学方案，包括对暴发性肝炎（FH）或晚发型肝衰竭（LOHF）患者进行I/II期研究，以检查该分子的安全性、药代动力学和临床疗效。通过rh-HGF临床前安全性试验确定的潜在不良反应包括血压（BP）降低和尿白蛋白排泄增加。因此，我们在临床前动物实验中进一步研究了rh-HGF对循环状态和肾毒性的影响。在一项临床试验中，评估了20例FH或LOHF患者是否参与该临床试验，并纳入了4例患者。受试者静脉注射rh-HGF （0.6 mg/m2/天）12 ~ 14天。我们建立了一种避免小型猪血压快速降低的输注方法，并证实了大鼠肾毒性的可逆性。虽然rh-HGF的使用适度降低了参与者的血压，但这种血压降低并不需要停止rh-HGF或任何血管加压治疗；rh-HGF输注完成后血压恢复到静息水平。重复剂量的rh-HGF没有引起肾毒性，也没有观察到严重的不良事件。两名患者存活，然而，没有证据表明rh-HGF对FH或LOHF治疗有效。FH或LOHF患者静脉注射剂量为0.6 mg/m2的rh-HGF耐受良好；因此，有必要进行进一步的研究，以确定rh-HGF在增加剂量时的疗效。
Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.
登录
查看更多内容
影响因子：
13.5
作者：
Kosai, K;Matsumoto, K;Nakamura, T
通讯作者：
Nakamura, T
影响因子：
13.5
作者：
Kumar, M.;Satapathy, S.;Sarin, S. K.
通讯作者：
Sarin, S. K.
影响因子：
12.4
作者：
Ozaki, M;Haga, S;Suzuki, S
通讯作者：
Suzuki, S
影响因子：
13.5
作者：
FUJIWARA, K;NAGOSHI, S;KUROKAWA, K
通讯作者：
KUROKAWA, K
DOI：
10.1073/pnas.0403412101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Borowiak, M;Garratt, AN;Birchmeier, C
通讯作者：
Birchmeier, C