Abstract
BackgroundHepatocyte 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.MethodsPotential 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.ResultsWe 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.ConclusionsIntravenous 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.
Highlights
Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and acts as an antiapoptotic factor
These results indicate that intravenous injection of rhHGF reduced blood pressure (BP) through dilatation of capacitance vessels
We first administered recombinant human HGF (rh-HGF) to a 67-year-old Japanese man with FHSA caused by hepatitis E virus infection
Summary
Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and acts as an antiapoptotic factor. HGF is a potential therapeutic agent for treatment of fatal liver diseases. Acute liver failure (ALF) is a rare but fatal clinical syndrome marked by the abrupt loss of hepatic cellular function, with the subsequent development of coagulopathy, jaundice and encephalopathy [1,2,3]. In Japan, ALF with the histological appearance of hepatitis, encephalopathy develops between 8 and 24 weeks after disease onset with PT less than 40% are diagnosed as having LOHF. This distinction is useful in guiding prognosis: the time to onset of encephalopathy is negatively correlated with outcome. Patients with FH who did not receive liver transplantation had extremely poor prognoses: the survival rates were 53.7% in FHA and 24.4% in FHSA, and 11.5% in LOHF in Japan [4]
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