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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of hepatocyte growth factor on endogenous hepatocarcinogenesis in rats fed a choline-deficient L-amino acid-defined diet.

Hepatocyte growth factor (HGF) is a promising agent for the treatment of intractable liver disease, due to its mitogenic, anti-apoptotic, and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on the development of both hepatocellular carcinoma (HCC) and preneoplastic nodules in rats fed a choline-deficient L-amino acid-defined (CDAA) diet, an animal model of hepatocarcinogenesis resembling human development of HCC with cirrhosis. From weeks 13 to 48 of the CDAA diet, rh-HGF (0.1 or 0.5 mg/kg/day) was administered intravenously to rats in four-week cycles, with treatment for five consecutive days of each week for two weeks, followed by a two-week washout period. Treatment with rh-HGF significantly inhibited the development of preneoplastic nodules in a dose-dependent manner at 24 weeks. Although the numbers and areas of the preneoplastic nodules in rats treated with rh-HGF were equivalent to those in mock-treated rats by 60 weeks, the incidence of HCC was reduced by HGF treatment. Although one rat treated with low-dose rh-HGF exhibited a massive HCC, which occupied almost the whole liver, and lung metastases, HGF treatment did not increase the overall frequency of HCC. Administration of high-dose rh-HGF, however, induced an increase in the urinary excretion of albumin, leading to decreased serum albumin at 60 weeks. These results indicate that long-term administration of rh-HGF does not accelerate hepatocarcinogenesis in rats fed a CDAA diet. However, these findings do not completely exclude the potential of HGF-induced hepatocarcinogenesis; this issue must be resolved before rh-HGF can be used for patients with intractable liver diseases, especially those with cirrhosis.

Navigator-echo-based MR provides high-resolution images and precise volumetry of swine livers without breath holding or injection of contrast media.

The accurate calculation of hepatic volume by computed tomography (CT) or magnetic resonance (MR) is complicated by the need for breath holding and the injection of contrast media. These are often contraindicated in patients with liver failure, and we examined the ability of unenhanced 3-dimensional (3-D) navigator-echo-based MR (NE-MR) to accurately image livers and measure volumes without breath holding compared to unenhanced (plain) or gadolinium-diethylene triamine pentaacetic acid enhanced MR (Gd-MR) in miniature swine (n = 8). Without breath holding, diaphragm movement monitoring with NE-MR reduced motion artifacts in hepatic images compared with the other modalities. Without the injection of contrast media, the signal-to-noise ratios of the images obtained using NE-MR were significantly higher than those from plain MR; Gd-MR was superior to NE-MR, however (79.5 +/- 7.5 vs. 63.2 +/- 6.0 or 97.8 +/- 8.1, respectively; P < 0.01 for each). Overall, NE-MR produced improved high-resolution liver images. Consequently, liver volumes calculated based on NE-MR images were more highly correlated with actual liver weights compared to plain or Gd-MR in the whole livers (n = 8; r = 0.937 vs. 0.835 or 0.904, respectively). Also, NE-MR demonstrated significantly strong correlation between actual weights and volumetry-calculated volumes in regenerative livers 7 days after massive hepatectomy (n = 10, r = 0.989, P < 0.01). In conclusion, our results indicate that without breath holding or the injection of contrast media, 3-D NE-MR can provide both high-resolution liver images and precise hepatic volumes in patients with liver failure due to liver surgery (massive hepatectomy and living donor liver transplantation) or fulminant hepatic failure.

A successful liver transplantation for refractory hepatic veno-occlusive disease originating from cord blood transplantation.

An 11-month-old boy with acute lymphoblastic leukemia (ALL) underwent umbilical cord blood transplantation (CBT) from an unrelated donor after a first complete remission. Despite the prophylactic use of low molecular weight heparin, prostaglandin E1 and ursodeoxycholic acid, hepatic veno-occlusive disease (VOD) occurred on the 29th day after CBT. Furthermore, neither defibrotide nor antithrombin-III improved the hepatic coma and coagulopathy due to the hepatic VOD. On the 42nd day after CBT, he underwent living related liver transplantation (LRLT) with a left lateral segment graft from his father. He received tacrolimus for the prevention of rejection and graft-vs.-host disease (GVHD) and also received aggressive antifungal and antiviral prophylaxis. Although he showed signs of acute rejection on postoperative days 5 and 10, the postoperative course was uneventful in general. At present, 17 months after LRLT, the patient shows stable liver function and no signs of either GVHD or a relapse of ALL. In conclusion, LRLT can be seen as a feasible option for the treatment of a hepatic VOD after CBT, though aggressive prophylaxis for infection and the anticipation of acute rejection are of importance.