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
<p>Abstract</p> <p>Background</p> <p>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 medici...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-05-01
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| Series: | Journal of Translational Medicine |
| Online Access: | http://www.translational-medicine.com/content/9/1/55 |
| _version_ | 1818564754997772288 |
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| author | Setoyama Hitoshi Yamaji Naohisa Marusawa Hiroyuki Teramukai Satoshi Murayama Toshinori Numata Masatsugu Moriuchi Akihiro Ido Akio Kim Il-Deok Chiba Tsutomu Higuchi Shuji Yokode Masayuki Fukushima Masanori Shimizu Akira Tsubouchi Hirohito |
| author_facet | Setoyama Hitoshi Yamaji Naohisa Marusawa Hiroyuki Teramukai Satoshi Murayama Toshinori Numata Masatsugu Moriuchi Akihiro Ido Akio Kim Il-Deok Chiba Tsutomu Higuchi Shuji Yokode Masayuki Fukushima Masanori Shimizu Akira Tsubouchi Hirohito |
| author_sort | Setoyama Hitoshi |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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/m<sup>2</sup>/day) intravenously for 12 to 14 days.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>Intravenous rh-HGF at a dose of 0.6 mg/m<sup>2 </sup>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.</p> |
| first_indexed | 2024-12-14T01:32:44Z |
| format | Article |
| id | doaj.art-e22391c264c2496fb375369436448f5c |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-14T01:32:44Z |
| publishDate | 2011-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-e22391c264c2496fb375369436448f5c2022-12-21T23:21:59ZengBMCJournal of Translational Medicine1479-58762011-05-01915510.1186/1479-5876-9-55Safety 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 safetySetoyama HitoshiYamaji NaohisaMarusawa HiroyukiTeramukai SatoshiMurayama ToshinoriNumata MasatsuguMoriuchi AkihiroIdo AkioKim Il-DeokChiba TsutomuHiguchi ShujiYokode MasayukiFukushima MasanoriShimizu AkiraTsubouchi Hirohito<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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/m<sup>2</sup>/day) intravenously for 12 to 14 days.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>Intravenous rh-HGF at a dose of 0.6 mg/m<sup>2 </sup>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.</p>http://www.translational-medicine.com/content/9/1/55 |
| spellingShingle | Setoyama Hitoshi Yamaji Naohisa Marusawa Hiroyuki Teramukai Satoshi Murayama Toshinori Numata Masatsugu Moriuchi Akihiro Ido Akio Kim Il-Deok Chiba Tsutomu Higuchi Shuji Yokode Masayuki Fukushima Masanori Shimizu Akira Tsubouchi Hirohito 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 Journal of Translational Medicine |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.translational-medicine.com/content/9/1/55 |
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