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Human hepatocyte growth factor (HGF) was administered to normal nonhuman primates to study its biological activities in vivo. Rhesus monkeys were treated intravenously with HGF (0.6 and 3 mg/kg) twice a day for 14 days. Before and during the treatment, the counts of red blood cells (RBC), platelets and white blood cells (WBC) were analyzed and serum levels of total protein, albumin and C-reactive protein (CRP) were measured. Body weight and temperature were also monitored during the experiment. Platelet counts began increasing on day 7. The maximum platelet increment for each monkey ranged from 18 to 84% of pre-administration levels. The differences were significant between the maximum and pre-administration platelet levels for each HGF treated monkey by paired Z-test (P<0.05). No changes were observed in WBC counts, however there was a small decrease in RBC counts. Serum biochemistry showed that HGF increased total protein levels but did not affect levels of CRP, one of the acute phase proteins. There were no changes in body weight or body temperature of the HGF treated-monkeys during the observation period. These results indicate that HGF is able to increase platelet counts in nonhuman primates without significant side effects.Hepatocyte Growth Factor (HGF) was originally identified as a potent growth factor for cultured primaiy hepatocytes (17). HGF also enhances proliferation of many other epithelial cells such as keratinocytes, melanocytes, lung alveolar cells and vascular endothelial cells (11, 12, 20, 18). In addition, HGF has been known to show tumor cytotoxic, scattering and morphogenic activities and has been recognized as a pleiotropic factor in organ regeneration (13). These biological actions are mediated through the specific c-Met/HGF receptor (2).The effect of HGF on hematopoietic cells has been studied in vino. HGF has a synergistic effect of colony formation of hematopoietic progenitor cells in vm/'0 with interleukin-3 (IL-3) and

Growth hormone (GH) replacement therapy has been proved to show beneficial effects on abnormalities of lipid metabolism in adult growth hormone deficiency (GHD) patients. To support this clinical evidence, we studied the effects of recombinant human growth hormone (rhGH) in combination with L-thyroxine (T4) and corticosterone (CS) on lipid metabolism in hypophysectomized (HPX) mature rats. Hypophysectomy resulted in marked increases of body fat and serum low density lipoprotein (LDL)-cholesterol similarly to the findings in adult GHD patients. At para-physiological doses, replacement therapy with rhGH, T4 and CS in HPX rats restored the increased body fat and LDL-cholesterol levels to normal. But replacement therapy with T4 only, or both of T4 and CS did not show clear effects. These results support that rhGH has an important role in maintaining lipid metabolism, providing with a rationale for the effectiveness of rhGH replacement therapy on normalizing impaired lipid metabolism in adult GHD patients.Growth hormone (GH) has been used for short stature in GHD children since GH treatment was proved to be effective in stimulating growth in GI-I deficiency (GHD) children (17). Since GHD was thought to cause only growth failure that was improved by GH, GH had neither been applied to GHD children, their height of which reached adult levels, nor applied to adult-onset GHD patients. However, it has been showed by various research groups that many symptoms such as abnormalities in body composition and lipid metabolic derangement are associated with GHD in adults (4). Furthermore, it was reported that untreated adult GHD patients had a higher mortality which might be caused by cardiovascular disease than the healthy population (18). Recently GH replacement therapy in GHD adults has improved high body fat mass and high levels of low density lipoprotein (LDL)-cholesterol (2, Correspondence to: H. Seki at the above address. Tel: +81-6~6-466-5299 Fax: +81-6-6466-5491 l2), which are regarded as risk factors of cardiovascular disease (1, 10). Most ofthe abnormalities found in GHD children and adults can be improved by GH replacement, suggesting that GH has an important role through the human life.In this study, in order to obtain supporting data that confirm the efficacy of GH replacement therapy in adult GHD patients, we investigated effects of recombinant human growth hormone (rhGH) on lipid metabolism in hypophysectomized (HPX) mature rats. Some adult GHD patients lack in pituitary hormones other than GH and the replacement with these hormones may affect on lipid metabolism (5). Therefore, HPX mature rats need to be replaced with Lthyroxine (T4) and corticosterone (CS) as well as GH. We first determined their optimum physiological doses for replacement in HPX mature rats and investigated effects of rhGH replacement on lipid metabolism in combination with T4 and CS.

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