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1.
Tissue Cell ; 82: 102121, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37285749

ABSTRACT

Complications caused by Primary ovarian insufficiency (POI), including infertility, osteoporosis, cardiovascular diseases and depression, severely affect the life quality of female patients. Although hormone replacement therapy (HRT) can alleviate some long-term complications, there is still no standard treatment for the restoration of ovarian reserve function. Currently, human umbilical cord mesenchymal stem cells (HUCMSC) transplantation showed considerable treatment effect for POI in both rat model and clinic. To improve the effectiveness of naïve HUCMSC (HUCMSC-Null) treatments on POI, an exogenous gene hepatocyte growth factor (HGF) which promotes follicular angiogenesis in POI ovaries was used to modify HUCMSC. Subsequently, HGF-overexpressed HUCMSC (HUCMSC-HGF) was transplanted into the ovaries of chemotherapy-induced POI Sprague-Dawley (SD) rats to observe the effectiveness on POI improvement and its related mechanisms. Our results showed that when compared with POI and HUCMSC-Null treatment group, HUCMSC-HGF significantly improved ovarian reserve function in POI group, which might be attributed to the decrease of ovarian tissue fibrosis and granulosa cells (GCs) apoptosis, and the increase of ovarian angiogenesis mediated by HGF over-expression. The findings suggest that HGF-modified HUCMSC may present a more superior capacity than HUCMSC alone for the rescue of ovarian reserve function in POI.


Subject(s)
Antineoplastic Agents , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Ovarian Reserve , Primary Ovarian Insufficiency , Rats , Humans , Female , Animals , Primary Ovarian Insufficiency/metabolism , Rats, Sprague-Dawley , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/metabolism , Mesenchymal Stem Cell Transplantation/methods , Apoptosis/genetics , Mesenchymal Stem Cells/metabolism , Umbilical Cord/metabolism
2.
Int Wound J ; 20(9): 3531-3539, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37230802

ABSTRACT

To evaluate the status of a 7-month phase 3 study conducted to test the effect of intramuscular injections of VM202 (ENGENSIS), a plasmid DNA encoding human hepatocyte growth factor, into the calf muscles of chronic nonhealing diabetic foot ulcers with concomitant peripheral artery disease. The phase 3 study, originally aimed to recruit 300 subjects, was discontinued because of slow patient recruitment. An unprespecified interim analysis was performed for the 44 subjects enrolled to assess the status and determine the future direction. Statistical analyses were carried out for the Intent-to-Treat (ITT) population and separately for subjects with neuroischemic ulcers, using a t-test and Fisher's exact test. A logistic regression analysis was also conducted. VM202 was safe and potentially should have benefits. In the ITT population (N = 44), there was a positive trend toward closure in the VM202 group from 3 to 6 months but with no statistical significance. Levels of ulcer volume or area were found to be highly skewed between the placebo and VM202 groups. Forty subjects, excluding four outliers in both arms, showed significant wound-closing effects at month 6 (P = .0457). In 23 patients with neuroischemic ulcers, the percentage of subjects reaching complete ulcer closure was significantly higher in the VM202 group at months 3, 4, and 5 (P = .0391, .0391, and .0361). When two outliers were excluded, a significant difference was evident in months 3, 4, 5, and 6 (P = .03 for all points). A potentially clinically meaningful 0.15 increase in Ankle-Brachial Index was observed in the VM202 group at day 210 in the ITT population (P = .0776). Intramuscular injections of VM202 plasmid DNA to calf muscle may have promise in the treatment of chronic neuroischemic diabetic foot ulcers (DFUs). Given the safety profile and potential healing effects, continuing a larger DFU study is warranted with modifications of the current protocol and expansion of enrolling sites.


Subject(s)
Diabetes Mellitus , Diabetic Foot , Humans , Diabetic Foot/therapy , Diabetic Foot/etiology , DNA , Genetic Therapy/adverse effects , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/adverse effects , Plasmids/genetics , Plasmids/therapeutic use , Protein Isoforms/genetics , Clinical Trials, Phase III as Topic , Randomized Controlled Trials as Topic
3.
Am J Respir Cell Mol Biol ; 69(1): 87-98, 2023 07.
Article in English | MEDLINE | ID: mdl-37094101

ABSTRACT

Pulmonary hypertension (PH) is a disease characterized by advanced pulmonary vasculature remodeling that is thought to be curable only through lung transplantation. The application of angiogenic hepatocyte growth factor (HGF) is reported to be protective in PH through its anti-vascular remodeling effect, but excessive HGF-mediated immature neovascularization is not conducive to the restoration of pulmonary perfusion because of apparent vascular leakage. As a canonical antiangiogenic molecule, pigment epithelium-derived factor (PEDF) inhibits angiogenesis and reduces vascular permeability in a variety of diseases. However, the effect of PEDF on HGF-based PH treatment remains to be determined. In this study, monocrotaline-induced PH rats and endothelial cells isolated from rat and human PH lung tissues were used. We assessed PH progression, right cardiac function, and pulmonary perfusion in HGF- and/or PEDF-treated rats with PH. Additionally, the receptor and mechanism responsible for the role of PEDF in HGF-based PH therapy were investigated. In this study, we found that HGF and PEDF jointly prevent PH development and improve right cardiac function in rats with PH. Moreover, PEDF delivery increases the pulmonary perfusion in PH lungs and inhibits immature angiogenesis and vascular endothelial (VE)-cadherin junction disintegration induced by HGF without affecting the therapeutic inhibition of pulmonary vascular remodeling by HGF. Mechanistically, PEDF targets VE growth factor receptor 2 and suppresses its phosphorylation at Y951 and Y1175 but not Y1214. Finally, VE growth factor receptor 2/VE protein tyrosine phosphatase/VE-cadherin complex formation and Akt and Erk1/2 inactivation were observed in rat and human PH lung endothelial cells. Collectively, our data indicate that PEDF additively enhances the efficacy of HGF against PH, which may provide new insights into treatment strategies for clinical PH.


Subject(s)
Hypertension, Pulmonary , Serpins , Rats , Humans , Animals , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/metabolism , Hypertension, Pulmonary/metabolism , Endothelial Cells/metabolism , Eye Proteins/pharmacology , Eye Proteins/metabolism , Serpins/pharmacology , Serpins/metabolism
4.
Int J Mol Sci ; 20(5)2019 Feb 28.
Article in English | MEDLINE | ID: mdl-30823442

ABSTRACT

Hepatocyte growth factor (HGF) was first identified as a potent mitogen for mature hepatocytes, and has also gained attention as a strong neurotrophic factor in the central nervous system. We found that during the acute phase of spinal cord injury (SCI) in rats, c-Met, the specific receptor for HGF, increases sharply, while the endogenous HGF up-regulation is relatively weak. Introducing exogenous HGF into the spinal cord by injecting an HGF-expressing viral vector significantly increased the neuron and oligodendrocyte survival, angiogenesis, and axonal regeneration, to reduce the area of damage and to promote functional recovery in rats after SCI. Other recent studies in rodents have shown that exogenously administered HGF during the acute phase of SCI reduces astrocyte activation to decrease glial scar formation, and exerts anti-inflammatory effects to reduce leukocyte infiltration. We also reported that the intrathecal infusion of recombinant human HGF (intrathecal rhHGF) improves neurological hand function after cervical contusive SCI in the common marmoset, a non-human primate. Based on these collective results, we conducted a phase I/II clinical trial of intrathecal rhHGF for patients with acute cervical SCI who showed a modified Frankel grade of A/B1/B2 72 h after injury onset, from June 2014 to May 2018.


Subject(s)
Hepatocyte Growth Factor/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Clinical Trials, Phase II as Topic , Hepatocyte Growth Factor/administration & dosage , Hepatocyte Growth Factor/adverse effects , Humans
5.
J Clin Pharmacol ; 59(5): 677-687, 2019 05.
Article in English | MEDLINE | ID: mdl-30536581

ABSTRACT

Hepatocyte growth factor is an endogenous pleiotropic factor shown to act as a potent neuroprotectant against disease progression in animal models of amyotrophic lateral sclerosis, which is a devastating, adult-onset motor neuron disease. To evaluate the safety, tolerability, and pharmacokinetics of recombinant 5-residue-deleted human hepatocyte growth factor (KP-100) injected intrathecally through an implantable catheter connected to a subcutaneous port, we conducted a first-in-human phase I trial of intrathecal KP-100 in 15 Japanese patients with amyotrophic lateral sclerosis. The regimen was a single injection of 3 escalating doses (0.2, 0.6, and 2.0 mg/body) in 9 subjects followed by 2 doses (0.6 and 2.0 mg/body) repeated 5 times at 1-week intervals in 6 subjects (3 subjects/group). With single-dose administration, the mean half-life of KP-100 in the cerebrospinal fluid was 1.2 to 1.4 days, with its maximum concentration increasing in a dose-dependent manner. With multiple-dose administration, the trough KP-100 concentrations in the cerebrospinal fluid generally remained constant for any dose, despite multiple dosing. There were no deaths, serious adverse events, or device malfunctions leading to discontinuation. In all subjects, plasma KP-100 concentrations were <1 ng/mL, or below the lower limit of detection at all time points of measurement. Anti-KP-100 antibody was not detected in the cerebrospinal fluid or plasma specimens from any of the subjects throughout the KP-100 dosing period. These results suggest that KP-100, as well as the device used to administer it, is safe and tolerable. A phase II trial is warranted in patients with various central nervous system diseases such as amyotrophic lateral sclerosis.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Hepatocyte Growth Factor/administration & dosage , Hepatocyte Growth Factor/pharmacokinetics , Adult , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Disease Progression , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/cerebrospinal fluid , Humans , Injections, Spinal , Male , Middle Aged , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/cerebrospinal fluid , Recombinant Proteins/pharmacokinetics
6.
Cochrane Database Syst Rev ; 6: CD011741, 2017 06 08.
Article in English | MEDLINE | ID: mdl-28594443

ABSTRACT

BACKGROUND: Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD. OBJECTIVES: To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies. SELECTION CRITERIA: We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta-analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome. MAIN RESULTS: We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF). AUTHORS' CONCLUSIONS: The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty.


Subject(s)
Fibroblast Growth Factors/therapeutic use , Hepatocyte Growth Factor/therapeutic use , Intermittent Claudication/drug therapy , Peripheral Arterial Disease/drug therapy , Vascular Endothelial Growth Factor A/therapeutic use , Amputation, Surgical/statistics & numerical data , Fibroblast Growth Factors/adverse effects , Hepatocyte Growth Factor/adverse effects , Humans , Intermittent Claudication/mortality , Leg/blood supply , Leg/surgery , Leg Ulcer/drug therapy , Peripheral Arterial Disease/mortality , Randomized Controlled Trials as Topic , Vascular Endothelial Growth Factor A/adverse effects
7.
Article in English | MEDLINE | ID: mdl-28166654

ABSTRACT

OBJECTIVE: To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). METHODS: Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. RESULTS: Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. CONCLUSIONS: Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Genetic Therapy/adverse effects , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/therapeutic use , Adult , Aged , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/physiopathology , Female , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/pharmacokinetics , Humans , Injections, Intramuscular , Male , Middle Aged , Muscle Strength , Muscle, Skeletal/pathology , Plasmids , Treatment Outcome , Vital Capacity , Young Adult
8.
Gene Ther ; 23(3): 306-12, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26649448

ABSTRACT

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.


Subject(s)
Extremities/blood supply , Extremities/injuries , Genetic Vectors/adverse effects , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/genetics , Aged , Female , Humans , Male , Middle Aged , Plasmids/adverse effects , Protein Isoforms/adverse effects , Protein Isoforms/genetics
9.
Laryngoscope ; 124(9): 2131-5, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24668496

ABSTRACT

OBJECTIVES/HYPOTHESIS: Previous animal studies demonstrated that hepatocyte growth factor (HGF) has the potential to regenerate scarred vocal folds. In addition, HGF is now produced under a good manufacturing practice (GMP) procedure. Therefore, human clinical trials of HGF are warranted in patients with vocal fold scarring. In the current study, we investigated the pharmacokinetics and the local tissue responses of HGF administered to rat vocal folds. STUDY DESIGN: Prospective animal experiment. METHODS: Five µg of recombinant human HGF was administered to the vocal folds of Sprague-Dawley rats (n = 60) using a microsyringe. The concentration of HGF in larynges and blood was investigated by enzyme-linked immunosorbent assay. To evaluate the local tissue responses caused by HGF administration, endoscopic and histological examinations were performed. RESULTS: HGF concentration in the larynges was 50.1 µg/g tissue 5 minutes after administration. The concentration decreased rapidly to 1.71 µg/g tissue at 12 hours after administration and to 0.29 ng/g tissue at 24 hours after administration. Seven days after administration, HGF concentration was minimal in one-half of the cases and was not detected in the other cases. Transmission of HGF to blood was detected in two of six cases at 5 minutes after administration, but was no longer detected 12 hours later. Endoscopic and histological examinations revealed no edema or erythema of the vocal folds in any of the cases. CONCLUSIONS: The current results contribute to the safety and pharmacokinetic management of future clinical trials using HGF administered to vocal folds.


Subject(s)
Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/pharmacokinetics , Vocal Cords/drug effects , Animals , Male , Rats , Rats, Sprague-Dawley , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics
10.
J Transl Med ; 9: 55, 2011 May 08.
Article in English | MEDLINE | ID: mdl-21548996

ABSTRACT

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.


Subject(s)
Hepatitis/drug therapy , Hepatocyte Growth Factor/pharmacokinetics , Hepatocyte Growth Factor/therapeutic use , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Adult , Aged , Animals , Blood Pressure , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Hepatic Encephalopathy/drug therapy , Hepatitis/physiopathology , Hepatocyte Growth Factor/administration & dosage , Hepatocyte Growth Factor/adverse effects , Humans , Injections, Intravenous , Kidney/pathology , Male , Middle Aged , Rats , Rats, Wistar , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Survival Analysis , Swine , Swine, Miniature
11.
Clin Exp Pharmacol Physiol ; 38(3): 192-201, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21251050

ABSTRACT

1. Hepatocyte growth factor (HGF) has the therapeutic potential to improve renal fibrosis and proteinuria in rodents with chronic kidney disease. In contrast, long-term administration of human HGF to normal rats reportedly elicits proteinuria. Thus, the role of HGF during proteinuria remains contentious. The aim of the present study was to demonstrate that human HGF is antigenic to rodents and that immune complex formation causes proteinuria. 2. We administered either human or rat HGF to normal rats for 28 days. Albuminuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The renal phenotypes of the two HGF treatments were examined using histological techniques. 3. Administration of human HGF (1 mg/kg per day, i.v.) to rats led to severe albuminuria and glomerular hypertrophy in association with increased blood levels of anti-human HGF IgG and IgG deposition in mesangial areas. Furthermore, an immune complex between human HGF and anti-human HGF IgG stimulated the production of proteinuric cytokines (including transforming growth factor-ß) in rat cultured mesangial cells. In contrast, treatment of healthy rats with rat HGF for 4 weeks caused neither mesangial IgG deposition nor elevated anti-HGF IgG in the blood. Overall, rat HGF did not provoke albuminuria. 4. We conclude that human HGF produces pseudotoxic effects in normal rat kidneys via an immune complex-mediated pathway, whereas syngenic HGF is safe due to less deposition of glomerular IgG. Our results affirm the safety of the repeated use of syngenic HGF for the treatment of chronic organ diseases, such as renal fibrosis and liver cirrhosis.


Subject(s)
Albuminuria/chemically induced , Albuminuria/drug therapy , Hepatocyte Growth Factor/adverse effects , Kidney Diseases/chemically induced , Kidney Diseases/drug therapy , Albuminuria/metabolism , Animals , Antigen-Antibody Complex/metabolism , Glomerular Mesangium/drug effects , Glomerular Mesangium/metabolism , Hepatocyte Growth Factor/pharmacology , Humans , Hypertrophy/chemically induced , Hypertrophy/metabolism , Immunoglobulin G/metabolism , Kidney Diseases/metabolism , Rats , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacology
12.
Int Heart J ; 50(3): 291-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19506333

ABSTRACT

Hepatocyte growth-promoting factor (pHGF) has the greatest potential as a therapeutic agent for vascular growth factor. The aim of this study was to investigate the effect of pHGF on myocardial ischemia and exercise capacity in patients with severe coronary artery disease (CAD). Forty-nine patients were enrolled for a two week treatment period. Treadmill graded exercise tests with gas analysis were conducted before and after therapy. Serum levels of HGF were significantly elevated after therapy. The degrees of exercise-induced ST segment depression were decreased more significantly in the pHGF group. Similar differences were also found in the maximum heart rate and the maximum heart rate when the ST segment was depressed 1 mm while undergoing the treadmill graded exercise test. Both were increased more significantly in the pHGF group. Total exercise time, systolic blood pressure in the peak of exercise, the length of time that ST segment depression of 1 mm is needed, and total work all were increased in both groups after intervention. Furthermore, total exercise time and total work were increased more significantly in the pHGF group. The levels of HGF increased significantly after pHGF treatment. pHGF could favorably improve exercise-induced myocardial ischemia and enhance exercise capacity in patients with severe CAD.


Subject(s)
Coronary Artery Disease/drug therapy , Electrocardiography/drug effects , Exercise Test/drug effects , Hepatocyte Growth Factor/therapeutic use , Myocardial Ischemia/drug therapy , Aged , Aged, 80 and over , Blood Pressure/drug effects , Cardiovascular Agents/therapeutic use , Coronary Artery Disease/blood , Double-Blind Method , Drug Therapy, Combination , Echocardiography, Doppler, Color , Female , Heart Rate/drug effects , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/blood , Humans , Infusions, Intravenous , Male , Middle Aged , Myocardial Ischemia/blood , Prospective Studies , Stroke Volume/drug effects
14.
Circulation ; 118(1): 58-65, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18559703

ABSTRACT

BACKGROUND: The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia (HGF-STAT trial) determined the effect of hepatocyte growth factor (HGF) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension (TcPo(2)) in patients with critical limb ischemia (CLI). METHODS AND RESULTS: Randomized patients with rest pain or ischemic ulcers and TcPo(2) <40 mm Hg and/or toe pressure <50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows: 0.4 mg at days 0, 14, and 28 (low dose); 4.0 mg at days 0 and 28 (middle dose); or 4.0 mg at days 0, 14, and 28 (high dose). Patients were evaluated for safety, changes in TcPo(2) and ankle and toe pressure, amputation, and wound healing. Ninety-three of 104 treated patients were evaluated for safety (mean age 70 years, 63% male, 53% diabetic, 64% with tissue loss, mean ankle-brachial index 0.41, and mean toe pressure 26 mm Hg). Adverse events occurred in 86% of the patients, most of which were related to CLI or comorbid conditions and were not different between groups. TcPo(2) (mean+/-SE) increased at 6 months in the high-dose group (24.0+/-4.2 mm Hg, 95% CI 15.5 to 32.4 mm Hg) compared with the placebo (9.4+/-4.2 mm Hg, 95% CI 0.9 to 17.8), low-dose (11.1+/-3.7 mm Hg, CI 3.7 to 18.7 mm Hg), and middle-dose (7.3+/-4.8 mm Hg, CI -2.2 to 17.0 mm Hg) groups (ANCOVA P=0.0015). There was no difference between groups in secondary end points, including ankle-brachial index, toe-brachial index, pain relief, wound healing, or major amputation. CONCLUSIONS: Intramuscular injection of HGF plasmid was safe and well tolerated. Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted.


Subject(s)
Extracorporeal Circulation/methods , Hepatocyte Growth Factor/administration & dosage , Ischemia/therapy , Leg Ulcer/therapy , Leg/blood supply , Plasmids/administration & dosage , Adult , Aged , Blood Gas Monitoring, Transcutaneous/methods , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions , Female , Genetic Therapy/methods , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/genetics , Humans , Injections, Intramuscular , Male , Microcirculation/drug effects , Middle Aged , Neovascularization, Pathologic/drug therapy , Placebos , Plasmids/adverse effects , Predictive Value of Tests
15.
Int J Mol Med ; 17(3): 503-9, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16465399

ABSTRACT

Hepatocyte growth factor (HGF) is a promising agent for the treatment of liver cirrhosis because of its mitogenic and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on cirrhosis development; its pharmacokinetics and nephrotoxicity in rats with liver cirrhosis induced by 4-week treatment with dimethylnitrosamine (DMN). rh-HGF (0.3 mg/kg) was intravenously administered to rats once a day for 4 weeks in parallel with DMN treatment or twice a day for the last 2 weeks of DMN treatment. Repeated doses of rh-HGF increased the liver weight and serum albumin, and reduced serum ALT. The development of hepatic fibrosis was inhibited more efficiently by extended low-dose treatment with rh-HGF. In cirrhotic rats, serum levels of rh-HGF increased and clearance was decreased, leading to an increase in the area under the plasma-concentration time curve and a decrease in the steady-state volume of distribution. Repeated doses of rh-HGF led to increased urinary albumin excretion, but no rh-HGF-treated animals developed increased serum creatinine levels. Urinary albumin excretion returned to baseline after the cessation of rh-HGF. These results suggest that extended treatment with rh-HGF is required for the attenuation of cirrhosis, and repeated doses of rh-HGF cause adverse effects in extra-hepatic organs. These issues must be resolved before the widespread application of rh-HGF in the treatment of liver cirrhosis.


Subject(s)
Albuminuria/chemically induced , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/therapeutic use , Liver Cirrhosis, Experimental/drug therapy , Recombinant Proteins/therapeutic use , Alanine Transaminase/blood , Animals , Body Weight/drug effects , Dimethylnitrosamine , Hepatectomy , Hepatocyte Growth Factor/administration & dosage , Hepatocyte Growth Factor/pharmacokinetics , Humans , Injections, Intravenous , Liver/pathology , Liver Regeneration/drug effects , Male , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Serum Albumin
16.
Hepatobiliary Pancreat Dis Int ; 3(3): 381-5, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15313673

ABSTRACT

BACKGROUND: The mortality rate of heavy type hepatitis is high. No special treatment is available except general treatment. This multicenter clinical study was designed to observe the safety and efficacy of promoting hepatic growth factor (PHGF) in the treatment of heavy type hepatitis and severe chronic hepatitis. METHODS: 347 patients with heavy type hepatitis and 324 with severe chronic hepatitis were subjected to administration of 120 microg of PHGF per day for 4 weeks on the basis of general treatment. Those who were being effectively treated would last additional 2 to 4 weeks. Blood routine, urine routine, blood urea nitrogen (BUN), blood creatinine (Cr), blood ammonia, alpha fetoprotein (AFP), electrolyte, alanine transaminase (ALT), aspartate transaminase (AST), serum total bilirubin (TBIL), serum direct bilirubin (DBIL), prothrombin time activity (PTA), total protein (TP) and albumin (ALB) were detected in the patients before treatment, 2 weeks after treatment, and at the end of the treatment. Any side-effect would be recorded. RESULTS: In the patients with severe chronic hepatitis, the total effective rate of the treatment was 88.9%. The levels of ALT, AST and TBIL decreased significantly (P<0.001), whereas those of PTA and ALB increased significantly (P<0.001), and the level of AFP increased slightly. In patients with heavy type hepatitis, the total effective rate of this treatment was 78.4%, and patients at different stage showed different results. The total effective rates of patients with early, medium and terminal stage heavy type hepatitis were 89.9%, 84.8% and 27.5%, respectively. No severe side-effect was shown. CONCLUSION: PHGF is effective and safe in the treatment of patients with heavy type hepatitis and severe chronic hepatitis. But it should be administered early in patients with heavy type hepatitis so as to get better curative effects.


Subject(s)
Hepatitis A/drug therapy , Hepatitis B, Chronic/drug therapy , Hepatocyte Growth Factor/administration & dosage , Acute Disease , Adolescent , Adult , Aged , Female , Hepatocyte Growth Factor/adverse effects , Humans , Male , Middle Aged , Severity of Illness Index , Treatment Outcome
17.
Hypertension ; 44(2): 203-9, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15238569

ABSTRACT

Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment for patients with critical limb ischemia (CLI). Because hepatocyte growth factor (HGF) has potent angiogenic activity, we investigated the safety and efficiency of HGF plasmid DNA in patients with CLI as a prospective open-labeled clinical trial. Intramuscular injection of naked HGF plasmid DNA was performed in ischemic limbs of 6 CLI patients with arteriosclerosis obliterans (n=3) or Buerger disease (n=3) graded as Fontaine III or IV. The primary end points were safety and improvement of ischemic symptoms at 12 weeks after transfection. Severe complications and adverse effects caused by gene transfer were not detected in any patients. Of particular importance, no apparent edema was observed in any patient throughout the trial. In addition, serum HGF concentration was not changed throughout the therapy period in all patients. In contrast, a reduction of pain scale of more than 1 cm in visual analog pain scale was observed in 5 of 6 patients. Increase in ankle pressure index more than 0.1 was observed in 5 of 5 patients. The long diameter of 8 of 11 ischemic ulcers in 4 patients was reduced >25%. Intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs. Although the present data are conducted to demonstrate the safety as phase I/early phase IIa, the initial clinical outcome with HGF gene transfer seems to indicate usefulness as sole therapy for CLI.


Subject(s)
Genetic Therapy/methods , Hepatocyte Growth Factor/administration & dosage , Peripheral Vascular Diseases/therapy , Adult , Aged , Female , Genetic Therapy/adverse effects , Hepatocyte Growth Factor/adverse effects , Hepatocyte Growth Factor/blood , Humans , Injections, Intramuscular , Leg/blood supply , Leg Ulcer/diagnosis , Leg Ulcer/therapy , Magnetic Resonance Angiography , Male , Middle Aged , Pain Measurement , Peripheral Vascular Diseases/diagnosis , Prospective Studies , Regional Blood Flow , Thromboangiitis Obliterans/classification , Thromboangiitis Obliterans/therapy , Treatment Outcome
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