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Objective: To explore the clinical effect of L-ornithine L-aspartate (LOLA) granules in treating chronic liver disease in patients with high-level serum gamma-glutamyltransferase (G-GT) using a 24-week treatment course., Methods: Two-hundred patients with chronic liver disease and above normal G-GT were given a 12-week course of LOLA granules (9 g/d) and then classified into the following three groups according to the change in serum Gamma-GT:group I:patients with Gamma-GT level returned to normal;group II:patients with serum Gamma-GT level that was reduced during the treatment; group III:patients with serum Gamma-GT level that did not decrease or that increased to a higher level than at start of treatment.After the 12-week treatment course, the patients in group I were divided into three subgroups for receipt of a control drug (compound glycyrrhizin, 50mg/d) or an additional 12-week course of Gamma-GT at a reduced dose (LOLA granules 3 g/d) or at the original dose; groups II and III were maintained on the initial dose for an additional 12 weeks.The groups were reassessed at the end of the second 12-week course (at the end of week 24 of the study's observation period).Count data were compared using the x2 test and measurement data were compared using the t-test., Results: In group I, the serum Gamma-GT level was 90.9% at the end of the first 12-week course and dropped to a mean level of 52.2% for both of the subgroups that received the reduced and original dose after the additional 12 weeks of LOLA granules treatment; the difference from week 12 to week 24 was significant (x2=8.213, P less than 0.05).The 24-week change in serum Gamma-GT levels for the group I reduced and original dose subgroups vs.the control subgroup were also significantly different from those seen in groups II and III (P less than 0.05).The percentage of patients in group I who achieved normal level serum Gamma-GT after 24 weeks of treatment (78.6%) was significantly higher than that for the control group (vs.55.0%, x2=11.452, P less than 0.05).When the patients in group 1 who had received the 12 additional weeks of LOLA granules treatment were measured again at two weeks after the treatments had been discontinued (end of week 26), the percentage of patients with normal serum Gamma-GT level was 92.7%, with only three cases showing obviously abnormal levels; in contrast, the group I patients in the control group of the second 12-week study period had on 66.7% of patients with normal-level serum Gamma-GT.The difference in change between the treated groups (both reduced and original dose) and the control group was significant (x2=14.964, P less than 0.05)., Conclusion: Patients whose serumGamma-GT levels returned to normal after receipt of LOLA granules for 12 weeks benefitted from an additional 12 weeks of consolidation treatment, and those given the treatment at the original dose benefitted most.Compared with the compound glycyrrhizin, LOLA granules provided a better maintenance of resolved Gamma-GT level.Therefore, the effect of LOLA appears to be reliable and stable as well as safe for clinical use.

Objective: To investigate the therapeutic efficacy and safety of aspartate-ornithine granules in patients with nonalcoholic steatohepatitis (NASH)., Methods: Seventy-two patients with NASH were included in this multiple-dose parallel controlled clinical trial and received a 12-week course of aspartate-ornithine granule treatment at either high-dose (6 g bid po; n = 38) or low-dose (3 g bid po; n = 34). Clinical efficacy was assessed by monitoring data from urinalysis, serologic tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and triglyceride (TG)), and abdominal computed tomography (CT) scan. Safety was assessed by occurrence of adverse events (fatigue, anorexia, abdominal distension, nausea, and vomiting). Statistical analyses were conducted to determine the significance of differences between parameters before (baseline) and after treatment., Results: After 12 weeks of treatment, the liver and spleen CT ratios in both the high-dose group (0.89 +/- 0.19) and the low-dose group (0.80 +/- 0.15) were significantly higher than at baseline (S = 329, P less than 0.0001 and S = 246, P less than 0.0001); the overall improvement was more robust in the high-dose group (52.63%) than in the low-dose group (38.23%) (Z = -2.1042, P less than 0.05). After 6 and 12 weeks of treatment, the serum ALT levels in both the high-dose group and the low-dose group were significantly lower than at baseline (6 weeks: S = 324.5, P less than 0.0001 and S = 223, P less than 0.0001; 12 weeks: S = 370.5, P less than 0.0001 and S = 297.5, P less than 0.0001); the overall improvement was more robust in the high-dose group (79.0%) than in the low-dose group (53.0%) (Z = -2.0533, P less than 0.05). Similar trends were seen for the serum levels of AST and GGT after 6 and 12 weeks of treatment (all P less than 0.01) and serum levels of TG after 12 weeks of treatment. The rate of adverse reactions was low and similar between the two groups (high-dose: 4.8% and low-dose: 4.4%; all gastrointestinal)., Conclusion: Aspartate-ornithine granule therapy was an effective and safe treatment of nonalcoholic steatohepatitis, with the higher dose of 6 g bid po providing more robust clinical benefit without affecting the safety profile.

Objective: To investigate the potential effects on cognitive function, prognosis, and neuropeptide levels of patients in response to combination therapy with ornithine aspartate plus naloxone for hepatic encephalopathy., Methods: Eighty-four consecutive patients diagnosed with hepatic encephalopathy were randomly divided into two equal groups. The control group (n = 42) received traditional medical treatment, and the research group (n = 42) received the traditional medical treatment as well as the combination therapy with ornithine aspartate plus naloxone. The supplemental treatment was comprised of daily intravenous injection of 10-15 g ornithine aspartate in 250 ml of 5% glucose plus intravenous drip of 3 mg naloxone in 100 ml of 5% glucose, and was given in 7-day cycles for one or two cycles. The cognitive function of patients was assessed by Hasegawa Intelligence Scale (HDS) and Mini-Mental State Examination (MMSE) questionnaires. The effective rate and time duration from coma to consciousness were recorded. Changes in blood ammonia level, markers of liver function, and neuropeptide levels were measured by standard biochemical assays. Intergroup differences were assessed by the Chi-squared test., Results: The HDS and MMSE scores of the research group were significantly higher than those of the control group after therapy. The effective rate, time duration from coma to consciousness, blood ammonia, the liver function markers alanine aminotransferase, gamma-glutamyl-transpeptidase and total bilirubin, and the neuropeptides arginine vasopressin and beta-endorphin were remarkably improved after treatment in the research group, as compared with that in the control group., Conclusion: Supplementing the traditional treatment for hepatic encephalopathy with ornithine aspartate plus naloxone combination therapy provides better therapeutic outcome than traditional treatment alone.

Objective: To explore the efficiency of GM6001 for the inhibition of choroidal neovascularization., Methods: Experimental study. Twenty-four Brown Norvy (BN) rats after photocoagulation were randomly divided into 3 groups as GM6001 group, DMSO group and CONT group. GM6001 (0.2 ml of 0.1% suspension) was injected retrobulbar for GM6001 group and 0.2 ml DMSO was injected for DMSO group on days 1, 3, 6, 9, and 12 after photocoagulation. No injection was performed in the CONT group. Fundus fluorescence angiography, histopathology, immunohistochemistry and quantitative analysis of choroidal neovascularization (CNV) were performed 3 weeks after photocoagulation. One-way ANOVA was used in conjunction with SNK-t test to assess statistical significance within groups., Results: The fluorescein leakage appeared in all three groups; but fluorescein leakage of GM6001 group (74.56 ± 2.33) was less than that of DMSO group (119.57 ± 1.15)and CONT group (122.36 ± 2.38) (F = 403.23, P = 0.001; LSD-t test, all P value < 0.01), whereas fluorescein leakage of DMSO group was similar to that in the CONT group. The retinal and choroidal capillaries in the CONT group were damaged and disordered; a great deal of CNV and migration and proliferation of retinal pigment epithelium cells, fibrocytes and collagen fibers were discovered. Pathological changes in DMSO group were similar to those in the CONT group. There were a small quantity of retinal pigment epithelium cells, fibrocytes and CNV in GM6001 group. Although the immunohistochemical staining for CD105 displayed positive results in all three groups, positive staining of GM6001 group (19.85 ± 1.59) was significantly less than that of the CONT group (38.02 ± 2.57) and DMSO group (39.02 ± 3.12) (F = 55.57, P = 0.001; LSD-t test, all P value < 0.01). Positive staining of CD105 in the CONT group was similar to that of DMSO group (P > 0.05). The size of CNV in GM6001 group (15.35 ± 0.77) was significantly less than that of CONT group (28.38 ± 1.60) and DMSO group (28.74 ± 1.19) (F = 114.85, P = 0.001; LSD-t test, all P value < 0.01). There was no statistical difference for the size of CNV between CONT group and DMSO group (P > 0.05)., Conclusion: GM6001 effectively inhibits CVS induced by krypton laser photocoagulation.

Objective: To observe the effect CA-074Me on the retinal neovascularization of C57BL/6J with retinal neovascularization, and to explore the new way of treatment for retinal neovascularization., Methods: It was a experimental study. Sixty-seven-days-old C57BL/6J mice were divided into four groups randomly including normal control group, blank control group, negative control group, experiment group. Blank control group, negative control group, experiment group were exposed to 75% oxygen to established a model of retinal neovascularization. Experiment group were injected with CA-074Me (5 mg x kg(-1) x d(-1)) by periocular injection one time every eye for 5 days after mice left oxygen box. Negative control group were received the same dose of DMSO at the same time. Normal control group and blank control group did not received any medicine. The Cathepsin B activity of the tissue of mice'eye were measured. The mean optical density of Cathepsin B of retina were measured by immunohistochemistry; the number of new vascular cell nuclei extending into the internal limiting membrane in cross-sections was measured. Retinal neovascularization were tested by the vascular pattern in adenosine diphosphate-ase (ADPase) stained retina flat-mounts., Results: CA-074Me reduced the Cathepsin B Activity, the number of new vascular cell nuclei extending into the internal limiting membrane, the non-vascular area of retina, and the ratio of the nonvascular area of retina and the whole retina area., Conclusion: The specific inhibitor-CA-074Me of Cathepsin B can reduce the retinal neovascularization of C57BL/6J to some extent, may be a new treatment for retinal neovascularization in the future.

Objective: To observe the changes in serum interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) after intravenous administration of alanyl-glutamine (Gln) in patients with severe pancreatitis., Methods: Fifty patients with severe pancreatitis were randomized equally into 2 groups and received standard total parenteral nutrition (TPN) with intravenous infusion of Gln or normal saline (control) for 1 week. The plasma glutamine level was measured with high-performance liquid chromatography (HPLC) in these patients one day before and on day 7 of Gln administration, and the serum IL-8, TNF-alpha and heat shock protein 70 (Hsp70) were detected with enzyme-linked immunosorbent assay., Results: On day of Gln administration, the plasma glutamine level in patients of Gln group increased significantly (P<0.01), and serum IL-8 and TNF-alpha levels decreased significantly (P>0.05) in comparison with those of the control group. The patients receiving Gln supplementation had significantly higher serum albumin level and greater body fat content with shorter hospital stay than those in the control group (P<0.05), and the mortality rate in Gln group was also significantly lower (P<0.05)., Conclusion: Gln-enriched TPN may improve the clinical outcomes of patients with severe pancreatitis probably by decreasing serum IL-8 and TNF-alpha levels.

Objective: To evaluate the effect of early parenteral glutamine (Gln) administration on heat shock protein (HSP70) expression and clinical outcome in critical patients., Methods: Forty-four Patients requiring parenteral nutrition (PN) for more than 7 days, admitted to emergency intensive care unit (EICU) and neurosurgical intensive care units (NICU) were randomly divided into two groups, one was the control group, the other was the Gln treatment group (each n=22). Patients in both group received PN and enteral nutrition (EN). In addition, glutamine 0.4 g/kg per day was given to patients of Gln treatment group for 7 days. Serum HSP70, Gln concentrations were measured at admission and 7 days after the nutritional supplementation. Observations of clinical outcome included the length of mechanical ventilation, the length of stay in intensive care unit (ICU), the incidence of liver and kidney dysfunction before and after treatment., Results: Serum HSP70 and Gln level showed no significant changes in control group and Gln treatment group before the treatment (both P>0.05), though they were mildly increased after conventional treatment compared with the control group, but without statistically significant difference. In Gln treatment group, between serum HSP70, Gln concentrations were significantly higher than those before treatment (both P<0.01), and they showed significant difference between control group and Gln group after treatment (both P<0.01). HSP70 level was significantly positively correlated with Gln level in critical patients (r=0.650 5, P=0.001). The ratios of liver dysfunction and the length of mechanical ventilation showed significant difference between Gln group and control group (both P<0.05). The ratios of kidney dysfunction and the length of stay in ICU showed no obvious changes between two groups (both P>0.05)., Conclusion: Early parenteral glutamine administration can improve clinical outcome, decrease the ratio of organ dysfunction possibly by the mechanism of increasing serum HSP70 in critical patients.

Background & Objective: There is an argument on whether or not glutamine-supplemented parenteral nutrition is beneficial to chemotherapy in gastrointestinal neoplasm patients. The aim of this study was to prospectively evaluate the effect of parenteral nutrition with alanyl-glutamine dipeptide on gastrointestinal neoplasm patients receiving chemotherapy., Methods: This study was a prospective, randomized double-blind clinical trial. Seventy-two patients were randomly divided into study group and control group (each group had 36 patients). The side effects during chemotherapy were observed. Serum albumin, serum pre-albumin, IgG, IgA, IgM, C3, C4 level were measured before chemotherapy and on day 4 and day 8 after chemotherapy. Nitrogen balance was also calculated simultaneously., Results: (1) Less side effects during chemotherapy in study group were revealed compared to those in control group (P<0.05). (2) Serum albumin and pre-albumin levels were both decreased in the two groups on day 4 after chemotherapy, and were markedly decreased in control group on day 8 after chemotherapy (P<0.05). (3) IgG, IgM, IgA levels were all decreased compared with the test results before chemotherapy on day 4 after chemotherapy in two groups, and were significantly decreased in control group on day 8 after chemotherapy (P<0.05). C3 and C4 levels were higher in study group compared with control group on day 8 after chemotherapy (P<0.05). (4) Nitrogen balance in study group was better than that in control group (P<0.05) on day 8 after chemotherapy., Conclusions: Alanyl-glutamine dipeptide is beneficial to chemotherapy in gastrointestinal neoplasm patients. It could reduce the side effects of chemotherapy, which helps to improve the nutritional status, the immune function and the survival quality of patients during chemotherapy.

Objective: To examine the effects of parenteral supplementation of glutamine dipeptide on the outcomes of surgical patients., Methods: The relevant data 1997 to March or May 2005 were retrieved from SCI, Medline, EMBASE, Chinese Cochrane Centre databases. The bibliographies of the retrieved papers and the personal file were searched as well. All the patients in the retrieved papers received parenteral nutrition, whether alanyl-glutamine dipeptide (Ala-Gln) was added was the only difference between the intervention and control groups. Methodological quality assessment was based on the Cochrane Reviewers' Handbook and Jadad's Score Scale. Statistical software RevMan4.2 was used for meta-analysis. The data were treated by intention-to-treat method., Results: A total of 1074 relevant papers were screened. Thirteen prospective randomized controlled clinical trials (RCTs) from European & Asian studies met the inclusion criteria. Ten RCTs reported 355 cases of infectious complications showed that Ala-Gln administration significantly reduced the prevalence of infectious complications with a pooled relative risk (RR) of 0.42 (95% CI 0.24 - 0.72; P = 0.002). Eight studies with 273 cases reported the postoperative length of stay (LOS) and showed that Ala-Gln significantly reduced the postoperative LOS by 3.25 days (95% CI = -4.87 to -1.62; P = 0.00009). There was no significant effect of Ala-Gln on cost of hospitalization, though there was a trend to reduction (2 studies, pooled n = 52, P = 0.2)., Conclusion: Parenteral Ala-Gln significantly reduces the post-operative infectious morbidity and LOS among surgical patients.

Objective: To observe the therapeutic effects of L-ornithine-L-aspartate on liver cirrhosis complicated by hepatic encephalopathy., Methods: Eighty-five patient with liver cirrhosis complicated by hepatic encephalopathy were divided into therapy group (n=45) and control group (n=40). Patients in the control group were treated with routine comprehensive therapy, and those in the therapy group received additional intravenous administration with 40 ml L-ornithine-L-aspartate in 250 ml 10% glucose and saline (once daily, 7 days for a treatment course)., Results: L-ornithine-L-aspartase significantly decreased blood ammonia and improved hepatic function (P<0.05 or 0.01). The therapeutic effects of therapy group was better than that of the control group (P<0.05), and no significant side effect was observed in L-ornithine-L-aspartate treatment., Conclusion: L-ornithine-L-aspartate is effective for hepatic encephalopathy and has not obvious side effect.

Objective: To explore the influence of glutamine dipeptide on the plasma endotoxin levels in severely burned patients., Methods: Thirty burned patients with TBSA of 30 - 70% and III degree burn area more than 20% were randomly divided into control (C) and study (S) groups. Glutamine dipeptide powder in dose of 0.5 g/kg/day was given orally in bolus to those patients in S group during 1 - 12 postburn days (PBDs). The plasma levels of glutamine were determined during 1 - 12 PBDs. Simultaneously, the plasma endotoxin level was detected on 1, 3, 6 and 12 PBDs. The wound healing rate at 30 PBD and total hospital stay days were recorded., Results: The plasma glutamine levels at 1 PBD in C and S groups were obviously lower than normal level (659.5 +/- 35 micromol/L), but there was no difference between these two groups (P > 0.05). The plasma glutamine levels in C group was much lower than that in S group at 12 PBD (P < 0.05). The plasma endotoxin concentration on 1 PBD in these two groups increased evidently compared with the normal value (P < 0.05), and there was no difference between the two groups (P > 0.05). The plasma endotoxin level in S group was much lower than that in C group on 3 PBD (P < 0.05). As for the wound healing rate at 30 PBD, it was markedly higher in S group than that in C group (91% vs 85%). On the other hand, the hospital stay days in S group were evidently lower than that in C group (52 vs 67)., Conclusion: Oral intake of glutamine dipeptide in burn patients could be beneficial to the maintenance of the plasma concentration of glutamine and in decreasing plasma endotoxin level. It would also enhance the wound healing rate at 30 PBD and shorten the hospital stay days.

Objective: To eva1uate the effect of synthetic inhibitors of matrix metalloproteinases (GM 6001) on the prevention of melting of rabbit corneas after alkali burn., Methods: Severe and moderate rabbit alkali burns were made by different concentrations of NaOH. Corneas with severe or moderate alkali injuries were topically treated with 400 mg/L or 200 mg/L GM 6001 for 30 days. Vehicle was used as control. All corneas were evaluated for melting, opacity and other pathological changes., Results: After severe alkali burns, all of the 8 corneas of the control group melted in 13 +/- 5 days, and 2 corneas perforated. Only did 2 corneas melt in 19 +/- 4 days after burn and not perforate in 400 mg/L GM 6001 group. The rates of corneal melting and perforation in 400 mg/L GM 6001 group were lower than that of the control (P < 0.05), and the initial time of melting was later than that of the control (P < 0.0l). After moderate alkali burn, all of the 6 corneas of control melted in 14 +/- 6 days, and 1 cornea perforated. Only did 2 of 200 mg/L GM 6001 treated corneas melt in 19 +/- 4 days without perforation after burn. The rate of corneal melting and the degree of corneal opacity were lower in 200 mg/L GM 6001 treated than that of the control, the difference being significant (P < 0.0l). Histologic section of GM 6001 treated corneas revealed much less collagen fiber destruction and inflammatory cell infiltration than that of the control., Conclusion: GM 6001 not only can prevent and delay the corneal melting after alkali burn, but also can reduce the destruction of corneal collagen fibers and infiltration of inflammatory cells in the corneal tissue.

Objective: To determine the effect of glutamine dipeptide on gut permeability in severe burns., Methods: Twenty-four severe burn patients were randomly divided into two groups: control group and GLN group. All patients received enteral nutrition for 12 days after burn. Both groups were isocaloric and isonitrogen. GLN group patients were given nutrition solution enriched with glutamine dipeptide at a dosage at 0.5 g.kg-1.day-1 (equivalent to L-glutamine 0.3 mg.kg-1.day-1). On the day 1 and 12 after burn, the plasma amino acid was measured by a standard amino acid analyzer. On the day 1, 3, 6 and 12, the gut permeability was detected with Lactulose and Manitol assay by HPLC-PED, and then wound healing rate of burn area was determined on the day 30 and hospital stay was recorded. ANOVA was done for data analysis., Results: The plasma GLN concentrations decreased in both groups on day 1, (control group: 361.3 +/- 70.8 microns/L, GLN group: 348.6 +/- 52.5 microns/L, P = 0.624, normal value: 659.5 +/- 35.0 microns/L), and the GLN group showed high plasma GLN concentration on day 12 (566.4 +/- 128.3 microns/L), with significant difference between control group (417.6 +/- 74.8 microns/L, P = 0.002). On day 1, L/M ratio value was the highest in both groups. On day 3, L/M ratio in the GLN group became lower than that of control group, and returned to normal on day 6 and maintained to day 12. There were significant differences of wound healing rate between the two groups and the length of hospital stay on day 30 (CONTROL GROUP: (81 +/- 7)%, GLN group: (89 +/- 7)%, 0.018) (CONTROL GROUP: 68 +/- 27 days, GLN group: 49 +/- 13 days, P = 0.049)., Conclusion: The glutamine-dipeptide enriched enteral nutrition can improve the plasma GLN level after severe burn, decrease the gut permeability from early stage, ameliorate wound healing rate on day 30, and reduce hospital stay.

The effect of TRH analogue, YM14673: N alpha-[[(S)-4-oxo-2-azetidinyl]-carbonyl)-L-histidyl-L-prolinamide] dihydrate, on traumatic brain edema were studied in male Wistar rats. The cerebral contusion was produced by Feeney's dropping weight method. Animals were randomly divided into 4 groups: normal group and YM14673 (0.1 mg.kg-1, i.p.), YM14673 (1.0 mg.kg-1, i.p.) and a control group (given equal volume of physiological saline, i.p.) after cerebral contusion. Contents of water in brain tissue were measured. These results suggest that treatments with YM14673 significantly reduced brain edema than control group (P < 0.05).

Since alpha-acetylaminoacetophenones are known to have antihepatitis activity, a series of aminoacyl and dipeptidyl derivatives were synthesized by replacement of the acetyl group with amino acid and dipeptide acyl groups or by changing the substituents on the benzene ring. Thirty-four compounds were submitted to pharmacological screen for antihepatitis and/or antipeptic ulcer activity. The results showed that the presence of methylene-dioxy group on the benzene ring showed favorable influence on the SGPT-lowering activity of the compounds.