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efficacy and safety of Sulfad tablets in the management of NASH

efficacy and safety of Sulfad tablets in the management of NASH
patients: A randomized ,prospective, open label, multi-center,
controlled, phase III clinical trial.

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Sulfad trial germany 2012 Sulfad trial germany 2012 Document Transcript

  • Published online 10 Nov 2012 [DOI:10.1026/gastro.1242217] Efficacy and safety of Sulfad tablets in the management of NASH patients: A randomized ,prospective, open label, multi-center, controlled, phase III clinical trial. Prof. Dr. S. Bzrah, M.D , Dr.M. Ishem,MD, PhD,v Dr. W. Zalawt MD,PhD, Dr.J Dien R.MD phD Germany 2012 ABSTRACT Non-alcoholic fatty liver disease (NAFLD), is a disease of our generation, this disease and its more complicated form NASH currently impacts virtually all fields of clinical medicine and will continue to do so with increasing prevalence and adversity to patients. The misconception that NAFLD is benign is fading due to its silence and serious complications. Objective To evaluate the efficacy and safety of Sulfad 1 gm tab (4 standardized phyto- pharmaceutical combination), in the management and improvement of NASH patients. Design A randomized, prospective, open label, multi-center, controlled, phase III clinical trial. Subjects Patients (total of 100) with confirmed U/S with fatty liver and elevated liver biomarkers Results At the end of 1st month there was a significant (p<0.0141) improvement in AST, very significant (p<0.0021) improvement in LDL, and very significant improvement (p<0.0047) in TGs No quite significant improvement in ALP or HDL levels was observed and there a slight improvement in other parameters in 65 % of patients. At the end of 2nd month there was a very significant improvement in liver biomarkers including ALT, AST, and GGT (p<0.0034 , p<0.01 ,and p<0.0025 respectively. Also extremely significant improvement in lipid profile including T.CH , LDL , and TGs (p<0.0001 , p< 0.0001 ,and p<0.0001 respectively compared with the initial results. No Significant improvement in ALP or HDL levels was observed. At the end of 3rd month there was extremely significant improvement in liver biomarkers including ALT ,AST, and GGT (p< 0.0009 , p<0.0001 , and p<0.0001 respectively). Also extremely significant improvement in T.CH , LDL , and TGs (p<0.0001 , p< 0.0001 ,and p<0.0001 respectively), and significant improvement in HDL (p<0.0138) compared with the initial results. There was a highly significant (p<0.0001) and rapid improvement in the mean scores of fatigue and frequent right upper quadrant pain in the 1st month of Sulfad usage. Conclusion Sulfad 1 gm tablets was well tolerated and extremely effective in the management of NASH patients.
  • Introduction Nonalcoholic steatohepatitis is a common cause of liver inflammation and may be associated with obesity, insulin resistance, and hyperlipidemia .The major feature in NASH is fat in the liver, along with inflammation, oxidative stress and damage. Some people with NASH feel well and are not aware to have a liver problem an early discovery is important Nevertheless, NASH can be severe needs urgent management as it can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly. The spectrum of fatty liver disease varies from simple steatosis to liver cirrhosis and unfortunately we don’t know when the patient will develop to next stage.(Fig.A) Table (A) shows the dilemma of NAFLD/NASH. Table (A) Despite the fact that liver biopsy is the differential diagnosis for NAFLD/NASH, it is usually diagnosed by other diagnostic method (due to the invasive nature of liver biopsy ) as abnormal U/S, Liver biochemical function tests, serum lipids and other laboratory results. In the management of NASH patient diet and exercise are actually not satisfactory for almost 75% of patients, the aim beside weight reduction is to improve lipid metabolism for the accumulated lipids in the liver, decreasing lipids level to decrease the out load on hepatocytes, decreasing the inflammatory mediators that can cause liver damage, decreasing the free radicals that harm hepatocytes, stabilizing hepatocytes and/or stimulating regeneration of the damaged cells, so such patients actually need a combination thereby. There are 4 phytopharmaceuticals known for their action on lipids metabolism, oxidative stress, inflammation, and hepatocellular stabilization, which are bioactive components of Cynara, Curcumin, Glycerrihizin (bioactive component of liqurice), and silibnin, these 4 phytopharmaceuticals are combined in one tablet form called SULFAD®. In this study we are evaluating the clinical efficacy, short and long term safety of SULFAD tablets for management of NASH patients. Fig. A (47) High prevalence of fatty liver disorders in communities with throughout the world Most common cause of abnormal liver tests in communitya?2–8% of population have NAFLD NASH now rivals alcoholic liver disease and chronic hepatitis C as reason for referral to gastroenterologist or liver clinic NASH is a potential cause of cirrhosis, which may be ‘cryptogenic’, and lead to end-stage liver disease Liver failure is most common cause of death in patients with cirrhosis resulting from NASH Standardized mortality of liver disease in type 2 diabetes greatly exceeds vascular disease NASH recurs after liver transplantation Hepatic steatosis as a cause of primary graft non- function after liver transplantation Role of metabolic determinants of NASH in pathogenesis of other liver diseases, particularly hepatitis C and alcoholic cirrhosis Possible effect of NASH/steatosis in hepatocarcinogenesis
  • Aim of study To evaluate the clinical efficacy, short- and long-term safety of Sulfad tablets for NASH patients. Study design A randomized, prospective, open label, multi-center, controlled, phase III clinical trial conducted at WWU hospital, RFW hospital, and EKU hospital Germany, with strict adherence with the GCP ethical guidelines. The study protocol, case report forms, regulatory clearance documents, product related information and informed consent form were submitted to the Institutional Ethics Committee, and were approved by the same. MATERIALS AND METHODS Inclusion criteria A total of 100 patients (61 male and 39 female) with diagnosis of steatohepatitis, and who were willing to give informed consent were included in the study. Exclusion criteria Pregnant women, patients with malignant jaundice, common bile duct obstruction, viral hepatitis, autoimmune hepatitis and those who were unwilling to give informed consent were excluded from the study. Study procedure At the initial visit, all patients agreed to take Sulfad for management of their condition, the nature of the study was explained to them. Randomization was done. A person unconnected with the study did randomization by using computer generated random number allocation for each center.(1st center 20 , 2nd center 40 ,3rd center 40). A detailed medical history was obtained from all enrolled patients, which was followed by thorough clinical examination. All patients were subjected to U/S , biochemical investigations, which included liver biomarkers (ALT, AST, GGT, ALP U/L), lipid profile including (T.CH , TGs , LDL ,HDL mg/dl), Hb and PC.(Hb and PC at the start and at the end only). All of them have at least 2 elevated liver biomarkers with 2 abnormal parameters of lipids profile. And all have confirmed U/S with fatty liver. 90 with high ALT ≥ 3 fold , 94 with high AST ≥ 2 fold ,53 with elevated ALP ≥150 U/L ,94 with elevated GGT ≥ 65 U/L , 72 with elevated T.CH ≥ 220 ,70 with elevated TGs ≥ 230 ,55 with elevated LDL ≥150 and 10 of them with low HDL ≤ 29. Study drugs The daily dose of 3 tablets of Sulfad has been shown to be potentially effective and safe in the management of steatohepatitis and was considered adequate for this study. The patients were advised to consume the drug in doses of 1 tablets three times-a-day, orally, for 3 months. Patients were not allowed to take any other medication, which would have any significant effect on LFT. Follow-up and monitoring All patients were followed up every 4 weeks for a period of 3 months. At each follow-up visit (1st, 2nd, and 3rd month), the investigator recorded any information about adverse events (either reported or observed), and symptomatic evaluation was conducted, The subjective symptomatic improvement (fatigue and right upper quadrant pain) was assessed on a predefined 0 to 3 score scale (0=poor, 1=average, 2=good, 3=excellent) which was followed by thorough clinical examination.
  • At the end of each month changes in the biochemical parameters, incidence of adverse events (either reported or observed) and patient compliance to the drug treatment were recorded. Adverse events All adverse events either reported or observed by patients were recorded with information about severity, duration and action taken regarding the study drug. Relation of adverse events to the study medication was predefined as "Unrelated" (a reaction that does not follow a reasonable temporal sequence from the time of administration of the drug), "Possible" (follows a known response pattern to the suspected drug, but could have been produced by the patient's clinical state or other modes of therapy administered to the patient), and "Probable" (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient's clinical state). For patients recorded as withdrawing from the study, efforts were made to ascertain the reason for dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not regarded as treatment failure, and reasons for non-compliance were recorded. Primary and secondary endpoints The predefined primary efficacy endpoints were rapid improvement, renormalization of hematological and biochemical parameters, and total duration of clinical recovery. The predefined secondary safety endpoints were incidence of adverse events (either reported or observed) during the study period and overall compliance to the drug treatment. Statistical analysis Statistical analysis was done according to intention-to-treat principles. "ANOVA Test" and “Dunnett and Bonferroni's Multiple Comparison Test" analyzed the mean score for monthly improvement. Changes in various parameters from baseline values and values at the end of the study were pooled and analyzed by "Unpaired 't' Test with two tailed p value". The minimum level of significance was fixed at 95% confidence limit and a 2-sided p value is applied. RESULTS A total of 100 patients were enrolled in this trial (61 males and 39 females). The demographic profile, clinical profile, and biochemical profile were similar in all centers. The mean age of the enrolled patients was 41.55 years (minimum=25, maximum=63, SD=13.76, SEM=1.95, Lower 95% CI of M=28.19 and Upper 95% CI of M=38.65). The common symptoms reported by patients were fatige (19%), right upper quadrant discomfort(25%) .The common clinical findings were hepatomegaly (26%), all have confirmed U/S with fatty liver , 90 with high ALT ≥ 3 fold , 94 with high AST ≥ 2 fold ,31 with elevated ALP ≥150 U/L ,94 with elevated GGT ≥ 65 U/L , 72 with elevated T.CH ≥ 220 ,70 with elevated TGs ≥ 230 ,55 with elevated LDL ≥150 and 10 of them with low HDL ≤ 29. At the end of 1st month there was a significant (p<0.0141) improvement in AST (table 4) ,very significant (p<0.0021) improvement in LDL( table 14) , and very significant improvement (p<0.0047) in TGs (table 12). No quite significant improvement in ALP or HDL levels was observed and there a slight improvement in other parameters in 65 % of patients. At the end of 2nd month there was a very significant improvement in liver biomarkers including ALT ,AST, and GGT (p<0.0034 , p<0.01 ,and p<0.0025 respectively (tables 2,4,6) ). Also extremely significant improvement in lipid profile including T.CH , LDL , and TGs (p<0.0001 , p< 0.0001 ,and p<0.0001 respectively (tables 10,14 ,12)) compared with the initial results. No significant improvement in ALP or HDL levels was observed.
  • At the end of 3rd month there was extremely significant improvement in liver biomarkers including ALT ,AST, and GGT (p< 0.0009 , p<0.0001 , and p<0.0001 respectively) (tables 2,4,6). Also extremely significant improvement in T.CH , LDL , and TGs (p<0.0001 , p< 0.0001 ,and p<0.0001 respectively) (tables 10,14 ,12), and significant improvement in HDL (p<0.0138) (table 16) compared with the initial results. There was a highly significant (p<0.0001) and rapid improvement in the mean scores of fatigue and frequent right upper quadrant pain in the 1st month of Sulfad usage.
  • Mean improvement in liver biomarkers ALT (SGPT) Table 1 Dunnett and Bonferroni's Multiple Comparison Test Table 2 AST (SGOT) Table 3 ANOVA Parameter Start 1st month 2nd month 3rd month Mean 154.83 99.91 53.61 40 SD 331.81 214.47 54.494 39.336 SEM 33.18 25.45 6.513 4.371 Lower 95% CL 88.9 49.09 40.6 31.29 Upper 95% CL 220.76 150.73 66.62 48.71 Significance Pv of 0.0014 which is very significant Parameter Mean difference T 95% CI of diff. P value Significance ALT start VS 2nd M -101.22 2.993 -168.26 To -34.181 0.0034 Very significant ALT start VS 3rd M -114.8 3.431 -181.21 To -48.45 0.0009 Extremely significant ANOVA Parameter Start 1st month 2nd month 3rd month Mean 125.71 80.72 55.08 43.26 SD 165.7 71.98 37.2 21.11 SEM 16.6 7.23 3.7 2.12 Lower 95% CL 92.8 66.3 47.6 39.04 Upper 95% CL 158.6 95.09 62.4 47.5 Significance Pv <0.0001 which is extremely significant
  • Dunnett and Bonferroni's Multiple Comparison Test Table 4 GGT Table 5 Dunnett and Bonferroni's Multiple Comparison Test Table 6 Parameter Mean difference T 95% CI of diff. P value Significance AST start VS 1st M -44.99 2.5 -80.8 To -9.22 0.0141 Significant AST start VS 2nd M -70.63 4.158 -104.30 To -36.964 <0.01 Very significant AST start VS 3rd M -82.5 4.9 -115.59 To -49.312 <0.0001 Extremely significant ANOVA Parameter Start 1st month 2nd month 3rd month Mean 269.51 213.9 147.3 93.3 SD 231.84 174.54 111.88 57.238 SEM 34.561 27.6 17.7 8.73 Lower 95% CL 199.81 158.09 111.54 75.68 Upper 95% CL 339.21 269.76 183.11 110.92 Significance Pv <0.0001 which is extremely significant Parameter Mean difference T 95% CI of diff. P value Significance GGT start VS 2nd M -122.19 3.147 -199.72 To -44.65 0.0025 Very significant GGT start VS 3rd M -176.21 4.943 -247.8 To 104.6 <0.0001 Extremely significant
  • ALP Table 7 Dunnett and Bonferroni's Multiple Comparison Test Table 8 Mean improvement in lipid profile T.CH Table 9 ANOVA Parameter Start 1st month 2nd month 3rd month Mean 159.48 121.72 115.65 113.76 SD 176.57 20.07 18.2 16.9 SEM 26.034 2.959 2.683 2.5 Lower 95% CL 107 115.8 110.24 108.74 Upper 95% CL 211.96 127.68 121.06 118.78 Significance P v 0.0510 Not quite significant Parameter Mean difference T 95% CI of diff. P value Significance ALP start VS 2nd M -43.83 1.68 -96.541 To -8.881 0.1009 Not significant ALP start VS 3rd M -45.7 1.75 -98.393 To -6.953 0.0873 Not quite significant ANOVA Parameter Start 1st month 2nd month 3rd month Mean 246.63 224.03 182.81 159.89 SD 77.689 138.33 40.516 33.33 SEM 9.867 17.568 5.146 4.233 Lower 95% CL 226.9 188.92 172.52 151.43 Upper 95% CL 266.36 259.18 193.1 168.35 Significance P v <0.0001 which is extremely significant
  • Dunnett and Bonferroni's Multiple Comparison Test Table 10 TGs Table 11 Dunnett and Bonferroni's Multiple Comparison Test Table 12 Parameter Mean difference T 95% CI of diff. P value Significance T.CH start VS 1st M -22.58 1.121 -62.58 To 17.42 0.2653 Not significant T.CH start VS 2nd M -63.82 5.735 -85.923 To -41.717 <0.0001 Extremely significant T.CH start VS 3rd M -86.74 8.079 -108.01 To -65.383 <0.0001 Extremely significant ANOVA Parameter Start 1st month 2nd month 3rd month Mean 240.83 184.1 155.97 138.49 SD 129.86 81.369 66.253 41.424 SEM 16.627 10.418 8.553 5.304 Lower 95% CL 207.58 163.26 138.85 127.88 Upper 95% CL 274.08 204.94 173.09 149.1 Significance P v <0.0001 which is extremely significant Parameter Mean difference T 95% CI of diff. P value Significance TGs start VS 1st M -56.73 2.891 -95.66 To -17.802 0.0047 Very significant TGs start VS 2nd M -84.86 4.54 -122.01 To -47.71 <0.0001 Extremely significant TGs start VS 3rd M -102.34 5.864 -137.13 To -67.55 <0.0001 Extremely significant
  • LDL Table 13 Dunnett and Bonferroni's Multiple Comparison Test Table 14 HDL Table 15 ANOVA Parameter Start 1st month 2nd month 3rd month Mean 169.167 139.08 123.678 112.37 SD 62.693 38.474 34.148 28.897 SEM 8.094 4.967 4.446 3.731 Lower 95% CL 152.97 129.14 114.78 104.9 Upper 95% CL 185.36 149.02 132.58 119.84 Significance P v <0.0001 which is extremely significant Parameter Mean difference T 95% CI of diff. P value Significance LDL start VS 1st M -30.087 3.168 -48.935 To -11.239 0.0021 Very significant LDL start VS 2nd M -45.489 4.926 -63.832 To -27.146 <0.0001 Extremely significant LDL start VS 3rd M -56.797 6.37 -74.526 To-39.07 <0.0001 Extremely significant ANOVA Parameter Start 1st month 2nd month 3rd month Mean 39.03 41.42 41.97 43.678 SD 9.377 9.343 8.51 10.75 SEM 1.221 1.216 1.117 1.4 Lower 95% CL 36.586 38.985 39.723 40.874 Upper 95% CL 41.474 43.855 44.208 46.482 Significance P v 0.0692 which is not quite significant
  • Dunnett and Bonferroni's Multiple Comparison Test Table 16 Table 17: Improvement in mean symptom score of fatigue Repeated Measures ANOVA Test Table 17 Parameter start 1st month 2nd month 3rd month Mean 2.52 1.52 1.00 0.00 SD 0.51 0.51 0.00 0.00 SE 0.10 0.10 0.00 0.00 Lower 95 % CI 2.24 1.24 1.00 0.00 Upper 95 % CI 2.81 1.81 1.00 0.00 significance ***F=367, R2 =0.9386, p<0.0001, Highly significant Bonferroni's Multiple Comparison Test Table 18 Parameter Mean difference T 95% CI of diff. P value Significance HDL start VS 1st M 2.39 1.387 -1.024 To 5.804 0.1682 Not significant HDL start VS 2nd M 2.94 1.777 -0.3381 To 6.218 0.0783 Not significant HDL start VS 3rd M 4.648 2.5 0.9671 To 8.329 0.0138 Significant Mean diff. t P value 95 % CL of diff. Start VS 1st M 1 12.66 p<0.001 0.754 to 1.245 1st M VS 2nd M 0.52 6.58 p<0.001 0.274 to 0.765 2nd M VS 3rd M 0 0 p>0.05 -0.245 to 0.245
  • Discussion Despite the fact that liver biopsy is the only differential diagnosis for NAFLD/NASH, it is usually diagnosed by other diagnostic method (due to the invasive nature of liver biopsy ) as abnormal U/S, Liver biochemical function tests, serum lipids and other laboratory results .Abnormal biochemical results (liver function tests) typically comprise minor (1.5- to 5-fold) elevations of ALT and gamma-glutamyl transpeptidase (GGT). The following laboratory tests may provide clues to the presence of cirrhosis: low platelet count, raised aspartate aminotransferase (AST) that is higher than ALT, and subtle changes in serum albumin or bilirubin that are not attributable to other causes. (44) Fasting hypertriglyceridemia is present in 25–40% of patients with NASH [8,9,10,16,39]. It may be associated with hypercholesterolemia (increased LDL cholesterol, particularly with low levels of HDL and a high LDL :HDL ratio). This pattern of lipid disorders is a feature of the insulin resistance syndrome.(44). In this study we are trying to evaluate the effect of Sulfad ,(a new medication composed of 4 phytopharmaceutical components) on the mean improvement of NASH patient on the level of liver biomarkers , lipid profile and occurred symptoms. This study observed a highly significant and rapid symptomatic improvement in the mean Score of fatigue by the 1st month of using Sulfad . There was an extreme significant and rapid mean improvement in most of the biochemical parameters of liver functions (ALT , AST , GGT) (figures 1,2,and 3 respectively) by the end of 2nd and 3rd month (the improvement starts from the 1st month) , there was no significant improvement in ALP till the end of 3rd month. (Fig 4) There was an extreme significant mean improvement in the lipid profile including (T.CH ,TGs ,and LDL) by the end of 2nd month , and much better mean improvement by the end of 3rd month (figures 5,6and 7 respectively), there was no significant improvement in HDL level by the end of 2nd month however it starts in improvement (significantly) by the end of 3rd month. (figure8) There were no clinically significant changes in other biochemical parameters such as Hb levels and PC, which indicate excellent short-and long-term safety profile of Sulfad.
  • Fig.9 Fig.10 There were no clinically significant adverse effects, either observed or reported; during the entire study period, and the overall compliance to the drug treatment was found to be excellent, These beneficial clinical efficacies of Sulfad in NASH patients might be due to the synergistic action of its ingredients, which had been well documented in various experimental and clinical studies by various researchers. 0 50 100 150 200 250 300 Start 1st month 2nd month 3rd month Time Liver biomarkersmean improvement ALT(6-49U/L) GGT (11-78U/L) ALP(50-140U/L) AST(6-40U/L) 0102030405060708090100110120130140150160170180190200210220230240250260 Start 1st month 2nd month 3rd month Time Lipid profile mean improvement HDL(30- 60mg/dl) T.Ch (up to 200 mg/dl) T.Gs(upto 180 mg/dl) LDL(100- 190mg/dl)
  • Cynara scolymus leaves extracts have long been used in folk medicine for their choleretic and hepatoprotective activities, that are often related to the cynarin content. These therapeutic properties are also attributed to mono-and di-caffeoylquinic acids and since commercial C. scolymus preparations can differ for their activities. Cynara showed that the extract with the highest content in phenolic derivatives (GAE) exerted the major effect on bile flow and liver protection. Aktay et al. isolated and identified the major constituents of Cynara scolymus17 and Gebhardt et al. identified the other chemical constituents as cynaropicrin, quinic acid derivatives and falvonoids.18 Adzet etal.andSeperonietal.observedthehepatoprotectiveeffect (confirmed by histopathological examination)of Cynara scolymus agains CCl4-induced hepatotoxicity and reported significant prevention of the elevation of malondialdehyde formation (plasma and hepatic)and enzyme levels(AST and ALT).12-18 Aktay etal .screened Cynara scolymus for antihepatotoxic activity and measured the degree of protection using biochemical parameters (AST, ALT, ALP and GGT).Potent antihepatotoxic activity (comparable to the silymarin) was observed with almost complete normalization of the tissues(as neither fatty accumulation nor necrosis was observed on histopathological study)17. Maros et al. studied the effects of Cynara scolymus on the immunotoxicity of ethanol and reported significant increase in the number of circulating leukocytes , the weights of concerned organs (liver, spleen and thymus), number of splenic plaque forming cells , hemagglutination titers and the secondary IgG antibody response . There were also significant increases in delayed-type hypersensitivity reaction, phagocytic activity, natural killer cell activity, cell proliferation and interferon gammasecretion.20 Maros etal. Reported that the presence of C ynara scolymus in the reaction mixture (containing calf thymus DNA and free radical generating system) protects DNA against oxidative damage to its deoxyribose sugar moiety. All these studies suggest that the observed hepatoprotective effect of Cynara scolymus might be due to its ability to suppress the oxidative degradation of DNA in the tissue debris.16- 21 The antioxidative activity (radical scavenging effects, inhibition of hydrogen peroxide, and iron chelation) of Cynara.19,21 Gurbuz etal.observed significant cytoprotection against ethanol-induced damage and these results were further confirmed by using histopathological techniques. Cynara scolymus extracts may reduce hepatic cholesterol biosynthesis in a physiologically favorable manner, i.e., by indirect inhibition that might avoid problems known to occur with strong direct inhibitors of HMGCoA-reductase during long-term administration. Because artichoke extracts may also enhance biliary cholesterol excretion as a result of the choleretic influence (Kirchhoff et al., 1994), both mechanisms may contribute to the clinically known reduction pf the blood cholesterol level.45 Cynara scolymus could play a relevant role in management of mild hypercholesterolemia favouring in particular the increase in HDL-C besides decreasing total cholesterol and LDL cholesterol.46. Curcuminoids (curcumin and curcuminoids) as the active ingredients of Curcuma longa were identified.22-27. Curcuma longa was investigated for its hepatoprotective activity againstCCl4- induced hepatic damage and it has shown remarkable hepatoprotective activity confirmed by evaluated biochemical parameters(AST,ALT,ALP and GGT). Curcuma longa protects DNA against the oxidative damage and the results suggest that the observed hepatoprotective effect of Curcuma longa might be due to the ability to suppress the oxidative degradation of DNA in the tissue debris. Curcuma increased activity of aminopyrine N- demethylase,uridinediphosphateglucuronyltransferaseandglutathioneS-transferase, without any alteration in levels of ALP ,ALT and gamma-glutamyl transferase levels in the serum (22-27). Curcumin could also reduce reactive oxygen species mediated insulin resistance in hepatocytes, at least in part through nuclear translocation of NF-E2-Related Factor-2 (Nrf2) ( a transcription factor that plays a crucial role in the cellular protection against oxidative stress).47
  • The triterpene saponins are identified as active ingredients of Glycyrrhiza glabra. Liquorice is reported to have potent anti-oxidant activity, which might be due to its effects on lipid peroxidation. The isoflavonoids from Glycyrrhiza glabra inhibit nitric oxide production and liquititigenin isolated from the above roots decreases inducible nitric oxide synthase levels in lipopolysaccharide-stimulated peritoneal macrophages. Liquorice has a potent antiviral activity by virtue of inhibition of viral attachment and penetration. Hepatoprotective effects of liquorice are reported in chemically induced liver damage. The roots of liquorice showed modulates hepatic enzymes and provides hepato protection against induced immunosuppression. It was observed that liquorice protects the gastric mucosal against aspirin-induced gastric ulcers28-35. Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Several trials have studied the effects of milk thistle for patients with liver diseases, cancer, hepatitis C, HIV, diabetes, and hypercholesterolemia. In addition, new established doses and improvement on the quality and standardization of this herb will provide the much-awaited evidence about the efficacy of milk thistle in the treatment of liver diseases. Milk thistle extracts are known to be safe and well tolerated, and toxic or adverse effects observed in the reviewed clinical trials seem to be minimal.4 Flavan-3-on-4-ols are isolated and identified as the active ingredients of Silybum marianum. This Silyarin mixture was found to possess potent hepatoprotective activity against CCl4, paracetamol (in vivo) and thioacetamide, galactosamine (in vitro) inducedHepatotoxicity1-11. Silymarin has potent antioxidant activity 5. In another study, it was shown that milk thistle prevents lipid peroxidation, bleaching of free radicals and autoxidation of iron ions .10. Therefore, as discussed above, these synergistic actions (hepatoprotective, choleretic, lipid lowering , free radical scavenging and anti-inflammatory)exhibited by the ingredients of Sulfad might explain the beneficial mechanisms of action of Sulfad in management of NASH patients. CONCLUSION This study observed a highly significant and rapid mean improvement of NASH patient on the level of liver biomarkers , lipid profile and occurred symptoms starting from the 1st month of therapy in most of the parameters, and extreme significant improvement in all liver biomarkers (except ALP only slight improvement) ,and in lipids profile by the end of 3rd month. There were no clinically significant adverse effects, either observed or reported during the entire study period, and the overall compliance to the drug treatment was found to be excellent. Therefore, it can be concluded that, Sulfad tablets are clinically effective and safe in the management of NASH patients.
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