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

1. 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.

2. 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

3. 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.

4. 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.

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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.

13. 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)

14. 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

15. 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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