Sulfad trial germany 2012

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


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


Table 4

GGT

Table 5


Table 6

Parameter Mean

difference


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


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


GGT start VS

2nd M

-122.19 3.147 -199.72

To

-44.65


GGT start VS

3rd M

-176.21 4.943 -247.8

To

104.6

<0.0001 Extremely

significant

ALP

Table 7


Table 8

Mean improvement in lipid profile

T.CH

Table 9

ANOVA


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


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


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


Table 10

TGs

Table 11


Table 12

Parameter Mean

difference


T.CH start VS

1st M

-22.58 1.121 -62.58

To

17.42


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


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


Parameter Mean

difference


TGs start VS 1st

M

-56.73 2.891 -95.66

To

-17.802


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


Table 14

HDL

Table 15

ANOVA


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


Parameter Mean

difference


LDL start VS 1st

M

-30.087 3.168 -48.935

To

-11.239


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


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


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


HDL start VS

1st M

2.39 1.387 -1.024

To

5.804


HDL start VS

2nd M

2.94 1.777 -0.3381

To

6.218


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 biomarkers mean improvement

ALT(6-49U/L)

GGT (11-78U/L)

ALP(50-140U/L)

AST(6-40U/L)

0102030405060708090100110120130140150160170180190200210220230240250260

Start 1stmonth

2ndmonth

3rdmonth

Time

Lipid profile mean improvement

HDL(30-60mg/dl)

T.Ch (up to 200mg/dl)

T.Gs(upto 180mg/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.

REFERENCES

1-Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA

Polymerase. Ahmed-Belkacem A, Ahnou N, Barbotte L, Wychowski C, Pallier C, Brillet R, Pohl RT,

Pawlotsky JM. Gastroenterology. 2009 Dec (In Press).

2-Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated

interferon/ribavirin therapy. Ferenci P, Scherzer TM, Kerschner H, Rutter K, Beinhardt S, Hofer H,

Schöniger-Hekele M, Holzmann H, Steindl-Munda P. Gastroenterology. 2008 Nov;135(5):1561-7.

3-Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Rambaldi A, Jacobs BP, Gluud C.

Cochrane Database Syst Rev. 2007. Review.

4-Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.).

Tamayo C, Diamond S. Integr Cancer Ther. 2007;6(2):146-57. Review.

5-Antioxidant and Hepatoprotective Effects of Silibinin in a Rat Model of Nonalcoholic Steatohepatitis.

Haddad Y, Vallerand D, Brault A, Haddad PS. Evid Based Complement Alternat Med. 2009 .

6-Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Shaker E,

MahmoudH, Mnaa S. Food Chem Toxicol. 2009

7-Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic

Hepatitis C. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH,

Afdhal NH, Navarro VJ, Berman J, Liu QY, Doo E, Fried MW. J Clin Pharmacol. 2009.

8-Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection.

Morishima C, Shuhart MC, Wang CC, Paschal DM, Apodaca MC, Liu Y, Sloan DD, Graf TN, Oberlies

NH, Lee DY, Jerome KR, Polyak SJ. Gastroenterology. .

9-Effects of dietary milk thistle on blood parameters, liver pathology, and hepatobiliary scintigraphy in

white carneaux pigeons (Columba livia) challenged with B1 aflatoxin. Grizzle J, Hadley TL, Rotstein DS,

Perrin SL, Gerhardt LE, Beam JD, Saxton AM, Jones MP, Daniel GB. J Avian Med Surg. 2009

Jun;23(2).:114-24.

10-Effects of Embelin on Lipid Peroxidation and Free Radical Scavenging Activity against Liver

Damage in Rats. Singh D, Singh R, Singh P, Gupta RS. Basic Clin Pharmacol Toxicol. 2009 May 26.

11-Combined therapy of silymarin and desferrioxamine in patients with beta-thalassemia major: a

randomized double-blind clinical trial. Gharagozloo M, Moayedi B, Zakerinia M, Hamidi M, Karimi M,

Maracy M, Amirghofran Z. Fundam Clin Pharmacol. 2009 Jun;23(3):359-65. Rambaldi A, Jacobs BP,

Gluud C: Cochrane Database Syst Rev. 2007 Oct 17;(4).

12-Artichoke leave extract for chronic hepatitis C - a pilot study. Huber R, Müller M, Naumann J, Schenk

T, Lüdtke R. Phytomedicine. 2009 Sep;16(9):801-4.

13-Effect of pretreatment with artichoke extract on carbon tetrachloride-induced liver injury and

oxidative stress. Mehmetçik G, Ozdemirler G, Koçak-Toker N, Cevikbaş U, Uysal M. Exp Toxicol

Pathol. 2008 Sep;60(6):475-80.

14-[Acute hepatic injury secondary to ingestion of artichoke extracts (Hepanephrol] Sinayoko L,

Mennecier D, El Jahir Y, Corberand D, Harnois F, Thiolet C, Farret O. Gastroenterol Clin Biol. 2007

Nov;31(11):1039-40. French. No abstract available. PMID: 18166904 [PubMed - indexed for

MEDLINE]Related articles

15-Efficacy of different Cynara scolymus preparations on liver complaints. Speroni E, Cervellati R,

Govoni P, Guizzardi S, Renzulli C, Guerra MC. J Ethnopharmacol. 2003 Jun;86(2-3):203-11

16-Prevention of taurolithocholate-induced hepatic bile canalicular distortions by HPLC characterized

extracts of artichoke (Cynara scolymus) leaves.Gebhardt R. Planta Med. 2002 Sep;68(9):776-9.

17-Hepatoprotective effects of Turkish folk remedies on experimental liver injury. Aktay G, Deliorman

D, Ergun E, Ergun F, Yeşilada E, Cevik C. J Ethnopharmacol. 2000 Nov;73(1-2):121-9.

18-Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke (Cynara

scolymus L.) extracts. Gebhardt R. J Pharmacol Exp Ther. 1998 Sep;286(3):1122-8.

19-Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in

isolated rat hepatocytes. Adzet T, Camarasa J, Laguna JC. J Nat Prod. 1987 Jul-Aug;50(4):612-7.

20-[Effect of Cynara scolymus-extracts on the regeneration of rat liver. 2] Maros T, Seres-Sturm L, Rácz

G, Rettegi C, Kovács VV, Hints M. Arzneimittelforschung. 1968 Jul;18(7):884-6.

21-[Effects of Cynara Scolymus extracts on the regeneration of rat liver. 1.] Maros T, Rácz G, Katonai B,

Kovács VV. Arzneimittelforschung. 1966 Feb;16(2):127-9

22-Curcumin protects rats against acetaminophen-induced hepatorenal damages and shows synergistic

activity with N-acetyl cysteine. Kheradpezhouh E, Panjehshahin MR, Miri R, Javidnia K, Noorafshan A,

Monabati A, Dehpour AR: Eur J Pharmacol. 2009

23-Effects of turmeric (Curcuma longa) on the expression of hepatic genes associated with

biotransformation, antioxidant, and immune systems in broiler chicks fed aflatoxin. Yarru LP, Settivari

RS, Gowda NK, Antoniou E, Ledoux DR, Rottinghaus GE: Poult Sci. 2009 Dec;88(12):2620-7.

24-:Pharmacological actions of curcumin in liver diseases or damage: Rivera-Espinoza Y, Muriel P:

Liver Int. 2009 Nov;29(10):1457-66.

25-Plant-derived health: the effects of turmeric and curcuminoids. Bengmark S, Mesa MD, Gil A: Nutr

Hosp. 2009 May-Jun;24(3):273-81.

26-Antiviral effect of Curcuma longa Linn extract against hepatitis B virus replication. Kim HJ, Yoo HS,

Kim JC, Park CS, Choi MS, Kim M, Choi H, Min JS, Kim YS, Yoon SW, Ahn JK: J Ethnopharmacol.

2009 Jul 15;124(2):189-96.

27-Study on antifibrotic effects of curcumin in rat hepatic stellate cells. Lin YL, Lin CY, Chi CW, Huang

YT. Phytother Res. 2009 Jul;23(7):927-32.

28-18{beta}-glycyrrhetinic acid ameliorated Propionibacterium acnes-induced acute liver injury through

inhibition of MIP-1{alpha} Xiao Y, Xu J, Mao C, Jin M, Wu Q, Zou J, Gu Q, Zhang Y, Zhang Y. J Biol

Chem. 2009

29-Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats. Amin KA,

Nagy MA. Diabetol Metab Syndr. 2009

30-Lipoprotein lipase expression, serum lipid and tissue lipid deposition in orally-administered

glycyrrhizic acid-treated rats. Lim WY, Chia YY, Liong SY, Ton SH, Kadir KA, Husain SN. Lipids

Health Dis. 2009 Jul 29;8:31.

31-Hepatoprotective and anti-hepatocarcinogenic effects of glycyrrhizin and matrine. Wan XY, Luo M, Li

XD, He P. Chem Biol Interact. 2009 Sep 14;181(1):15-9.

32-Hepatic protection by glycyrrhizin and inhibition of iNOS expression in concanavalin A- induced liver

injury in mice. Tsuruoka N, Abe K, Wake K, Takata M, Hatta A, Sato T, Inoue H. Inflamm Res. 2009

Sep;58(9):593-9.

33-Study on the pharmacokinetics drug-drug interaction potential of Glycyrrhiza uralensis, a traditional

Chinese medicine, with lidocaine in rats. Tang J, Song X, Zhu M, Zhang J. Phytother Res. 2009

May;23(5):603-7.

34-Histopathological and biochemical effects of green tea and/or licorice aqueous extracts on thyroid

functions in male albino rats intoxicated with dimethylnitrosamine. El Mgeed AA, Bstawi M, Mohamed

U, Gabbar MA. Nutr Metab (Lond). 2009 Jan 12;6:2.

36-[Prescription rules of Chinese herbal medicines in treatment of gastric cancer] Cao W, Zhao AG.

Zhong Xi Yi Jie He Xue Bao. 2009 Jan;7(1):1-8. Chinese.

37-Glycyrrhizic acid modulates t-BHP induced apoptosis in primary rat hepatocytes. Tripathi M, Singh

BK, Kakkar P.Food Chem Toxicol. 2009 Feb;47(2):339-47.

38-Isoflavone daidzein possesses no antioxidant activities in cell-free assays but induces the antioxidant

enzyme catalase. Kampkötter A, Chovolou Y, Kulawik A, Röhrdanz E, Weber N, Proksch P, Wätjen W.

Nutr Res. 2008 Sep;28(9):620-8.

39-Liquiritigenin, a flavonoid aglycone from licorice, has a choleretic effect and the ability to induce

hepatic transporters and phase-II enzymes. Kim YW, Kang HE, Lee MG, Hwang SJ, Kim SC, Lee CH,

Kim SG. Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G372-81.

40-Investigation of the anti-obesity action of licorice flavonoid oil in diet-induced obese rats.

Kamisoyama H, Honda K, Tominaga Y, Yokota S, Hasegawa S. Biosci Biotechnol Biochem. 2008

Dec;72(12):3225-31.

41-Effect of the extracts from Glycyrrhiza uralensis Fisch on the growth characteristics of human cell

lines: Anti-tumor and immune activation activities. Chung WT, Lee SH, Kim JD, Sung NS, Hwang B,

Lee SY, Yu CY, Lee HY. Cytotechnology. 2001 Sep;37(1):55-64.

42-Free radical scavenging activity, metal chelation and antioxidant power of some of the Indian spices.

Yadav AS, Bhatnagar D. Biofactors. 2007;31(3-4):219-27.

43-Hepatoprotective Activity of Licorice Water Extract against Cadmium-induced Toxicity in Rats. Lee

JR, Park SJ, Lee HS, Jee SY, Seo J, Kwon YK, Kwon TK, Kim SC. Evid Based Complement Alternat

Med. 2009 Jun;6(2):195-201.

44- Fatty Liver Disease: NASH and Related Disorders 2005

Geoffrey C. Farrell, Jacob George, Pauline de la M. Hall, Arthur J. McCullough

45-Inhibition of Cholesterol Biosynthesis in Primary Cultured Hepatocytes by

Artichoke (Cynara scolymus L.) Extracts1THE JOURNAL OF PHARMACOLOGY AND

EXPERIMENTAL THERAPEUTICS Vol. 286, No. 3 Copyright © 1998 by The American Society for

Pharmacology and Experimental Therapeutics.

46-Beneficial effects of artichoke leaf extract supplementation on increasing HDL-

cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind,

randomized, placebo controlled trial. 2013 Feb;64(1):7-15. doi:

10.3109/09637486.2012.700920. Epub 2012 Jun 29.

Rondanelli M, Giacosa A, Opizzi A, Faliva MA, Sala P, Perna S, Riva A, Morazzoni P, Bombardelli E.

University of Pavia , Pavia Italy.

47-Role of Obesity and Lipotoxicity in the Development of Nonalcoholic

Steatohepatitis: Pathophysiology and Clinical Implications

KENNETH CUSI

Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida

GASTROENTEROLOGY 2012;142:711–725

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