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1 Evidence Based Medicine: Herbal Medicines in Liver Diseases Radha K. Dhiman, MD, DM, MNAMS, FACG Department of Hepatology, PGIMER, Chandigarh.

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Presentation on theme: "1 Evidence Based Medicine: Herbal Medicines in Liver Diseases Radha K. Dhiman, MD, DM, MNAMS, FACG Department of Hepatology, PGIMER, Chandigarh."— Presentation transcript:

1 1 Evidence Based Medicine: Herbal Medicines in Liver Diseases Radha K. Dhiman, MD, DM, MNAMS, FACG Department of Hepatology, PGIMER, Chandigarh

2 2 Hepatoprotective Drugs Phyllanthus amarus Milk thistle (Silymarin) Glycyrrhizin (lecorice root extract) Liv 52 (mixture of herbs) Picroliv Ursodeoxy cholic acid SAMe Lecithin/Phosphatidyl Choline L-Carnitine Selenium Vitamin E

3 3 Herbal Medicine China - 2100 BC India - Vedic period First written reports India - 600 BC with Charaka Samhita China - 400 BC Popular but not acceptable treatment modalities

4 4 Herbal Medicine Lack of standardization and lack of identification of active ingredient(s) Lack of randomized controlled clinical trials (RCTs) Lack of toxicological evaluation

5 5 Quality of Evidence Grade I:Randomized controlled trials, systematic reviews Grade II-1:Controlled trials without randomization Grade II-2:Cohort or case-control analytic studies Grade II-3:Multiple time series, dramatic uncontrolled experiments, retrospective studies Grade III:Opinions of respected authorities; descriptive epidemiology

6 6 Phyllanthus Tropical and subtropical countries P. amarus, P. niruri, P. myrtifolius, P urinaria Inhibit DNA polymerase activity, mRNA transcription and replication

7 7 Phyllanthus: Clinical Trials N=213 (7 clinical trials from India) Patients with Mean HBsAg clearance 25.6% Mean HBeAg seroconversion rate 55.3% Only 3 trials are controlled trials (n=78,22,16) (Thyagarajan, IJG 1999)

8 8 Phyllanthus:Metanalysis 22 RCTs N=1947 with chronic HBV infection Quality of trials High (Jadad score  3)5 Low (Jadad score < 3)17 Follow-up >6 mo6 None16 Mortality, QOL, cirrhosis/HCC X Liu, J Viral Hepatitis 2001

9 9 Phyllanthus:Metanalysis 22 RCTs Phyllanthus v Controls6 No Rx1 Nonspecific Rx3 Interferon2 Thymosin2 Other herbs6 Phyllanthus + IFN v Interferon2 Liu, J Viral Hepatitis 2001

10 10 Phyllanthus v Placebo Loss of HBsAg 1.0110.1100 Favors PhyllanthusFavors Controls 5.6 (1.9-17.2), p=.002 Loss of HBeAg 1.0110.1100 Favors PhyllanthusFavors Controls 1.7 (.7-4.1), p=NS

11 11 Phyllanthus v Other Medicines Loss of HBsAg Favors Phyllanthus Loss of HBeAg 1.0110.1100 Favors ControlsFavors Phyllanthus 2.3 (1.3-4.3),p-.008 1.0110.1100 Favors PhyllanthusFavors Controls 3.1 (2.2-4.4), p=.00001

12 12 Phyllanthus + IFN v IFN Loss of HBsAgLoss of HBeAg 1.0110.1100 Favors Controls 0.8 (.13-5.5), p=NS 1.0110.1100 Favors Phyllanthus + IFNFavors Controls 1.6 (1.1-2.3), p=.03 Favors Phyllanthus + IFN

13 13 Phyllanthus + Thymosin v Thymosin Loss of HBsAgLoss of HBeAg 1.0110.1100 Favors PhyllanthusFavors Controls 2.1 (.7-6.4), p=NS 1.0110.1100 Favors PhyllanthusFavors Controls 2.0 (1.1-3.4), p=.02

14 14 Phyllanthus: Loss of HBV DNA Phyllanthus v other med. Phyllanthus +IFN v IFN 1.0110.1100 Favors PhyllanthusFavors Controls 1.0110.1100 Favors PhyllanthusFavors Controls 2.9 (2.0-4.3), p=.0001 1.5 (1.1-2.2), p=.03

15 15 Phyllanthus:Conclusions Phyllanthus has positive effect on clearance of HBV markers (Grade 1) No major adverse effects (Grade 1)

16 16 Phyllanthus:Conclusions Poor methodological quality (17/22 RCTs) Mostly from China No data on clinically relevant outcomes Not recommended for clinical use Further large trials are needed.

17 17 Silymarin (Milk Thistle) Silybum marianum (Milk thistle) - daisy family Pliny the El-der (A.D. 77), a noted naturalist, “ excellent for carrying off bile. ” Silymarin: silybin, silychristin and silydianin

18 18 Silymarin (Milk Thistle) Antioxidant:  free radical production and lipid peroxidation Antifibrotic:  procollagen type III Toxin blockade agent: inhibit toxin binding to hepatocyte membrane receptors

19 19 Silymarin : Animal Studies Acetaminophen Carbon tetra chloride Radiation Iron overload Phenylhydrazine Alcohol Cold ischemia Amanita phalloides

20 20 Silymarin : Human Studies Alcoholic liver disease Acute viral hepatitis Chronic viral hepatitis Toxin-induced hepatitis

21 21 Silymarin: Metanalysis 14 RCTs N=1209 Alcohol 7, viral 3, mixed 3,drug 1 Sample size 20-200 Quality of trials High (Jadad score  3)14 Low (Jadad score < 3)3 Jacobs, Am J Med 2002

22 22 Silymarin: Effect on Mortality. 1.0110.1100 Favors controlFavors Silymarin.33 RR = 0.8 (.5-1.5), p=NS

23 23 Silymarin: Effect on ALT. Favors controlFavors Silymarin 0-45-15-30-60-75-90609075453015 -9 IU/L (-18 to -1), p=.05 Duration <90 days Duration >90 days

24 24 Silymarin: Effect on AST. Favors controlFavors Silymarin 0-45-15-30-60-75-90609075453015 -5 IU/L (-15 to 5), p+NS

25 25 Silymarin: Effect on Prothrombin Time. Favors controlFavors Silymarin 0-15-5-10-20-25-3020302515105 -2 s (-6 to 2), p=NS

26 26 Silymarin: Side effects 18/7000 Seroius side effects 3 patients Gastroenteritis  Collapse Anaphylactic reactions Minor2-10% GI symptoms, headaches, dermatological reactions

27 27 Silymarin: Conclusions 1. Milk thistle (Silymarin) appears to be safe and well tolerated (Grade 1) 2. It does not reduce mortality among patients with chronic liver disease (Grade 1) 3. It does not improve histology at biopsy among patients with chronic liver disease (Grade 1) 4. It does not improve biochemical markers among patients with chronic liver disease (Grade 1) 5. At present “Silymarin” can not be recommended for treatment of liver disease

28 28 Glycyrrhizin Extract of the licorice root, Glycyrrhizin glabra Major constituents – glycyrrhizic acid, multiple flavonoids, isoflavonoids, hydroxy- coumarins and sterols Stronger Neominophagen C (SNMC) - 0.2% glycyrrhizin, 0.1% cysteine and 2% glyceine

29 29 Glycyrrhizin: Mechanisms of Action Anti-inflammatory:  PGE2 and arachodonic acid metabolism Antioxidant:  glutathione-S-transferase and catalase activity Stimulate endogenous interferon production Inhibits TNF mediated cytotoxicity

30 30 SNMC: Uses Subacute hepatic failure (SAHF) Chronic hepatitis Cirrhosis with activity Renal allograft recipients with CHC ATT induced hepatitis Severe acute sporadic hepatitis E

31 31 SNMC: SAHF (Acharya, ICMR 1992-1997) N=56 Open trial Dose 100 mL/day for 30 days, then EOD for 8 weeks Survival rate 73% v 33% (98 historical control) (p <0.001) Clinical and biochemical improvement+ + Liver failure related complications  Viral clearance  Chronic sequalae 

32 32 SNMC: Chronic Hepatitis (Acharya, ICMR 1992-1997) Open labeled (n=21), RCT (n=26) HBV 25, HCV 9, Both 5, None 9) Dose 60 mL/day for 1 mo, then EOD for 5 mo Biochemical improvement+ + Histological improvement 25% Viral clearance HCVNone HBV (seroconversion)3/25 (12%)

33 33 SNMC: Cirrhosis with Activity (Acharya, ICMR 1992-1997) RCT (n=43, SNMC 21, Placebo 22) HBV 25, HCV 8, Both 2, None 8) Dose 60 mL/day for 1 mo, then EOD for 5 mo Mortality and complications  Biochemical improvement+ + 36% relapse Viral clearance No effect

34 34 SNMC: Long-Term Results Arase Cancer 1997 Kumada, Oncology 2002 SNMCControlsSNMCControls N (CHC)84109178100 Cirrhosis28%40% HCC - 15 yr12%25%13%25% Retrospective, nonrandomized, varying doses

35 35 Renal Allograft Recipients with Ch Hepatitis C N=6 N=12 Anand, IJG,2004

36 36 SNMC: Conclusions SNMC has no antiviral effect (Grade I) Improves mortality in patients with SAHF (Grade II-3) Improve liver functions in patients with SAHF (Grade II-3) and in CH and cirrhosis with activity (Grade I) SNMC does not reduce mortality among patients with cirrhosis with activity (Grade I)

37 37 SNMC: Conclusion Prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C (Grade II-3) Ribavirin + SNMC is more effective than ribavirin monotherapy in renal allograft recipients with ch hepatitis C (Grade II-1) Small number of patients

38 38 Liv. 52: Ingredients Capparins spinosa (Himsara), Cichorium intybus (Kasani), Tamarix gallica (Jhavaka) Solanum nigrum (Kalcamachi), Terminalia arjuna (Arjuna), Cassia accidentalis (Kasamarda), Achillea millefolium (Biranjasipha) Tamarix gallica (Jhavaka) Mandur bhasma,

39 39 Liv. 52: Indications 1. In the prevention and treatment of: a. Viral hepatitis b. Alcoholic liver disease c. Pre-cirrhotic conditions and early cirrhosis d. Protein energy malnutrition e. Loss of appetite f. Radiation and chemotherapy-induced liver damage 2. As an adjuvant with hepatotoxic drugs 3. A valuable adjuvant during convalescence and prolonged illness

40 40 Liv. 52: Animal Studies In market for over 50 years Medline search (1966 to date) 49 papers, 22 animal studies Experimental data: Inhibits lipid peroxidation Protective effect on alcohol induced fetotoxicity Inhibit TNF activity

41 41 Liv. 52: Human Studies European Multicenter Study Group (Fleig, J Hepatol, 1997) N=188, alcohol related cirrhosis Child A & B127 Child C59 Prospective, randomized, placebo-controlled trial, 2 yr MortalityLiv. 52Placebo Child A & BNS Child C81%S40% Liver related22/23 (96%)S 3/11 (27%)

42 42 Liv. 52: Human Studies de Silva, J Ethnopharmacol 2003 N=80, alcohol liver disease Prospective, randomized, double-blind, placebo-controlled trial, 2 yr Groups Liv. 5240 patients Placebo40 patients N o significant difference in clinical outcome and liver chemistry

43 43 Liv. 52: Conclusion No evidence to suggest that Liv. 52 is useful in the treatment of any of the liver conditions that have been claimed

44 44 Picroliv Alcoholic extract from the root of Picrorhiza kurroa Iridoid alkaloids: kutkoside and picroside Antioxidant similar to superoxide dismutase, metal-ion chelators, xanthine oxidase inhibitors

45 45 Picroliv: Animal Studies Ameliorates toxic effects of carbon tetrachloride, thioacetamide, galactosamine, paracetamol, aflatoxin B1 in a concentration-dependant manner

46 46 Picroliv: Human Studies Picroliv 375 mg tds Placebo AVH (HBsAg –ve)1518 Time in days required for total bilirubin to drop to 2.5 mg% 27 days80 days Bilirubin, SGOT and SGPT 

47 47 Conclusion When things are investigated, then true knowledge is achieved. -Confucius

48 48 Conclusion Methodological quality of clinical trials Larger randomized, double blind, placebo-controlled trials Outcome measures should include molecular methods, such as, HBV DNA, HCV RNA estimation etc, liver histology, and end-point events.

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