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Phyllanthus niruri and Chronic hepatitis B

Phyllanthus niruri and Chronic hepatitis B. Nor Shahidah Khairullah 1 ,Ismail Merican 2 ,Munavvar Zubaid 3 ,NL Phang 4 1. Institute For Medical Research, 2 Selayang Hospital, 3 Science University of Malaysia, 4 Nova Laboratories Sdn Bhd. Electron micrograph of hepatitis B virus.

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Phyllanthus niruri and Chronic hepatitis B

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  1. Phyllanthus niruri and Chronic hepatitis B Nor Shahidah Khairullah1,Ismail Merican2,Munavvar Zubaid 3,NL Phang4 1.Institute For Medical Research,2 Selayang Hospital,3Science University of Malaysia,4Nova Laboratories Sdn Bhd

  2. Electron micrograph of hepatitis B virus. Dane particles (43 nm) Sherical and tubular hepatitis B surface antigen particles (22 nm in diameter).

  3. How Do You Acquire The Infection In Asia Pacific? Newborns of long-term carriers Transfusion and transplant recipients Individuals with multiple sexual partners Intravenousdrug users Healthcare workers Prisoners and other institutionalised people

  4. Hepatitis B Is A Devastating Global Healthcare Issue • 350 million long-term carriers worldwide1 • 25-40% will die due to hepatitis B or related complications1,2 • Up to 2 million die each year from HBV infection2, making it the 9th leading cause of death worldwide3 RoW Asia Pacific75% • 75% of long-term carriers live in Asia Pacific4 1 WHO 1998; 2 Zuckerman 1996; 3 Boag 1991; 4 Gust 1996

  5. HBV AND CHRONIC LIVER DISEASE • HBV is the leading cause of chronic hepatitis, cirrhosis and HCC worldwide (Asia, Middle East and Africa) • HBV accounts for 80% of HCC in Asian countries • 200-300 fold greater risk of HCC in “carriers” compared with the general population

  6. Stages in the evolution of HCC from chronic hepatitis through cirrhosis and large nodules

  7. The small finely nodular liver of micronodular cirrhosis

  8. The grossly distorted coarsely nodular liver of macronodular cirrhosis

  9. Ultrasound shows a small hepatocellular carcinoma (marked xx) This was surgically resected and the specimen is shown

  10. Goals of treatment • Eliminate or permanently suppress HBV • Will decrease pathogenicity and infectivity and thereby resolve or reduce hepatic necroinflammatory activity • In clinical terms, short-term goal • Reduce hepatic activity • Prevent development of hepatic decompensation • Achieve HBeAg seroconversion, and / or • HBV DNA with ALT normalisation • The long-term goal is to • Prevent progression to cirrhosis and / or HCC • Prolong survival

  11. Treatment Options • Alpha-IFN • Nucleoside analogues • Immune modulators • Thymosin • Combination treatment • Therapeutic vaccination • Cytokine therapies eg. IL12 • Molecular approaches eg. Use of antisense RNA and DNA constructs

  12. Treatment: Interferon Wong et al. Effect of alpha-interferon treatment in patients with HBeAg positive chronic hepatitis B. A meta-analysis. Annals Int Med, 1993: 119:312-323. (15 studies: 837 adults)

  13. Lamivudine in Asian Study 71 % HBeAg seroconversion with negative HBV DNAafter lamivudine 100 mg daily 5 7 46 % YMDD 15% 38% 49% 12 26 29 % 27 % 16 % 14 % 16 58 25 93 23 143 4 29 Year 1 Year 2 Year 3 < 2 > 2 > 5 xULN ALT

  14. Extended Asian Study • Over 4 years: • Incremental increase in HBeAg seroconversion • 22%,29%,40% and 47% • Emergence of YMDD mutants • 17%,40%,55% and 67% • Unpredictable behaviour • Best predictor: high HAI score and possibly, high pre-treatment ALTs and HBV DNA • Those achieving seroconversion: durability is 73% when treatment stopped

  15. Unresolved Issues • Patients with ALTs of 1-2 x ULN • Direct antiviral agents in children • HBeAg-negative, HBV DNA positive patients with CHB (pre-core mutants) • YMDD Mutants • Other immune modulators • Innovative approaches • Herbal remedies

  16. The Plant Phyllanthus niruri Pokok Dukung anak

  17. Why Phyllantus ?

  18. The Tradition Phyllanthus niruri has long been used by: Malay* - As a traditional remedy in the treatment of jaundice, diarrhea, kidney trouble, etc. Chinese** – Jaundice, diarrhea, kidney trouble. Indian* - Jaundice, for sores and apply to head for vertigo after childbirth (The Medical Book) *Burkill and Haniff. 1930,Gard. Bull. S.S. 6. P.246, Med. Book Mal. Med. P. 379 & 408.**Chinese Herbal Medicinal Study

  19. The Reference for Hepatitis B Blumberg (Nobel Prize Winner): • Phyllanthus niruri binds to Hepatitis B surface antigen (HBsAg)* • inhibits viral DNA polymerase of HBV.** • Venkateswaran PS, Blumberg BS, Milliman I, 1987. Proc.Natl. Sci. Acad;84: 274-278. • ** Blumberg BS, Milliman I 1989. Treatment of HBV carriers with Phyllanthus amarus. Cancer detection and prevention 14, 195-201.

  20. The Reference Thyagarajan and Blumberg* have shown that P. niruri when given trice a day for 30 days: • 59% (22/37) of treated patients lost HBsAg, 15-20 days after end of treatment • 4 % (1/23) placebo treated controls (p < 0.0001, Fisher’s exact test) • No adverse events of causality to Phyllanthus reported * Thyagarajan SP, Blumberg BS 1988. Effect of Phyllanthus niruri on chronic carriers of hepatitis B virus: a preliminary study.Lancet:764-766.

  21. Placebo No intervention Non specific treatment Other herbal medicine Interferon Interferon vs interferon and phyllanthus Phyllanthus Liu et al.J Viral Hepatitis,8(5):358-366 (2001) Systemic review of RCTs on the use of Phyllanthus species for CHB

  22. Results 219 articles 197 excluded : duplicates,nonclinical or different study objectives,different inclusion criteria 22 RCTs analysed ( 1947 patients) • 1. Phyllanthus species had positive effect on: • Clearance of serum HBsAg compared with placebo or no intervention • 2. No significant difference on clearance of serum HBsAg,HBeAg HBV DNA between Phyllanthus & IFN

  23. 3. Phyllanthus better than non specific treatment or other herbal medicines for clearance of : HBsAg, HBeAg, HBV DNA, Liver enzyme normalisation • 4. Phyllanthus & IFN was better than IFN alone for clearance of HBeAg and HBV DNA • 5. No serious adverse event was reported

  24. Conclusions • Phyllanthus species may have a positive effect on antiviral activity and liver biochemistry in CHB • Evidence need to be substantiated due to the general low methodological quality and variations in herb preparation • Larger and longer trials required

  25. The Product

  26. The History Our Precious Kampung Herb

  27. Phyllanthus niruri A Product Made From Our Precious Kampung Herb

  28. The Composition • Marker compounds of HEPAR-P: • Corilagin ……………………..…. 10 mg • 2. Total Phyllanthus flavonoids …. 45 mg

  29. The Active Compound • Corilagin • A polyphenol with anti- Hepatitis B viral activity

  30. The Active Compound 2. Phyllanthus flavonoids Possess potent free radical scavenging effects. One of the Phyllanthus flavonoids: Rutin

  31. PART 2 PHARMCOLOGICAL ACTIVITIES

  32. Uncoating DNA completion Reverse transcription Polymerase Packaged RNA DNA repair mRNA Pregenomic RNA Cell nucleus Transcription RNA Polymerase ccc DNA Viral RNA Cytoplasm Hepatitis B In vitro inactivation activity of HBsAg by HEPAR-PTM Step B: Inhibited by Phyllanthus Step A: Inhibited by Phyllanthus

  33. The Mechanism In Vitro Inhibition of HBsAg

  34. The Injury Liver Injury caused by CCl4 ALT AST

  35. The Mode of Action Oxidation P450 CCl4 CCl3• Free radical CCl4 Liver injury ↑ ALT ↑ AST

  36. The Recovery Recovery by HEPAR-PTM capsule

  37. Oxidation P450 The Protection Protected by HEPAR-PTM CCl4 CCl3• Free radical CCl4 Liver injury ↑ ALT ↑ AST This suggests that HEPAR-PTM also posses antioxidant activity or free radical scavenging activity.

  38. Liver Protection In vivo liver protection effect of HEPAR-PTM capsule against carbon tetrachloride (CCl4) induced liver injury in mice

  39. Dosage and administration Dosage for maintenance of health: 1 capsule, 2 to 3 times a day Recommendation for liver protection: 2 capsules, 2 to 3 times a day

  40. PART 3 The Safety Profile

  41. Objective To determine the toxic effect of HEPAR-PTM on normal physiological functions of adult Sprague-Dawley (SD) rat

  42. Materials and Method -- HEPAR-PTM -- Animals Sprague-Dawley (SD) rat (150g - 250g) of both sexes Kept separately under room temperature in an animal room. Fixed amount of laboratory pellets(approximately 180g every 6 animals) were given and water was given freely.

  43. The design Volume of Injection is 1.0 ml / 100 gm Body Weight Daily Observations: Pharmacotoxic Symptoms, Mortality, Body Weight Changes and Feed Consumption

  44. Methodology • HEPAR-PTM was suspended in distilled water. Preparations were then administered via oral route to animals in a single dose • Animals were observed daily on pharmacotoxic symptoms, mortality, body weight and feed consumption • Animals were observed for two consecutive weeks. • Blood was collected via cardiac puncture after two weeks • Blood and plasma were analyzed for haematological and biochemical parameters in Lam Wah Ee Hospital, Penang

  45. Result (Weight) Statistically not significant at P = 0.05

  46. Result (Weight) Statistically not significant at P = 0.05

  47. Result (Haematology) Statistically not significant at P = 0.05

  48. Result (Haematology) Statistically not significant at P = 0.05

  49. Result (Haematology) Statistically not significant at P = 0.05

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