Poster Presentation

1
Drugs for therapy of HCV and liver disease
Glycyrrhiza glabra Dr BN TandonNew Delhi
2
GLYCYRRHIZA GLABRA

• Indian Herbal Pharmacopeia
• Japanese Pharmacopeia
• Russian Pharmacopeia

Source Peeled or unpeeled roots, stolons of
various species of licorice (Glycyrrhiza)
3
Glycyrrhizin

• Source
• Licorice
• 4-7 is Glycyrrhizin
• Composition
• 2 molecules glucuronic acid
• 1 molecule glycyrrhetinic acid

4
Chemistry

• 20?-carboxy-11-oxo-30-norolean-
• 12-en-3?-y12O-?-D-
• glucopyranuronosyl-B-D-
• glucopyranosiduronic acid

5
Pharmacokinetics

• intravenous glycyrrhizin
• metabolized in liver by ?-D-glucuronidase to
  3-mono-glucuronide-glycyrrhetinic acid
• excreted into bile and so into the intestine
• bacteria metabolize it to glycyrrhetinic acid
  (GA), which is reabsorbed

6

Pharmacokinetics

• After iv injection of GL
• terminal half-life (t½) 3 h
• total body clearance (CLtot) 16-25 ml/ kg/ h
• maximum plasma conc. (80 mg dose) 30 µg/ ml

7

Pharmacokinetics

• In chronic hepatitis patients (120 mg dose)
• terminal half-life (t½) 6.0h (range 4.3-10.7h)
• total body clearance (CLtot) 8 ml/ kg/ h
  (range4.5-12.7mL/kg/h)

8

Pharmacokinetics

• Compared to healthy subjects the t½ was doubled,
  and the total body clearance was halved in
  patients with liver disease
• The total body clearance inversely correlated
  with the transaminases (with ALT, r - 0.8)

9

Pharmacokinetics

• Pharmacokinetic profiles after intravenous
  administration of GL are correlated with the
  functional capacity of the liver

• The pharmacokinetic behavior of glycyrrhizin
  (GZ) has also been examined in D-galactosamine-int
  oxicated (GAL) rats with similar results

• After oral administration of glycyrrhizin there
  is a slow conversion of glycyrrhizin into
  glycyrrhetinic acid in the intestine

10

• Pharmacological actions

Antiviral Cytoprotective Immunomodulation Anti-oxi
dant
11
Antiviral

• Antiviral A action prevents entry of Hepatitis A
  virus into the cell
• Antiviral action also has been reported against
  herpes simplex virus type-I, Japanese
  encephalitis virus and HI

12
Cytoprotective

• Glycyrrhizin acts as a cytoprotective drug by the
  following actions
• a) Inhibition of activation of phospholipase A
  which induces lysis of cell membrane
• b) Prevention of permeability of cell membrane
• c) Action as hydroxyl-radical scavenger
• Glycyrrhetinic acid is many times more
  cytoprotective than glycyrrhizin

13
Immunomodulatory

• Glycyrrhizin inhibits salvation of HBsAg which
  improves humoral antibody and cell mediated
  response of patients
• Glycyrrhizin in mice induces two peaks of gamma
  interferon. Glycyrrhizin is superior to
  glycyrrhetinic acid in this respect
• Glycyrrhizin in mice selectively activates T
  cells in liver which through CD4 and CD8 system
  may have cytotoxicity against virally infected
  cells

14
Modulation of cortisol metabolism

• Anti-inflammatory actions and reduction of ALT
  by glycyrrhizin in liver disease is related to
  inhibition of conversion of cortisol to cortisone
  by glycyrrhizin metabolite glycyrrhetinic acid

15
Antioxidant action

• Glycyrrhizin in vitro studies has shown
  antioxidant action

16
Clinical trials

• Glycyrrhizin has been used for treatment of
  chronic liver disease in Japan for more than 20
  years. Its therapeutic efficacy has been also
  reported in acute hepatitis
• Most of these studies are open clinical trials of
  the drug
• At present 1000 million ampoules of SNMC each
  containing 40mgm. glycyrrhizin are used each
  year in Japan

17
Double blind study

• A double blind trial published in 1983
  recently in 2002 demonstrated therapeutic
  efficacy of glycyrrhizin in improving liver
  functions in chronic hepatitis. This has been
  confirmed by a recent European study.
  Histological improvement too has been published
  in another double blind study

18
Current therapeutic use of iv glycyrrhizin

• HCV related liver cirrhosis
• Non responders relapsed HCV related chronic
  hepatitis
• Prevention of HCC in HCV related CLD
• Post renal transplant HCV liver disease

19
Toxicology

• The LD50 value (determined in mouse, rat and
  guinea pig) was always higher than 5000 mg/kg
• In chronic toxicity studies glycyrrhizin is well
  tolerated without specific organ toxicity
• No histological alterations have been observed

20
Non mutagenic

• No evidence for mutagenic or carcinogenic
  properties of the compound

21
Reproductive safety

• No influence of glycyrrhizin has been observed
  on the competences of mating and pregnancy in the
  male or female animals
• No adverse influence of the drug observed on the
  fetal growth, skeletal formation, surface or
  organ at the terminal pregnant stage

22
Administration

• Doses 40ml (80mgm Glyc) IV OD
• or
• 75 mg tid orally
• Duration 8 week followed by maintenance
  therapy

23
ICMR Clinical Research

Multicenter trials in progress