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INTRODUCING. A HERBAL REMEDY for Hepatoprotection. Andrographis paniculata Nees. Flower. Aerial Part. Background. Known in Ayurveda since 5000 B.C Used widely in India Standardised from “Seed to Shelf”

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slide1

INTRODUCING

A HERBAL REMEDY for Hepatoprotection

slide3

Background

  • Known in Ayurveda since 5000 B.C
  • Used widely in India
  • Standardised from “Seed to Shelf”
  • Broad range of pharmacological effects : promotes healthy immune system, normal liver functions and others
  • Safe for human administration
  • Advisable and suitable as a dietary supplement
slide4

Phytochemistry

The main bioactive constituents of Andrographis paniculata are diterepene lactones, andrographolide, neoandrographolide, 14-Deoxy-11,12-dihydroandrographolide, andrographiside and andrograpanin.

14 Deoxy-11,12-dihydroandrographolide

Neoandrographolide

Andrographolide

slide5

Pharmacokinetics of Andrographis paniculata

  • Rapid metabolism of drug in the body
  • After oral administration

Bioavailability : 44.06%

Peak absorption at : 30.75 minutes

Peak plasma concentration : 16μg/ml

  • Crosses brain barrier rapidly
  • Peak drug concentration seen in gall bladder, stomach, liver & small intestine after 30 minutes
  • Excreted through urine and feces.

Ref: Chang HM, But PPH, (Ed), Pharmacology and applications of Chinese Materia Medica (Vol. 1&2),

1987, World Scientific, Singapore

slide6

Protection Against Paracetamol Induced Damage in Rat Hepatocytes

Animals were given a single oral toxic dose of paracetamol 2g/kg

Andrographolide dose: 0.75, 1.5, 3, 6, 12 mg/kg for 7 days

Silymarin dose: 3, 6, 12, 20 mg/kg for 7 days

Both Andrographolide and Silymarin pretreatment as compared to paracetamol treated animals showed

  • Dose dependent increase in viability of isolated hepatocytes
  • Dose dependent increase in oxygen uptake by isolated hepatocytes.
  • The increase in both parameters was more with Andrographolide than with silymarin
slide7

Biochemical parameters

  • In isolated hepatocytes the levels of GOT, GPT and ALP were significantly lower
  • In serum GOT, GPT and ALP levels decreased significantly.
  • The decrease in both parameters was more with Andrographolide than with silymarin

“Andrographolide was found to be more potent than Silymarin (Milk thistle) a standard hepatoprotective agent”

Ref: Visen et. al. (1993) J. Ethnopharmacol. 40: 131-136

slide8

Effect of Andrographolide and Silymarin on percent viability of hepatocytes

% Viability

Effect of Andrographolide and Silymarin on Oxygen uptake

% Viabiity

slide9

Hepatoprotective effects against Carbon Tetrachloride induced Liver damage

Liver damage was caused by 1 ml/kg CCl4 subcutaneously twice weekly for eight weeks.

300 mg/kg alcoholic extract of Andrographis intragastric daily for 8 weeks in rats caused

  • significant decrease in SGPT & Alkaline phosphatase levels as compound to CCl4 treated control group
  • significant decrease in hypnosis [(sleeping time) (improvement in the functioning of liver cells)]

Ref. Rana AC, Avadhoot Y (1991) Arch Pharm Res 14(1); 93-95

slide11

Choleretic effect of Andrographolide in Rats and Guinea pigs

Andrographolide at a dose ranging (1.5 – 12mg/kg) orally produced significant dose dependent choleretic effect as evidenced by ;

  • Increase in bile flow
  • Increase in bile salt
  • Increase in bile acids

Paracetamol induced decrease in volume and content of bile was prevented by Andrographolide

“Effect was more potent than silymarin”

Ref: Shukla et al 1992, Planta medica, 58,146 – 149.

slide14

Hepatoprotection against Carbon tetrachloride induced toxicity

Liver damage was caused by CCl4, 2ml/kg bw sc in equal vol of olive oil on 2nd and 3rd days.

  • Rats were treated for 4 days with
  • Andrographolide :100 mg/kg i.p.
  • Methanolic extract extract: 861.33 mg/kg ip
  • Andrographolide free met. ext. : 761.33 mg/kg ip
  • Andrographolide treatment
  • exerted max. inhibition against CCl4 induced increase in five biochemical parameters - SGOT, SGPT ALP, Bilirubin and Hepatic triglycerides
  • Significantly ameliorates toxin induced histopathological changes in liver.

Ref. Handa SS, Sharma A (1990) Ind. J. Med. Res. [B] 92: 276-283

slide16

Hepatoprotection against galactosamine induced toxicity

  • Acute hepatitis induced in rats by single dose of :
  • Galactosamine 800 mg/kg i.p.

Treatment of rats with 400 mg/kg i.p. or 800 mg/kg (orally) 48, 24 & 2 h before galactosamine administration leads to

  • Complete normalization of toxin induced increase of all five biochemical parameters - SGOT, SGPT ALP, Bilirubin and Hepatic triglycerides
  • Significantly ameliorates toxin induced histopathological changes in liver.

Ref. Handa SS, sharma A (1990) Ind. J. Med. Res. [B] 92: 284-292

slide17

Effect of pretreatment with different doses of Andrographolide on galatosamine intoxicated rats

Andrographolide was administed 48,24 and 2 hours prior to GaiN

slide18

Hepatoprotection against Paracetamol induced toxicity

Acute hepatitis induced in rats by single dose of Paracetamol 3 g/kg p.o.

Treatment of rats with 200 g/kg i.p. 1, 4 & 7 h after paracetamol administration leads to

  • Complete normalization of toxin induced increase of all five biochemical parameters - SGOT, SGPT ALP, Bilirubin and Hepatic triglycerides
  • Significantly ameliorates toxin induced histopathological changes in liver.

Ref. Handa SS, sharma A (1990) Ind. J. Med. Res. [B] 92: 284-292

slide19

Effect of pretreatment with different doses of Andrographolide on Paracetamol intoxicated rats

slide20

Antihepatotoxic effects of major diterpenoid constituents of A. paniculata

  • Hepatotoxicity was induced in mice by CCl4 or tert-butylhydroperoxide (tBHP)
  • Pretreatment of mice with the diterpenes-
  • Andrographolide,
  • Andrographiside,
  • Neoandrographolide
  • (100 mg/kg, i.p.) for 3 consecutive days in either group of the toxin-treated animals produced
  • significant reduction in malondialdehyde formation,
  • reduced glutathione (GSH) depletion and
  • enzymatic leakage of glutamic-pyruvate transaminase (GPT) and alkaline phosphatase (AP)
slide21

Contd

Comparison with silymarin revealed that

Andrographolide exhibited a lower protective potential than andrographiside and neoandrographolide which were as effective as silymarin with respect to their effects on

  • the formation of the degradation products of lipid peroxidation
  • release of GPT and AP in the serum.

The greater protective activity of Andrographiside and Neoandrographolide could be due to their glycosidic nature which may act as strong antioxidants.

Ref: Kapil et. al. (1993) Biochem Pharmacol. Jul 6;46(1):182-5.

slide22

In vivo effects of Andrographis leaf extract and Andrographolide on Hepatic Lipid peroxidation

Singe or repeated dose(15 days) of Andrographis extract(500mg/kg) or Andrographolide (5mg/kg) in rats produced

  • No significant change in NADPH induced microsomal Lipid peroxidation

CCl4 (5ml/kg) induced hepatic microsomal Lipid peroxidation was decreased when;

Rats were pretreated (4 hr) but only with singe dose and not long term administration of both Andrographis extract(500mg/kg) or Andrographolide (5mg/kg)

Ref: Choudhury et. al. (1984) Methods Find Exp Clin Pharmacol. 6(9):481-5

slide23

In vitro effects of Andrographis leaf extract and Andrographolide on Hepatic Lipid peroxidation

In vitro CCl4 (1 ul) induced hepatic microsomal Lipid peroxidation was completely normalized by both

  • Andrographis leaf extract (0.5 and 5 mcg/mg protein)
  • Andrographolide (0.5 and 5 mcg/mg protein)

At higher concentration of CCl4 (2ul)

Hepatic microsomal Lipid peroxidation remained

  • significantly increased in presence of Andrographolide (0.5mcg/mg pr.)
  • but not in presence of Andrographis leaf extract (0.5 mcg/mg protein)

Ref: Choudhury et. al. (1984) Methods Find Exp Clin Pharmacol. 6(9):481-5

slide24

Effect of Andrographis extract on mouse hepatic drug metabolising enzymes

Dose – 50 and 100mg/kg of 80% hydroalc extract for 14days in mice.

Both dose levels cause significant increase in levels of ;

  • Acid soluble sulphydryl (-SH) content
  • Cytochrome P450
  • Cytochrome P450 reductase
  • Cytochrome b5 reductase
  • Glutathione S-Transferase
  • DT-diaphorase
  • Superoxidase dismutase

Ref: Singh et al, (2001) Phytoether. Res. 15,382-390

slide25

In vivo effect on Hepatic Microsomal Drug metabolizing Enzymes in rats

Single oral doses of

  • Kalmegh extract = 0.5 and 1.0 g/Kg
  • Andrographilide = 5 and 10 mg/kg
  • Inhibited
  • Aniline hydroxylase
  • N-demethylase
  • O-demethylase

Repeated doses for 7 to 30 days produced induction of all the above enzymes.

Ref: Choudhury et al, (1987), Planta medica, 135-140

slide26

In vitro effect on Hepatic Microsomal Drug metabolizing Enzymes in rats

  • Kalmegh extract : 50 and 500µg/mg protein
  • Andrographilide : 0.5 and 5 µg/mg protein
  • did not cause the inhibition of the
  • Aniline hydroxylase activity
  • Not produced any appreciable effect on
  • N-demethylase activity
  • O-demethylase activity

Ref: Choudhury et al, (1987), Planta medica, 135-140

slide27

Effect of Andrographis extract on liver tumor

Liver damage ultimately leading to tumor was induced in albino mice by hexachloro cyclohexane (BHC)(500 ppm/kg of food for 1 to 8 month)

In animals supplemented with AP extract, compared to BHC control animals.

  • The liver marker enzymes viz. SGOT, SGPT & ALP were lowered
  • The protein levels were increased

This confirms hepatoprotective property of AP and its probable role in delaying hepatic tumorogenic condition.

Ref. Trivedi A, Rawal UM (1998) IJP 30; 318-322

slide28

Hepatoprotection of Andrographis extract against BHC induced severe liver damage

Liver damage was caused by BHC (500 ppm/kg food for 1 to 8 months)

Mice supplemented with Andrographis extract 12 mg/kg orally showed compared to BHC control group

  • Significant decline in ALT and AST
  • Significant decrease in ALP & gama glutamyl transpeptidase
  • Significant decrease in lipid peroxidase activity as compared to BHC
  • Significant increase in GSH levels

Ref. Trivedi N, Raval UM (2000) Indian Journal of Pharmacology 32: 288-293

slide29

Hepatoprotective and Antioxidant property of AP

Liver damage was caused by BHC (500 ppm/kg food for 1 to 8 months) in mice.

Animals supplemented with Andrographis extract, 12 mg/kg b.w./day orally.

  • Increased activity of Glutathione reductase (GR) with parallel increase in GSH levels
  • Significant decrease in activity of lipid peroxidation
  • Less of GST activity
  • Reduction in  GPT activity
  • Increase in SOD, CAT and GSH-PX

Ref. Trivedi NP, Rawal UM (2001) Ind. J. Exp. Biol. 39; 41-46

slide30

Clinical Study

Effect of Kalmegh in patients with Infective Hepatitis

slide36

Analytical Specification

Tests METHOD

1. Description

2. Physico-chemical analysis

a. Moisture (%w/w)

b. Acid insoluble Ash (%w/w)

3. Particle Size

a. Bulk Density (g/cc)

b. Tapped bulk density (g/cc)

c. Material Passing through 30# BS/35 ASTM (%w/w)

4. Heavy metal analysis

a. Lead

b. Cadmium

c. Arsenic

5. Microbiological analysis As per FIP Guidelines

a. Total Viable Aerobic count

b. Total Enterobacteriaceae

c. Total Fungal Count

6. Test for Specific Pathogen As per FIP Guidelines

a. E. coli (1g)

b. Salmonella Sp. (10g)

c. S.aureus (1g)

slide37

7. Mycotoxin analysis

Aflatoxins (B1 +B2 +G1 + G2)

8. Residual solvent analysis As per ICH Guidelines

a. Methanol

b. Ethyl acetate (%w/w)

9. Pesticide residue analysis As per USP & BP Limits

a. Organochlorine Pesticides

b. Organophosphorus Pesticides

c. Synthetic Pyrethroids

10. Phytochemical Analysis

Andrographolide (%w/w)

Total Andrographolides (%w/w)

Calculated as sum of Andrographolide,

Neoandrographolide, Isoandrographolide,

Andrograpanin and 14-Deoxy 11,12 Didehydroandrographolide

Protocol: As per USP, AOAC

slide38

366nm

254nm

Visible

Identification of Extract by TLC

slide41

For Details Please Contact:

NATURAL REMEDIES PVT. LTD.,

BANGALORE, INDIA

E-MAIL: extracts@naturalremedy.com

Thank You for your time