6. brief resume of the intended work: 1 Need for the study

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6.1 Need for the study:

Drug induced liver injury is a potential complication of most of the drug therapy since liver is central to the metabolic disposal of the drugs and xenobiotics.

Drug induced liver injury has been the most frequent single reason for removing approved drugs from the market.1

The Directly Observed Treatment, Short Course (DOTS) constitutes cornerstone of the current strategy for tuberculosis. However, the three drugs, Isoniazid, pyrazinamide and Rifampicin, used in the regimen are potentially hepatotoxic and may lead to drug associated hepatitis.2

Semecarpus anacardium LINN. (Family: Anacardiaceae) also called the “marking nut” has found many applications in Indian medicine in the treatment of gout, rheumatic pain and cancer.3

The nut extract has anticancer, hepatoprotective activity, anti-inflammatory, antioxidant property.4

Systemic studies on any possible effect of Bhallataka fruit on antitubercular drug induced hepatic damage seems to be scarce. Hence the present study is planned to explore the effect of aqueous extract of fruit part of Semecarpus Anacardium on biochemical and histopathological changes associated with antitubercular drugs induced liver damage in albino rats.
6.2 Review of literature:

Drug induced liver toxicity accounts for approximately one half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease.5

Liver injury by another definition is, when on definite exposure to a particular drug there is two fold rise in alanine transaminase (ALT) or alkaline transferase or bilirubin.6

Isoniazid, Rifampicin the first line drugs used for treating tuberculosis are associated with hepatotoxicity.7

Injury to the liver is the most serious adverse effect of Pyrazinamide.8

Semecarpus anacardium (marking nut) is a widely distributed plant throughout India and is a popular folk medicine.

Studies have been done in proving the anticancer and hepatoprotective activity of Semecarpus anacardium nut milk extract and establishing its protective role on deranged cell membrane in aflatoxin B1 induced hepatocarcinoma.9,10

Kangralkar VA, Burli SC et al investigated hepatoprotective activity of various fruit extract of Semecarpus anacardium in paracetamol induced liver damage model in Wistar rats. The aqueous as well as alcoholic extract showed significant hepatoprotective activity.11

6.3 Objectives of the study:

1. To study the effect of aqueous extract of fruit of Semecarpus anacardium on biochemical and histopathological changes induced by antitubercular drugs in rats, so as to know its hepatoprotective effect.

2. To study whether aqueous extract of fruit of Semecarpus anacardium reverses the hepatic damage caused due to antitubercular drugs.

3. To compare the effect of administration of aqueous extract of fruit of Semecarpus anacardium after stopping the antitubercular drug with mere withdrawal of antitubercular drug.

7.1 Source of data:

This study is going to be conducted in healthy adult albino rats of either sex weighing between 150-250 grams, which will be randomly collected from central animal facility, Bidar Institute of Medical Sciences, Bidar. Fruits of Semecarpus Anacardium will be collected from the local Market.

7.2 Methods of collection of data:
A. Study design: An experimental study.

B. Study period: November 2011 to May 2013.

C. Place of study: Bidar Institute of Medical Sciences, Bidar.

D. Study sample size: This study will be done in two phases. First phase containing four groups and second phase containing three groups of six albino rats in each group.

G. Methodology for data collection:

In the first phase Group I receiving vehicle control gum acacia suspension orally for 30 days. Group II receiving antitubercular drugs (Isoniazid+Rifampicin+Pyrazinamide) suspension for 30 days. Group III receiving (Isoniazid+Rifampicin+Pyrazinamide) suspension + Propylene glycol as vehicle control for 30 days. Group IV receiving (Isoniazid+Rifampicin+Pyrazinamide) suspension + aqueous extract of Semecarpus anacardium for 30 days. At the end of 30th day blood samples shall be tested for liver function test and livers shall be removed for histopathological examination to know whether it prevents hepatotoxicity.

In the second phase Group I receiving (Isoniazid+Rifampicin+Pyrazinamide) suspension orally for 30 days. Group II (Isoniazid+Rifampicin+Pyrazinamide) suspension orally for 30 days + No treatment from day 31 to day 50. Group III (Isoniazid+Rifampicin+Pyrazinamide) for 30 days + aqueous extract of fruit of Semecarpus anacardium from day 31 to day 50. Group I animals shall be sacrificed at the end of 30 days for biochemical and histopathological study. Group II and Group III shall be sacrificed at the end of 50 days for biochemical and histopathological test to know whether it reverses the hepatotoxic effect and not by mere withdrawal of the antitubercular drugs. After using different doses of aqueous extract of Semecarpus anacardium fruit, the suitable dose shall be used.
H. Methodology for data analysis:

Results will be statistically analysed by using ANOVA test followed by unpaired‘t’ test and p<0.05 will be taken as significant.

7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly.
YES (only on animals)
Investigations and interventions required:

  1. Serum alanine aminotransferase – By Reitman and frankel method.

  2. Serum aspertate aminotransferase – By Reitman and frankel method.

  3. Serum alkaline phosphatase – Colorimetric method.

  4. Serum bilirubin – modified Jendrassik and Grofs method.

  5. Total serum protein – Biuret method.

  6. Histopathological assessment of liver damage – By using a method of scoring of the structural changes described by National health services Meryland, USA.

7.3 Has ethical clearance has been obtained from your institution in case of 7.2?

YES”. The ethical clearance has been obtained from the Institutional Animal Ethics Committee of Bidar Institute of Medical Sciences, Bidar.

8.List of references :

  1. Temple RJ, Himmel MH. Safety of newly approved drugs: implication for prescribing [editorial]. JAMA. 2002 May 1;287(17):2273-2275.

  2. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd ed. WHO/CDS/TB/2003.313.World Health Organization, Geneva, 2003.

  3. Nandakari AK. Indian Materia Medica. 3rd ed. Bombay: Popular Book Depot, Ltd; 1954. P. 119.

  4. Ramprasath VR, Shanthi P, Sachdanandam P. Evaluation of antioxidant effect of semecarpus anacardium Linn. Nut extract on the components of immune system in adjuvant arthritis. Vascular pharmacology 2005;42(4):179-186.

  5. Kaplowitz N. Drug induced liver disorders: implications for drug development and regulation. Drug Saf 2001;24:483-90.

  6. Farell GC. Liver disease caused by drugs, anaesthetics, and toxins. In: Feldman M, Sleisenger MH, Scharschmidt BF, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 6th ed. Philadelphia: WB Saunders; 1998. P. 1221-52.

  7. Tasduq SA, Peerzad K, Koul S, Bhat R, Johri RK. Biochemical manifestation of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol. Res 2005;31:132-135.

  8. Petri WA. Chemotherapy of Tuberculosis, Mycobacterium avium complex disease, and leprosy. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, Medical Publishing Division; 2006. P. 1211.

  9. Premlatha B, Sachdanandam P. Effect of Semecarpus anacardium nut extract against aflatoxin B1 induced hepatocellular carcinoma. Fitoteria 1999 oct;70(5):484-492.

  10. Premlatha B, Sachidanandam P. Semecarpus anacardium L. nut extract administration induces the in vivo antioxidant defence system in aflatoxin B1 mediated hepatocellular carcinoma. Journal of Ethno pharmacology 1999 Aug;66(2):131-139.

  11. Kangalkar VA, Burli SC, Nandagaon VS. Protective activity of Semecarpus anacardium fruit extracts against paracetamol induced hepatic damage in Wistar rats. IJPSR 2010;1(8):72-76.

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