“EVALUATION OF ANTIDIABETIC ACTIVITY OF HELICTERES



“EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF ACE- INHIBITORS / ANGIOTENSIN II TYPE I RECEPTOR BLOCKERS AGAINST PARACETAMOL INDUCED LIVER DAMAGE IN RATS”

Synopsis for registration of M.Pharm Dissertation

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

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In partial fulfillment

Of the requirement for the Degree of

MASTER OF PHARMACY IN PHARMACOLOGY

Under the Guidance of

Dr.D.SHESHADRI SHEKAR

M.Pharm., Ph.D.

BY

P.Madhavi Latha

I M. PHARM.

DEPARTMENT OF PHARMACOLOGY

SRI K.V.COLLEGE OF PHARMACY, CHICBALLAPUR-562101

(2013-14)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

| | | |

|1. |Name of the candidate and address |P.Madhavi Latha |

| | |D/O late P.C.Dasari |

| | |C/o M. Vengal Reddy |

| | |26/349-B, M.S Nagar, Nandyal, |

| | |Kurnool (Dist), Andhra pradesh. |

| | | |

|2. |Name of the Institution |SRI K.V.COLLEGE OF PHARMACY, |

| | |M.G.ROAD, CHICKBALLAPUR, |

| | |KARNATAKA-562101 |

| |Course of study and subject | |

|3. | |MASTER OF PHARMACY IN PHARMACOLOGY |

| |Date of the admission | |

|4. | |13/08/2012 |

| |Title of the topic: |

|5. |“EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF ACE- INHIBITORS / ANGIOTENSIN II TYPE I RECEPTOR BLOCKERS AGAINST PARACETAMOL |

| |INDUCED LIVER DAMAGE IN RATS” |

| | |

|6. |6.1. NEED FOR THE STUDY: |

| | |

| |Liver disease has become one of the major causes of morbidity and mortality all over the world. About 20,000 deaths found every|

| |year due to liver disorders. The liver transforms and excretes many drugs and toxins. These substances are frequently converted|

| |to inactive form by reactions that occur in the hepatocytes1, 2. The liver damage may involve mainly the hepatic parenchymal |

| |cells, cells of the excretory tree or both. In the case of some hepatotoxic agents, vascular structures are the primary focus |

| |of injury, acute hepatic injury may be translated into chronic liver diseases, expressed as cirrhosis or even as carcinoma . |

| |Liver damage is associated with cellular necrosis, increase in tissue lipid peroxidation and depletion in the tissue |

| |glutathione (GSH) levels. In addition serum levels of many biochemical markers like Aspartate Transaminase (AST), Alanine |

| |Transaminase (ALT), triglycerides, cholesterol, bilirubin & alkaline phosphatase (ALP) are elevated3. The liver may be |

| |considered as the most important organ in drug toxicity for two reasons: on the one hand it is functionally interposed between |

| |the site of absorption and the systemic circulation and is a major site of metabolism and elimination of foreign substances; |

| |but on the other hand these features also render it a preferred target for drug toxicity4. Many times liver is damaged due to |

| |chemicals, alcohol consumption and because of few drugs which are normally used for therapy5. |

| |Drug-induced liver injury (DILI) therefore poses a major clinical problem. Overdosage of paracetamol (PCM) leads to the |

| |saturation of conjugation pathway leading to GSH depletion and increase in the formation of toxic reactive metabolites6, 7 |

| |which increase the level of hepatotoxicity. Intrinsic hepatotoxicity following acetaminophen and alcohol overdose accounts for |

| |the majority of cases of drug-induced acute liver failure. In contrast, hepatotoxicity associated with most other drugs is |

| |idiosyncratic, which implies by definition that DILI develops in only a small proportion of subjects exposed to a drug in |

| |therapeutic doses, and the risk of acute liver failure associated with idiosyncratic hepatotoxins is usually less than 1 per |

| |10,000 exposed patients. DILI also represents a major challenge for industry and regulatory authorities, it is a leading cause |

| |for termination of further substance development in preclinical and clinical phases, and it is also the most common single |

| |adverse drug reaction leading to refusal of market approval4. |

| |Hepatoprotective agents are those compounds, which mitigate the liver injury caused by hepatotoxic agents. The compounds which |

| |have been reported to possess the hepatoprotective activity are Glycine8, Tocopherol9, Rimonabant10, Methionine11, |

| |N-acetylcysteine12 , Cystathionine13, ACE-Inhibitors14 and Angiotensin II type I receptor blockers15. As such no information is|

| |available regarding the hepatoprotective activity of ACE- Inhibitors and Angiotensin II type I receptor blockers against |

| |Paracetamol induced liver damage in rats. Hence present study has been undertaken to find out the hepatoprotective activity of|

| |Ace- inhibitors and Angiotensin II type I receptor blockers against Paracetamol induced liver damage in rats. |

| | |

| |6.2. REVIEW OF LITERATURE: |

| |ACE Inhibitor drugs inhibit competitively the activity of ACE (also termed kininase II) to prevent formation of the active |

| |octapeptide, angiotensin II, from the inactive decapeptide, angiotensin I. This occurs in blood and tissues including kidney, |

| |heart, blood vessels, adrenal gland and brain. Angiotensin II is a potent vasoconstrictor, promotes aldosterone release, |

| |facilities sympathetic activity and has other potentially harmful effects on the cardiovascular system. Reduction in blood |

| |pressure secondary to vasodilatation following ACE inhibition is greatest when the renin-angiotensin system is stimulated (e.g.|

| |following diuretic therapy or in renal artery stenosis) but ACE inhibitors also lower blood pressure when there is normal or |

| |low activity of the renin-angiotensin system. Recent evidences showed that ACE Inhibitors like Captopril and Enalapril showing |

| |hepatoprotective activity against paraquat toxicity.14 |

| |Angiotensin II type I receptor blockers, act competitively antagonise  angiotensin II receptor type1 (AT1) receptor, reducing |

| |the end organ responses to angiotensin II. Administration of this results in a decrease in total peripheral resistance |

| |(afterload) and cardiac venous return (preload) All of the physiological effects of angiotensin II, including stimulation of |

| |release of aldosterone, are antagonized in the presence of Angiotensin II type I receptor blockers. Reduction in blood pressure|

| |occurs independently of the status of the renin-angiotensin system. A growing number of studies have suggested that rennin |

| |angiotensin system (RAS), an important factor in regulating blood pressure and body fluid homeostasis, is also involved in |

| |hepatic fibriogenesis. Patient with chronic liver disease, showed an increase in plasma activity.Experimental studies have |

| |revealed that blockade of RAS with ACE inhibitors or the AT1 receptor blockers can significantly slow down the progression of |

| |fibrotic disease.15 |

| |6.3. OBJECTIVE OF STUDY: |

| |The objective of the proposed study is to evaluate hepatoprotective activity of Ace- inhibitors and Angiotensin II type I |

| |receptor blockers against Paracetamol induced liver damage in rats. |

| |MATERIALS AND METHODS : |

| |7.1. SOURCE OF DATA: |

| |Whole work is planned to generate data from laboratory studies i.e. experiments are performed as described in references. |

| |Experimental studies in journals and in text books available with college and other libraries. Literature is searched from |

| |various web sites in the internet. |

| | |

| |7.2. METHOD OF COLLECTION OF DATA: |

| |The data collected will be based on animal experimentation as per the parameters studied, which are mentioned in objective of |

| |the study. |

| | |

| |EXPERIMENTAL DESIGN: |

| |REQURIEMENTS: |

| |Animal : Rat [Albino Wistar strain] |

| |Sex : Male and Female. |

| |Body weight : 150-220 g |

| |Chemicals : Ace- inhibitors , Angiotensin II type I receptor blockers, PCM, & Biomarkers kits (MERCK). |

| | |

| |METHODOLOGY : |

| |The rats were divided into the following groups each containing 6 rats and the study was being carrying out with three models |

| |as follows |

| |PARACETAMOL INDUCED 16 |

| |Group 1: Vehicle control |

| |Group 2: Curative studies will be performed by administration of PCM (2g PCM/kg BW p.o) for first three days followed by |

| |therapeutic dose (TD) of ACE Inhibitor alone for next 6days. |

| |Group 3: Curative studies will be performed by administration of PCM (2g PCM/kg BW p.o) for first three days followed by the |

| |(TD) Angiotensin II type I receptor blockers of alone for next 6days. |

| |Group 4: Prophylactic studies will be carried out by the simultaneous administration of TD of ACE Inhibitor followed by PCM (2g|

| |PCM/kg BW p.o) for 10days. |

| |Group 5: Prophylactic studies will be carried out by the simultaneous administration of TD Angiotensin II type I receptor |

| |blockersof followed by PCM (2g PCM/kg BW p.o) for 10days. |

| |Finally, treated rats receive Thiopentone sodium (40mg/kg b.w.) on next day of the last dose treated in all groups and the |

| |study was terminating after 24hr post administration. All the animals were sacrifice, for blood analysis and histopathological |

| |studies. |

| |PARAMETERS TO BE EVALUATED: |

| |1. Liver will be isolated and weighed. |

| |2. Blood samples will be collected and estimated ALT, AST, ALP, Albumin, total serum bilirubin and total proteins etc. |

| |3. Liver will be isolated and processed for the estimation of anti-oxidant enzymes like catalase (CAT), Glutathione (GSH), |

| |superoxide dismutase (SOD), Glutathione peroxidase (GPX) and lipid peroxidation (LPO) etc. |

| |4. Liver will be subjected for histopathological studies. |

| | |

| |7.3 STATISTICAL ANALYSIS: |

| | |

| |The statistical significance of the results will be analyzed by multiple analysis of variance (ANOVA). p ................
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