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SCREENING MODELS OF ANTIDYSLIPIDEMIC AGENT.docx

The document explores screening models of antidyslipidemic agents, detailing their role in managing hyperlipidemia characterized by elevated lipid levels in the blood. It discusses various lipoproteins, risk factors for hyperlipidemia, dietary cholesterol sources, and classifications of antihyperlipidemic agents, followed by in vivo and in vitro screening models for testing their efficacy. Specific methodologies for animal testing, including procedures and evaluations for different animal models, are also provided.

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SCREENING MODELS OF ANTIDYSLIPIDEMIC AGENT TUSHAR UNDHAD M.PHARM SEM - 1 IN PHARMACOLOGY SUBJECT: MPL103T
1 INDEX SR. NO CONTENT PG. NO 1. INTRODUCTION 02 2. LIPOPROTEIN 02 3. RISK FACTORS 03 4. DIETARY SOURCE OF CHOLESTEROL 04 5. CLASSIFICATION OF ANTIHYPERLIPIDEMIC AGENT 05 6. SCREENING MODELS OF ANTIDYSLIPIDEMIC AGENT 06
2 1. INTRODUCTION:  Antihyperlipidemic agents that are used in the treatment of high levels of fats (lipids) in the blood.  They are also called lipid lowering drugs.  Hyperlipidemia:  Hyperlipidemia is a disorder of high levels of lipids and lipoproteins in the blood, characterized byhigh cholesterol, triglycerides (TGs), orlow HDL levels.  Hyperlipidemia is complex disease caused by the interplay of genetic, dietary and physiologic factors  LDL ≥ 130mg/dl (borderline high or higher) 2. LIPOPROTEINS:  Classificationoflipoproteins: 1. Chylomicrons (ULDL) – 0 to 0.4mg/dl 2. Very low-density lipids (VLDL) – 2 to 30mg/dl 3. Low density lipids (LDL) – less than 100mg/dl 4. High density lipids (HDL) – more than 60mg/dl
3 lipoprotein  A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. 3. RISK FACTORS: I.Risk factor Alcohol overuse Cigarette smoking Diabetes mellitus Hyper- tension Liver disease Obesity Low HDL < 40mg/dl
4 4. DIETARY SOURCE OF CHOLESTEROL: Type of fat Source Effect on cholesterol level Monounsaturated Olive oil, Peanut oil, Almonds, Nuts, LDL HDL Polyunsaturated Corn, soyabean, sunflowers, fish LDL HDL Saturated Milk, Butter, Cheese, Coconuts, Egg, Chicken LDL HDL
5 5. CLASSIFICATION OF ANTIHYPERLIPIDEMIC AGENT: Class of Drugs Name of Drugs 1.HMG COA Reductase Inhibitors Atorvastatin, Simvastatin, Rosuvastatin, Lovastatin. 2.Fibric acid derivatives Clofibrate, Fenofibrate, Ciprofibrate, 3.Bile Acid Resin Colestipol, Cholestyramine 4.Cholesterol Absorption Inhibitors Ezetimibe 5.LDL Oxidation Probueol 6.Pyridine Derivatives Nicotinic acid, Nicotinamide.
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7 6.SCREENING MODEL OF ANTIDYSLIPIDEMIC AGENT: (A) In Vivo Models: 1.Triton induced hyperlipidemia in Wistar rat 2.Cholesterol diet induced atherosclerosis in rabbits (High fat diet) 3.Hereditary hyperlipidemia in rabbits 4.Hypolipidemic activity in Syrian hamsters 5.Transgenic animal model 6.Hereditary hypercholesteremia in rats 7. IV lipid tolerance test in rat 8.Efect of HMG COA reduction inhibition in vivo 9.Fructose induce hyperglycemia in rat 10.Cholestylamine binding (B) In Vitro Models: 1.Inhibition of isolated HMG COA reductase inhibitors 2.ACAT inhibitory model
8 (A) In Vivo Models: 1. Triton induced hyperlipidemia in Wistar rat:  Purpose and Rational:  The systemic administration of the triton to rats’ results in the biphasic elevation of plasma cholesterol and triglycerides.  Requirement:  Chemicals: Triton, surfactant  Animal: Wistar strain male albino rats.  Procedure:  Rats are divided into 7 groups such that each group contains 6 rats.  The animals are starved for 18hr and 10% aqueous solution of triton at 400mg/kg body weight given i.p.  The test drugs and the solvent for control is administered simultaneously with triton injection.  After administration of triton, blood is collected by retro orbital puncture under ether anesthesia and subjected to centrifugation to obtain serum after 24hr and 48hr  Evaluation:  Serum is analyzed fortriglyceride, totalcholesterol, HDL, LDL, VLDL, serum glucose.  The result is evaluated by ANOVA test and Dunnett’s Multiple comparison test.
9 2. Cholesterol diet induced atherosclerosis in rabbits:  Purpose and Rational:  Rabbits are susceptible to hypercholesterolemia and atherosclerosis after an excessive cholesterol feeding, so this model is chosen for studying atherosclerotic activity.  Requirement:  Chemical: Dimethyl sulfoxide  Animal: White New Zealand male rabbits  Procedure:  Male White New Zealand rabbits (8-10 weeks)  Blood is withdrawn from marginal ear vein for determination of Total cholesterol, Total triglycerides, Blood sugar.  Dividing into 2 Groups Control and Treatment with drug. (10 animals in each group)  Rabbits feed with food containing cholesterol (0.3-2%) for 10-12 weeks.  One group is kept with normal diet.  At the end, blood is collected and tested for Total cholesterol, and triglyceride levels.  Animals are sacrificed, thoracic aorta is removed, cleaned of surrounding tissue.  Cut opened longitudinally and fixed with formaldehyde.  Tissue is stained with oil red.  In animal fed a normal diet, the aorta does not show any staining.  Cholesterol fed rabbit the aorta shows severe atherogenic lesion.
10  Evaluation:  Cholesterol-fed rabbits the aorta shows severe atherogenic lesions.  Statistical evaluation is performed by Dunnett`s or Schefft’s test. 3. Hereditary hyperlipidemia in rabbit:  Purpose and Rational:  To produce hereditary hyperlipidemia in rabbit.  To study the effect of potential anti- arteriosclerosis drugs.  Requirement:  Chemical: Probucol  Animal: Homozygous Wistar Hereditary Hyperlipidemic rabbits  Procedure:  At two month of age, 8 rabbits are divided into 2 groups (group A and group B) having 2 male and 2 female rabbits in each group.  Group A (two males and two female) are feed standard rabbit chow for six months.  Group B (two males and two female) rabbit chow with 1% (wt/wt) probucol for 6 months.  The amount of daily diet for each animal is restricted to 100 g during the study period.  After six months, sacrifice rabbits and analyze blood and aortas of rabbits.
11  Evaluation:  The average value of total glycerol and total cholesterol of the treated group are compared with the control group using student’s t test. 4. Hypolipidemic activity in Syrian hamsters:  Purpose and Rational:  The lipoprotein and bile acid metabolism of the hamster is close to human. Easy to handle and more human like.  The Syrian hamster (Mesocricetus auratus) is a widely used animal to study the effects of drugs and diet on lipoprotein metabolism.  Approved lipid lowering drug like HMG-CoA reductase inhibitors, or cholestyramine lower plasma cholesterol in hamster.  Requirement:  Chemical: HMG-CoA reductase inhibitor  Animal: Syrian hamsters  Procedure  Male Syrian hamster weighing 95-125g are taken.  Test and control group are administered with cholesterol rich food.  Along with food in test group the compound mixed with the food and given (0.4-4% of test drug with food)
12  After 1-2 weeks of this diet the anesthetize with isoflurane.  Blood is withdrawn from retro orbital vein plexus.  Atherosclerosis can be induced in Syrian hamster by feeding diet with cholesterol and saturated fat.  Evaluation:  Dose response curves of standard and test drug are compared  The plasma is analyzed for total cholesterol using a colorimetric enzymatic assay (Merck, CHOD-iodine, BDH).
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