د/ خالد علي الحميضه قسم الأدوية والسموم كلية الصيدلة - جامعة القلمون الخاصة

1. Study of possible benefit interaction between pravastatin and cyclophosphamide in adult albino male rats. د/ خالد علي الحميضه قسم الأدوية والسموم كلية الصيدلة - جامعة القلمون الخاصة

2. Outline • Introduction: Drug interaction Cyclophosphamide pravastatin • Aim of work • Materials and Methods • Results • Conclusion

3. Drug interaction • Drug interaction is the modification of the action of one drugby another. • A drug–drug interaction occurs when one drug interacts with or interferes with the action of another drug.

4. Drug interaction • For example, taking an antacid with oral tetracycline causes a decrease in the effectiveness of the tetracycline.

10. Cyclophosphamide Cyclophosphamide (CP) is an alkylating agent that is used to treat: chronic and acute leukemia immunosuppressant after organ transplantation solid tumors autoimmune diseases, such as rheumatoid arthritis.

11. cause lethal cardiotoxicityin patients during cancer treatment Cyclophosphamide

12. Cyclophosphamide • symptoms and signs of myopericarditis • Lead to congestive heart failure, cardiomyopathy, • and myocardial depression

13. Cyclophosphamide Lipid peroxidation antioxidants Myocardial necrosis and myocarditis Extravasation of plasma fluid, erythrocytes, and toxic metabolites fibrin platelet microthrombiin areas of capillary damage Direct endothelial damage Fibrin deposition in cardiac myocytes, edemaand hemorrhage Thickened LV wall, diastolic dysfunction, and restrictive cardiomyopathy myocardial effusions Hemorrhagemyocarditis

14. Pravastatin Pravastatin (Prv) prevented the reperfusion-induced ventricular tachy- cardia and ventricular fibrillation in rats thus evidencing its beneficial role in decreasing cardiovascular mortality. Prv has antioxidant effect and prevent reactive oxygen species production.

15. pravastatin ↓nuclear factor κB ↓TNF-α ↑eNOS ↓ROS ↑NO ↓apoptosis ↓IL-6 Decrease oxidative stress Enhance antioxidant enzymes cardioprotection

16. Aim of work

17. Investigate possible benefit interaction between pravastatin and cyclophosphamide that induced cardiorenal toxicity in albino rats. Aim of work

18. Materials and Methods

20. Parameters

21. Parameters

22. Parameters Heart and kidney GSH SOD MDA Tissues samples Histopathological examination

23. Results

24. Effect of Prv on body, heart & renal weight, in addition to heart:body weight ratio, and renal:bodyweight ratio in CP-treated rats

25. Effect of pravastatinonheart ratein cyclophosphamide treated rats. @ * Heart Rate (beat/min) * Significant from normal control @ Significant from CP

26. Electrocardiogram (ECG) measurement in rats Electrocardiogram (ECG) measurement in rats Electrocardiogram (ECG) measurement in rats Normal pattern of P wave, QRS duration and T wave Normal pattern of P wave QRS duration and T wave Normal pattern of P wave QRS duration and T wave Normal pattern of P wave QRS duration and T wave Prv–treated rats Prv–treated rats Prv–treated rats Control

27. Electrocardiogram (ECG) measurement in rats P wave inversion and splitting QRS and depressed ST segment P wave inversion, splitting QRS and depressed ST segment CP –treated rats CP–treated rats

28. Electrocardiogram (ECG) measurement in rats NormalECG pattern in P wave and QRS duration CP plus Prv–treated rats

29. Effect of pravastatinoncreatine kinase (CK) in cyclophosphamide-treated rats. * Serum CK (U/L) @ @ * Significant from normal control @ Significant from CP

30. Effect of pravastatinonserum creatine kinase isoenzyme (CK-MB) in cyclophosphamide-treated rats. * CK-MB (U/L) @ @ * Significant from normal control @ Significant from CP

31. Effect of pravastatin on serum lactate dehydrogenase (LDH) in cyclophosphamide-treated rats. * @ Serum LDH (U/L) @ * Significant from normal control @ Significant from CP

32. Effect of taurine, pravastatin and their combination On serum triglyceridein cyclophosphamide-treated rats. * @ Serum triglyceride (mg/dL) * @ * Significant from normal control @ Significant from CP

33. Effect of taurine, pravastatin and their combination On reduced glutathione (GSH) content in heart tissues in cyclophosphamide-treated rats. @ @ * GSH (mg/g. tissue) * Significant from normal control @ Significant from CP

34. Effect of pravastatin on malondialdehyde (MDA) in heart tissues in cyclophosphamide-treated rats. * @ MDA (nmol/g. tissue) @ * Significant from normal control @ Significant from CP

35. Effect of pravastatin on superoxide dismutase in heart tissues in cyclophosphamide-treated rats. @ @ * SOD (U/g. tissue) * Significant from normal control @ Significant from CP

36. Effect of pravastatinonreduced glutathione (GSH) content in renal tissues in cyclophosphamide-treated rats. @ @ * GSH (mg/g. tissue) * Significant from normal control @ Significant from CP

37. Effect of pravastatinonmalondialdehyde (MDA) in renaltissues in cyclophosphamide-treated rats. * @ @ MDA (nmol/g. tissue) * Significant from normal control @ Significant from CP

38. Effect of pravastatinon superoxide dismutase in renal tissues in cyclophosphamide-treated rats. @ @ * SOD (U/g. tissue) * Significant from normal control @ Significant from CP

39. Effect of taurine, pravastatinon serum creatininein cyclophosphamide-treated rats. * Serum CR (mg/dL) @ @ * Significant from normal control @ Significant from CP

40. Effect of pravastatinon in serum blood urea nitrogen in cyclophosphamide- treated rats. * @ @ Serum BUN (mg/dL) * Significant from normal control @ Significant from CP

41. Conclusion

42. Lipid peroxidation Antioxidants → oxidative damage Direct endothelial damage Hemorrhagic changes in the renal cortex and glomerular inflammation Cardiotoxicity Renal toxicity

43. pravastatin Lipid peroxidation Antioxidants → ↓oxidative damage Direct endothelial damage Hemorrhagic changes in the renal cortex and glomerular inflammation Cardiotoxicity Renal toxicity

44. pravastatin Lipid peroxidation Antioxidants → ↓oxidative damage Direct endothelial damage Hemorrhagic changes in the renal cortex and glomerular inflammation Cardioprotection Renal protection

45. Thank you