Basic Informations

C.V

Marwa Mahmoud Ahmed Khalaf

Master Title

PHARMACOLOGICAL STUDIES ON THE PROTECTION OF THE KIDNEY AGAINST CISPLATIN INDUCED NEPHROTOXICITY IN RATS

Master Abstract

English summary Cisplatin (cis-diaminedichloroplatinum II, CDDP) is an antitumor agent which is widely used with a broad spectrum of activity in human cancers. However, its clinical use is limited by the onset of a severe dose-limiting nephrotoxicity. Regarding the mechanisms of nephrotoxicity of cisplatin, so far several hypotheses have been put forward, among which oxidative stress is a noticeable one. Many chemoprotectors have been evaluated to alleviate the severity of this toxic side-effect. In recent years, different types of antioxidant interventions have been reported, one of them included the renin angiotensin system inhibition therapy. Captopril, is an angiotensin converting enzyme inhibitor, effectively used as antihypertensive agent: It contains a free SH-group, and is suggested to ameliorate chemically-induced nephrotoxicity. Losartan, is an angiotensin II receptor blocker, clinically used as antihypertensive, and is reported to prevent oxidative stress. This suggests the promising role of losartan as angiotensin II receptor blocker in treatment of cisplatin-induced nephrotoxicity. The present study is an experimental trial to assess the nephrotoxic effect of cisplatin as well as the nephroprotective potential of either captopril or losartan. Another goal of this study, is to investigate the possible protective mechanism(s) by which ACE inhibitor (captopril) or angiotensin receptor blocker (losartan) counteract cisplatin-induced nephrotoxicity. In view of the previously mentioned results, the following could be concluded: ? Cisplatin administration produces severe nephrotoxicity in rats, where oxidative stress plays an important role as evidenced by increased kidney content of lipid peroxides and depletion of GSH (although not apparent in-vivo). ? The present study clearly demonstrates that captopril and losartan could be promising drugs for clinical use as nephroprotectors against cisplatin-induced nephrotoxicity. Furthermore, this study sheds light on the mechanisms involved in their nephroprotective effect. They ameliorated the kidney injury induced by cisplatin and guard against oxidative stress by restoring cellular defense mechanism, through increasing the kidney GSH content and reducing lipid peroxidation. In addition, the nephroprotective activity of captopril is most likely attributed to its structure as a sulfur-containing nucleophile. ? It should be mentioned that the nephroprotective abilities of captopril or losartan were not mediated through lowering platinum uptake by the kidney tissue. ? Captopril and losartan are equipotent in their nephroprotective potential. Since the two drugs are used clinically this may simplify their introduction as protective agents. ? Further investigations are clearly warranted to establish the clinical applicability of these drugs in patients with kidney diseases especially those associated with cisplatin administration, and to explore the possible interference of these drugs with the antitumor activity of cisplatin.

PHD Title

PHARMACOLOGICAL STUDY OF THE POSSIBLE INTERACTIONS BETWEEN CERTAIN ANTIDIABETICS AND SOME TRACE ELEMENTS IN EXPERIMENTAL ANIMALS

PHD Abstract

English Summary The present study was performed to evaluate the effect of two trace elements namely zinc sulfate and vanadyl sulfate and two antidiabetic drugs namely glimepiride and rosiglitazone on certain parameters related glycemic status and oxidative stress in STZ-diabetic rats. The trace elements were given separately or in combination with the antidiabetic drugs. The effect was studied after single dose as well as after two weeks of daily dose administration. The parameters estimated were serum glucose level, serum insulin level, liver glycogen content, serum MDA, blood GSH and blood SOD levels. Furthermore, the effect of test drugs and their combination on glucose (6 mmol/L)-stimulated insulin secretion from isolated rat pancreatic islets was studied. From the previous findings it could be concluded that: 1- Zinc sulfate and vanadyl sulfate possess hypoglycemic actions in diabetic rats. 2- Zinc sulfate and vanadyl sulfate possess antioxidant actions in diabetic rats. 3- The hypoglycemic action of zinc sulfate and vanadyl sulfate is not due to insulin release but is probably due to its extrapancreatic effects. 4- Zinc sulfate and vanadyl sulfate did not affect the hypoglycemic action or antioxidant action of glimepiride or rosiglitazone when given together in the selected doses. This indicates that the coadministration of zinc sulfate or vanadyl sulfate with glimepiride or rosiglitazone does not produce serious reactions on serum glucose and insulin levels. In conclusion, the current results clearly indicate the beneficial effects of zinc sulfate or vanadyl sulfate in both controlling hyperglycemia and the protection against oxidative stress in diabetes. According to the findings of the present study, it could be stated that there is no significant interaction between zinc sulfate or vanadyl sulfate and glimepiride or rosiglitazone when used in combination on any of the aforementioned parameters. It follows that the two drugs can be taken together safely without fear of any serious reactions. The absence of additive action between the two drugs observed in this study may be attributed to the use of doses which give maximal response, thus no potentiation of action could be observed. However, this conclusion cannot be considered final except after clinical investigation to confirm this conclusion for efficacy and safety.