Application of antioxidants and other agents to prevent cisplatin ototoxicity

OBJECTIVE/HYPOTHESIS: To review the recent data from experiments performed in this laboratory to test the hypothesis that cisplatin ototoxicity is related to depletion of glutathione and antioxidant enzymes in the cochlea and that the use of antioxidants or protective agents would protect the cochlea against cisplatin damage and prevent hearing loss. STUDY DESIGN/METHODS: Data were reviewed from experiments performed in this laboratory. Control rats were treated intraperitoneally with cisplatin 16 mg/kg. Experimental rats were given cisplatin in combination with one of the following protective agents: diethyldithiocarbamate, 4-methylthiobenzoic acid, ebselen, or lipoic acid. Animals in each group underwent auditory brainstem response (ABR) threshold testing before and 3 days after treatment. Cochleae were removed after final ABR testing and analyzed for glutathione and activities of the enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and malondialdehyde. RESULTS: Rats in the control group receiving cisplatin were found to have significant ABR threshold shifts. This was accompanied by a reduction of glutathione and the activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase) and an elevation of malondialdehyde. Experimental animals had preservation of ABR thresholds and levels of glutathione, antioxidant enzyme activity, and malondialdehyde that were similar to untreated animals. CONCLUSION: Cisplatin ototoxicity appears to be initiated by fee-radical production, which causes depletion of glutathione and antioxidant enzymes in the cochlea, and lipid peroxidation, manifested by an increase in malondialdehyde. These effects were blocked by each of a series of antioxidant compounds given in combination with cisplatin. A mechanism for cisplatin ototoxicity is elaborated with a proposed plan of chemoprevention using agents with different mechanisms of action. These substances could be used alone or in combination to reduce the severity of cisplatin ototoxicity in patients.     

DEMONSTRATION OF α-ADRENOCEPTOR ANTAGONISM BY THE 5HT2 ANTAGONIST, KETANSERIN (R49945), IN SHEEP

Serotonin causes a dose related (0.1-20 micrograms/kg i.v.) increase in mean arterial blood pressure (MAP) and heart rate in conscious sheep. Ketanserin (0.1 mg/kg per h i.v.) causes a decrease in blood pressure, and an increase in heart rate. In the presence of ketanserin, serotonin induced increases in MAP are attenuated, or abolished, but the increases in heart rate are enhanced. Ketanserin (10 mg/kg per h i.v.) attenuates or abolishes the increase in blood pressure induced by the alpha-adrenoceptor agonist phenylephrine in conscious sheep. When administered in the presence of the alpha-adrenoceptor antagonist prazosin, ketanserin (0.1 mg/kg per h i.v.) fails to induce a further hypotensive response. These data suggest that in the conscious sheep ketanserin exhibits predominantly alpha-adrenoceptor antagonism.     

Acute post-streptococcal glomerulonephritis without proteinuria.

Two cases of histologically proven acute post-streptococcal glomerulonephritis presenting as congestive cardiac failure with normal blood pressure are reported. Proteinuria was not a finding. These features are discussed.     

The effect of protein restriction on the progression of renal insufficiency

Dietary protein intake may be an important determinant of the rate of decline in renal function in patients with chronic renal insufficiency. We conducted a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment. The study lasted 18 months and included 64 patients with serum creatinine concentrations ranging from 350 to 1000 micromol per liter. The patients were randomly assigned to follow either a regular diet or an isocaloric protein-restricted diet (0.4 g of protein per kilogram of the body weight per day). Blood-pressure levels and the balance between calcium and phosphate were similar in the two groups. End-stage renal failure developed in 9 of the 33 patients (27 percent) who followed the regular diet during the study, as compared with 2 of the 31 patients (6 percent) who followed the protein-restricted diet (P less than 0.05). The mean (+/- SE) glomerular filtration rate, as measured by the clearance of 51Cr bound to EDTA, fell from 0.25 +/- 0.03 to 0.10 +/- 0.05 ml per second (P less than 0.01) in the group on the regular diet, whereas it fell from 0.23 +/- 0.04 to 0.20 +/- 0.05 ml per second (P not significant) in the group on the protein-restricted diet. We conclude that dietary protein restriction is effective in slowing the rate of progression of chronic renal failure.     

Cardiovascular consequences of cortisol excess

Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cortisol. Cardiovascular disease is the major cause of morbidity and mortality in Cushing's syndrome, and excess risk remains even in effectively treated patients. The cardiovascular consequences of cortisol excess are protean and include, inter alia, elevation of blood pressure, truncal obesity, hyperinsulinemia, hyperglycemia, insulin resistance, and dyslipidemia. This review analyses the relationship of cortisol excess, both locally and at tissue level, to these cardiovascular risk factors, and to putative mechanisms for hypertension. Previous studies have examined correlations between cortisol, blood pressure, and other parameters in the general population and in Cushing's syndrome. This review also details changes induced by short-term cortisol administration in normotensive healthy men.