Cisplatin (cis-diaminedichloroplatinum II, CDDP) is extensively used for the treatment of several cancers. Its major side effect; namely, nephrotoxicity, is a dose-limiting factor in CDDP therapy.1) The exact mechanisms of nephrotoxicity induced by CDDP are still not fully elucidated. However, lipid peroxidation and free radical generation in the renal tubular cells have been suggested to be responsible for CDDP-induced renal failure.2) Zhang et al. showed that CDDP significantly depletes glutathione (GSH) and increases lipid peroxidation in the mitochondria prepared from the rat renal cortical slices.3) In addition, the activities of superoxide dismustase (SOD) and catalase in the rat kidney tissues are significantly suppressed by CDDP. 4)Capsaicin (Cap) is the major pungent ingredient of hot red peppers. It has been used as a tool in the study of pain sensations which are caused by stimulation of Cap receptor or vanilloid receptor 1, an ion channel protein expressed by nociceptive primary afferent neurons. 5,6) On the other hand, Cap potentially inhibits the peroxidation of various lipids [7][8][9][10] and generates reactive oxygen species in rat peritoneal macrophages.11) However, the mechanism responsible for the potent inhibitory effects of Cap on lipid peroxidation in vivo is still unclear.Several studies have examined the effects of decreased lipid peroxidation and nephrotoxicity induced by CDDP using various agents including antioxidants. [12][13][14] The purpose of the present study was to investigate whether the administration of Cap exerts any protective effect against cisplatin-induced lipid peroxidation and nephrotoxicity in rats. MATERIALS AND METHODS ChemicalsCap with a purity of 98.6% was kindly supplied by Maruishi Pharmaceutical Co., Ltd. (Osaka, Japan). CDDP was purchased from Sigma (MO, U.S.A.). All other chemicals and reagents used were of analytical grade.Animals Male Sprague-Dawley rats weighing 200 to 250 g were purchased from Nippon SLC Inc. (Shizuoka, Japan). The rats had free access to standard rat chow and water ad libitum, were individually housed in metal cages, and kept in a room maintained at 23Ϯ2°C with a 12 h/12 h light/dark cycle. The study adhered to the guidelines of Osaka University of Pharmaceutical Sciences for the experimental use of animals.Animal Treatments The rats were divided at random into 4 groups of 4 or 5 animals each. The first group (control) received a vehicle (5% carboxymethyl cellulose sodium solution (CMC-Na), 5 ml/kg body wt., p.o.) used for Cap. The second group received Cap (10 mg/kg/d, p.o.) in 5% CMC-Na (5 ml/kg), and the third received 5% CMC-Na for 6 consecutive days injected with CDDP (5 mg/kg in physiological saline solution, i.p.). The fourth group received Cap (10 mg/kg/d, p.o.) in 5% CMC-Na for 6 consecutive days after CDDP injection (5 mg/kg, i.p.). For all groups, Cap or vehicle was given twice daily. The selected Cap concentration and the dose administration schedule without inducing any rat intestinal damage were chosen using data from our p...

Possible involvement of nitric oxide (NO) in the protective effect of ischemic preconditioning against the ischemia/reperfusion-induced acute renal failure was investigated. Ischemic preconditioning, which consists of three cycles of 2-minute ischemia followed by 5-minute reperfusion, was performed prior to 45-minute ischemia. Ischemic preconditioning significantly improved the renal dysfunction induced by 45-minute ischemia followed by 24-hour reperfusion. Histopathological examination of the kidney of ischemia/reperfusion rats revealed severe renal damage, and suppression of the damage was seen with the ischemic preconditioning treatment. NO metabolites (NOx) production in the kidney after 45-minute ischemia and reperfusion was markedly increased in ischemia/reperfusion rats with ischemic preconditioning, compared with animals not subjected to ischemic preconditioning, and these increases correlated with changes in endothelial NO synthase (eNOS) protein expression in renal tissues. The improvement of renal dysfunction in ischemic preconditioning rats was abolished by the pretreatment with NG-nitro-L-arginine, a nonselective NOS inhibitor, but not with aminoguanidine, an inducible NOS inhibitor. In addition, increment of endothelin-1 (ET-1) content in the kidney after the reperfusion was markedly suppressed by ischemic preconditioning treatment. These findings suggest that the protective effect of ischemic preconditioning on ischemia/reperfusion -induced acute renal failure is closely related to the renal nitric oxide production following the increase in eNOS expression after the reperfusion and that the suppressive effect of ischemic preconditioning on the ischemia/reperfusion -induced renal ET-1 overproduction may be partly involved in the ameliorating effect of ischemic preconditioning.

Background/Aim: Docetaxel (DTX) is metabolized by liver cytochromes P450 (CYP) 3A4 (CYP3A4) and 3A5 (CYP3A5) CYP3A4 activity is considered the main factor affecting the effectiveness in DTX clearance. We, therefore, explored the association between DTX-induced febrile neutropenia (FN) and concomitant polypharmacy involving CYP3A4 inhibitors in cancer patients. Patients and Methods: Among patients who received docetaxel, we compared the number of concomitant medications between patients with and without FN, and risk factors associated with FN were identified. Results: The total number of concomitant CYP3A4 inhibitors and substrates used was significantly higher in patients with FN [mean: 2.1 (95% confidence interval (CI)=1.5-2.9)] than in those without FN [mean: 1.4 (95% CI=1.0-1.8)] (p=0.01). The only risk factor for FN was the use of ≥2 concomitant CYP3A4 inhibitors and substrates in total (OR=4.82, 95% CI=1.77-14.1; p=0.002). Conclusion: Polypharmacy involving CYP3A4 inhibitors and substrates increases the risk of DTX-induced FN.

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