Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(؉)-and R-(؊)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(؉)-and R-(؊)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(؉)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C max ) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t 1/2 ) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(؉)-ibuprofen was 183% of the control value (P < 0.001) and its mean C max was 116% of the control value (P < 0. Voriconazole is a novel triazole antifungal agent, available as oral and intravenous formulations, with potent activity against a broad spectrum of clinically significant pathogens, including Aspergillus, Cryptococcus, and Candida species (5,8,27). Voriconazole is metabolized by the cytochrome P450 (CYP) enzyme system, mainly by the polymorphic enzyme CYP2C19 and to a lesser extent by the polymorphic enzymes CYP2C9 and CYP3A4 (13; G. Mikus, M. Drzevinska, V. Schoevel, J. Burhenne, K. D. Riedel, T. Thomsen, M. M. Hoffmann, J. Weis, J. Rengelshausen, and W. E. Haefeli, Abstr. 7th Congr. Eur. Assoc. Clin. Pharmacol. Ther., abstr. 418, 2005). In vivo studies have shown that addition of voriconazole at 300 mg twice daily to a 30-mg oral dose of warfarin in healthy volunteers resulted in a doubling of the prothrombin time from 8.4 to 16.6 s (28), probably due to inhibition of CYP2C9. In addition, coadministration of voriconazole has significantly increased the area under the plasma concentration-time curve (AUC) of phenytoin, a substrate of CYP2C9 (30); the AUC of omeprazole, a substrate of CYP2C19 (http://www.emea.eu .int./humandocs/Humans/EPAR/vfend/vfend.htm); and the AUC of cyclosporine, which is metabolized by CYP3A4 (31).Fluconazole is another azole antifungal agent and a welldocumented potent inhibitor of CYP2C9-catalyzed reactions both in vitro (3,20) and in vivo (4, 18) and a weaker inhibitor of CYP3A4-catalyzed reactions (23). It has also been found to inhibit CYP2C19-catalyzed reactions both in vitro (34) and in vivo (17). However, there are few data on the possible interactions between fluconazole and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatment with fluconazole significantly increased the AUC of the CYP2C9 substrate celecoxib (7), and recently, it has been shown that coadministration of fluconazole and a novel cyclooxygenase 2 (COX-2)-selective inhibitor,...

Background Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown. Methods We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery. Results Of the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013–0.32, P = 0.033). The occurrence of adverse events was similar among the groups. Conclusions Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects.

The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.