Voriconazole and fluconazole increase the exposure to oral diazepam

Conclusion Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly

Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

Conclusion Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-d-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved

Enhancement of GABAergic activity:neuropharmacological effects of benzodiazepines and therapeutic use in anaesthesiology

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABAAR) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABAARs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABAARs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABAARs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABAAR agonist remimazolam, have recently been published.</p

Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction

This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine.We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured.Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC(0-a)) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (C-max) 1.37-fold (P < 0.013) and half-life (t (A1/2) ) 1.37-fold (P < 0.001). Posaconazole increased the AUC0(0-a) of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases.Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance

Cerebral autoregulation after aneurysmal subarachnoid haemorrhage. A preliminary study comparing dexmedetomidine to propofol and/or midazolam

Background Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH. Methods Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 mu g/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mm Hg above the baseline. Results Data from nine patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean +/- SD) 1.20 +/- 0.14, 1.17 +/- 0.13 (P = .93), 1.14 +/- 0.09 (P = .72) and 1.19 +/- 0.18 (P = 1.0) and sROR% was 150.89 +/- 84.37, 75.22 +/- 27.75 (P = .08), 128.25 +/- 58.35 (P = .84) and 104.82 +/- 36.92 (P = .42) at baseline and during 0.7, 1.0 and 1.4 mu g/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 mu g/kg/h dexmedetomidine (P = .02). Conclusions Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of zolpidem in healthy subjects

Conclusion: Voriconazole caused a moderate increase in exposure to zolpidem in healthy young subjects but no clear pharmacodynamic changes were observed between the groups

Azole interactions with multidrug therapy in pediatric oncology

Patients with cancer receive multidrug therapy. Antineoplastic agents and supportive care drugs are often administered together, leading to potential drug-drug interactions. These interactions may have significant clinical implications in terms of toxicity or a decrease in the efficacy of the treatment administered. Here, we focus on the role of azoles and their main pharmacokinetic interactions with the principal classes of drugs used in pediatric oncology. The co-administration of azoles and antineoplastic agents, corticosteroids, immunosuppressants, antacids, antiemetics, antiepileptic drugs and analgesics was investigated, and a practical guide on the management of these drugs when administered together is provided