Significant receptor affinities of metabolites and a degradation product of mometasone furoate

Mometasone furoate (MF) is a highly potent glucocorticoid used topically to treat inflammation in the lung, nose and on the skin. However, so far no information has been published on the human glucocorticoid receptor activity of the metabolites or degradation products of MF. We have now determined the relative receptor binding affinities of the known metabolite 6β-OH MF and the degradation product 9,11-epoxy MF to understand their possible contribution to undesirable systemic side effects. In competition experiments with human lung glucocorticoid receptors we have determined the relative receptor affinities (RRA) of these substances with reference to dexamethasone (RRA = 100). We have discovered that 6β-OH MF and 9,11-epoxy MF display RRAs of 206 ± 15 and 220 ± 22, respectively. This level of activity is similar to that of the clinically used inhaled corticosteroid flunisolide (RRA 180 ± 11). Furthermore we observed that 9,11-epoxy MF is a chemically reactive metabolite. In recovery experiments with human plasma and lung tissue we found a time dependent decrease in extractability of the compound. Hence, we provide data that might contribute to the understanding of the pharmacokinetics as well as the clinical effects of MF

Cardiovascular safety of second-generation anthistamines

Reports of serious cardiac arrhythmia associated with some second-generation antihistamines have prompted concern for their prescription. This article reviews the nature of the adverse events reported and concludes that the blockade of potassium channels, particularly the subtype responsible for the rapid component of the delayed rectifier current (IKr), is largely responsible for such adverse cardiac events. Consequently, antihistamines with little or no interaction with these channels are expected to have the greatest safety margin. The main cardiac arrhythmia of concern is that of torsades de pointes, a potentially fatal phenomenon characterized by prolonged ventricular depolarization that manifests as a prolonged QT interval and polymorphic ventricular tachycardia, with twisting of the QRS complexes. Based on pre-clinical and clinical evidence, it appears that loratadine, cetirizine, and fexofenadine are safe from cardiac arrhythmia via the IKr channel, whereas astemizole and terfenadine have a propensity to cause ventricular tachyarrhythmias

Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate

What is already known about this subjectMometasone furoate (MF) is a new inhaled glucocorticoid for which the first reports suggested a low degree of systemic side-effects and low systemic availability.Recent studies of Fardon and colleagues have shown that MF's cortisol suppression is similar to that of fluticasone.Pharmacokinetic/dynamic evaluations of MF's systemic side-effects, probing whether systemic side-effects can be explained by systemic availability, plasma protein binding and receptor binding affinity, are lacking in the literature.What this study addsThis study shows that the systemic availability of MF and fluticasone propionate (FP) are similar and that systemic availability is directly related to the dose.It also shows that the metabolites of MF are present only in very low concentrations at most, contrary to results in rats.The observed cortisol suppression of FP and MF is related to the trough plasma concentrations and seems to be in agreement with its observed systemic availability, plasma protein binding and receptor binding affinity