However, exhaled nitric oxide is a sensitive biomarker of the effects of inhaled corticos teroids. In contrast, the effects of the leukotriene receptor antagonist singulair are more variable, with no inhibition observed of nitric oxide observed in some stu dies. The usefulness of exhaled nitric oxide as a biomarker appears to vary with the class of drug, and our results selleck products suggest that airway nitric oxide production is a PDE4 independent mechanism. Alternative explana tions are that the current study was too short or under powered to detect a reduction in exhaled nitric oxide. There were few adverse effects in this study, although larger studies are needed to fully explore the safety pro file.

However, the lack of nausea and/or gastro intestinal side effects usually associated with oral PDE4 inhibitors indicates that the inhaled delivery of a PDE4 inhibitor may Inhibitors,Modulators,Libraries minimise the potential for systemic side effects. The pharmacokinetic analysis performed showed that systemic exposure to GSK256066 was extremely Inhibitors,Modulators,Libraries low, as some subjects did not have quantifiable exposure at any time point despite measurement with a very sen sitive analytical assay. Furthermore, the majority of subjects had levels below the LLOQ after 4 hrs on days 1 and 7. Additionally, the mean Cmax of GSK256066 was 20 pg/ml on both of these days, while measurable levels of the active metabolite GSK614917 were even lower, underscoring the value of inhaled delivery to limit systemic exposure and the potential for systemic side effects.

In contrast, the mean Cmax of roflumilast administered orally is over 2,000 pg/ml with levels Inhibitors,Modulators,Libraries of the active metabolite roflumilast N Oxide being even higher. Clearly orally adminis tered drugs will have higher plasma levels, but this comparison serves to highlight the low levels of systemic exposure with inhaled delivery for GSK256066. Inhibitors,Modulators,Libraries Two subjects were withdrawn from this study with high creatinine clearance values. This is because the protocol stated that subjects with abnormal creatinine clearance values defined by Inhibitors,Modulators,Libraries the laboratory reference range should be withdrawn, in order to exclude patients who developed renal dysfunction. High creatinine clear ance indicates good renal function, so there was no clin ical concern about keeping these patients in the study. However, the wording of the protocol stated that we had to withdraw these patients as the values were out side the laboratory reference range.

In retrospect, the protocol should have stated that patients with low crea tinine clearance would be withdrawn. It has recently been reported that the inhaled PDE4 inhi bitor UK kinase inhibitor Z-VAD-FMK 500,001 had no effect on FEV1 after 6 weeks of treatment in patients with COPD. Oral PDE4 inhibi tors have been reported to show clinical efficacy in COPD patients, but with a significant rate of side effects.