Charlotte A. Baidoo

Fluticasone propionate aqueous nasal spray provided significantly greater improvement in daytime and nighttime nasal symptoms of seasonal allergic rhinitis compared with montelukast

BACKGROUND The safety and efficacy of intranasal corticosteroids for the treatment of allergic rhinitis is well documented in the literature. Additionally, an expert panel has concluded that intranasal corticosteroids are the first line of therapy when obstruction is a major component of rhinitis. Montelukast is a leukotriene receptor antagonist recently approved for the treatment of seasonal allergic rhinitis (SAR). OBJECTIVE This randomized, double-blind, double-dummy, parallel-group study was conducted to compare the effectiveness of a 15-day course of intranasal fluticasone propionate 200 microg, once daily (FP200QD), to oral montelukast 10 mg, once daily (MON10QD), in relieving daytime and nighttime nasal symptoms associated with SAR. METHODS The intent-to-treat (ITT) analysis population consisted of 705 eligible males and females (> or = 15 years) with SAR randomized to either FP200QD (N = 353) or MON10QD (N = 352). The primary efficacy endpoint was the mean change from baseline in subject-rated daytime total nasal symptom scores (the sum of four individual scores: nasal congestion, itching, rhinorrhea, and sneezing), evaluated via visual analog scales, and averaged over weeks 1 to 2. Secondary endpoints included the four daytime individual nasal symptom scores, the nighttime total, and individual nasal symptom scores (each evaluated on a four-point scale from 0 to 3). RESULTS Statistically significant differences favoring FP200QD over MON10QD were observed for the mean change from baseline in daytime total nasal symptom scores (P < 0.001), daytime individual nasal symptom scores (P < 0.001), nighttime total (P < 0.001), and all individual nasal symptom scores (P < or = 0.002) over the 15-day treatment period. FP200QD and MON10QD were both well tolerated. CONCLUSIONS The results of this well controlled study demonstrated that FP200QD was consistently superior to MON10QD with regard to every efficacy endpoint evaluated, including daytime and nighttime nasal congestion, in subjects with SAR.

Inhibition of p38 Mitogen-Activated Protein Kinase Reduces Inflammation After Coronary Vascular Injury in Humans

Objective—To evaluate whether a p38&agr;/&bgr; mitogen-activated protein kinase inhibitor, SB-681323, would limit the elevation of an inflammatory marker, high-sensitivity C-reactive protein (hsCRP), after a percutaneous coronary intervention (PCI). Methods and Results—Coronary artery stents provide benefit by maintaining lumen patency but may incur vascular trauma and inflammation, leading to myocardial damage. A key mediator for such stress signaling is p38 mitogen-activated protein kinase. Patients with angiographically documented coronary artery disease receiving stable statin therapy and about to undergo PCI were randomly selected to receive SB-681323, 7.5 mg (n=46), or placebo (n=46) daily for 28 days, starting 3 days before PCI. On day 3, before PCI, hsCRP was decreased in the SB-681323 group relative to the placebo group (29% lower; P=0.02). After PCI, there was a statistically significant attenuation in the increase in hsCRP in the SB-681323 group relative to the placebo group (37% lower on day 5 [P=0.04]; and 40% lower on day 28 [P=0.003]). There were no adverse safety signals after 28 days of treatment with SB-681323. Conclusion—In the setting of statin therapy, SB-681323 significantly attenuated the post-PCI inflammatory response, as measured by hsCRP. This inflammatory dampening implicates p38 mitogen-activated protein kinase in the poststent response, potentially defining an avenue to limit poststent restenosis.

Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Background We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. Methods and Results Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. Conclusions Lp-PLA2 inhibition does not enhance platelet aggregation. Trial Registration 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257

Ethanol Does Not Alter the Pharmacokinetic Profile of the Controlled‐release Formulation of Carvedilol

The concomitant ingestion of alcohol may alter the release of a drug from a modified‐release dosage form, posing a potential risk to patients. In a randomized, open‐label, 4‐period cross‐over study, the pharmacokinetic profiles of R(+) and S(−) carvedilol were compared after a single oral dose of carvedilol controlled‐release formulation (administered following a standard meal) was given alone or concomitantly with ethanol. Thirty‐nine healthy subjects participated in this study. Following coadministration of carvedilol controlled‐release 40 mg with ethanol (approximately 38 g), ethanol ingestion 2 hours before or 2 hours after carvedilol controlled‐release administration, area under the curve for the R(+) and S(−) carvedilol enantiomers was similar compared with carvedilol controlled‐release given alone. Carvedilol exposure was not affected by the concomitant administration of ethanol and carvedilol controlled‐release. Maximum plasma concentrations for the R(+) and S(−) carvedilol enantiomers were similar except when ethanol was ingested 2 hours after carvedilol controlled‐release administration, where there was a modest decrease in maximum plasma concentration for R(+) and S(−) carvedilol (16% and 17%, respectively). Carvedilol controlled‐release given alone or concomitantly with ethanol ingestion was generally well tolerated, and no serious or severe adverse events were reported. Ethanol did not alter the pharmacokinetic profile of carvedilol controlled‐release.

Operating Characteristics of a Partial‐Block Randomized Crossover Bioequivalence Study for Dutasteride, a Drug with a Long Half‐Life: Investigation Through Simulation and Comparison with Final Results

Studies to establish bioequivalence (BE) of a drug are important elements in support of drug applications. A typical BE study is conducted as a single dose, randomized, 2‐period crossover design. For drugs with long half lives (≥ 48 hours) and evaluation of multiple BE objectives in 1 trial, this design may not be adequate. A parallel design may then be a more appropriate choice. However, parallel designs require increased sample size, which can become substantial.