16 research outputs found
Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A<sub>2</sub> Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials
<div><p>Background</p><p>We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A<sub>2</sub> (Lp-PLA<sub>2</sub>) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials.</p><p>Methods and Results</p><p>Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA<sub>2</sub> 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 EC<sub>50</sub> 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. EC<sub>50</sub> 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-PLA<sub>2</sub> 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 EC<sub>50</sub> examination.</p><p>Conclusions</p><p>Lp-PLA<sub>2</sub> inhibition does not enhance platelet aggregation.</p><p>Trial Registration</p><p>1) Study 1: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01745458?term=NCT01745458&rank=1andwww.clinicaltrials.gov/ct2/show/NCT01750827?term=NCT01750827&rank=1" target="_blank">NCT01745458</a> 2) Study 2: ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00387257?term=NCT00387257&rank=1" target="_blank">NCT00387257</a></p></div
Predictors of treatment delay in patients with acute myocardial infarction undergoing primary angioplasty: An analysis from the CADILLAC trial
In vitro platelet aggregation results of (A) ADP, (B) collagen, and (C) PAF. ADP, adenosine diphosphate; PAF, platelet-activating factor.
Comparison of the EC<sub>50</sub> for collagen-induced platelet aggregation (Study 2).
a<p>EC<sub>50</sub> rilapladib/EC<sub>50</sub> placebo.</p>b<p>Corresponding to the predose time during treatment.</p>c<p>Corresponding to the 6 hours postdose time during treatment.</p><p>EC<sub>50</sub>, 50% maximal platelet aggregation; CI, confidence interval.</p
Concentration response curves for collagen-induced platelet aggregation 14 days post-dosing (treatment A = rilapladib, treatment B = placebo).
Demographics of the study participants in the crossover and E<sub>max</sub> studies.
<p>SD, standard deviation; NA, not available.</p