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PII‐3
Author(s) -
Shaddinger B. C.,
Gao L.,
Cai G.,
Wentzell L. M.,
Johnson A. G.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.128
Subject(s) - placebo , crossover study , platelet , medicine , agonist , gastroenterology , pharmacology , anesthesia , receptor , pathology , alternative medicine
BACKGROUND/AIMS Lipoprotein‐associated phospholipase A 2 (Lp‐PLA 2 ) is an independent predictor of CV events and a potential therapeutic target. As Lp‐PLA 2 is also known as the enzyme involved in PAF degradation (PAF‐AH), the purpose of this study was to assess the effects of an Lp‐PLA 2 inhibitor, SB‐480848, on platelet aggregation in healthy volunteers. METHODS This placebo‐controlled, repeat dose, randomized, period balanced, 2 period, crossover study evaluated A) SB‐480848 160 mg for 10 days, B) SB‐480848 matched placebo for 10 days in double‐blinded fashion to 21 adult healthy males subjects with a washout period of 27 days. The dosage of SB‐480848 administered in the current study is expected to produce >70% plasma Lp‐PLA 2 inhibition at steady‐state (Day 10) based on previous studies. Platelet aggregation tests were performed on Days −1, 1 and 10 (at 0, 6 and 24 hours) in duplicates. The agonists used in the platelet lumiaggregometry were ADP (1, 2 and 10 μM) and collagen (0.5, 0.7, and 10 μg/mL). RESULTS There were no clinically significant differences in ADP or collagen induced platelet aggregation. Both the mean difference between SB‐480848 and placebo and the 90% upper bounds of the CI were <15% (a pre‐specified criteria) across all time points. (See Table)Agonist Day Time (hr) 480848 Placebo Mean difference 90% CI of difference SDwADP 1 0 −1.7 −2.0 0.2 (−1.9, 2.4) 4.046 −4.6 −2.8 −1.8 (−3.9, 0.3)24 −1.8 −1.6 −0.1 (−2.2, 2.0)10 0 1.8 1.0 0.8 (−1.3, 3.0)6 0.1 0.3 −0.2 (−2.4, 1.9)24 0.6 −0.1 0.6 (−1.5, 2.7)Collagen 1 0 −1.5 0.1 −1.6 (−7.5, 4.4) 11.546 −3.2 −2.7 −0.5 (−6.5, 5.5)24 0.0 0.1 −0.1 (−6.1, 5.9)10 0 12.3 10.8 1.5 (−4.6, 7.5)6 4.8 4.0 0.8 (−5.2, 6.9)24 7.3 −0.3 7.5 (1.5, 13.6)CONCLUSIONS The results indicate that Lp‐PLA 2 inhibition has no significant effect on platelet aggregation in healthy volunteers. Clinical Pharmacology & Therapeutics (2005) 79 , P36–P36; doi: 10.1016/j.clpt.2005.12.128