塞来昔布
前列环素
药理学
耐受性
前列腺素E2
安慰剂
医学
药效学
前列腺素
离体
加药
化学
内分泌学
药代动力学
不利影响
生物化学
体外
病理
替代医学
作者
Yan Jin,C. Wayne Smith,Lei Hu,Kristina M. Campanale,Randall Stoltz,LG Huffman,T. A. McNearney,Yang Xy,Ackermann Bl,Robert A. Dean,Arie Regev,William Landschulz
摘要
To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.
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