Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors.

A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 µM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.

Cytokine responses following laparoscopic or open pyeloplasty in children.

BACKGROUND: The present study evaluated the cytokine response in children following laparoscopic pyeloplasty (LP) or open pyeloplasty (OP). A series of cytokines were measured postoperatively, including interkin1-beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). METHODS: A total of 31 patients, with an average age of 9.1 +/- 3.0 years (range 2.5-14 years) were studied. Fourteen patients underwent LP and 17 underwent OP. Blood serum concentrations of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, and CRP were measured via enzyme-linked immunosorbent assay (ELISA) before surgery as well as 4, 24, and 48 h following the operation. In addition, the procedure duration, hospital stay, incidence of wound infection, and the recurrence rate of stenosis in both groups were compared. RESULTS: Serum IL-6 and CRP concentrations were significantly elevated in both groups at 4, 24, and 48 h relative to preoperative levels. However, the rise in IL-6 and CRP in OP group was significantly more robust than in LP group. No significant changes were observed in serum levels of IL-1beta, IL-8, IL-10, or TNF-alpha in either group. The procedure duration was significantly longer for LP (193.6 +/- 74.7 min, range 120-360 min) versus OP (120.1 +/- 27.5 min, range 90-165 min, p < 0.05), but the hospital stay following LP was shorter (LP group: 5.3 +/- 1.1 days versus OP group: 9.3 +/- 2.1 days, p < 0.05). No severe complications were noted in either group, however, one child experienced wound infection following OP procedure. An incident of recurrent stenosis following the operation occurred in both groups. There was no postoperative morbidity or severe implications at 12 month follow-up in either group. CONCLUSIONS: Both OP and LP are safe and effective procedures for the treatment of ureteropelvic junction obstruction in the pediatric population. However, the shorter hospital stay and decreased cytokine response following LP indicates potential benefits over traditional invasive procedures.