The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696.

CP-105696, (+)-1-(3S,4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl] cyclopentane carboxylic acid, is a structurally novel, selective and potent leukotriene B4 (LTB4) receptor antagonist. In vitro, CP-105696 inhibited [3H]LTB4 (0.3 nM) binding to high-affinity LTB4 receptors on human neutrophils with an IC50 value of 8.42 +/- 0.26 nM. Scatchard analyses of [3H]LTB4 binding to these high-affinity receptors indicated that CP-105696 acted as a noncompetitive antagonist. CP-105696 inhibited human neutrophil chemotaxis mediated by LTB4 (5 nM) in a noncompetitive manner with an IC50 value of 5.0 +/- 2.0 nM. Scatchard analyses of [3H]LTB4 binding to low-affinity receptors on neutrophils indicated that CP-105696 acted as a competitive antagonist at this receptor, and inhibition of LTB4-mediated CD11b upregulation on human neutrophils was competitively inhibited by CP-105696 (pA2 = 8.03 +/- 0.19). CP-105696 at 10 microM did not inhibit either human neutrophil chemotaxis or CD11b upregulation mediated through alternate (i.e., C5a, IL-8, PAF) G-protein coupled chemotactic factor receptors. In isolated human monocytes, LTB4 (5 nM)-mediated Ca++ mobilization was inhibited by CP-105696 with an IC50 value of 940 +/- 70 nM. In vivo, after oral administration, CP-105696 blocked neutrophil and eosinophil infiltration in cavine dermis mediated by either LTB4 or arachidonic acid with ED50 values of 0.3 +/- 0.1 mg/kg. 12(R)-Hydroxyeicosatetraenoic acid-mediated neutrophil infiltration was blocked by 76.4 +/- 14.8% at 3 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis.

Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. The role of LTB4 in such diseases has not yet been defined but in this paper we provide direct evidence that LTB4 plays a critical role in a murine model of RA. CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)- 4-hydroxychroman-7-yl]cyclopentane carboxylic acid, is an LTB4 receptor antagonist that inhibits LTB4 binding to human neutrophil membranes with an IC50 of 3.7 nM and inhibits LTB4-induced chemotaxis of these cells with an IC50 of 5.2 nM. CP-105,696 inhibits LTB4-induced neutrophil influx in mouse skin when administered orally with an ED50 of 4.2 mg/kg. CP-105,696 had a dramatic effect on both the clinical symptoms and histological changes of murine collagen-induced arthritis when administered at doses of 0.3-10 mg/kg. Inhibition was not associated with suppression of the humoral immune response to collagen and was equally effective if drug treatment was commenced just prior to the onset of arthritis or throughout the experiment. These results suggest that LTB4 receptor antagonists may be effective therapeutic agents for the treatment of RA.

The maternal-fetal transfer of bisheteroypiperazine (U-87201-E) in the ex vivo human placenta.

OBJECTIVE: The purpose of this study was to elucidate the maternal-fetal transfer of bisheteroypiperazine (U-87201-E), a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus-1. STUDY DESIGN: Placentas from normal term deliveries were used in this study to determine the maternal-fetal transfer of bisheteroypiperazine. The studies were conducted at several concentrations with the circulation either open-open or closed-closed. RESULTS: In this study we determined that the clearance index of bisheteroypiperazine was 0.72 +/- 0.17 at maternal concentrations of 1.0 and 20.0 micrograms/ml. This is at least twice the clearance index of 3'-azido-2',3'-dideoxythymidine and more than five times greater than that of 2',3'-dideoxyinosine. CONCLUSIONS: Bisheteroypiperazine crosses the maternal-fetal membranes by simple diffusion, in some instances almost equivalent to the reference compound antipyrine. Placental tissue concentrations were equivalent at all maternal concentrations, suggesting saturation. This high rate of maternal-fetal transfer suggests that it may be an effective prophylactic drug for fetuses of human immunodeficiency virus-infected mothers.

Cyclooxygenase inhibitors enhance tumour necrosis factor production and mortality in murine endotoxic shock.

Intraperitoneal administration of E. coli lipopolysaccharide (5-15 mg/kg) produced a dose-related increase in mortality which was maximal 72 h after induction of shock. Using a suboptimal dose of LPS (10 mg/kg i.p.), pretreatment with indomethacin (0.1-10 mg/kg p.o) or ibuprofen (1-100 mg/kg p.o) 30 min prior to induction of shock led to a significant enhancement of mortality. This enhancement was associated with a 2-3 fold increase in the peak circulating levels of tumour necrosis factor (TNF-alpha) in the serum of animals treated with indomethacin or ibuprofen compared to vehicle-treated control animals. These results indicate that TNF-alpha production is modulated by endogenous prostaglandins in vivo and that enhanced production of TNF-alpha by cyclooxygenase inhibitors may lead to exacerbation of some inflammatory processes.