OC-229

The infiltration of neutrophils after ischemia and reperfusion (I/R) is facilitated by the expression of adhesion molecules on the surface of both leukocytes and endothelial cells. Adhesion molecules of the selectin family are of particular importance at the onset of neutrophil mediated injury, as demonstrated by the occurrence of many cellular interactions with the final extravasation of inflammatory leukocytes at the site of I/R damage. Previous studies demonstrated a prevention of neutrophil extravasation and protection of ischemic damage when a small anti-selectin molecule was used. In this study, we tested a new small anti-selectin compound (OC-229) in a murine model of partial hepatic I/R. The aim of this study was to determine the effect of OC-229 on liver function and histology after I/R and to evaluate its role in the modulation of the inflammatory molecular signaling pathways of NF-kappa B and AP-1 under the same experimental condition. Mice subjected to 90 min of partial (70-80%) hepatic ischemia and 3 h of reperfusion were divided into three groups (n = 9/group): sham, ischemic control, and treated group, which received 25 mg/kg of the anti-selectin small molecule OC-229. These groups were studied when the treatment was given at the time of reperfusion (no pretreatment was given). The parameters measured at 3 h of reperfusion included liver function tests (ALT and AST), liver histology, and liver tissue electrophoretic mobility shift assay (EMSA) for NF-kappa B and AP-1. It was demonstrated that the multiselectin inhibitor OC-229 offered significant protection for the ischemic liver when given at 25 mg/kg at the time of reperfusion. ALT and AST serum levels significantly decreased when the ischemic control and the group receiving OC-229 were compared (p = .01). Treated animals demonstrated better histological findings as well. The EMSA showed dissociation of NF-kappa B and AP-1 activity in the liver nuclear extracts after selectin inhibition treatment. A reduction in the activity of AP-1 and an increment in NF-kappa B activation was seen. In this work, we obtained evidence that the small-molecule selectin inhibitor OC-229 offered functional and histological protection of the ischemic liver when given at 25 mg/kg at the time for reperfusion. There was dissociation in the activation signals of NF-kappa B and AP-1. Increase in NF-kappa B and reduction of the activation of AP-1 were noted at 3 h of reperfusion.

Breast milk volume and composition and infant growth were measured at three- and four-week intervals, up to six months, in a multicenter randomized double-blind trial comparing a low-dose combined oral contraceptive (OC) with a progestogen-only OC. A nonrandom group using nonhormonal methods was also studied in the three centers: Szeged, Hungary; Bangkok, Thailand; and Khon Kaen, Thailand. A fourth group, users of depot-medroxyprogesterone acetate (DMPA) was included in the two Thai centers. Altogether, 341 women were recruited into the study. Combined OCs caused a significant decrease in milk output and total energy content as well as widespread changes in milk constituents. In the DMPA group, no significant changes were observed in milk volume, and only minor shifts occurred in milk composition, which varied between centers. No differences were found between the progestogen-only pill and DMPA. No hormonal contraceptive was associated with any significant difference in infant weight or fat fold, nor in the rate of discontinuation for failure to gain weight. This study reiterates the need to avoid combined OCs during the first few weeks or months of lactation. Both norgestrel and DMPA appear to be safe for use in both developing and developed countries, at least when the nutritional status of the mother and infant are adequate, but further research is needed on the safety of these contraceptives in populations with malnutrition.