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A M Lefer

Publications and source records attributed to A M Lefer.

507 records · Page 29Linked to original sources
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Platelet-activating factor (PAF) antagonistic actions of two new analogs of tetrahydrofurans.

Platelet-activating factor (PAF) has been implicated as a mediator involved in the pathogenesis of several types of inflammatory and shock states. The following group of experiments were designed to examine the effects of two new PAF receptor antagonists termed JS-1 and JS-3. The chemical structures of the two compounds were synthesized based on computer modeling of PAF and previously reported PAF receptor antagonists (e.g., tetrahydrofurans). Both JS-1 (1.3 mumols/kg) and JS-3 (9.5 mumols/kg) were found to significantly reverse PAF-induced (0.3 microgram/kg) hypotension in the rat when compared to their respective vehicles. In washed rabbit platelets, pretreatment with JS-1 (10 microM) and JS-3 (60 microM) inhibited aggregation induced by PAF at concentrations from 185 pM to 18.5 nM. These data indicate that both JS-1 and JS-3 are effective receptor antagonists of platelet-activating factor, and that computer modeling of molecular structures can be an important tool in developing analogs of known mediators of circulatory disease.

Animals↗
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Protective effects of a monoclonal antibody against lipid A in endotoxic shock.

Bacterial lipopolysaccharide given intravenously at 30 mg/kg to anesthetized rats results in rapid systemic hypotension and hypovolemia, elaboration of cytokines, increased proteolysis and vascular endothelial dysfunction. When a monoclonal antibody SdJ5-1.17.15 (SdJ5) directed against the lipid A moiety of lipopolysaccharide was administered at (1.25 or 5.0 mg/kg) 5 min prior to the endotoxin, significant protection was afforded to rats. This protection was manifested by a significant reduction in the early hypotension, as well as attenuation of hypovolemia and proteolysis. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats 4 h after endotoxic challenge. Lipopolysaccharide (LPS) significantly reduced superior mesenteric artery vasorelaxation to acetylcholine and A23187, two endothelium-dependent vasodilators, but not to NaNO2, an endothelium-independent vasodilator. SdJ5 significantly preserved vasorelaxation responses to both acetylcholine and A23187, indicating a marked degree of endothelial preservation by this anti-lipid A monoclonal antibody. The protection was dose-dependent since 0.3 mg/kg of SdJ5 did not provide significant protection in any variable measured. Moreover, there was no significant difference between the 1.25 mg/kg and 5.0 mg/kg dose of SdJ5. Furthermore, plasma concentrations of TNF-alpha, a cytokine involved in mediating many of the effects associated with endotoxemia, was significantly reduced in SdJ5-treated animals. Thus, SdJ5 appears to be capable of counteracting many of the in vivo sequelae of endotoxemia in rats.

Acetylcholine↗