zithromax and Endotoxemia

Despite the severity and common occurrence of equine endotoxaemia, the available anti-endotoxic treatments do not effectively target key inflammatory mechanisms such as leucocyte activation and cytokine production. In this study, four compounds with potential anti-endotoxic effects, namely rolipram, azithromycin, ethyl pyruvate and metformin, were investigated in vitro using equine whole blood stimulated with bacterial lipopolysaccharide. TNF-α and IL-1β production were measured in plasma. Rolipram was the most potent inhibitor of cytokine production (IC50 0.84 and 4.68 μm for TNF-α and IL-1β, respectively) with almost complete inhibition of TNF-α, but inhibited IL-1β by only 39.46%. Azithromycin produced almost complete inhibition of both cytokines, but tended to be less potent than rolipram (IC50 10.66 and 17.4 μm for TNF-α and IL-1β, respectively). Metformin inhibited TNF-α production with similar potency to rolipram and azithromycin (IC50 3.35 μm) but showed significantly lower efficacy (45.93%; P < 0.05), and had no inhibitory effect on IL-1β. Ethyl pyruvate was the least potent (IC50 68.35 μm and >10 mm for TNF-α and IL-1β production, respectively). Further work is required to investigate whether these or related compounds may have potential use in the treatment of equine endotoxaemia in vivo.

Topics: Animals; Anti-Inflammatory Agents; Azithromycin; Endotoxemia; Horse Diseases; Horses; In Vitro Techniques; Interleukin-1beta; Lipopolysaccharides; Metformin; Pyruvates; Rolipram; Tumor Necrosis Factor-alpha

The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Dexamethasone; Endotoxemia; Endotoxins; Glomerular Filtration Rate; Immunosuppressive Agents; Interleukin 1 Receptor Antagonist Protein; Lipopolysaccharides; Male; Rats, Wistar; Renal Elimination; Xenobiotics

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Blood Cell Count; Endotoxemia; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Serum Amyloid A Protein