Novel agents in the therapy of endotoxic shock

Endotoxic shock, or Gram-negative septic shock, can occur as a component of Gram-negative sepsis and is characterised by hypotension, poor tissue perfusion and multi-organ dysfunction. Despite antibiotic therapy and intensive care management, the morbidity and mortality rates of Gram-negative septic shock remain high. Endotoxin mediates its effects through interaction with receptors on the surface of a variety of host cells. These interactions result in the production and release of numerous biochemical mediators including nitric oxide, cytokines, prostaglandins and leukotrienes and toxic oxygen radicals. It is these biochemical mediators that exert toxic effects during endotoxic shock and which are often the target of novel treatment strategies. Several of these pharmacological agents are currently being investigated for use in Gram-negative septic shock and include inhibitors of the enzyme responsible for nitric oxide production, scavengers of the nitric oxide molecule and cytokine modulators. Although many agents have been studied for potential use as modulators of cytokine levels, this study will focus on pentoxifylline and the 21-aminosteroids, or lazaroids. Examination of the literature regarding pharmacological agents used to treat endotoxic shock often yields confusing and contradictory results. The reasons for these mixed results include differences in models, drug dosages, dosing methods and intervals and timing of administration relative to disease duration and severity. However, despite mixed results, several of the drugs discussed in this paper offer promise in the therapy of an often frustrating and lethal condition.