e-5531 and Shock--Septic

Therapy for Gram-negative sepsis remains unsatisfactory despite a concerted effort to develop new treatments for this common, life-threatening syndrome. Current research continues on several fronts to improve the treatment options available to clinicians in the management of these critically ill patients. Recently, a greater understanding of the complex molecular basis of endotoxin-mediated pathophysiological effects in humans has generated a number of novel therapeutic agents for sepsis. Several of these treatment strategies have already entered clinical trials and it is hoped that some of these therapies will become widely available in the near future. In this review, the current status of the most promising new antiendotoxin agents is summarised, and the major obstacles to the successful clinical development of these therapies are described. New antiendotoxin therapies include those which interrupt the synthesis of endotoxin, bind and neutralise its activity, prevent endotoxin interactions with host effector cells and interfere with endotoxin-mediated signal transduction pathways. Potential therapeutic strategies involving these agents consist of endotoxin analogues, antibodies, subunit vaccines, binding columns, recombinant human proteins and small molecule inhibitors of endotoxin synthesis and intracellular signalling. The pitfalls of previous antiendotoxin clinical investigations and the perils of future clinical trial designs are discussed in the context of unmet needs and realistic expectations for success. While considerable progress has been made, effective and new treatments for Gram-negative bacterial sepsis continues to elude us at the present time. This has been to the detriment of patients, investigators and pharmaceutical companies alike. It will require focused efforts by basic scientists, continued support by industry and enlightened study designs by clinical investigators to successfully develop antiendotoxin in therapies for use in septic patients in the future.

Topics: Anti-Bacterial Agents; Antibodies; Antigen-Antibody Complex; Antimicrobial Cationic Peptides; Bacterial Vaccines; Blood Proteins; Endotoxemia; Endotoxins; Gram-Negative Bacteria; Humans; Lipid A; Lipopolysaccharide Receptors; Lipopolysaccharides; Membrane Proteins; Recombinant Proteins; Shock, Septic

Lipid As from non-toxic bacteria such as Rhodobacter capsulatus and Rhodobacter sphaeroides have been shown to antagonize the immunostimulatory effects of lipid A and LPS from pathogenic bacteria. We have biologically characterized a series of synthetic LPS antagonists including the proposed structures of the lipid A and R. sphaeroides containing fatty acid side chains ester-linked to the disaccharide backbone, as well as an analog of R. capsulatus lipid A containing ether-linked alkyloxy side chains (E5531). In vitro assays utilizing LPS-stimulated human monocytes or whole blood demonstrated that low nanomolar concentrations of E5531 inhibited cellular activation as indicated by decreased release of the cytokines TNF-a, and interleukins-1, 6, and 8. E5531 also inhibited LPS-induced release of cytokines and nitric oxide from murine macrophages. Synthetic antagonists at up to 100 microM were devoid of agonistic activity in murine and human in vitro systems. In vivo, E5531 blocked induction of TNF-a by LPS and reduced LPS-induced lethality in mice. These in vitro and in vivo results indicate that E5531 may have clinical therapeutic utility as an antagonist of endotoxin-mediated morbidity and mortality.

Topics: Animals; Carbohydrate Sequence; Disease Models, Animal; Endotoxins; Humans; In Vitro Techniques; Lipid A; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Monocytes; Nitric Oxide; Shock, Septic; Tumor Necrosis Factor-alpha