DOI: 10.1097/CCM.0000000000001047
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PMID: 26079240
Issn Print: 0090-3493
Publication Date: 2015/07/01
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Excerpt
Many biological pathways are involved in the evolution of the clinical condition of sepsis. Infection triggers complex and variable host responses. Proinflammatory mechanisms can lead to bacterial clearance but may also, together with anti-inflammatory responses, lead to tissue injury. The infecting organism is not the only factor that affects the outcome of sepsis. Individual host responses, some of which may be inherited, also play an important role. Pathophysiological pathways of importance in the development of sepsis include innate immunity, the coagulation system, and immune- and neural-based anti-inflammatory pathways (2).
In view of the multiple and complex pathways playing a role in sepsis and the limitations of available animal models, it is not surprising that drug development for sepsis is fraught with difficulty. In fact, beyond antibiotics and supportive measures there are no drugs currently available to improve the outcome of sepsis. Innumerable drug candidates have failed at various stages of clinical development, and the only drug ever to gain Food and Drug Administration (FDA) approval for sepsis, drotrecogin alfa, did not show efficacy in a large postmarketing trial, resulting in withdrawal by the manufacturer (3).
So how do we find the next drug? Vascular leakage is a critical component of sepsis that may lead to organ failure, in particular acute respiratory distress syndrome (ARDS). So this may be a good area to explore. Tie2 is a receptor expressed by endothelial cells. Activation of Tie2 leads to destabilization of endothelial cells and capillary leak. Angiopoietin (Angpt)-2 activates the Tie2 receptor, leading to capillary leak, whereas Angpt-1 inhibits the Tie2 receptor and reduces capillary leak. There is mounting evidence that signaling through the Tie2 pathway may play an important role in sepsis (4). Angpt-2 is induced in sepsis, and circulating levels are associated with disease severity and mortality. In patients presenting with suspected infection, elevated and rising Angpt-2 levels are associated with worse outcome, and in animal models of experimental sepsis, inhibition of Angpt-2 signaling reduces vascular leak and improves survival (5). Inhibition of Tie2 has been achieved by expression of Angpt-1 (6) or by reducing expression of Angpt-2. Deletion of one Angpt-2 allele, RNA interference against Angpt-2, or a targeted antibody against Angpt-2 all improve survival in experimental models of sepsis (4, 7). As reported in this issue of Critical Care Medicine, this body of data persuaded Ghosh et al (8) to try to find a compound that may inhibit Angpt-2 production and see if this may have an effect in sepsis.
Development of a new drug is not cheap. A recent Forbes analysis (9) suggests that the average cost of developing a new drug may be in the region of $5 billion dollars. So how did an academic group succeed in finding and testing a new drug for sepsis targeted to the Angpt-2 pathway and performing a clinical trial? It would have been unimaginable 30 years ago that aspirin, a common over-the-counter remedy for mild pain, would become the cornerstone for prevention of myocardial infarction. Similarly, approved medications may not always work along the mechanistic pathway initially presumed and may have other unrecognized actions. So Ghosh et al (8) turned to a panel of 650 compounds that were already approved for clinical use by the FDA to try to repurpose an old drug for a new indication.
