Current pharmaceutical design
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Sepsis is a common and devastating syndrome that represents a significant healthcare burden worldwide. The average annual cost to care for patients with sepsis has been estimated to being $16.7 billion. Uniform definitions have been developed for the spectrum of sepsis syndrome, including the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock. ⋯ Seasonal variations also exist, with sepsis being more common in the winter months. Fortunately, the case fatality rates for both sepsis and severe sepsis have diminished over the last two decades. However, patients who survive their episode of sepsis continue to have increased morbidity and mortality up to five years after their initial illness.
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The role of the hypothalamic-pituitary adrenal axis in the host response to infection is crucial. The initial inflammatory response to sepsis activates the endogenous release of cortisol, which in turn modulates the synthesis and release of both pro- and anti-inflammatory mediators to restrict inflammation in infected tissues. However, a number of factors, including vascular or ischemic damage, inflammation and apoptosis within the hypothalamic-pituitary adrenal axis, as well as use of drugs that alter cortisol metabolism, may cause adrenal insufficiency. ⋯ The diagnostic value of measuring salivary free cortisol in this setting remains to be investigated. While sepsis adrenal insufficiency is undoubtedly associated with a poor prognosis, the indication and practical modalities of corticosteroids therapy remained controversial. Based on the two largest randomised, placebo-controlled trials, many investigators, myself included, contend that septic shock patients with hypotension poorly responsive to fluid replacement and vasopressors should receive a seven day treatment with the combination of hydrocortisone at a dose of 200 mg per day and fludrocortisone at the dose of 50 microg per day.
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Sepsis and septic shock, are complex disorders that are a major cause of mortality in the intensive care unit. In spite of major advances in our understanding of the pathophysiology of sepsis, accurate prediction of susceptibility to sepsis, multi-organ dysfunction, and death, even in the setting of a seemingly similar burden of infection, continues to challenge critical care clinicians. ⋯ This review will summarize and integrate the results of studies testing for associations between sequence variations in genes from these functional classes and susceptibility to sepsis and related clinical outcomes. The important insights on sepsis pathophysiology provided by these studies will be discussed along with the relevance of these findings to the design of future diagnostic approaches and therapeutic trials.
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Pain is a complex phenomenon involving both a peripheral innate immune response and a CNS response as well as activation of the hypothalamic-pituitary-adrenal axis. The peripheral innate immune response to injury involves the rapid production and local release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-/alpha), interleukin-1 (IL-1) and IL-6. Recent studies into the CNS response to peripheral chronic inflammatory pain strongly implicates a role for glia, and local synthesis of proinflammatory cytokines and growth factors. ⋯ In addition, inflammatory pain induces changes in blood-brain barrier (BBB) permeability and alters transport of clinically relevant drugs used to treat pain into the brain. Despite the increasing body of evidence for the involvement of glia in chronic pain and the role of glia in maintaining the BBB, few studies have addressed glial/endothelial interactions and the mechanisms by which glia may regulate the BBB during inflammatory pain. Further studies into the cellular mechanisms of glial/endothelial interactions may identify novel therapeutic targets for reversing chronic inflammatory induced BBB dysfunction and innovate therapies for modulating the severity of chronic inflammatory pain.
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Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid beta-peptide (Abeta) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty Abeta clearance from the brain appears to mediate focal Abeta accumulations in AD. ⋯ In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Abeta binding to sLRP in plasma. This, in turn, may increase Abeta brain levels through a decreased efflux of brain Abeta at the BBB and/or reduced sequestration of plasma Abeta associated with re-entry of free Abeta into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Abeta "sink" activity of sLRP, hold potential to control brain Abeta accumulations, neuroinflammation and cerebral blood flow reductions in AD.