Current drug targets
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Current drug targets · Jan 2009
ReviewPathophysiology of sepsis in the elderly: clinical impact and therapeutic considerations.
The aging world population will increase the incidence and mortality of severe sepsis. The aim of the present article is to review the pathophysiological differences in sepsis and its clinical impact on the elderly. The impact of immunosenescence on innate and acquired immunity is associated with relative immunologic depression that may favor the spreading of inflammation. ⋯ The initial clinical picture of sepsis in the elderly may be ambiguous but the specific pathopysiological changes of aging increase the risk of a sudden deterioration to severe sepsis with the development of a serious cardiovascular dysfunction. The reduced stress tolerance characteristic of aged tissues explains the high incidence of multi-organ failure in such patients. The specific pathophysiological and clinical picture of sepsis underlies the increased mortality in such patients and prompts research on therapeutic strategies with particular benefits to elderly septic patients.
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Current drug targets · May 2008
ReviewHypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis.
Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. ⋯ This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.
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Current drug targets · Oct 2007
ReviewKinetics, role and therapeutic implications of endogenous soluble form of receptor for advanced glycation end products (sRAGE) in diabetes.
Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in diabetes. ⋯ In the former part of this paper, we review the role of the AGE-RAGE system in the pathogenesis of diabetic vascular complications. Then we summarize in the latter part of this review the kinetics and pathophysiological role of endogenous sRAGE in diabetes. We also discuss the possibility that endogenous sRAGE may be a therapeutic target for the prevention of diabetic vascular complications.
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Stroke is a disease with impacts ranging from death and disability, to reduced health-related quality of life and depression. To truly understand the burden of this disease we must investigate not only the mortality and prevalence of stroke, but also its incidence within populations. Stroke mortality and incidence declined rapidly during the 1980s and early 1990s; however, this trend appears to have slowed in more recent times. ⋯ Fortunately, stroke is largely a preventable disease. The major risk factor for stroke, hypertension, can be controlled using both population-wide approaches, such as changes in the salt content of processed foods, and high-risk individual approaches, such as use of antihypertensive medications. Implementation of effective primary and secondary prevention strategies is likely to have an enormous benefit in reducing the burden of stroke, particularly in developing regions.
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Ischemic brain injury can be anticipated in a number of clinical settings such as procedures associated with a high-risk for stroke, patients with transient ischemic attacks or minor strokes who are at substantial risk for early recurrence and patients with multiple vascular risk factors with an enhanced risk for ischemic stroke over many years. In such high-risk settings, it may be possible to employ neuroprotective drugs prophylactically to reduce the extent and clinical consequences of ischemic events. The concept of prophylactic neuroprotection can be envisioned for varying time periods and with a variety of drug classes depending upon the target population. This review will focus on which target populations should be considered for prophylactic neuroprotection trials and which drugs might be used in such trials.