Current medicinal chemistry
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Eosinophils are major pro-inflammatory cells that make a major contribution to diseases that affect the upper and lower airways, skin and gastrointestinal tract. Interleukin (IL)-5 is central to their maturation and release from the bone marrow together with their subsequent accumulation and activation in the tissues. Mepolizumab is a humanized monoclonal antibody (mAb) with potent IL-5 neutralizing effects that represents a potential treatment for eosinophilic diseases. ⋯ More recently two studies, one in in patients with refractory eosinophilic asthma with a history of recurrent severe exacerbations and the other in patients with persistent sputum eosinophilia and symptoms despite systemic treatment with prednisone treatment, reported that monthly intravenous mepolizumab reduced sputum/blood eosinophilia, asthma exacerbations together with improvments in quality of life. Mepolizumab also appears to be an effective therapy for hypereosinophilic syndrome while other trials have shown efficacy of mepolizumab therapy in eosinophilic esophagitis. This review will consider the current status of the clinical development of mepolizumab for diseases with a significant eosinophilic component to their pathology.
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Micro- and macrovascular complications are major causes of disability and death in patients with diabetes mellitus. Functional impairment of endothelial activity precedes the development of morphological alterations during the progression of diabetes. This endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO), mainly due to accelerated NO degradation by reactive oxygen species (ROS). ⋯ Novel therapeutic approaches designed to inhibit AGEs formation, reduce PKC activation, decrease inflammatory signals and restore the ox/redox balance of endothelium may be predicted to ameliorate vascular function in diabetic state. This review summarizes the current knowledge on the most important mechanisms involved in endothelial dysfunction during diabetes. In addition, novel therapeutic strategies that may result from recently identified targets are also described.
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Pharmacologic blockade of beta-adrenergic receptors is a frequent therapeutic intervention in critically ill patients. Today's strategies predominantly include the treatment of cardiovascular diseases like hypertension and cardiac arrhythmias. ⋯ Therefore, the immunomodulatory properties of beta-adrenergic antagonists have been established during the last years and the scientific focus was addressed on the proposed immunologic side effects of a beta-adrenergic blockade and its potential effect on the clinical course of critical illness. This manuscript reviews the rational and the effect of the therapeutic use of beta-adrenergic antagonists in critically ill patients on the base of the current literature and further emphasizes on potential immunologic side effects.
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Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of cardiovascular diseases (CVD), and in particular atherosclerosis. These ROS are released from different sources, such as xanthine oxidase, lipoxygenase, nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling of nitric oxide synthase and, in particular, mitochondria. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. ⋯ Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. This review considers the process of atherosclerosis from a mitochondrial perspective, and assesses strategies for the targeted delivery of antioxidants to mitochondria that are currently under development. We will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for atherosclerosis.
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Opioids have been used as pain control medications for thousands of years. Opioids are highly effective analgesics clinically available for controlling moderate and severe pain. Recent genetic knockout and knockin studies have definitively demonstrated that the analgesic effect is mediated through opioid receptors. ⋯ Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the non-analgesic effects, which may be mediated through both opioid receptor signaling and other non-opioid receptor molecular entity-mediated signaling. This review tries to bring the attention of the medicinal chemistry community to new developments and advances in the research areas of opioid-mediated cell proliferation and survival. Further investigation of the molecular mechanism of these non-analgesic opioid effects may eventually yield useful information such as new drug targets, which may be explored to benefit for clinical treatments such as targeted cancer therapy, cancer pain management, regeneration of neurons, and recovery from drug addiction.