Current pharmaceutical design
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Population studies have identified diabetes mellitus as a risk factor for cardiac and vascular events, with a common association with hypertension. Observational studies have consistently demonstrated blood glucose as a continuous cardiovascular risk factor. ⋯ However, an unconvincing temporal relationship (raised blood glucose preceding cardiovascular events) and the limited impact of glucose reduction in patients with diabetes on cardiovascular events do not support blood glucose as a major cause of cardiovascular disease. In this review, we discuss the relationship between hyperglycaemia and a hypercoagulable state in diabetes and the implications of this relationship for the treatment of patients with diabetes, who also commonly have hypertension.
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Human ether-a-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current, IKr, which is crucial for repolarization of cardiac action potentials. Moderate hERG blockade may produce a beneficial class III antiarrhythmic effect. In contrast, a reduction in hERG currents due to either genetic defects or adverse drug effects can lead to hereditary or acquired long QT syndromes characterized by action potential prolongation, lengthening of the QT interval on the surface ECG, and an increased risk for "torsade de pointes" arrhythmias and sudden death. ⋯ Recently, mutations in hERG have been shown to cause current increase and hereditary short QT syndrome with a high risk for life-threatening arrhythmias. Finally, the discovery of adrenergic mechanisms of hERG channel regulation as well as the development of strategies to enhance hERG currents and to modify intracellular hERG protein processing may provide novel antiarrhythmic options in repolarization disorders. In conclusion, the increasing understanding of hERG channel function and molecular mechanisms of hERG current regulation could improve prevention and treatment of hERG-associated cardiac repolarization disorders.
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The intention of this review is to give a brief overview of the continuously expanding field of sepsis therapy based on recent studies with animal models and clinical trials. Over the past few years, it has become apparent that the mechanisms controlling this disease are more complex than was previously thought, with factors such as free radicals, nuclear factors, and enzyme co-factors all contributing in the control of the pathogenesis of sepsis as well and improvements in the morbidity. Recent advances at the molecular biology level have facilitated the development of a whole new field of research. ⋯ Further elucidation of the signals that influence the production and actions of free radicals will, without doubt, further our understanding of the numerous pathophysiological processes involved in sepsis. For these reasons, there is considerable interest in alternative treatment modalities which focus on recent animal studies. These recent experimental approaches to the therapy of sepsis are discussed in light of each step in the complex inflammatory cascade involved and compared to traditional approaches to the prevention and therapy of sepsis and septic shock.
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Fibromyalgia syndrome is a nonarticular rheumatic disorder characterised by diffuse musculoskeletal pain, stiffness, fatigue, disturbed sleep and tender points. The pathophysiology is not well understood and treatment remains a challenge. Although pharmacological therapy is still the primary treatment choice, a long-term effective intervention has not been demonstrated yet. ⋯ Although, there is a great number of exercise studies, the large diversity of outcome measures and measurement instruments that have been used in studies, varying intensity and types of exercises, small sample sizes, high attrition rates, large variability in baseline function, symptom severity and psychosocial status limit to come to a conclusion about the efficacy of exercise in the treatment of fibromyalgia syndrome. There are also inconclusive results about the efficacy of cognitive-behavioural treatment because of limited number of studies with small sample sizes of patients with fibromyalgia syndrome. However, the results of the trials overall demonstrate the beneficial effects of both different types of exercise and cognitive-behavioural treatment, on the other hand, there is still a need for larger, more systematic and randomised controlled trials to evaluate the effectiveness.
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Asthma is a complex disease caused by a poorly characterized set of genetic and environmental factors whose pathology is a result of immune dysregulation. Toll-like receptors are pathogen associated molecular pattern receptors expressed by many airway and pulmonary tissues as well as cells of the innate and adaptive immune system. ⋯ These ligands and their receptors are therefore prime candidates in the search for immunotherapeutic treatments of asthma. The use of murine models of allergic asthma as tools for the genetic dissection of this disease should allow the molecular mechanisms underlying asthma to be identified and possibly used as further immunotherapeutic targets.