Articles: human.
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Current drug targets · Jan 2015
ReviewTargets Involved in Cardioprotection by the Non-Anesthetic Noble Gas Helium.
Research data from the past decade indicate that noble gases like xenon and helium exert profound cardioprotection when applied before, during or after organ ischemia. Of all noble gases, especially helium, has gained interest in the past years because it does not have an anesthetic "side effect" like xenon, allowing application of this specific gas in numerous clinical ischemia/reperfusion situations. ⋯ Investigations in animals as well as in humans have proven that this noble gas is not completely inert and can induce several biological effects. Though the underlying molecular mechanisms of helium-induced cardiac protection are still not yet fully understood, recently different signaling pathways have been elucidated.
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Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. ⋯ This has been replicated in rat and sheep models of sepsis. In addition, some data show that α 2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock.
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Pharmacological interventions in Alzheimer's disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain. ⋯ Here we reviewed the evidence demonstrating that neurons of the IC system show neurofibrillary tangles in the earliest stages of AD, prior to cortical pathology, and how this involvement may explain pre-amnestic symptoms, including depression, agitation, and sleep disturbances in AD patients. In fact, clinical and animal studies show a significant reduction of AD cognitive and behavioral symptoms following replenishment of neurotransmitters associated with the IC network. Therefore, the IC network represents a unique candidate for viable therapeutic intervention and should become a high priority for research in AD.
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The confinement of critically ill patients in intensive care units (ICU) imposes environmental constancy throughout both day and night (continuous light, noise, caring activities medications, etc.), which has a negative impact on human health by inducing a new syndrome known as circadian misalignment, circadian disruption or chronodisruption (CD). This syndrome contributes to poor sleep quality and delirium, and may impair septic states frequently observed in critically ill patients. ⋯ Delirium, the most serious condition because it has a severe effect on prognosis and increases mortality, as well as sleep impairment and sepsis, all three of them linked to disorganization of the circadian system in critically ill patients, will be revised considering the functional organization of the circadian system, the main input and output signals that synchronize the clock, including a brief description of the molecular circadian clock machinery, the non-visual effects of light, and the ICU light environment. Finally, the potential usefulness of increased light/dark contrast and melatonin treatment in this context will be analyzed, including some practical countermeasures to minimize circadian disruption and improve circadian system chronoenhancement, helping to make these units optimal healing environments for patients.
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In this perspective article, we explain how quantitative and translational pharmacology, when well-implemented, is believed to lead to improved clinical candidates and drug targets that are differentiated from current treatment options. Quantitative and translational pharmacology aims to build and continuously improve the quantitative relationship between drug exposure, target engagement, efficacy, safety and its interspecies relationship at every phase of drug discovery. ⋯ We offer different approaches to set an initial effective concentration or pharmacokinetic-pharmacodynamic target in man and to predict human pharmacokinetics that determine together the predicted human dose and dose schedule. All concepts are illustrated with ample literature examples.