Current pharmaceutical design
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Coronary heart disease (CHD) is the leading cause of death among elderly patients and >80% of all coronary deaths occur in patients >65 years. Cerebrovascular events are also associated with older age. Since elevated cholesterol concentrations are a risk factor for cardiovascular disease, lipid-lowering drugs, especially statins, are in widespread use for prevention. ⋯ Their prescription should not be denied to patients for reasons of age alone. Other lipid-lowering drugs play only a minor role in cardiovascular disease (CVD) event prevention because convincing outcome studies are largely missing. A primary prevention statin trial in the very elderly is urgently needed.
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The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. ⋯ Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.
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Severe asthma is a complex and heterogeneous phenotype characterized by persistent symptoms and poor control. While some patients respond to high doses of inhaled corticosteroids in combination with long-acting beta-agonists, a significant subset require oral corticosteroids to achieve symptom control. ⋯ The article then reviews alternative therapeutic strategies including macrolide antibiotics, biologic agents, modulators of signal transduction pathways and bronchial thermoplasty. The challenge remains to determine the appropriate phenotype for each therapeutic strategy in view of the heterogeneity of severe asthma.
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Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer stem cell (CSC). ⋯ Glioma stem cells (GSCs) are enriched in functional niches--prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce cellular plasticity towards a stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control.
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Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. ⋯ However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.