Current pharmaceutical design
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Recent investigations of the cellular and molecular mechanisms of pain provide new hopes for more effective treatments for patients with chronic pain. At the molecular and genetic levels, new proteins and genes related to sensory sensation have been identified. ⋯ This disconnect between discovery and better treatment options is due, in part to the negative side effects associated with new treatment options, and also as a result of the ineffectiveness of these new drugs for inhibiting chronic pain. In this review, I will explore this disconnect between discovery and treatment, and propose that the failure of previous medicines can be due to their limited effects on injury-related plasticity, and question the common misperception of seeking compounds for high efficacy before understanding basic mechanisms of the target proteins in pain-related plasticity.
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Neuropathic pain is characterized by complicated combination of positive (e.g., hyperalgesia and allodynia) and negative (e.g., hypoesthesia and hypoalgesia) symptoms, and is often refractory to conventional pharmacological agents, including morphine. Although the molecular mechanisms for positive symptoms are extensively studied, those for negative symptoms are poorly understood. There is convincing evidence that altered gene expression within peripheral and central nervous systems is a key mechanism for neuropathic pain; however, its transcriptional mechanisms are poorly understood. ⋯ Importantly, there is emerging evidence that a variety of genes undergo epigenetic regulation via DNA methylation and histone modifications within peripheral and central nervous systems, thereby contributing to the alterations in both pain sensitivity and pharmacological efficacy in neuropathic pain. In this review, we will highlight the epigenetic gene regulation underlying neuropathic pain, especially focusing on the negative symptoms. Moreover, we will discuss whether epigenetic mechanisms can serve as a potential target to treat neuropathic pain.
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The cardiovascular system exhibits significant daily rhythms in physiologic processes (heart rate, blood pressure, cardiac contractility and function), and molecular gene and protein expression. An increasing number of clinical and experimental studies demonstrate the circadian system is an important underlying mechanism that coordinates these rhythmic processes for the health of the cardiovascular system. ⋯ We also discuss therapeutic applications of circadian rhythms for the cardiovascular system. Cardiovascular disease is a leading cause of death worldwide, and applying circadian biology to cardiology (and indeed medicine in general) provides a new translational approach to benefit patients clinically.
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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.