Pharmacology & therapeutics
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Although chronic pain states are highly prevalent, the underlying neurobiological mechanisms involved in causing pain are incompletely understood. This is especially true for the so-called chronic functional pain syndromes and pain syndromes of unknown origin, such as fibromyalgia (FM), in which no structural correlates of pain experience, in terms of a nociceptive source, can clearly be defined. ⋯ The current review aims to provide an overview of existing pharmacotherapies for FM, and their implication for the underlying pathophysiology. Further we discuss some of the potential targets that have been recently identified that may hold promise for the development of novel treatments.
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This review describes the cellular and molecular mechanism heterogeneity of dehydroepiandrosterone (DHEA) and its putative therapeutic role in vascular remodeling diseases such as pulmonary artery hypertension (PAH). PAH is characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation, constriction and resistance to apoptosis, all of which contribute to increase the pulmonary artery wall thickness, resistance and therefore pressure. The etiology of PAH remains elusive. ⋯ We and others have demonstrated that DHEA, a clinically available drug with a low adverse effect profile, is able to achieve these effects. In several animal models of vascular remodeling diseases such as PAH, DHEA has been demonstrated to be a good anti-proliferative and pro-apoptotic drug, decreasing vascular remodeling, and a potent vasodilator. A better understanding of the DHEA mechanisms of action may allow the development of new and better therapies to treat vascular remodeling diseases such as pulmonary hypertension.
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Millions of people worldwide suffer from neuropathic pain as a result of damage to or dysfunction of the nervous system under various disease conditions. Development of effective therapeutic strategies requires a better understanding of molecular and cellular mechanisms underlying the pathogenesis of neuropathic pain. It has been increasingly recognized that spinal cord glial cells such as microglia and astrocytes play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as proinflammatory cytokines and chemokines. ⋯ Although CCL2 was implicated in neuronal-to-microglial signaling, a recent study shows a novel role of CCL2 in astroglial-to-neuronal signaling after nerve injury. In particular, CCL2 rapidly induces central sensitization by increasing the activity of NMDA receptors in dorsal horn neurons. Insights into the role of chemokines in neuronal-glial interactions after nerve injury will identify new targets for therapeutic intervention of neuropathic pain.
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Cannabis has been used to treat gastrointestinal (GI) conditions that range from enteric infections and inflammatory conditions to disorders of motility, emesis and abdominal pain. The mechanistic basis of these treatments emerged after the discovery of Delta(9)-tetrahydrocannabinol as the major constituent of Cannabis. Further progress was made when the receptors for Delta(9)-tetrahydrocannabinol were identified as part of an endocannabinoid system, that consists of specific cannabinoid receptors, endogenous ligands and their biosynthetic and degradative enzymes. ⋯ Pharmacological agents that act on these targets have been shown in preclinical models to have therapeutic potential. Here, we discuss cannabinoid receptors and their localization in the gut, the proteins involved in endocannabinoid synthesis and degradation and the presence of endocannabinoids in the gut in health and disease. We focus on the pharmacological actions of cannabinoids in relation to GI disorders, highlighting recent data on genetic mutations in the endocannabinoid system in GI disease.
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Review
Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy.
Drug-induced cardiotoxicity is emerging as an important issue among cancer survivors. For several decades, this topic was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the limiting step in their use. Although a number of efforts have been directed towards prediction of risk, so far no consensus exists on the strategies to prevent and monitor chemotherapy-related cardiotoxicity. ⋯ From the pharmacological standpoint, putative molecular mechanisms involved in chemotherapy-induced cardiotoxicity will be reviewed. From the clinical standpoint, current strategies to reduce cardiotoxicity will be critically addressed. In this perspective, the precise identification of the antitarget (i.e. the unwanted target causing heart damage) and the development of guidelines to monitor patients undergoing treatment with cardiotoxic agents appear to constitute the basis for the management of drug-induced cardiotoxicity.