Pharmacology & therapeutics
-
Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. ⋯ In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.
-
Asthma is a chronic disorder characterized by persistent inflammation of the airways with mucosal infiltration of eosinophils, T lymphocytes, and mast cells, and release of proinflammatory cytokines and lipid mediators. The natural resolution of airway inflammation is now recognized as an active host response, with highly coordinated cellular events under the control of endogenous pro-resolving mediators that enable the restoration of tissue homeostasis. Lead members of proresolving mediators are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid-derived lipoxins, eicosapentaenoic acid-derived E-series resolvins, and docosahexaenoic acid-derived D-series resolvins, protectins, and maresins. ⋯ In this review, we highlight cellular and molecular mechanisms for successful resolution of inflammation, and describe the main specialized pro-resolving mediators that drive these processes. Furthermore, we report recent data suggesting that the pathobiology of severe asthma may result in part from impaired resolution of airway inflammation, including defects in the biosynthesis of these specialized pro-resolving mediators. Finally, we discuss resolution-based therapeutic perspectives.
-
Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP). The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. ⋯ Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release. This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile.
-
The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of Δ9-tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. ⋯ The neurodevelopmental data in humans and animals suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe.
-
Bronchial Thermoplasty (BT) is an endoscopic treatment for moderate-to-severe asthma patients who are uncontrolled despite optimal medical therapy. Effectiveness of BT has been demonstrated in several randomized clinical trials. ⋯ This review will provide an overview of the different components of airway pathophysiology including remodeling, with the ASM as the key player. Current concepts in the understanding of BT clinical effectiveness with a focus on its impact on airway remodeling will be reviewed.