Handbook of experimental pharmacology
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Handb Exp Pharmacol · Jan 2013
ReviewSoluble guanylate cyclase stimulators in pulmonary hypertension.
Soluble guanylate cyclase (sGC) is a key enzyme in the nitric oxide (NO) signalling pathway. On binding of NO to its prosthetic haem group, sGC catalyses the synthesis of the second messenger cyclic guanosine monophosphate (cGMP), which promotes vasodilation and inhibits smooth muscle proliferation, leukocyte recruitment, platelet aggregation and vascular remodelling through a number of downstream mechanisms. The central role of the NO-sGC-cGMP pathway in regulating pulmonary vascular tone is demonstrated by the dysregulation of NO production, sGC activity and cGMP degradation in pulmonary hypertension (PH). ⋯ These promising results suggest that sGC stimulators may constitute a valuable new therapy for PH. Other trials of riociguat are in progress, including a study of the haemodynamic effects and safety of riociguat in patients with PH associated with left ventricular diastolic dysfunction, and long-term extensions of the phase 3 trials investigating the efficacy and safety of riociguat in patients with PAH and chronic thromboembolic PH. Finally, sGC stimulators may also have potential therapeutic applications in other diseases, including heart failure, lung fibrosis, scleroderma and sickle cell disease.
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Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availability, and how these are interpreted by the cell to generate permissive or silenced states for transcription. CLOCK-BMAL1-mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. ⋯ Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Here we will discuss the evidence demonstrating that chromatin remodeling is at the crossroads of circadian rhythms and regulation of metabolism and cellular proliferation.
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The influence of sex and gender on anesthesia and analgesic therapy remains poorly understood, nevertheless the numerous physiological and pharmacological differences present between men and women. Although in anesthesiology sex-gender aspects have attracted little attention, it has been reported that women have a greater sensitivity to the non-depolarizing neuroblocking agents, whereas males are more sensitive than females to propofol. It has been suggested that men wake slower than women after general anesthesia and have less postoperative nausea and vomiting. ⋯ In particular, females seem to be more sensitive than males to opioid receptor agonists. Women may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. Evidently, there is an obvious need for more research, which should include psychological and social factors in experimental preclinical and clinical paradigms in view of their importance on pain mechanism, in order to individualize analgesia to optimize pain relief.
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Handb Exp Pharmacol · Jan 2012
ReviewPrimary prevention of ischaemic cardiovascular disorders with antiplatelet agents.
In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-the benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). ⋯ These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses.
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Platelet P2Y12 receptor inhibition plays a pivotal role in preventing thrombotic vascular events in patients with ACS and in patients undergoing percutaneous coronary intervention (PCI). Among the P2Y12 receptor inhibitors, the group of thienopyridines include ticlopidine, clopidogrel and prasugrel, all of which are orally administered prodrugs leading to irreversible P2Y12 receptor inhibition. Non-thienopyridine derivatives including ticagrelor, cangrelor and elinogrel do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition in contrast to thienopyridines. ⋯ Insufficient platelet inhibition, termed high platelet reactivity (HPR) is associated with an increased risk for ischemic events after PCI whereas exceeding platelet inhibition results in an increased bleeding risk. Pharmacologic properties and clinical outcome data differ substantially between the existing P2Y12 receptor inhibitors. Whether individualized antiplatelet treatment incorporating different P2Y12 receptor inhibitors improves patients' clinical outcomes warrants further investigation.