Mini reviews in medicinal chemistry
-
Review
Pharmacological pre- and post- conditioning agents: reperfusion-injury of the heart revisited.
Ischemic preconditioning (PC) and postconditioning (PostC) are endogenous mechanisms of protection of the ischemic heart. In brief, short cycles of sublethal ischemia separated by brief periods of reperfusion render the heart resistant to infarction from a subsequent lethal episode of prolonged ischemia. Although PC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. ⋯ Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as PostC analogues. We summarize recent studies focused on the pharmacological interventions and on the discovery of novel agents that may reduce the infarct size.
-
Traumatic brain injury affects over a million Americans annually, but pharmacological therapy remains limited. Current standards of care in acute, subacute and chronic phases of injury are primarily supportive. This review discusses pharmacological strategies and future directions in patient treatment emphasizing pleiotropic agents targeting inflammation, oxidative damage, and glutamate excitotoxicity.
-
Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. ⋯ In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.
-
Review Comparative Study
Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone.
Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. ⋯ We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.
-
Since the introduction of (+)-tubocurarine into anaesthetic and surgical practice (1942), a number of non-depolarizing neuromuscular blocking agents (NMBs) with improved pharmacological properties have been developed during the last sixty years. However, after withdrawal of rapacuronium from clinical use, there is still a need for an ultra-short acting non-depolarizing muscle relaxant with rapid onset as substitution for the polarizing suxamethonium, which has several undesirable side-effects. In this paper, structure-activity relationships within four different series of NMBs (tetrahydroisoquinolinium, bistropinyl diester, aminosteroid, and amino peptide analogues) published in this millennium have been reviewed. The NMB properties of the most promising drug candidates from each series were discussed and compared to those of the already existing muscle relaxants.