Assessment of capillary volumetric blood microsampling for the analysis of central nervous system drugs and metabolites

Development of an advanced analytical method coupling capillary dried blood spots and LC-MS/MS for the TDM of patients undergoing treatment with CNS drugs.

Drug induced liver damage in a universitary hospital

<strong>Background:</strong> Drug Induced Liver Injury (DILI) is responsible for wide spectrum of liver injury. Clinically, these events are presented in various forms and for reaching a different diagnosis other injury causes must be excluded. <strong>Aim:</strong> Identify and characterize cases of hepatotoxicity induced by drugs, herbal and dietary supplements in University Hospital in Brazil. <strong>Material and Methods: </strong>Observational and retrospective study. Was collected in records of University Hospital, between August 2009 at August 2014. The causality of the drug reactions suspected were evaluated Council for International Organizations of Medical Sciences (CIOMS). <strong>Results:</strong> We selected 30 suspected cases, 50% was female and average was 39 years. The therapeutic classes most common was: anti-infectives; antineoplastic agents; central nervous system drugs, anabolic steroid and herbal and dietary supplements (HDS). Cholestatic or mixed injury was observed in 73% these cases; 60% were highly probable, according to CIOMS. <strong>Conclusion:</strong> DILI is caused by a wide variety of drugs, dietary supplements and dietary supplements. Anti-infectives and chemotherapy were responsible for much of the response

In Silico Prediction of P-glycoprotein Binding: Insights from Molecular Docking Studies

The P-glycoprotein is an efflux transporter that expels substances out of the cells and has an important impact on the pharmacokinetic and pharmacodynamic properties of drugs. The study of the interactions between ligands and the P-glycoprotein has implications in the design of Central Nervous System drugs and their transport across the blood-brain barrier. Moreover, since the P-glycoprotein is overexpressed in some types of cancers, the protein is responsible for expelling the drug therapies from the cells, and hence, for drug resistance. In this review, we describe different P-glycoprotein binding sites reported for substrates, inhibitors and modulators, and focus on molecular docking studies that provide useful information about drugs and P-glycoprotein interactions. Docking in crystallized structures and homology models showed potential in the detection of the binding site and key residues responsible for ligand recognition. Moreover, virtual screening through molecular docking discriminates P-glycoprotein ligands from decoys. We also discuss challenges and limitations of molecular docking simulations applied to this particular protein. Computational structure-based approaches are very helpful in the study of novel ligands that interact with the P-glycoprotein and provide insights to understand the P-glycoprotein molecular mechanism of action.

Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience

The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.

Prospects for repurposing CNS drugs for cancer treatment

Drug repurposing is the idea of using an already approved drug for another disease or disorder away from its initial use. This new approach ensures the reduction in high cost required for developing a new drug in addition to the time consumed, especially in the tumor disorders that show an unceasing rising rate with an unmet success rate of new anticancer drugs. In our review, we will review the anti-cancer effect of some CNS drugs, including both therapeutic and preventive, by searching the literature for preclinical or clinical evidence for anticancer potential of central nervous system drugs over the last 8 years period (2010-2018) and including only evidence from Q1 journals as indicated by Scimago website (www.scimagojr.com). We concluded that Some Central Nervous system drugs show a great potential as anti-cancer in vitro, in vivo and clinical trials through different mechanisms and pathways in different types of cancer that reveal a promising evidence for the repurposing of CNS drugs for new indications.