1,721,239 research outputs found
Strategies for early prediction and timely recognition of drug-induced liver injury: The case of cyclin-dependent kinase 4/6 inhibitors
Full text linkThe idiosyncratic nature of drug-induced liver injury (Dili) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized Dili potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of Dili, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of Dili and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of Dili signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences
Targeting the arrhythmogenic substrate in atrial fibrillation: focus on structural remodeling
No full textAtrial fibrillation (AF) is an emerging clinical problem with multifaceted issues: current and expected prevalence, significant morbidity, potentially fatal outcome (e.g., stroke) and gaps in therapeutic approaches. Current antiarrhythmic strategies not only fail to guarantee effective rhythm control, but also cause “on target” (i.e., pro-arrhythmia, namely torsade de pointes) and “off target” (i.e., extra-cardiac toxicities) side effects. Although a number of drugs have just come out of the pipeline with promising results (e.g., dronedarone), the question arises whether channel-targeted drugs represent the only viable approach. A body of evidence has emerged supporting structural remodeling as the main arrhythmogenic substrate perpetuating AF. Fibrosis, inflammation and oxidative stress appear strongly interconnected in the pathogenesis of remodeling-induced abnormalities. Moreover, insights into extracellular matrix network strongly suggested an active cross-talk within the cardiac microenvironment, which should be further investigated as promising “anti-remodeling” approach. Therefore, pharmacological modulation of non-ionic targets (the so called “upstream” therapy) has gained interest as a preventive strategy in AF. At the present state of knowledge, renin-angiotensinaldosterone system blockers and statins offer evidence for potential clinical exploitation, while several remodeling targeted therapies have been tested only experimentally or failed when studied for human validation. Fascinating and innovative strategies have been proposed (e.g., miRNAs modulation), but the actual benefit is debated. This review will provide mechanistic insights into structural remodeling and highlight emerging upstream strategies in AF management
Reduced neuropsychiatric events as “beneficial reactions” to drugs: Seek associations with caution
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Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: Insight from a pharmacovigilance study
Full text linkBackground: The management of Klebsiella pneumoniae carbapenemase producing (KPC) infections represents a major challenge. Several safety and efficacy concerns are shared by available antibiotics used in KPC infections, leading to the occurrence of serious adverse drug reactions (ADRs), with ceftazidime-avibactam possibly showing a more favourable risk-benefit profile. We investigated the potential impact of resistance on ADR reports in countries with different prevalence of KPC isolates (Italy vs. United Kingdom [UK]), and described safety profile of newer and older antibiotics used in KPC infections. Methods: Three spontaneous reporting systems (SRSs) with different features (Italy, UK and worldwide FAERS) were used to describe safety profiles of colistin, meropenem, tigecycline, gentamicin and ceftazidime-avibactam in terms of System Organ Class and Preferred Term level. ADRs were plotted with prevalence of KPC isolates in Italy and UK. A comparison between before-after the KPC outbreak period (1999-2008 vs. 2009-2018) of overall and serious ADRs for selected antibiotics in each SRS was performed. Relationship between total and serious number of ADR reports per year and KPC isolates per year after KPC outbreak (2009-2017) was investigated for both Italy and UK. Results: A total of 16,329 ADR reports were collected in the three SRSs, with meropenem (42.6%) and gentamicin (36.9%) having the highest number of reports. Significant increase in total and serious ADR reports after the KPC outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01). No significant increase in tigecycline ADRs was reported in FAERS and UK database. Unexpected safety signals involving selected antibiotics were not detected. Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p < 0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found. Conclusion: KPC outbreak led to significant increase in ADRs to selected antibiotics, and a close relationship with antimicrobial resistance was found, both in countries with high and low resistance rate. New safety signals were not detected for selected agents. Active surveillance should be maintained to promptly identify unexpected safety issues
Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis
Full text linkPurpose: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis
Peptidi e neurotrasmettitori nel controllo della motilità gastrointestinale.
No full textProceedings of the symposium 'Critical Review and New Trends in Diagnosis and Rehabilitation of Urogenital and Intestinal Function', Sirmione, aprile 1991, p. 109-124
Fisiofarmacologia generale dell'apparato digerente con cenni sul sistema neuroparacrino enterico.
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