N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients-focus on the antioxidant and anti-inflammatory properties.

Oxidative stress (OS) has been recognized as a pathophysiologic mechanism underlying the development and progression of chronic kidney disease (CKD). OS, which results from the disturbance of balance among pro-oxidants and antioxidants favoring the pro-oxidants, is present even in early CKD and increases progressively along with deterioration of kidney function to end-stage kidney disease (ESKD). In ESKD, OS is further exacerbated mainly due to dialysis procedures per se and predisposes to increased cardiovascular morbidity and mortality. Therefore, since OS plays a pivotal role in the pathogenesis and progression of atherosclerosis in uremic patients, several strategies aiming to ameliorate OS in these patients have been proposed. Among those, N-acetylcysteine (NAC), a thiol-containing antioxidant agent, has attracted special attention due to its pleiotropic functions and beneficial effect in various OS-related entities including paracetamol overdose and prevention of contrast-induced nephropathy. In this review, we present the currently available literature on the antioxidant and anti-inflammatory properties of NAC in CKD, including hemodialysis and peritoneal dialysis.

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Safety of antipsychotic drugs: A systematic review of disproportionality analysis studies.

Antipsychotic drugs are commonly prescribed, mainly for the treatment of schizophrenia and other psychotic disorders. Disproportionality analysis of pharmacovigilance data from national and international databases have been recently utilized to investigate the side-effect profiles of antipsychotics and have provided unique insights of their safety. Among several national and international spontaneous reporting databases the databases of the World Health Organization (VigiBase), of the European Medicines Agency (EudraVigilance) and the US Food and Drug Administration (FAERS) incorporate millions of Individual Case Safety Reports. The aim of our study was to systematically review published disproportionality analyses on antipsychotic drugs, in order to summarize the current state of methodology and potential strengths of this analysis while highlighting safety signal generated for these pharmacological group. PubMed was searched using a search algorithm combining terms for antipsychotic drugs and disproportionality analysis. A total of 39 articles were found to be eligible corresponding to 38 original disproportionality studies. Different measures of disproportionality were used in each study: reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM) and the information component (IC). Despite the inherent limitations of the pharmacovigilance databases disproportionality analysis provides complemented evidence from RCTs on the safety of antipsychotics, especially regarding participants often excluded from RCTs, such as pregnant and breastfeeding women, children and participants with drug abuse, comorbidities or concomitant medications.

Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study.

An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting "infective-pneumonia" and "pneumonia-aspiration" and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

Massive Localized Lymphedema in the Morbidly Obese Patient: A Clinical Entity Mimicking Lymphosarcoma.

Massive localized lymphedema (MLL) is a rare benign soft tissue lesion that develops in morbidly obese patients, most commonly on the medial thigh (though other locations have also been described). The cause of MLL remains unknown, but the common denominator in all reported cases is obesity. The diagnosis of MLL is usually made based on clinical history and presentation but it is believed to be underdiagnosed due to a lack of awareness of this distinct entity. When left untreated, MLL can degenerate into angiosarcoma. This report describes a case of MLL of the right lower abdominal wall in an obese 61-year-old female (BMI = 42 kg/m(2)).