Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase).

Tramadol, a weak µ-opioid receptor agonist, has been used worldwide for pain management. It is considered to have a favorable safety profile without serious adverse events; however, safety issues of respiratory depression were proposed by regulatory governments. We aimed to examine the risk and contributing factors associated with tramadol-related respiratory depression using a real-world database, VigiBase. Disproportionality analysis of tramadol and tramadol/paracetamol was performed using proportional reporting ratios, reporting odds ratios, and information components for all drugs and opioids. Factors related to respiratory depression, including sex, age, presence of abuse, death, and various concomitant medications, were evaluated. Among 140,721 tramadol reports, respiratory depression was reported in 1126 cases, 81.3% of which were deemed serious. Five adverse events were detected as signals of tramadol-related acute central respiratory depression (ACRD) in 882 reports. A higher proportion of ACRD cases in children and adolescents was observed than all adverse events cases of tramadol. Concomitant users of CYP2D6 inhibitors, opioids, benzodiazepines, and anti-depressant drugs showed a higher proportion in ACRD cases than non-ACRD cases. ACRD was related to drug abuse and death. This pharmacovigilance study, using VigiBase, confirmed a high risk of respiratory depression (a serious, potentially fatal adverse event) secondary to the use of tramadol, especially in pediatric patients, drug abusers, or during concomitant use of opioids, benzodiazepines, or antidepressants.

In Vitro, In Vivo, and In Silico Analysis of Pyraclostrobin and Cyprodinil and Their Mixture Reveal New Targets and Signaling Mechanisms.

Pyraclostrobin and cyprodinil are broad-spectrum fungicides that are used in crops to control diseases. However, they are excessively used and, as a result, end up in the environment and threaten human health and ecosystems. Hence, knowledge of their mechanisms of action is critical to revealing their environmental fate and negative effects and regulating their use. In the present study, we conducted a comprehensive study to show the adverse effects of pyraclostrobin, cyprodinil, and their mixture using zebrafish larvae and different cell lines. Several end points were investigated, including mortality, development, gene expression, reporter assays, and molecular docking simulations. We found that both compounds and their mixture caused developmental delays and mortality in zebrafish, with a higher effect displayed by pyraclostrobin. Both compounds altered the expression of genes involved in several signaling pathways, including oxidative stress and mitochondrial function, lipid and drug metabolisms, the cell cycle, DNA damage, apoptosis, and inflammation. A noteworthy result of this study is that cyprodinil and the mixture group acted as NFκB activators, while pyraclostrobin demonstrated antagonist activity. The AHR activity was also upregulated by cyprodinil and the mixture group; however, pyraclostrobin did not show any effect. For the first time, we also demonstrated that pyraclostrobin had androgen receptor antagonist activity.

A risk of serious anaphylatic reactions to asthma biologics: a pharmacovigilance study based on a global real-world database.

Asthma is a chronic inflammatory condition that affects the lung airways. Chronic use of oral glucocorticoids in patients with severe asthma is associated with several adverse events (AEs). Biologics (omalizumab, benralizumab, mepolizumab, reslizumab, and dupilumab) have been developed as alternative therapies for the treatment of asthma. In this study, we aimed to evaluate the risk of anaphylactic reactions associated with these five biologics based on a large global database. We utilized individual case reports from the Uppsala Monitoring Center from January 1968 to December 29, 2019. A disproportionality analysis was performed over all drugs and monoclonal antibodies. Anaphylactic reactions were defined according to the "anaphylactic reaction" of the standardized MedDRA queries. Contrary to dupilumab, omalizumab, benralizumab, and mepolizumab demonstrated positive signals related to anaphylactic reactions over all drugs and monoclonal antibodies. Reslizumab, which represented only 315 cases of all AEs, requires more reports to determine its association with anaphylactic reactions. More anaphylactic reactions have been identified than are known, and most cases (96.2%) are reported to be serious. Our findings indicate that omalizumab, benralizumab, and mepolizumab for asthma treatment are associated with a high risk of anaphylactic reactions; thus, more careful monitoring in the post-administration period is recommended.

Optimal Nutritional Support Strategy Based on the Association between Modified NUTRIC Score and 28-Day Mortality in Critically Ill Patients: A Prospective Study.

Malnutrition in critically ill patients is closely linked with clinical outcomes. During acute inflammatory states, nutrition cannot reverse the loss of body cell mass completely. Studies on nutritional screening and strategy considering metabolic changes have not yet been conducted. We aimed to identify nutrition strategies using the modified Nutrition Risk in the Critically ill (mNUTIRC) score. Nutrition support data, laboratory nutrition indicators, and prognosis indices were prospectively collected on the 2nd and 7th day after admission. It was to identify the effect of the changes on the metabolic status and critical target of nutrition intervention. To discriminate the high-risk group of malnutrition, receiver operating characteristic curves were plotted. Risk factors associated with 28 day-mortality were evaluated using multivariable Cox proportional hazards regression. A total of 490 and 266 patients were analyzed on the 2nd and 7th day, respectively. Only the mNUTRIC score showed significant differences in nutritional risk stratification. The use of vasopressors, hypoprotein supply (<1.0 g/kg/day), high mNUTRIC score, and hypoalbuminemia (<2.5 mg/dL) in the recovery phase were strongly associated with a 28-day mortality. The implementation of the mNUTRIC score and protein supply in the post-acute phase is critical to improve 28-day mortality in critically ill patients.

In Vitro and In Vivo Cholesterol Reducing Ability and Safety of Probiotic Candidates Isolated from Korean Fermented Soya Beans.

Hypercholesterolemia is a risk factor for cardiovascular diseases, and hence, reducing serum cholesterol levels could reduce the incidence. In this study, we ascertained the cholesterol-reducing potential of lactic acid bacteria (LAB) isolated from Korean fermented soybean paste. Live, resting, and dead cells of all the bacteria reduced cholesterol in liquid media in a strain-dependent manner. Live cells of Weissella cibaria SCCB2306, Pediococcus acidilactici SDL1402, P. acidilactici SDL1406, and Lactobacillus rhamnosus JDFM6 reduced the most cholesterol in liquid media by 78 ± 3%, 72 ± 3%, 76 ± 3%, 75 ± 5%, and 79 ± 2%, respectively. As the cholesterol levels in the media reduced, cell membrane lipids of P. acidilactici SDL1402, P. acidilactici SDL1406, and L. rhamnosus JDFM6 increased by 23.36 mg/mL, 6.53 mg/mL, and 8.14 mg/mL, respectively, indicating that cholesterol was incorporated into the bacteria cell membranes. All the bacteria displayed bile salt hydrolase activities in a strain-dependent manner. Though all four LAB significantly reduced cholesterol levels in Caenorhabditis elegans irrespective of the order of feeding, L. rhamnosus JDFM6 reduced the most cholesterol in vivo (up to 40% of ingested cholesterol). None of the four LAB hydrolyzed mucin or gelatin and none was toxic to C. elegans. The concentrations of phenylethylamine, putrescine, cadaverine, histamine, and tyramine produced by the LAB were below the toxic limits of biogenic amines set by the European Food Safety Authority. Taken together, our results demonstrate that Weissella cibaria SCCB2306, P. acidilactici SDL1402, P. acidilactici SDL1405, and L. rhamnosus JDFM6 could be safe cholesterol-reducing probiotic candidates for preventing or managing hypercholesterolemia.