C-reactive protein and cognitive impairment: A bidirectional Mendelian randomization study.

OBJECTIVES: While C-reactive protein (CRP) has been solidly linked as a risk factor for cognitive impairment, observational research alone cannot definitively demonstrate a causal relationship. This study therefore sought to determine whether there was an association between CRP and the development of cognitive impairment. METHODS: This study employed bidirectional Mendelian randomization (MR) to investigate the genetic association between CRP and cognitive impairment. genome-wide association studies (GWAS) summary statistics for both were sourced from IEU Open GWAS or prior reports. Cognitive GWAS's used were on tests designed to assess cognitive performance, fluid intelligence, prospective memory, and reaction time. The MR analysis applied several methods, including inverse variance-weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode approaches, then use of MR sensitivity analyses to interrogate findings. RESULTS: Forward MR analysis showed that genetically proxied CRP was associated with prospective memory (P = 0.009), whereas there is little evidence to support an association between CRP and other cognitive tests. Reverse MR analysis indicated a potential association between genetic proxy cognitive performance (P = 0.002) and fluid intelligence score (P = 0.019) with CRP levels. For genetically proxied CRP on prospective memory, the level of pleiotropy (P > 0.05) and no genetic variant heterogeneity (P > 0.05) made bias unlikely, and leave-one-out tests also confirmed robust associations. CONCLUSIONS: The effect of genetically proxied CRP on prospective memory, with little evidence on other cognitive tests. The reverse MR shows some evidence of genetically proxied cognition (cognitive performance and fluid intelligence) on CRP levels.

Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal.

OBJECTIVE: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF). RESEARCH DESIGN AND METHODS: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold. RESULTS: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold. CONCLUSIONS: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF.

Postmarketing safety profile of brexanolone: a pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS).

OBJECTIVE: Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone. METHODS: In our case/non-case pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS), the reporting odds ratio and information component with 95% confidence intervals were estimated as measures of disproportionate reporting. Primary disproportionality analyses were performed by comparing brexanolone with all other drugs or selective serotonin reuptake inhibitors (SSRIs). Sensitivity analyses were performed on a subset of perinatal depression. RESULTS: We identified 267 cases using brexanolone. Brexanolone was reported as a primary or secondary suspect drug in most cases (n = 260, 97.38%). Of the total brexanolone cases, positive dechallenge and discontinuation accounted for 12.36% (n = 33) and 26.22% (n = 70), respectively. Serious outcomes were reported in 11.61% (n = 31) patients. Compared to all the other drugs or SSRIs within the same time window, the reporting risks of brexanolone were mainly from psychiatric and nervous systems. Sensitivity analyses indicated that these significant disproportionalities were mostly retained. CONCLUSION: Our pharmacovigilance analysis showed a high reporting frequency of psychiatric and nervous system ADRs associated with the use of brexanolone. In additional prospective research, these signals urgently need to be clarified.

Disturbed hippocampal histidine metabolism contributes to cognitive impairment induced by recurrent nonsevere hypoglycemia in diabetes.

Hypoglycemia is a common adverse reaction to glucose-lowering treatment. Diabetes mellitus (DM) combined with recurrent nonsevere hypoglycemia (RH) can accelerate cognitive decline. Currently, the metabolic pattern changes in cognition-related brain regions caused by this combined effect of DM and RH (DR) remain unclear. In this study, we first characterized the metabolic profiles of the hippocampus in mice exposed to DR using non-targeted metabolomic platforms. Our results showed that DR induced a unique metabolic pattern in the hippocampus, and several significant differences in metabolite levels belonging to the histidine metabolism pathway were discovered. Based on these findings, in the follow-up experiment, we found that histidine treatment could attenuate the cognitive impairment and rescue the neuronal and synaptic damage induced by DR in the hippocampus, which are closely related to ameliorated mitochondrial injury. These findings provide new insights into the metabolic mechanisms of the hippocampus in the progression of DR, and l-histidine supplementation may be a potential metabolic therapy in the future.

Direct-acting antiviral agent use and gastrointestinal safety in patients with chronic hepatitis C: a pharmacovigilance study based on FDA Adverse Event Reporting System.

BACKGROUND: Gastrointestinal adverse drug reactions (GADRs) of direct-acting antiviral agents (DAAs) in patients with chronic hepatitis C are underestimated. AIM: This study aimed to comprehensively evaluate the gastrointestinal safety of DAAs in patients with chronic hepatitis C. METHOD: The US FDA Adverse Event Reporting System database was searched for GADR cases reported from 01 to 2012 to 30 September 2021. Twelve DAA types used for hepatitis C virus were included. The top 30 GADRs were assessed based on the use of DAAs, number of cases, and clinical features. A case-non-case disproportionality approach was used to confirm pharmacovigilance signals, whereby reporting odds ratios (ROR) with 95% CI were calculated. RESULTS: Nausea (70.01/1000), diarrhoea (39.10/1000), and vomiting (31.68/1000) accounted for the highest number of cases. The pooled median time-to-onset of the top 30 GADRs was 13 days (Q1-Q3: 2-38) and the proportion of drug discontinuation was 19.17%. The highest number of DAA-related cases involved ledipasvir/sofosbuvir (21.86%), sofosbuvir/velpatasvir (21.77%), and sofosbuvir (13.41%). When DAAs were considered as a class drug, after adjusting for age, sex, concomitant diseases and drugs that potentially induced GADRs, significant RORs for specific GADRs were noted, including abdominal discomfort (1.62, 95% CI 1.32-1.99), constipation (1.54, 95% CI 1.26-1.89), dyspepsia (1.25, 95% CI 1.01-1.55), abdominal distension (1.36, 95% CI 1.05-1.75), faeces discoloured (1.77, 95% CI 1.15-2.73), and gastric ulcer (2.37, 95% CI 1.28-4.41). CONCLUSION: Clinicians should have a deeper understanding of GADRs to improve the gastrointestinal tolerance of patients with chronic hepatitis C.

Anti-tumor Necrosis Factor-Alpha Therapy and Hypoglycemia: A Real-World Pharmacovigilance Analysis.

INTRODUCTION: An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet. OBJECTIVE: The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use. METHODS: Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels. RESULTS: In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable. CONCLUSIONS: Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.

Hypoglycemia associated with direct-acting anti-hepatitis C virus drugs: An epidemiologic surveillance study of the FDA adverse event reporting system (FAERS).

BACKGROUND AND OBJECTIVE: Hypoglycemia induced by direct-acting antiviral agents (DAAs) for chronic hepatitis C virus (HCV) infection is a rare but potentially life-threatening adverse reaction, which led to warnings by competent authorities. We therefore aimed to examine the hypoglycemic safety signal for DAAs. METHODS: Reports to the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 1 October 2012 to 31 March 2020 were analyzed. The Medical Dictionary for Regulatory Activities was used to identify hypoglycemia cases. A case by non-case disproportionality approach was used whereby reporting odds ratio (ROR) with 95% confidence intervals (CI) were calculated. RESULTS: In HCV infection with diabetes patients, the cumulative frequency of hypoglycemic ADRs was 21.85/1000 for reports involving DAAs versus 13.50/1000 for reports involving other medications; For DAAs as a class drug, a nearly double increased reporting odds for hypoglycemia was observed (ROR: 1.63, 95% CI: 1.11-2.41). However, in DAAs subgroup analysis, only telaprevir (ROR: 1.66, 95% CI: 1.01-2.74) and elbasvir/grazoprevir (ROR: 2.25, 95% CI: 1.05-4.83) were associated with increased reporting risk of hypoglycemia during corresponding marketing period; when combined with insulins and sulfonylureas, DAAs were associated with increased reporting risk for hypoglycemia (ROR: 1.98, 95% CI: 1.36-2.88; ROR: 1.62, 95% CI: 1.06-2.48), but concomitant biguanides, dipeptidyl peptidase IV (DPP-4) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) were not significant. CONCLUSIONS: This study supports the current recommendation for cautious about hypoglycemic risk relating to the use of DAAs. Treatment with DAAs and antidabetic agents (especially insulins and sulfonylureas) will increase hypoglycemia reporting risk. Physicians and pharmacists should be aware of this risk when prescribing DAAs for patients suffering from diabetes, advanced age or liver decompensation.