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The Journal of Experimental Medicine Nov 2023Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release...
Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved β1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.
Topics: Humans; Receptors, Chimeric Antigen; Interleukin-6; Cytokine Release Syndrome; Cytokines; Metoprolol; Immunotherapy, Adoptive
PubMed: 37584653
DOI: 10.1084/jem.20230577 -
Emergencias : Revista de La Sociedad... Jan 2024In the article "Management of atrial fibrillation in hospital emergency services: update to 2023 of the consensus of the Spanish Society of Emergency Medicine (SEMES),...
In the article "Management of atrial fibrillation in hospital emergency services: update to 2023 of the consensus of the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Cardiology (SEC) and the Spanish Society of Thrombosis and Haemostasis ( SETH)" published in volume 35, number 5, October 2023, there were some errors that are detailed and corrected below: On page 368, Table 3, in the dose column of the ENSURE-AF study, where it says " Adequate anticoagulant or TEE + Rivaroxaban at least 2 hours before VC" should say "Appropriate anticoagulant or TEE + Edoxaban at least 2 hours before VC." On page 370, Table 4, in the metoprolol loading dose column where it says "2.5-5 mg/kg in 2 min up to a maximum of 3 doses" it should say "2.5-5 mg in 2 min up to a maximum of 3 doses."
PubMed: 38318748
DOI: 10.55633/s3me/005.2024 -
Cureus Aug 2023Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease and is a prevalent cause of sudden cardiac death (SCD). This study aims to establish the... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease and is a prevalent cause of sudden cardiac death (SCD). This study aims to establish the benefits and therapeutic value metoprolol or verapamil offer to patients who suffer from symptoms caused by HCM, with regard to resolving left ventricular outflow tract obstruction (LVOTO), as well as improving a patient's quality of life and reducing symptoms. We conducted a systematic review to find clinical studies that described the use of metoprolol or verapamil in the management of HCM. Three databases were analyzed for studies, PubMed, Google Scholar, and ScienceDirect. We discovered 6,260 potentially eligible records across all the databases. According to our eligibility criteria, we included four studies in this review. Metoprolol showed median left ventricular outflow tract (LVOT) gradients of 25 mm Hg versus 72 mm Hg (P = 0.007) at rest, 28 mm Hg versus 62 mm Hg (P < 0.001) at peak exercise, and 45 mm Hg versus 115 mm Hg (P < 0.001) post-exercise. Verapamil also showed a statistically significant increase in exercise capacity. Both drugs have been shown to be safe to use with a good side effect profile; however, metoprolol was better tolerated in the patient population that was tested in the studies collected. In this study, metoprolol was effective in reducing LVOT and improving the quality of life in patients, while verapamil showed variable effects on both exercise capacity and baseline hemodynamics.
PubMed: 37565181
DOI: 10.7759/cureus.43197 -
BMC Pulmonary Medicine Nov 2023Pulmonary hypertension (PH) in COPD confers increased risk of exacerbations (ECOPD). Electrocardiogram (ECG) indicators of PH are prognostic both in PH and COPD. In the... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Pulmonary hypertension (PH) in COPD confers increased risk of exacerbations (ECOPD). Electrocardiogram (ECG) indicators of PH are prognostic both in PH and COPD. In the Beta-Blockers for the Prevention of Acute Exacerbations of COPD (BLOCK-COPD) trial, metoprolol increased risk of severe ECOPD through unclear mechanisms.
OBJECTIVE
We evaluated whether an ECG indicator of PH, P-pulmonale, would be associated with ECOPD and whether participants with P-pulmonale randomized to metoprolol were at higher risk of ECOPD and worsened respiratory symptoms given the potential detrimental effects of beta-blockers in PH.
METHODS
ECGs of 501 participants were analyzed for P-pulmonale (P wave enlargement in lead II). Cox proportional hazards models evaluated for associations between P-pulmonale and time to ECOPD (all and severe) for all participants and by treatment assignment (metoprolol vs. placebo). Linear mixed-effects models evaluated the association between treatment assignment and P-pulmonale on change in symptom scores (measured by CAT and SOBQ).
RESULTS
We identified no association between P-pulmonale and risk of any ECOPD or severe ECOPD. However, in individuals with P-pulmonale, metoprolol was associated with increased risk for ECOPD (aHR 2.92, 95% CI: 1.45-5.85). There was no association between metoprolol and ECOPD in individuals without P-pulmonale (aHR 1.01, 95% CI: 0.77-1.31). Individuals with P-pulmonale assigned to metoprolol experienced worsening symptoms (mean increase of 3.95, 95% CI: 1.32-6.58) whereas those assigned to placebo experienced a mean improvement in CAT score of -2.45 (95% CI: -0.30- -4.61).
CONCLUSIONS
In individuals with P-pulmonale, metoprolol was associated with increased exacerbation risk and worsened symptoms. These findings may explain the findings observed in BLOCK-COPD.
Topics: Humans; Adrenergic beta-Antagonists; Disease Progression; Metoprolol; Morbidity; Pulmonary Disease, Chronic Obstructive
PubMed: 37946165
DOI: 10.1186/s12890-023-02748-2 -
Orphanet Journal of Rare Diseases Dec 2023Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of... (Review)
Review
BACKGROUNDS
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of concern due to its rarity and insufficient recognition of this disorder, particularly in developing countries like China.
AIMS AND METHODS
We reported six catecholaminergic polymorphic ventricular tachycardia (CPVT) children diagnosed in our center along with a comprehensive review of Chinese pediatric CPVT patients reported in domestic and overseas literature between January 2013 and December 2021 to provide an essential reference for physicians to deepen their understanding of pediatric CPVT.
RESULTS
A total of 95 children with CPVT, including our six patients from 21 medical centers were identified. The median age of symptom onset is 8.7 ± 3.0 years. Diagnosis occurred at a median age of 12.9 ± 6.8 years with a delay of 4.3 ± 6.6 years. Selective beta-blockers (Metoprolol and Bisoprolol) were prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker (Propranolol and Nadolol) treatment. Six patients accepted LCSD and seven received ICD implantation at the subsequent therapy. A total of 13 patients died during the disease course. Of the 67 patients with positive gene test results, variants in RYR2 were 47 (70.1%), CASQ2 were 11 (16.4%), and RYR2 accompanied SCN5A were 7 (10.4%). Patients with CASQ2 gene mutations presented with younger symptom onset age, higher positive family history rate and better prognosis than those with RYR2 mutations.
CONCLUSION
Chinese pediatric patients with CPVT had a poorer prognosis than other cohorts, probably due to delayed/missed diagnosis, non-standard usage of beta-blockers, unavailability of flecainide, and a lower rate of LCSD and ICD implantation.
Topics: Adolescent; Child; Child, Preschool; Humans; Young Adult; East Asian People; Genetic Profile; Mutation; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular
PubMed: 38053087
DOI: 10.1186/s13023-023-02991-0 -
Frontiers in Cardiovascular Medicine 2023Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and... (Review)
Review
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and recommend better drug treatments for adults with HCM.
METHODS
A review of PubMed, Embase, the Cochrane Controlled Register of Trials (CENTRAL), ClinicalTrials.gov and CNKI databases was conducted for studies on the efficacy and safety of drugs for adults with HCM. A frequentist random effects model was used in this network analysis.
RESULTS
This network meta-analysis included 7 studies assessing seven medications, 6 studies evaluating monotherapy and 1 study evaluating combination therapy. Based on the network meta-analysis results, xiaoxinbi formula plus metoprolol (MD -56.50% [-72.43%, -40.57%]), metoprolol (MD -47.00% [-59.07%, -34.93%]) and mavacamten (MD -34.50% [-44.75%, -24.25%]) significantly reduced the resting left ventricular outflow tract gradient (LVOTG) in comparison with placebo. Resting LVOTG could also be reduced with N-acetylcysteine (NAC). The incidence of adverse drug reactions was not significantly different between the placebo group and the treatment group.
CONCLUSION
For adults with HCM, the top 4 treatments included xiaoxinbi formula plus metoprolol, metoprolol, mavacamten and NAC.: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=374222], identifier [CRD42022374222].
PubMed: 37645523
DOI: 10.3389/fcvm.2023.1190181 -
Drug Metabolism and Disposition: the... Jun 2024Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute...
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.
PubMed: 38849209
DOI: 10.1124/dmd.124.001772