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Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide. Pharmacogenetic and chronotherapeutic approaches are increasingly applied to optimize therapy in chronic cardiovascular diseases. While gene variants are known to influence long-term drug efficacy, their role in modulating drug-induced cardioprotection in acute conditions such as myocardial infarction is unclear. Similarly, the impact of circadian timing on cardioprotective responses remains insufficiently defined. To address these questions, we evaluated metoprolol as a model cardioprotective agent. Here we examine, in a non–pre-specified exploratory analysis of the METOCARD-CNIC trial (NCT01311700), the influence of ADRB1 Arg389Gly polymorphism and the time of AMI onset on metoprolol efficacy. We found that metoprolol reduced infarct size only in patients homozygous for the ADRB1 Arg389 allele, consistent with its genotype-dependent inhibition of neutrophil migration. In-silico docking and binding studies revealed unstable interactions of metoprolol with the Gly389 variant of ADRB1. Moreover, metoprolol was associated with reduced infarct size when AMI onset occurred between 6:00 and 12:00 h. Restricted cardioprotection to the light phase was confirmed in male mice and in neutrophil-specific Adrb1-knockout models. Collectively, these findings highlight the critical roles of genetic background and circadian timing in shaping the efficacy of acute cardioprotective therapies, supporting the rationale for personalized interventions in acute myocardial infarction. It remains uncertain whether genetic variants and day–night cycles affect the efficacy of drugs in acute disease settings. Here, the authors show that metoprolol reduces risk only in patients who carry two Arg389 alleles of the beta-1 adrenoceptor, and specifically when myocardial infarction occurs at the beginning of the light cycle.

Background Guidelines recognized dual combination in initial antihypertensive therapy. Studies found that low-dose quadruple combination were superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg), both in a single pill, in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded. The main outcomes were the reduction of blood pressure and safety outcomes. Analyses were per intention to treat. Results A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age was 43.88 years (SD 10.31), and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Compared to the standard-dose dual treatment, the half-dose quadruple treatment resulted in a further reduction in mean 24-h blood pressure by 4.72/4.17 mm Hg ( P  < 0.001 for both systolic and diastolic blood pressure), mean daytime blood pressure by 5.52/4.73 mm Hg ( P  < 0.001 for both), mean nighttime blood pressure by 2.37/2.25 mm Hg ( P  = 0.034 and 0.014, respectively), and mean office blood pressure by 2.91/1.73 mm Hg ( P  < 0.001 and 0.014, respectively). Apart from significant increases of fasting blood glucose ( P  = 0.029) and blood uric acid ( P  < 0.001) in the half-dose quadruple group, no other adverse events or changes in laboratory values differed significantly between the two treatments. Conclusions Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable. Trial registration ClinicalTrials.gov Identifier: NCT05377203.

This study evaluated the effects of allisartan isoproxil combined with amlodipine besylate tablets (Group A+C) or metoprolol succinate extended‐release tablets (Group A+B) on sexual function and nighttime blood pressure (nBP) in 130 male patients with essential hypertension (EH). Patients were randomized to two groups. After 6‐month, the IIEF‐15 total score (ITS) of sexual function significantly improved in Group A+C (p = 0.015), including intercourse satisfaction (IS) (p = 0.003), orgasmic function (OF) (p = 0.021), and overall satisfaction (OS) (p = 0.019), while erectile function (EF) (p = 0.081) and sexual desire (SD) (p = 0.08) were unchanged. In contrast, the ITS was decreased (p = 0.008), including EF (p = 0.005), IS (p = 0.048), SD (p = 0.003), and OS (p = 0.010), but OF remained unchanged (p = 0.076) in Group A+B. Between‐group comparisons confirmed significant differences across IIEF‐15 domains (all p < 0.05). Compared to baseline, office systolic BP (OSBP), office diastolic BP (ODBP), nighttime average SBP (nSBP), and nighttime average DBP (nDBP) were significantly reduced at 6 months in two groups (all p < 0.05). Although nSBP fall (nSBPF) (p = 0.010) and nDBP fall (nDBPF) (p = 0.002) significantly increased in Group A+C. In Group A+C, the nighttime‐daytime BP fall ratio of SBP was 1.04 (0.45, 1.70) and that of DBP was 1.13 (0.38, 1.44) after treatment, with a median value > 1, indicating that nBP fall after treatment was greater than dBP fall. Compared to Group A+B, ODBP (difference = −4.00 mmHg, 95% CI [−7.64, −0.36], p = 0.032), daytime average DBP (difference = −5.47 mmHg, 95% CI [−10.05, −0.79], p = 0.023) and 24‐h average DBP (difference = −5.77 mmHg, 95% CI [−10.31, −1.24], p = 0.014) decreased more significantly in Group A+C, nDBPF increased significantly (difference = 4.99 mmHg, 95% CI [0.04, 9.93], p = 0.048), and the decrease in the nighttime‐daytime BP fall ratio of SBP and DBP was higher (p < 0.05). It was concluded that combined antihypertension of allisartan isoproxil with amlodipine besylate tablets improved sexual function in male hypertensive patients in terms of the ITS, IS, OF, and OS, but there was no significant improvement in EF and SD. Both combined antihypertensive regimens were effective in lowering BP, but allisartan isoproxil combined with amlodipine besylate tablets demonstrated more advantageous in lowering DBP and nBP.

Despite previous randomised trials of early β-blocker therapy in the emergency treatment of myocardial infarction (MI), uncertainty has persisted about the value of adding it to current standard interventions (eg, aspirin and fibrinolytic therapy), and the balance of potential benefits and hazards is still unclear in high-risk patients. 45 852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were randomly allocated metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22 929) or matching placebo (n=22 923). 93% had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital (mean 15 days in survivors) and 89% completed it. The two prespecified co-primary outcomes were: (1) composite of death, reinfarction, or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Comparisons were by intention to treat, and used the log-rank method. This study is registered with ClinicalTrials.gov, number NCT 00222573. Neither of the co-primary outcomes was significantly reduced by allocation to metoprolol. For death, reinfarction, or cardiac arrest, 2166 (9·4%) patients allocated metoprolol had at least one such event compared with 2261 (9·9%) allocated placebo (odds ratio [OR] 0·96, 95% CI 0·90–1·01; p=0·1). For death alone, there were 1774 (7·7%) deaths in the metoprolol group versus 1797 (7·8%) in the placebo group (OR 0·99, 0·92–1·05; p=0·69). Allocation to metoprolol was associated with five fewer people having reinfarction (464 [2·0%] metoprolol vs 568 [2·5%] placebo; OR 0·82, 0·72–0·92; p=0·001) and five fewer having ventricular fibrillation (581 [2·5%] vs 698 [3·0%]; OR 0·83, 0·75–0·93; p=0·001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5·0%] vs 885 [3·9%]; OR 1·30, 1·19–1·41; p<0·00001). This excess of cardiogenic shock was mainly during days 0–1 after admission, whereas the reductions in reinfarction and ventricular fibrillation emerged more gradually. Consequently, the overall effect on death, reinfarction, arrest, or shock was significantly adverse during days 0–1 and significantly beneficial thereafter. There was substantial net hazard in haemodynamically unstable patients, and moderate net benefit in those who were relatively stable (particularly after days 0–1). The use of early β-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting β-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised.

Background and Objective Activity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity. Methods In a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios. Results The Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1′-hydroxymidazolam concentrations after pretreatment of samples with β-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio. Conclusions Inhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies. ClinicalTrials.gov-ID : NCT01386593.

Background We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). Methods A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. Results In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (− 8.6 ± 9.0% to − 14.5 ± 8.0%; P  < 0.001), while no changes in the remote zone strain were observed (− 19.5 ± 5.9% to − 19.2 ± 3.9%; P  = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week ( P  = 0.038) and at 6 months ( P  = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without ( P  < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH ( P  < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI ( P  = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed. Conclusions Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol. Trial registration ClinicalTrials.gov, NCT01311700 . Registered 8 March 2011 - Retrospectively registered.

Background. Chinese herbal medicine Dingji Fumai Decoction (DFD) is widely clinically used for ventricular premature contraction (VPC). This real-word trial was designed to assess the safety and effectiveness of DFD for VPC. Methods. This was a double-blinded, randomized placebo-controlled trial. Patients with VPC were randomized (1 : 1) to treatment with DFD combined with metoprolol (DFD arm) or metoprolol combined with placebo (MET arm). A primary end point was a composite of clinical symptoms and signs determined by the traditionalChinese medicine syndrome score and the number of VPC determined by the Holter examination. Second outcomes were adverse events, medication compliance, and laboratory examination. Results. 144 patients were randomized to DFD arm (76 patients) or MET arm (68 patients), and 136 cases (71 in DFD arm and 65 in MET arm) finally completed this trial. After a 12-week follow-up, DFD arm significantly decreased traditional Chinese medicine syndrome score and the number of VPC compared with MET arm (P=0.003 and 0.034, respectively). There was no adverse drug effect and patient medication compliance was good. Conclusions. Superiority with DFD arm for VPC was demonstrated over MET arm for both the safety and effectiveness end points.

PurposeFedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail.MethodsAn open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15.Results Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration–time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27–2.47) for metoprolol, 2.82-fold (90% CI 2.26–3.53) for omeprazole, and 3.84-fold (90% CI 2.62–5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib.ConclusionFedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

Patients undergoing vascular surgery comprise the highest risk group for perioperative cardiac mortality and morbidity after noncardiac procedures. Many current guidelines recommend the use of β-blockers in all patients undergoing vascular surgery. We report a trial of the perioperative administration of metoprolol and its effects on the incidence of cardiac complications at 30 days and 6 months after vascular surgery. Patients undergoing abdominal aortic surgery and infrainguinal or axillofemoral revascularizations were recruited to a double-blind randomized controlled trial of perioperative metoprolol versus placebo. Patients were randomized to receive study medication, starting 2 hours preoperatively until hospital discharge or maximum of 5 days postoperatively. Primary outcome were postoperative 30-day composite incidence of nonfatal myocardial infarction, unstable angina, new congestive heart failure, new atrial or ventricular dysrhythmia requiring treatment, or cardiac death. Patients were randomized to receive either metoprolol (n = 246) or placebo (n = 250). Primary outcome events at 30 days postoperative occurred in 25 (10.2%) versus 30 (12.0%) ( P = .57) in metoprolol and placebo groups, respectively (relative risk reduction 15.3%, 95% CI −38.3% to 48.2%). Observed effects at 6 months were not significantly different ( P = .81) (relative risk reduction 6.2%, 95% CI% −58.4% to 43.8%). Intraoperative bradycardia requiring treatment was more frequent in the metoprolol group (53/246 vs 19/250, P = .00001), as was intraoperative hypotension requiring treatment (114/246 vs 84/250, P = .0045). Our results showed metoprolol was not effective in reducing the 30-day and 6-month postoperative cardiac event rates. Prophylactic use of perioperative β-blockers in all vascular patients is not indicated.