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Scientific Reports Nov 2023Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high...
Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high blood pressure. The first spectrofluorimetric method for quantifying aspirin, olmesartan, and metoprolol in spiked human plasma is described here. The emission/excitation wavelengths of Aspirin, olmesartan, and metoprolol were 404 nm/290 nm, 372 nm/250 nm, and 302 nm/230 nm, respectively. The native fluorescence spectra of metoprolol do not overlap with those of aspirin or olmesartan, although the spectra of aspirin and olmesartan overlap. As a result, metoprolol could be measured directly in a mixture at 302 nm following excitation at 230 nm. Using synchronous fluorescence spectrometry at Δλ = 110 allowed for the determination of olmesartan at 364 nm with no interference from aspirin and metoprolol. Coupling the synchronous fluorescence spectrometry with second-order derivative allowed for the determination of aspirin at 426 nm with no interference from olmesartan and metoprolol. The suggested approach has been validated using ICH M10 criteria for bioanalytical method validation and was effectively utilized for quantification of tested medications in human plasma with reasonable accuracy and precision findings. Furthermore, using two greenness metrics, the Green Analytical Procedure Index and the Analytical GREEnness, the suggested method obtained a high greenness score.
Topics: Humans; Metoprolol; Aspirin; Spectrometry, Fluorescence; Antihypertensive Agents
PubMed: 37978204
DOI: 10.1038/s41598-023-46042-x -
International Journal of Molecular... Sep 2023Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are...
Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K4.3 isoforms to explore their potential for isoform-specific therapy. K4.3 isoforms were expressed in Xenopus oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K4.3 L by 77 ± 2% and K4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K4.3 L) and 35 ± 4% (K4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K4.3 protein expression. Carvedilol inhibited K4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K4.3. Blockade of repolarizing K4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.
Topics: Humans; Metoprolol; Bisoprolol; Carvedilol; Heart; Heart Failure; Protein Isoforms
PubMed: 37762145
DOI: 10.3390/ijms241813842 -
European Journal of Case Reports in... 2024Studies have shown major cardiovascular effects associated with ketamine use disorder including dose-dependent negative inotropic effects. Preoperative ketamine use has...
BACKGROUND
Studies have shown major cardiovascular effects associated with ketamine use disorder including dose-dependent negative inotropic effects. Preoperative ketamine use has been linked to ketamine-induced stress cardiomyopathy.
CASE PRESENTATION
A 28-year-old female with a history of recurrent cystitis and ketamine use disorder (twice weekly for 14 years) presented with bilateral lower extremity oedema and shortness of breath for 3 months. She was tachycardic with a troponin level of 0.07 ng/ml and a B-type natriuretic peptide (BNP) level of 2511 pg/ml. Electrocardiogram showed normal sinus rhythm and transthoracic echocardiography (TTE) showed left ventricular ejection fraction (EF) of 15%, dilated left ventricle, and severe tricuspid and mitral regurgitation. Computed tomography (CT) scan of the chest and abdomen showed bilateral pleural effusions with congestive hepatopathy and ascites. The patient was started on intravenous furosemide, metoprolol, and sacubitril/valsartan. Rheumatological workup including complement levels, and antinuclear anti-double-stranded DNA was negative. A repeat TTE 2 weeks later revealed an EF of 25% and moderate tricuspid regurgitation. Four months later, the EF was 54% with normal left ventricular cavity size.
CONCLUSION
Although ketamine use disorder is increasing, data on long-term side effects is minimal. Screening for ketamine use disorders should be considered in patients presenting with acute systolic heart failure. Long-term studies are needed to evaluate the benefits of adding ketamine screening to standard urine toxicology.
LEARNING POINTS
Ketamine use disorder can lead to severe cardiovascular complications, including acute systolic heart failure, likely due to its direct negative inotropic effects and dose-dependent impact on cardiac function.Clinicians should consider screening for ketamine use disorder in young adults presenting with acute systolic heart failure, especially when other common aetiologies have been ruled out.Early recognition and prompt treatment of ketamine-induced heart failure with diuretics and guideline-directed medical therapy can lead to significant improvement in cardiac function, but long-term management should also focus on ensuring cessation of ketamine use disorder.
PubMed: 38846645
DOI: 10.12890/2024_004470 -
Pharmacology Research & Perspectives Oct 2023Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by...
Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
Topics: Adult; Humans; Amiodarone; Heart Rate; Cross-Sectional Studies; Metoprolol; Bradycardia; Cytochrome P-450 CYP2D6
PubMed: 37732835
DOI: 10.1002/prp2.1137 -
Scientific Reports Feb 2024Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus, however, its underlying biological mechanisms remain poorly understood....
Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus, however, its underlying biological mechanisms remain poorly understood. We examined single nucleotide polymorphisms linked to 486 blood metabolites through extensive genome-wide association studies conducted on individuals of European ancestry. The FinnGen Biobank database served as a reference to define DR. Two-sample MR analysis was conducted to reveal the association between the levels of genetically predicted circulating metabolites and the susceptibility to DR. To validate the robustness of the obtained findings, sensitivity analyses with weighted median, weighted mode, and MR-Egger were conducted. 1-oleoylglycerophosphoethanolamine (odds ratio [OR] (OR per one standard deviation [SD] increase) = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 7.613E-07, P = 6.849E-06), pyroglutamine (OR per one SD increase = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 8.31E-04, P = 0.007), phenyllactate (PLA) (OR per one SD increase = 0.591; 95% confidence interval [CI] 0.418-0.836; P = 0.003, P = 0.026), metoprolol acid metabolite (OR per one SD increase = 0.978; 95% confidence interval [CI] 0.962-0.993; P = 0.005, P = 0.042), 10-undecenoate (OR per one SD increase = 0.788; 95% confidence interval [CI] 0.667-0.932; P = 0.005, P = 0.049), erythritol (OR per one SD increase = 0.691; 95% confidence interval [CI] 0.513-0.932; P = 0.015, P = 0.034), 1-stearoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.022, P = 0.099), 1-arachidonoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.030, P = 0.099) showed a significant causal relationship with DR and could have protective effects. stachydrine (OR per one SD increase = 1.146; 95% confidence interval [CI] 1.066-1.233; P = 2.270E-04, P = 0.002), butyrylcarnitine (OR per one SD increase = 1.117; 95% confidence interval [CI] 1.023-1.219; P = 0.014, P = 0.062), 5-oxoproline (OR per one SD increase = 1.569; 95% confidence interval [CI] 1.056-2.335; P = 0.026, P = 0.082), and kynurenine (OR = 1.623; 95% CI 1.042-2.526; P = 0.041, P = 0.097) were significantly associated with an increased risk of DR. This study identified metabolites have the potential to be considered prospective compounds for investigating the underlying mechanisms of DR and for selecting appropriate drug targets.
Topics: Humans; Diabetic Retinopathy; Genome-Wide Association Study; Mendelian Randomization Analysis; Prospective Studies; Databases, Factual; Diabetes Mellitus
PubMed: 38424453
DOI: 10.1038/s41598-024-55704-3 -
Advances in Therapy Nov 2023Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study.
METHODS
In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety.
RESULTS
Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs.
CONCLUSION
Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents.
TRIAL REGISTRATION
Clinical Trial ID NCT03085095.
PRIOR PRESENTATION
Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.101 .
Topics: Male; Humans; Leuprolide; Antihypertensive Agents; Fibrinolytic Agents; Antineoplastic Agents, Hormonal; Prostatic Neoplasms; Testosterone; Gonadotropin-Releasing Hormone
PubMed: 37713020
DOI: 10.1007/s12325-023-02634-7 -
Current Problems in Cardiology Mar 2024While beta-blockers are considered the cornerstone of treatment for heart failure with reduced ejection fraction, the same may not apply to patients with heart failure... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
While beta-blockers are considered the cornerstone of treatment for heart failure with reduced ejection fraction, the same may not apply to patients with heart failure with preserved ejection fraction (HFpEF). To date, the benefit of beta-blockers remains uncertain, and there is no current consensus on their effectiveness. This study sought to evaluate the efficacy of beta-blockers on mortality and rehospitalization among patients with HFpEF.
METHODS
A systematic review and meta-analysis of randomized or observational cohort studies examined the efficacy of beta-blocker therapy in comparison with placebo, control, or standard medical care in patients with HFpEF, defined as left ventricular ejection fraction ≥50 %. The main endpoints were mortality (i.e., all-cause and cardiovascular), rehospitalization (i.e., all-cause and for heart failure) and a composite of the two.
RESULTS
Out of the 13,189 records initially identified, 16 full-text records met the inclusion criteria and were analyzed recruiting a total of 27,188 patients. The mean age range was 62-84 years old, predominantly female, with HFpEF in which 63.4 % of patients received a beta-blocker and 36.6 % did not. The pooled analysis of included cohort studies, of variable follow-up durations, showed a significant reduction in all-cause mortality by 19 % (odds ratio (OR) 0.81; 95 % confidence interval (CI): 0.65-0.99, p = 0.044) whereas rehospitalization for heart failure (OR 1.13; 95 % CI: 0.91-1.41, p = 0.27) or its composite with all-cause mortality (OR 1.01; 95 % CI: 0.78-1.32, p = 0.92) were similar between the beta-blocker and control groups.
CONCLUSION
This meta-analysis showed that beta-blocker therapy has the potential to reduce all-cause mortality in patients with HFpEF based on observational studies. Nevertheless, it did not affect rehospitalization for heart failure or its composite with all-cause mortality. Large scale randomized trials are needed to clarify this uncertainty.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Stroke Volume; Heart Failure; Ventricular Function, Left; Patient Readmission; Hospitalization; Adrenergic beta-Antagonists; Observational Studies as Topic
PubMed: 38184132
DOI: 10.1016/j.cpcardiol.2024.102376 -
Annals of Cardiac Anaesthesia 2023Ivabradine is a specific heart rate (HR)-lowering agent which blocks the cardiac pacemaker I channels. It reduces the HR without causing a negative inotropic or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ivabradine is a specific heart rate (HR)-lowering agent which blocks the cardiac pacemaker I channels. It reduces the HR without causing a negative inotropic or lusitropic effect, thus preserving ventricular contractility. The authors hypothesized that its usefulness in lowering HR can be utilized in patients undergoing off-pump coronary artery bypass (OPCAB) surgery.
OBJECTIVE
To study the effects of preoperative ivabradine on hemodynamics (during surgery) in patients undergoing elective OPCAB surgery.
METHODS
Fifty patients, New York Heart Association (NYHA) class I and II, were randomized into group I (control, n = 25) and group II (ivabradine group, n = 25). In group I, patients received the usual anti-anginal medications in the preoperative period, as per the institutional protocol. In group II, patients received ivabradine 5 mg twice daily for 3 days before surgery, in addition to the usual anti-anginal medications. Anesthesia was induced with fentanyl, thiopentone sodium, and pancuronium bromide as a muscle relaxant and maintained with fentanyl, midazolam, pancuronium bromide, and isoflurane. The hemodynamic parameters [HR and mean arterial pressure (MAP)] and pulmonary artery (PA) catheter-derived data were recorded at the baseline (before induction), 3 min after the induction of anesthesia at 1 min and 3 min after intubation and at 5 min and 30 min after protamine administration. Intraoperatively, hemodynamic data (HR and MAP) were recorded every 10 min, except during distal anastomosis of the coronary arteries when it was recorded every 5 min. Post-operatively, at 24 hours, the levels of troponin T and brain natriuretic peptide (BNP) were measured. This trial's CTRI registration number is CTRI/005858.
RESULTS
The HR in group II was lower when compared to group I (range 59.6-72.4 beats/min and 65.8-80.2 beats/min, respectively) throughout the study period. MAP was comparable [range (78.5-87.8 mm Hg) vs. (78.9-88.5 mm Hg) in group II vs. group I, respectively] throughout the study period. Intraoperatively, 5 patients received metoprolol in group I to control the HR, whereas none of the patients in group II required metoprolol. The incidence of preoperative bradycardia (HR <60 beats/min) was higher in group II (20%) vs. group I (8%). There was no difference in both the groups in terms of troponin T and BNP level after 24 hours, time to extubation, requirement of inotropes, incidence of arrhythmias, in-hospital morbidity, and 30-day mortality.
CONCLUSION
Ivabradine can be safely used along with other anti-anginal agents during the preoperative period in patients undergoing OPCAB surgery. It helps to maintain a lower HR during surgery and reduces the need for beta-blockers in the intraoperative period, a desirable and beneficial effect in situations where the use of beta-blockers may be potentially harmful. Further studies are needed to evaluate the beneficial effects of perioperative Ivabradine in patients with moderate-to-severe left ventricular dysfunction.
Topics: Humans; Ivabradine; Metoprolol; Pancuronium; Troponin T; Hemodynamics; Coronary Artery Bypass, Off-Pump; Fentanyl
PubMed: 37470523
DOI: 10.4103/aca.aca_97_22 -
Frontiers in Pharmacology 2023Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive...
Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive landscape of culprit-drug of QT prolongation and TdP is currently lacking. To identify the top drugs reported in association with QT prolongation and TdP and provide information for clinical practice. We reviewed the reports related to QT prolongation and TdP in the FDA Adverse Event Reporting System (FAERS) database from January 1, 2004 to December 31, 2022, and summarized a potential causative drug list accordingly. Based on this drug list, the most frequently reported causative drugs and drug classes of QT prolongation and TdP were counted, and the disproportionality analysis for all the drugs was conducted to in detect ADR signal. Furthermore, according to the positive-negative distribution of ADR signal, we integrated the risk characteristic of QT prolongation and TdP in different drugs and drug class. A total of 42,713 reports in FAERS database were considered to be associated with QT prolongation and TdP from 2004 to 2022, in which 1,088 drugs were reported as potential culprit-drugs, and the largest number of drugs belonged to antineoplastics. On the whole, furosemide was the most frequently reported drugs followed by acetylsalicylic acid, quetiapine, citalopram, metoprolol. In terms of drug classes, psycholeptics was the most frequently reported drug classes followed by psychoanaleptics, analgesics, beta blocking agents, drugs for acid related disorders. In disproportionality analysis, 612 drugs showed at least one positive ADR signals, while citalopram, ondansetron, escitalopram, loperamide, and promethazine were the drug with the maximum number of positive ADR signals. However, the positive-negative distribution of ADR signals between different drug classes showed great differences, representing the overall risk difference of different drug classes. Our study provided a real-world overview of QT prolongation and TdP to drugs, and the presentation of the potential culprit-drug list, the proportion of reports, the detection results of ADR signals, and the distribution characteristics of ADR signals may help understand the safety profile of drugs and optimize clinical practice.
PubMed: 38186652
DOI: 10.3389/fphar.2023.1259611 -
Saudi Medical Journal Oct 2023To focus on evaluating the clinical influence of metoprolol on sepsis-induced cardiomyopathy (SICM).
OBJECTIVES
To focus on evaluating the clinical influence of metoprolol on sepsis-induced cardiomyopathy (SICM).
METHODS
A total of 90 patients with SICM was enrolled from December 2018 to February 2021 and divided into 2 groups according to the use of metoprolol during hospitalization in Suzhou Municipal Hospital in Suzhou, China. We compared them with the cardiac function, sequential organ failure assessment score, and clinical outcomes.
RESULTS
Between the 2 groups, the oxygenation indices and Glasgow coma scale in the metoprolol group were higher on the first day of treatment, with Glasgow coma scale higher on the third day of treatment. However, the doses of norepinephrine in patients with metoprolol showed no significant differences with the control group. The all-causemortality at 28 days in the metoprolol group was lower, and the time of removing from ventilator support as well as the number of failured organs also significantly differed between the 2 groups.
CONCLUSION
Metoprolol can reduce the 28-day mortality and shorten the duration of mechanical ventilation in SICM. It can also reduce the number of organ failures and improve the oxygenation index and Glasgow coma scale of these patients. Meanwhile, metoprolol did not affect the norepinephrine dose in patients with SICM.
Topics: Humans; Metoprolol; Retrospective Studies; Sepsis; Cardiomyopathies; Norepinephrine
PubMed: 37777259
DOI: 10.15537/smj.2023.44.10.20230149