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Biochemical Pharmacology Sep 2023Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity...
Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2), develop cardiac hypertrophy followed by dilated cardiomyopathy, in association with accumulation of autophagosomes, fibrosis and oxidative stress. We investigated the effect of drugs used to treat heart failure and of LAMP2 gene therapy on the phenotype, molecular markers and ROS in LAMP2 cardiomyopathy. L2 mice were treated with Angiotensin II, Ramipril, Metoprolol or Spironolactone. Gene therapy was delivered by IP injection of Adeno-associated-virus (AAV9) -LAMP2 vector to neonates ("AAVPrevention"), or at 15 weeks of age ("AAVTreatment"). Angiotensin II markedly aggravated the cardiac phenotype. Ramipril and Spironolactone were effective in attenuating left ventricular hypertrophy and preserving the systolic function. Cardiac protection was associated with decreased autophagosome accumulation, reduced fibrosis and oxidative stress. Gene therapy effectively attenuated autophagosome accumulation and ROS in L2 hearts, lowering troponin release to nearly normal levels. AAVPrevention protected against systolic dysfunction and decreased hypertrophy. AAVTreatment prevented ventricular dilatation and dysfunction but had no effect on wall thickness. We conclude that RAAS inhibitors are highly effective against cardiomyopathy progression in an experimental mouse model of Danon's and shall be considered in human patients for this purpose until novel therapies become clinically available.
Topics: Humans; Mice; Animals; Ramipril; Spironolactone; Angiotensin II; Reactive Oxygen Species; Heart Failure; Glycogen Storage Disease Type IIb; Cardiomegaly; Genetic Therapy; Fibrosis
PubMed: 37572991
DOI: 10.1016/j.bcp.2023.115735 -
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 -
The Annals of Pharmacotherapy Jul 2024To review treatment options and updates that exist for the management of paroxysmal supraventricular tachycardia (PSVT). (Review)
Review
OBJECTIVE
To review treatment options and updates that exist for the management of paroxysmal supraventricular tachycardia (PSVT).
DATA SOURCES
A literature search of PubMed was performed including articles from 1974 to June 2023 using the terms: , , , , , , , , , , , , , , , . Primary literature and guidelines were reviewed.
STUDY SELECTION AND DATA EXTRACTION
Studies were considered if they were available in English and conducted in humans.
DATA SYNTHESIS
PSVT is a subset of supraventricular tachycardia (SVT) that presents as a rapid, regular tachycardia with an abrupt onset and termination. Due to frequent emergency department (ED) visits annually with symptoms of PSVT, appropriate and efficient management of these patients is vital. This review provides an overview of the pathophysiology of PSVT, while also describing the literature behind nonpharmacologic and pharmacologic management of PSVT.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
This review describes new literature regarding the improved success of the modified Valsalva maneuver as a nonpharmacologic therapy in PSVT. In addition, it describes a new technique in administration of adenosine that has improved outcomes, defines dose adjustments needed for drug interactions with adenosine, compares the utilization of nondihydropyridine calcium channel blockers with adenosine, and provides management recommendations for patients in special populations.
CONCLUSIONS
With high annual rates of ED visits for SVT, providers should be aware of the data behind management and modifications of therapy based on patient-specific factors (ie, patient preference, pharmacokinetics/pharmacodynamics, drug interactions, and special populations).
Topics: Humans; Tachycardia, Supraventricular; Anti-Arrhythmia Agents
PubMed: 37743672
DOI: 10.1177/10600280231199136 -
The Annals of Pharmacotherapy Mar 2024To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. (Review)
Review
OBJECTIVE
To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment.
DATA SOURCES
A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients.
STUDY SELECTION AND DATA EXTRACTION
Articles written in English or French related to the aim of our study were retained for analysis.
DATA SYNTHESIS
Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment.
CONCLUSION
Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.
Topics: Humans; Heart Failure; Valsartan; Metoprolol; Carvedilol; Body Size; Adrenergic beta-Antagonists
PubMed: 37338205
DOI: 10.1177/10600280231179484 -
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 -
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 -
Frontiers in Pharmacology 2023We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including β-blockers, calcium channel blockers,...
We compared and ranked the efficacy and tolerability of multiple prophylactic treatments for vestibular migraine (VM), including β-blockers, calcium channel blockers, antiseizure medications, and antidepressants such as tricyclics and serotonin-noradrenaline reuptake inhibitors. PubMed, Web of Science, Embase, and Cochrane Center for Clinical Trials were systematically searched for relevant randomized clinical trials (RCTs) from March 2023 to May 2023. Studies on the efficacy and tolerability of prophylactic treatments for VM were included. Efficacy was measured using the average vertigo frequency per month and dizziness handicap inventory (DHI) improvement after 3-6 months of treatment. Tolerability was measured by the number of patients reporting at least one adverse event (AE). Network meta-analyses were performed according to a Bayesian framework and a random-effects model based on odds ratios or mean differences (MDs) and 95% confidence intervals (CIs). A sequence of ranking probability was calculated according to the surface under the cumulative ranking (SUCRA) curve. This network meta-analysis was previously registered with PROSPERO (CRD42023422258). Five RCTs comprising 334 patients were analyzed by synthesizing the published evidence. Considering the examined prophylactic therapies, there is significant evidence that valproate acid (VPA) is superior to placebo or abortive treatment alone (MD = -4.12, 95% CI = -8.09, -0.15) in reducing the frequency of vertigo. Flunarizine (MD = 20.00, 95% CI = 10.90, 29.10), valproate acid (MD = 18.88, 95% CI = 10.42, 27.34), and venlafaxine (MD = 11.48, 95% CI = 9.84, 13.12) were significantly more effective than placebo or abortive treatment in reducing DHI. VPA most strongly reduced the frequency of vertigo according to SUCRA, but it ranked third-to-last in tolerability. Flunarizine ranked best in DHI improvement but worst in tolerability. Metoprolol ranked worst for efficacy but best for tolerability. VPA and flunarizine reduced the frequency of vertigo and improved DHI, but they had unfavorable tolerability. The effects of metoprolol on vertigo require further study. Given the low certainty and limited sample, additional head-to-head RCTs are warranted to further confirm efficacy. https://www.crd.york.ac.uk/PROSPERO/; Identifier CRD42023422258.
PubMed: 38186654
DOI: 10.3389/fphar.2023.1332973 -
American Journal of Kidney Diseases :... Jan 2024Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at...
Associations of Baseline and Longitudinal Serum Uromodulin With Kidney Failure and Mortality: Results From the African American Study of Kidney Disease and Hypertension (AASK) Trial.
RATIONALE & OBJECTIVE
Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at lower levels. We evaluated whether serum UMOD levels were associated with the risks of incident kidney failure with replacement therapy (KFRT) and mortality.
STUDY DESIGN
Prospective cohort.
SETTING & PARTICIPANTS
Participants in AASK (the African American Study of Kidney Disease and Hypertension) with available stored serum samples from the 0-, 12-, and 24-month visits for biomarker measurement.
PREDICTORS
Baseline log-transformed UMOD and change in UMOD over 2 years.
OUTCOMES
KFRT and mortality.
ANALYTICAL APPROACH
Cox proportional hazards and mixed-effects models.
RESULTS
Among 500 participants with baseline serum UMOD levels (mean age, 54y; 37% female), 161 KFRT events occurred during a median of 8.5 years. After adjusting for baseline demographic factors, clinical factors, glomerular filtration rate, log-transformed urine protein-creatinine ratio, and randomized treatment groups, a 50% lower baseline UMOD level was independently associated with a 35% higher risk of KFRT (adjusted HR, 1.35; 95% CI, 1.07-1.70). For annual UMOD change, each 1-standard deviation lower change was associated with a 67% higher risk of KFRT (adjusted HR, 1.67; 95% CI, 1.41-1.99). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply for metoprolol versus ramipril (P<0.001) as well as for intensive versus standard blood pressure goals (P = 0.002).
LIMITATIONS
Small sample size and limited generalizability.
CONCLUSIONS
Lower UMOD levels at baseline and steeper declines in UMOD over time were associated with a higher risk of subsequent KFRT in a cohort of African American adults with chronic kidney disease and hypertension.
PLAIN-LANGUAGE SUMMARY
Prior studies of uromodulin (UMOD), the most abundant protein in urine, and kidney disease have focused primarily on urinary UMOD levels. The present study evaluated associations of serum UMOD levels with the risks of kidney failure with replacement therapy (KFRT) and mortality in a cohort of African American adults with hypertension and chronic kidney disease. It found that participants with lower levels of UMOD at baseline were more likely to experience KFRT even after accounting for baseline kidney measures. Similarly, participants who experienced steeper annual declines in UMOD also had a heightened risk of kidney failure. Neither baseline nor annual change in UMOD was associated with mortality. Serum UMOD is a promising biomarker of kidney health.
Topics: Adult; Humans; Female; Middle Aged; Male; Uromodulin; Prospective Studies; Black or African American; Hypertension; Renal Insufficiency; Renal Insufficiency, Chronic; Glomerular Filtration Rate; Biomarkers
PubMed: 37690632
DOI: 10.1053/j.ajkd.2023.05.017 -
Cureus Sep 2023The current guidelines state that propafenone can be used in combination with a beta-blocker or a calcium channel blocker for pharmacologic cardioversion of recent-onset...
The current guidelines state that propafenone can be used in combination with a beta-blocker or a calcium channel blocker for pharmacologic cardioversion of recent-onset atrial fibrillation in patients without structural heart disease. To prevent the conversion from atrial fibrillation to atrial flutter with a rapid ventricular rate, it is recommended to administer propafenone following the administration of a beta-blocker or a calcium channel blocker. However, this combination carries the potential risk of cardiogenic shock. There are several scenarios where this combination can lead to shock, attributed to the variable pharmacokinetics of propafenone among individuals and its significant drug interactions with commonly used AV nodal blockers, such as metoprolol and diltiazem. Additionally, a significant proportion of the population has genetic polymorphisms that affect the metabolism of these medications. While pill-in-the-pocket propafenone is also employed in outpatient settings, unexpected severe and life-threatening reactions have been reported. In this context, we present a case report of severe propafenone toxicity in a closely monitored inpatient setting aimed at converting atrial fibrillation.
PubMed: 37908936
DOI: 10.7759/cureus.46282