Population pharmacokinetics of carvedilol enantiomers and their metabolites in healthy subjects and type-2 diabetes patients

Nardotto, Glauco Henrique Balthazar; Lanchote, Vera Lúcia; Coelho, Eduardo Barbosa; Pasqua, Oscar Della

doi:10.1016/j.ejps.2017.05.033

Cited by 13 publications

(10 citation statements)

References 66 publications

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“…While amiodarone can cause QT prolongation, another explanation for its interaction is its inhibitory effect on CYP2D6, 39 the cytochrome that also metabolizes HCQ and CQ. HCQ and CQ are both substrates and inhibitors of CYP2D6, potentially leading to interactions with a variety of drugs, among them carvedilol, propranolol and metoprolol 40 . In our study, BB were more frequently coadministered in reports of heart failure, cardiomyopathy and bradyarrhythmias.…”

Section: Discussionmentioning

confidence: 53%

“…HCQ and CQ are both substrates and inhibitors of CYP2D6, potentially leading to interactions with a variety of drugs, among them carvedilol, propranolol and metoprolol. 40 In our study, BB were more frequently coadministered in reports of heart failure, cardiomyopathy and bradyarrhythmias. These findings may reflect drug interactions although there are other possible explanations: BB use may reflect pre-existing cardiac disease and increased bradyarrhythmia frequency may be due to their negative chronotropic effect.…”

Section: Possible Drug-drug Interactionsmentioning

confidence: 58%

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Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre‐COVID‐19 reports

Goldman

Bomze

Dankner

et al. 2020

Brit J Clinical Pharma

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There is a clinical need for safety data regarding hydroxychloroquine (HCQ) and chloroquine (CQ) during the coronavirus (COVID-19) pandemic. We analysed realworld data using the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) database to assess HCQ/CQ-associated cardiovascular adverse events (CVAEs) in pre-COVID-19 reports. Methods: We conducted disproportionality analysis of HCQ/CQ in the FAERS database (07/2014-9/2019), using reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC 025). Results: The full database contained 6 677 225 reports with a mean (±SD) age of 53 (±17) years and 74% females. We identified 4895 reports of HCQ/CQ related adverse events, of which 696 (14.2%) were CVAEs. Compared with the full database, HCQ/CQ use was associated with a higher reporting rate of major CVAEs, including cardiomyopathy (n = 86 [1.8%], ROR = 29.0 [23.3-35.9]), QT prolongation (n = 43 [0.9%], ROR = 4.5 [3.3-6.1]), cardiac arrhythmias (n = 117 [2.4%], ROR = 2.2 [1.8-2.7]) and heart failure (n = 136 [2.8%], ROR = 2.2 [1.9-2.7], all IC₂ > 0). No statistically significant differences were observed between sex and age groups. CVAEs were reported more often in patients with systemic lupus erythematosus and Sjogren's syndrome. HCQ/CQ-associated CVAEs demonstrated subsequent hospitalization and mortality rates of 39% and 8%, respectively. Overdose reports demonstrated an increased frequency of QT prolongation and ventricular arrhythmias (35% and 25%, respectively). Conclusion: In a real-world setting, HCQ/CQ treatment is associated with higher reporting rates of various CVAEs, particularly cardiomyopathy, QT prolongation, cardiac arrhythmias and heart failure. HCQ/CQ-associated CVAEs result in high rates of severe outcomes and should be carefully considered as an off-label indication, especially for patients with cardiac disorders.

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Section: Discussionmentioning

confidence: 53%

Section: Possible Drug-drug Interactionsmentioning

confidence: 58%

Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre‐COVID‐19 reports

Goldman

Bomze

Dankner

et al. 2020

Brit J Clinical Pharma

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“…By inducing apoptosis, carvedilol inhibits cancer cells, prevents the invasion of breast cancer, and reduces cancer risk, which has been confirmed through oxidation resistance. [6][7][8][9][10] Also, antioxidant effects have been proven for carvedilol and its metabolites. One way to increase carvedilol's solubility, a waterinsoluble drug, is to convert the drug's crystal structure to its amorphous form.…”

Section: Introductionmentioning

confidence: 99%

Niosome-carvedilol protects DNA damage of supraphysiologic concentrations of insulin using comet assay: An in vitro study

2021

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Introduction: Hyperinsulinemia occurs in type 2 diabetic patients with insulin resistance. This increase in insulin levels in the blood increases reactive oxygen species production and oxidative stress, resulting in DNA damage. Carvedilol (CRV) is a non-selective beta-blocker, and research has shown that this compound and its metabolites have anti-oxidative properties. Carvedilol can, directly and indirectly, reduce reactive oxygen species (ROS) and has a protective effect on DNA damage from oxidative stress. Given the insolubility of CRV in water, finding new methods to increase its solubility can be an essential step in research. This study aimed to determine whether carvedilol could have a protective effect on insulin-induced genomic damage. Methods: We treated cells with insulin alone, amorphous-CRV alone, and amorphous-CRV and niosomal-CRV with insulin and DNA damage were investigated using the comet method to achieve this goal. Results: Our results showed that insulin in the studied concentration has a significant genotoxic effect and non-cytotoxic at higher concentrations. CRV, both in amorphous and niosome form, reduced insulin-induced DNA damage by reducing ROS production. The comet assay results demonstrate that treating HUVEC cells in pretreatment condition with amorphous-CRV and niosome-CRV significantly reduces DNA damage of insulin.

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“…Unfortunately, there is a paucity of studies assessing the utility of carvedilol's stereo-selective pharmacokinetics for integration into clinical practice, whether pertaining to clinical efficacy or to need for dose adjustments due to drugdrug interactions. The very limited data available to date suggest that no dose adjustment is necessary in diabetic patients, despite the potential inhibition of carvedilol's CYP2C9-dependent metabolism by oral hypoglycemic agents like glibenclamide [14]. This is probably due to the higher CYP2D6-mediated metabolism of carvedilol compensating for the blocked CYP2C9-dependent elimination [14].…”

mentioning

confidence: 99%

“…The very limited data available to date suggest that no dose adjustment is necessary in diabetic patients, despite the potential inhibition of carvedilol's CYP2C9-dependent metabolism by oral hypoglycemic agents like glibenclamide [14]. This is probably due to the higher CYP2D6-mediated metabolism of carvedilol compensating for the blocked CYP2C9-dependent elimination [14]. Additionally, in portal hypertension, one of the major therapeutic indications of carvedilol, the drug's efficacy against liver fibrosis is unaltered, despite delayed clearance due to reduced hepatic blood flow and CYP2D6 expression levels [15].…”

mentioning

confidence: 99%

Clinical Pharmacogenomics of Carvedilol: the Stereo-Selective Metabolism Angle

2018

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Population pharmacokinetics of carvedilol enantiomers and their metabolites in healthy subjects and type-2 diabetes patients

Cited by 13 publications

References 66 publications

Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre‐COVID‐19 reports

Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre‐COVID‐19 reports

Niosome-carvedilol protects DNA damage of supraphysiologic concentrations of insulin using comet assay: An in vitro study

Clinical Pharmacogenomics of Carvedilol: the Stereo-Selective Metabolism Angle

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