5-FU Cardiotoxicity: Vasospasm, Myocarditis, and Sudden Death

More, Luis Alberto; Lane, Sarah; Asnani, Aarti

doi:10.1007/s11886-021-01441-2

Cited by 38 publications

(32 citation statements)

References 37 publications

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“…Anthracyclines could result in mitochondrial damage in cardiomyocytes and apoptosis through several distinct signaling pathways ( 74 ). Fluorouracil is a powerful inhibitor of the tricarboxylic acid cycle, interfering with cardiomyocyte energy metabolism and causing cardiomyocyte necrosis ( 75 ). Taxanes might cause myocardial injury by inhibiting tubulin activity and blocking cell division ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundPD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors.Materials and methodsWe searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs).ResultsA total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36, P=0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99, P=0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39, P=0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41, P=0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27, P=0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66, P=0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46, P=0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80, P=0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77, P=0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15, P=0.01).ConclusionsOur results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022303115.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

et al. 2022

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“…However, the pathology and its specific mechanisms have not yet been fully elucidated [ 14 , 15 ]. Different mechanisms including direct drug or drug metabolite of 5-FU induced cardiotoxicity are proposed.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Kaempferol and Its Nanoparticles on 5-Fluorouracil-Induced Cardiotoxicity in Rats

Safarpour

Pirzadeh

Ebrahimpour

et al. 2022

BioMed Research International

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Background. Fluorouracil (5-FU) is the third most common chemotherapeutic agent used in the treatment of solid tumors. 5-FU-associated cardiotoxicity ranks the second causes of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. Kaempferol (KPF), a common flavonoid, possessing anti-inflammatory, antiapoptotic, antioxidative properties, and its protective effects on cardiovascular disease has been reported in various studies. The current study is aimed at appraising the effect of KPF and KPF nanoparticles (NPs) on 5-FU-induced cardiotoxicity in rats. Methods. Thirty Male Wistar rats were divided into five groups as follows: control, 5-FU, 5-FU+10 mg/kg vitamin C, 5-FU+ 1 mg/kg KPF, and 5-FU+ 1 mg/kg KPF-NPs. Cardiotoxicity was induced with an intraperitoneal injection of a single dose of 5-FU (100 mg/kg). The control group received normal saline, and the treatment groups received KPF and KPF-NPs with an intraperitoneal injection for 14 days. Each heart histopathological lesions were given a score of 0 to 3 in compliance with the articles for statistical analysis. Results. 5-FU resulted in a significant cardiotoxicity represented by an increase in cardiac enzymes, MDA (malondialdehyde) levels, COX-2 (cyclooxygenase-2) expression, and histopathological degenerations. 5-FU treatment also decreased body weight, TAC (total antioxidant capacity) values, VEGF (vascular endothelial growth factor) expression, blood cells, and hemoglobin (Hb) levels. Treatment with KPF and KPF-NPs reduced oxidative stress, cardiac enzymes, COX-2 expression, and VEGF expression. The number of blood cells, Hb levels, and histopathological degenerations, in cardiac tissue also body weight of animals, increased, followed by treatment with KPF and KPF-NPs. Conclusion. Our results demonstrated that treatment with KPF and KPF-NPs significantly improved cardiotoxicity induced by 5-FU in rats.

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“…While, 21.83 ± 3.44 and 60.19 ± 5.92% of orally administered 5FU dose was retained in the colon and caecum tissues. The deposition of 5FU in the heart decreased after administration through oral LbL lm that could decrease cardiotoxicity of 5FU 57 . Taken together, drug delivery through LbL lm offers longer residence time and localization of drug within gastrointestinal tract, thereby minimizing unwanted distribution to healthy tissues.…”

Section: Discussionmentioning

confidence: 95%

Colon targeted layer-by-layer self-assembled film: pharmacokinetic analysis of model drugs after oral administration

Janardhanam

Deokar

Bollareddy

et al. 2022

Preprint

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The aim of the study was to investigate the pharmacokinetic parameters of 5-fluorouracil (5FU) and moxifloxacin (MF) after oral administration using layer-by-layer assembled film in enteric coated capsule. The LbL film was prepared by sequential layering of chitosan and sodium alginate polyelectrolytes containing either 5FU or MF. The films were characterized for physical characteristics, drug loading and release behaviour. Pharmacokinetic studies were performed in the rat model for three different drug concentrations after oral administration and compared with intravenous administration. The results showed that the thickness of 10 bilayerd film was 147 ± 11.66 and 212.3 ± 7.19 µm after 5FU and MF loading, respectively. The amount of 5FU and MF loaded was found to be 1.93 ± 0.48 and 4.64 ± 0.33 mg/cm2, respectively. The DSC and PXRD results showed crystalline nature of 5FU and MF after entrapment in LbL film. The LbL film with backing layer provided directional release of 5FU and MF, where 63.81 ± 4.52% and 101.38 ± 5.08%, respectively was released in 24 h. 5FU showed non-linear pharmacokinetics compared with linear pharmacokinetics showed by MF after oral administration. There is a dose dependent increase in Cmax after oral administration of 5FU and MF LbL film. The Tmax was found to be 720 and 840 mins for 5FU and MF after oral administration. The mean residence time and AUC0-t at 45 mg/kg were 871.4 ± 6.45 min and 198.6 ± 5.03 x 103 min. ng/mL and 1267 ± 142.4 min and 1590 ± 55.60 103 min. ng/mL for 5FU and MF, respectively. Biodistribution studies showed significantly (p<0.01) greater disposition of 5FU within colon tissue after administration using oral LbL film. Taken together, colon targeted LbL film can be developed for oral administration of drugs for local and systemic applications.

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5-FU Cardiotoxicity: Vasospasm, Myocarditis, and Sudden Death

Cited by 38 publications

References 37 publications

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Protective Effect of Kaempferol and Its Nanoparticles on 5-Fluorouracil-Induced Cardiotoxicity in Rats

Colon targeted layer-by-layer self-assembled film: pharmacokinetic analysis of model drugs after oral administration

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