Toward a broader view of mechanisms of drug cardiotoxicity

Mamoshina, Polina; Rodríguez, Blanca; Bueno‐Orovio, Alfonso

doi:10.1016/j.xcrm.2021.100216

Cited by 61 publications

(52 citation statements)

References 180 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important class of agents with anti-inflammatory properties that target one or both prostaglandin synthases (cyclooxygenase-1 (COX-1) and COX-2) [ 2 ]. NSAID-induced cardiotoxic side effects such as gastrointestinal toxicity are associated with the inhibition of COX-1 and COX-2 [ 82 ].…”

Section: Pharmacological Classes Involved In Cardiotoxicity and Neuro...mentioning

confidence: 99%

See 1 more Smart Citation

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

et al. 2022

View full text Add to dashboard Cite

Different drug classes such as antineoplastic drugs (anthracyclines, cyclophosphamide, 5-fluorouracil, taxanes, tyrosine kinase inhibitors), antiretroviral drugs, antipsychotic, and immunosuppressant drugs are known to induce cardiotoxic and neurotoxic effects. Recent studies have demonstrated that the impairment of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway is a primary event in the pathophysiology of drug-induced cardiotoxicity and neurotoxicity. The Nrf2 pathway regulates the expression of different genes whose products are involved in antioxidant and inflammatory responses and the detoxification of toxic species. Cardiotoxic drugs, such as the anthracycline doxorubicin, or neurotoxic drugs, such as paclitaxel, suppress or impair the Nrf2 pathway, whereas the rescue of this pathway counteracts both the oxidative stress and inflammation that are related to drug-induced cardiotoxicity and neurotoxicity. Therefore Nrf2 represents a novel pharmacological target to develop new antidotes in the field of clinical toxicology. Interestingly, carnosine (β-alanyl-l-histidine), an endogenous dipeptide that is characterized by strong antioxidant, anti-inflammatory, and neuroprotective properties is able to rescue/activate the Nrf2 pathway, as demonstrated by different preclinical studies and preliminary clinical evidence. Starting from these new data, in the present review, we examined the evidence on the therapeutic potential of carnosine as an endogenous antidote that is able to rescue the Nrf2 pathway and then counteract drug-induced cardiotoxicity and neurotoxicity.

show abstract

Section: Pharmacological Classes Involved In Cardiotoxicity and Neuro...mentioning

confidence: 99%

“…They can be the result of a drug overdose, or due to drug toxicity that is linked to the use of inappropriate dosages and/or unexpected drug interactions [ 1 ]. Cardiotoxicity represents one of the most common adverse drug effects [ 2 ], but different drugs have also been shown to induce clinically relevant neurotoxic effects [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

et al. 2022

View full text Add to dashboard Cite

show abstract

“…mtDNA can be interfered with by the inhibition of mitochondrial DNA polymerase and topoisomerase II ( Table 6 ). DOX [ 158 ], mitoxantrone [ 215 ], and daunorubicin [ 130 , 207 ] inhibit DNA topoisomerase II β and disturb mtDNA stability and expression. DOX also decreases mtDNA and mtDNA-encoded subunit COX I in complex IV [ 96 ].…”

Section: Main Properties Of Mitochondria and Drug-induced Mitochondri...mentioning

confidence: 99%

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Tang

Wang

et al. 2022

Pharmaceutics

View full text Add to dashboard Cite

Drug-induced cardiotoxicity not only leads to the attrition of drugs during development, but also contributes to the high morbidity and mortality rates of cardiovascular diseases. Comprehensive testing for proarrhythmic risks of drugs has been applied in preclinical cardiac safety assessment for over 15 years. However, other mechanisms of cardiac toxicity have not received such attention. Of them, mitochondrial impairment is a common form of cardiotoxicity and is known to account for over half of cardiovascular adverse-event-related black box warnings imposed by the U.S. Food and Drug Administration. Although it has been studied in great depth, mitochondrial toxicity assessment has not yet been incorporated into routine safety tests for cardiotoxicity at the preclinical stage. This review discusses the main characteristics of mitochondria in cardiomyocytes, drug-induced mitochondrial toxicities, and high-throughput screening strategies for cardiomyocytes, as well as their proposed integration into preclinical safety pharmacology. We emphasize the advantages of using adult human primary cardiomyocytes for the evaluation of mitochondrial morphology and function, and the need for a novel cardiac safety testing platform integrating mitochondrial toxicity and proarrhythmic risk assessments in cardiac safety evaluation.

show abstract

“…Since drugs that prolong the QT interval are thought to be responsible for life threatening arrhythmias (e.g., torsades de pointes), the effect of a drug on the QT interval is investigated intensively even beyond antiarrhythmic drugs [105]. For that purpose, a strongly simplified model of a strand of cells (e.g., 1 × 1 × 20 mm) representing a transmural wedge can be sufficient under specific conditions.…”

Section: Drug-induced Changes In the Ecgmentioning

confidence: 99%

Computer Modeling of the Heart for ECG Interpretation—A Review

Dössel

Luongo

Nagel

et al. 2021

Hearts

View full text Add to dashboard Cite

Computer modeling of the electrophysiology of the heart has undergone significant progress. A healthy heart can be modeled starting from the ion channels via the spread of a depolarization wave on a realistic geometry of the human heart up to the potentials on the body surface and the ECG. Research is advancing regarding modeling diseases of the heart. This article reviews progress in calculating and analyzing the corresponding electrocardiogram (ECG) from simulated depolarization and repolarization waves. First, we describe modeling of the P-wave, the QRS complex and the T-wave of a healthy heart. Then, both the modeling and the corresponding ECGs of several important diseases and arrhythmias are delineated: ischemia and infarction, ectopic beats and extrasystoles, ventricular tachycardia, bundle branch blocks, atrial tachycardia, flutter and fibrillation, genetic diseases and channelopathies, imbalance of electrolytes and drug-induced changes. Finally, we outline the potential impact of computer modeling on ECG interpretation. Computer modeling can contribute to a better comprehension of the relation between features in the ECG and the underlying cardiac condition and disease. It can pave the way for a quantitative analysis of the ECG and can support the cardiologist in identifying events or non-invasively localizing diseased areas. Finally, it can deliver very large databases of reliably labeled ECGs as training data for machine learning.

show abstract

Toward a broader view of mechanisms of drug cardiotoxicity

Cited by 61 publications

References 180 publications

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

The Therapeutic Potential of Carnosine as an Antidote against Drug-Induced Cardiotoxicity and Neurotoxicity: Focus on Nrf2 Pathway

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

Computer Modeling of the Heart for ECG Interpretation—A Review

Contact Info

Product

Resources

About