Cardiovascular toxicity

Prolongation of QT interval may be predicted in vitro by patch clamp electrophysiology in mammalian cells transfected with the human ether-d-go-go-related gene (hERG), a subunit of the (cardiac rapidly activating delayed rectifier potassium channel), or by measuring a compound s abihty 

Drug Discovery Toxicology From Target Assessment to Translational Biomarkers, First Edition. Edited by Yvonne Will, J. Eric McDuffie, Andrew J. Olaharski, and Brandon D. Jeffy. 

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Therapeutic plasma concentrations are 0.15—0.50 )J.g/mL. The elimination half-life of lorcainide is about 8 h and that of norlorcainide, 26 h (32). Lorcainide has low cardiovascular toxicity (32). 

Compounds Causing Cardiovascular Toxicity Alcohols are the most important compounds causing vascular toxicity. Ethanol depresses cardiac muscle and attenuates its contractivity when the concentration of ethanol in the blood exceeds 0.75 mg/100 mL. Ethanol also causes arrhythmias, and a metabolite of ethanol, acetaldehyde, also depresses the heart. Furthermore, high concentrations of acetaldehyde cause cardiac arrhythmias. The cardiovascular toxicity of methanol is about the same as that of ethanol, whereas al cohols with longer chains are more toxic than ethanol. 

DES was once a mainstay of prostate cancer therapy. While very effective in androgen ablation, DES-treated patients experienced increased cardiovascular mortality.41 LHRH agonists, with equivalent efficacy and decreased cardiovascular toxicity, supplanted DES as a mainstay of therapy. 

Simeonova, P.P. and Erdely, A. (2009) Engineered nanoparticle respiratory exposure and potential risks for cardiovascular toxicity predictive tests and biomarkers. Inhalation Toxicology,... 

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

Domperidone [133], one of the most potent D2-dopamine blockers and antagonists of apomorphine-induced emesis with limited brain-blood barrier permeability, did not establish a position as an antiemetic, especially against cisplatin [134], Recently, the use of domperidone as a parenteral antiemetic has been discontinued because of serious cardiovascular toxicity. 

Cardiovascular Effects. Only limited reports of cardiovascular toxicity of endrin were located. Diffuse degenerative lesions of the heart were observed in dogs administered lethal doses of endrin (Treon et al. 1955), and enlarged hearts were observed at sublethal doses. The health significance of these finding is unclear, as the effects were not observed in other animal species. 

Approximately 10% of new chemical entities (NCEs) show serious adverse drug reactions (ADRs) after market launch. Such events usually result in new black box warnings by the US Food and Drug Administration (FDA), label change or market withdrawal. The most common causes for these actions are hepatic toxicity, hematologic toxicity and cardiovascular toxicity [2], Reasons for such ADRs, which are identified only after NCEs are launched on the market, include the narrow spectrum of clinical disorders and participating patient profiles in clinical studies as well as the fact that serious ADRs are often rare and that the number of patient exposures required to identify such occurrences sometimes may range over a few millions [3],... 

Especially cardiovascular toxicity and hepatotoxicity played a crucial role in the decisions for withdrawing drugs from the market. These data suggest that there are... 

Hepatic toxicity 26 Cardiovascular toxicity incl. Arrhythmias 19 (12)... 

Scott JA, Incardona JP, Pelkki K, Shepardson S, Hodson PV (2011) AhR2-mediated, CYPlA-independent cardiovascular toxicity in zebrafish (Danio rerio) embryos exposed to retene. Aquat Toxicol 101 165-174... 

Cardiovascular disorders Use with extreme caution in patients with cardiovascular disorders because of the possibility of conduction defects, arrhythmias, CHF, sinus tachycardia. Ml, strokes, and tachycardia. These patients require cardiac surveillance at all dose levels of the drug. In high doses, TCAs may produce arrhythmias, sinus tachycardia, conduction defects, and prolonged conduction time. Tachycardia and postural hypotension may occur more frequently with protriptyline. Hyperthyroid patients Hyperthyroid patients or those receiving thyroid medication require close supervision because of the possibility of cardiovascular toxicity, including arrhythmias. 

Cardiovascular Effects. Inhalation and oral studies in humans and animals have not revealed any treatment-related histopathological lesions of heart tissue, or impairment of cardiac functions, even at dose levels causing severe liver and kidney damage (Adams et al. 1952 Stewart et al. 1961 Umiker and Pearce 1953). It is possible that high-level carbon tetrachloride exposure may produce cardiac arrhythmias by sensitization of the heart to catecholamines (Reinhardt et al. 1971). Accordingly, there is some concern for cardiovascular toxicity following substantial exposure to carbon tetrachloride. 

Regarding side-effect profiles, all three SSNRIs are generally well tolerated, most adverse events occurring early in treatment, with a mild to moderate severity and a tendency to decrease or disappear with continued treatment. Venlafaxine (1) seems to be the least weU-toIerated SNRI, combining a higher level of serotonergic adverse events (nausea, sexual dysfunction, withdrawal problems) with dose-dependent hypertension. In contrast, milnacipran (2) and duloxetine (3) appear better tolerated and essentially devoid of cardiovascular toxicity. 

Lessard E, Yessine MA, Hamelin BA, O Hara G, LeBlanc J, Turgeon J (1999) Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9 435-443 Lockhart DJ, Winzeler EA (2000) Genomics, gene expression and DNA arrays. Nature 405 827-836... 

Although its cardiovascular toxicity is minimal, mexiletine should be used with caution in patients who are hypotensive or who exhibit severe left ventricular dysfunction. 

Cardiovascular toxicity as evidenced by hypotension and ventricular fibrillation and anaphylaxis occurs rarely. 

Bupropion overdose (n = 58) and combined overdoses of bupropion and benzodiazepines (n = 9) have been associated with symptoms of neurological toxicity, including lethargy, tremors, and seizures, and an absence of cardiovascular toxicity (Spiller et ah, 1994). 

Cardiovascular Effects. Limited information on the cardiovascular toxicity of HDl was available. 

Selective COX-2 inhibitors were developed in an effort to spare gastric COX-1 so that the natural cytoprotection by locally synthesized PGE2 and PGI2 is undisturbed (see Chapter 36). However, this benefit is seen only with highly selective inhibitors and may be offset by increased cardiovascular toxicity. 

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