-
Journal of Pharmacological and... 2020Any adverse event is reliant on three properties: the appropriate pharmacology to trigger the event, the appropriate exposure of compound, and intrinsic patient factors....
Any adverse event is reliant on three properties: the appropriate pharmacology to trigger the event, the appropriate exposure of compound, and intrinsic patient factors. Each alone is necessary but insufficient to predict the event. The Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative attempts to predict the risk of torsade de pointes (TdP) by focusing on an in-silico model with thresholds determined at modest multiples of the therapeutic exposure for the parent molecule. This emphasizes the pharmacologic properties necessary for TdP but does not account for situations where clinical exposure may be higher, or where hERG potassium channel active metabolites are involved. Could accounting for clinical worst-case scenarios and metabolites, as is already standard practice in thorough QTc studies, improve the prediction algorithm? Terfenadine, a drug classed as "Intermediate" risk by CiPA, was assessed differently in the in-silico model validation. The clinical concentration of terfenadine used for the model was the exposure in the presence of metabolic inhibition representing a 14 to 40-fold increase in exposure compared to the therapeutic plasma concentration. However, several other "Intermediate" risk compounds are also known to be sensitive to metabolic inhibition and/or to have therapeutically active major metabolites, some of which are known to block hERG. Risperidone and astemizole are relevant examples. If only parent exposure is used to calculate a therapeutic window, risperidone has a relatively large multiple between clinical exposure and the hERG potency. Using this exposure of risperidone, the drug borders the "Intermediate" and "Low/No" risk categories for the CiPA in-silico model's TdP metric. The desmethyl metabolite of astemizole likely contributes significantly to the effects on cardiac repolarization, being equipotent on hERG but circulating at much higher levels than parent. Recalculating the TdP metric and margin values for terfenadine, risperidone and astemizole using the unbound concentration normally associated with treatment and a clinical worst case changes the qNet metric to higher risk values and illustrates the potential benefit to the algorithm of consistently using a clinical high exposure scenario accounting for all "hERG-active species". This exercise suggests repeating the model qualification accounting for clinical exposures and metabolites under 'stressed' scenarios would improve prediction of the TdP risk.
Topics: Astemizole; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Humans; Risk Assessment; Risperidone; Terfenadine; Torsades de Pointes
PubMed: 31730936
DOI: 10.1016/j.vascn.2019.106654 -
ACS Sensors Oct 2019Detection of adverse effects of cardiac toxicity at an early stage by in vitro methods is crucial for the preclinical drug screening. Over the years, several kinds of...
Detection of adverse effects of cardiac toxicity at an early stage by in vitro methods is crucial for the preclinical drug screening. Over the years, several kinds of biosensing platforms have been proposed by the scientific society for the detection of cardiac toxicity. However, the proposed tissue platforms have been optimized to measure either mechanophysiology or electrophysiology of the cardiomyocytes but not both. Herein, we demonstrate in detail our successful attempt toward developing a novel "multifunctional microphysiological system" also known as "organs-on-chips" to measure simultaneously the mechanical and electrical characteristics of cardiomyocytes in vitro. The proposed device can rapidly recognize drug-induced cardiovascular toxicity in real time, which is one of the most significant factors for drug discovery and postmarketing surveillance. We confirm that the proposed sensor delivers the direct relationship between the contraction force and cell impedance of cardiomyocytes under the influence of different cardiovascular drugs such as verapamil, astemizole, and lidocaine. The obtained assay results provide a great potential for a deep understanding of the drug effects on the cardiomyocytes in vitro.
Topics: Animals; Astemizole; Biosensing Techniques; Cardiotoxicity; Cardiotoxins; Cells, Cultured; Drug Evaluation, Preclinical; Electric Impedance; Electrophysiological Phenomena; Lidocaine; Microelectrodes; Myocytes, Cardiac; Rats; Verapamil
PubMed: 31535848
DOI: 10.1021/acssensors.9b00852 -
Cardiac safety of second-generation H -antihistamines when updosed in chronic spontaneous urticaria.Clinical and Experimental Allergy :... Dec 2019The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine... (Review)
Review
The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.
Topics: Age Factors; Cardiotoxicity; Chronic Urticaria; ERG1 Potassium Channel; Female; Histamine H1 Antagonists; Humans; Long QT Syndrome; Male; Risk Factors; Torsades de Pointes
PubMed: 31519068
DOI: 10.1111/cea.13500 -
European Journal of Pharmacology Jul 2019Chloroquine (CQ) is an old antimalarial drug currently being investigated for its anti-tumor properties. As chloroquine has been shown to inhibits several potassium...
Chloroquine (CQ) is an old antimalarial drug currently being investigated for its anti-tumor properties. As chloroquine has been shown to inhibits several potassium channels, we decided to study its effect on the tumor-related Kv10.1 channel by using patch-clamp electrophysiology and cell migration assays. We found that chloroquine inhibited Kv10.1 channels transiently expressed in HEK-293 cells in a concentration- and voltage-dependent manner acting from the cytoplasmic side of the plasma membrane. Chloroquine also inhibited the outward potassium currents from MDA-MB-231 cells, which are mainly carried through Kv10.1 channels as was confirmed using astemizole. Additionally, chloroquine decreased MDA-MB-231 cell migration in the in vitro scratch wound healing assay. In conclusion, our data suggest that chloroquine decreases MDA-MB-231 cell migration by inhibiting Kv10.1 channels. The inhibition of Kv10.1 channels could represent another mechanism of the antitumoral action of chloroquine, besides autophagy inhibition and tumor vessel normalization.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Cell Movement; Chloroquine; Cytoplasm; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Potassium Channel Blockers
PubMed: 31082369
DOI: 10.1016/j.ejphar.2019.05.017 -
International Journal of Cancer Jul 2019Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of...
Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR-positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small-molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer.
Topics: Animals; Astemizole; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Polycomb Repressive Complex 2; Prostatic Neoplasms; Receptors, Androgen; Sequence Analysis, RNA; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 30628724
DOI: 10.1002/ijc.32118