Possibility as an anti-cancer drug of astemizole: Evaluation of arrhythmogenicity by the chronic atrioventricular block canine model.

Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.

• Publication year

  2016

• Venue

  Journal of Pharmacological Sciences

• Publication date

  2016-06-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1016/j.jphs.2016.04.024PMID 27262902
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• The proarrhythmic dose of astemizole appears to be lower than the dose associated with anti-cancer activity, which limits its repurposing as an anti-cancer drug.

  Confidence 0.90

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• An oral dose of 30 mg/kg astemizole increased short-term variability of repolarization and induced premature ventricular contractions in every animal, with torsade de pointes occurring in 1 of 4 animals.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• An oral dose of 3 mg/kg astemizole prolonged the QT interval without affecting QTc in the chronic atrioventricular block canine model.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review

• anti-cancer dose

  dose

  The oral dose level previously reported to show anti-cancer activity in mice.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• anti-cancer drug repurposing

  therapeutic strategy

  Reusing an existing drug candidate as a treatment for cancer.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• astemizole

  drug

  A histamine H1 antagonist examined here for its cardiac safety and potential anti-cancer use.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• chronic atrioventricular block canine model

  animal model

  A dog model with chronic atrioventricular block used to assess proarrhythmic risk.

  Aliases: chronic AV block canine model

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• premature ventricular contractions

  arrhythmia

  Premature heartbeats originating from the ventricles.

  Aliases: PVCs

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• proarrhythmic dose

  dose

  The dose level at which a compound triggers arrhythmogenic effects.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• qtc

  electrophysiology measure

  The QT interval adjusted for heart rate to allow comparison across conditions.

  Aliases: corrected QT interval

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• qt interval

  electrophysiology measure

  The duration of ventricular depolarization and repolarization on an electrocardiogram.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• short-term variability of repolarization

  electrophysiology measure

  A beat-to-beat measure of repolarization instability used as an arrhythmia marker.

  Aliases: STV of repolarization, STV

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review
• torsade de pointes

  arrhythmia

  A polymorphic ventricular tachyarrhythmia associated with prolonged repolarization.

  Aliases: TdP

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewB (s683577b42) reviewAK (4715169a40) review

• Quantitative Polymerase Chain Reaction Analysis of the Mouse Cyp2j Subfamily: Tissue Distribution and Regulation

  2015cited by this paper
• Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator

  2015cited by this paper
• Antiproliferative and Proapoptotic Effects of Astemizole on Cervical Cancer Cells

  2014cited by this paper
• In vivo dual targeting of the oncogenic Ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors

  2014cited by this paper
• Eag and HERG potassium channels as novel therapeutic targets in cancer

  2010cited by this paper
• Sensitive and reliable proarrhythmia in vivo animal models for predicting drug‐induced torsades de pointes in patients with remodelled hearts

  2008cited by this paper
• QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals.

  2005cited by this paper
• DrugBank: a comprehensive resource for in silico drug discovery and exploration

  2005cited by this paper
• Increased Short-Term Variability of Repolarization Predicts d-Sotalol–Induced Torsades de Pointes in Dogs

  2004cited by this paper
• Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.

  2003cited by this paper
• Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole.

  2001cited by this paper
• A STUDY OF THE INTERACTION BETWEEN DIRITHROMYCIN AND ASTEMIZOLE IN HEALTHY ADULTS

  1997cited by this paper
• Rapid rates during bradycardia prolong ventricular refractoriness and facilitate ventricular tachycardia induction with cesium in dogs.

  1996cited by this paper
• Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.

  1996cited by this paper

• Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation using 6 drugs with pharmacologically-distinct profile.

  2022cites this paper
• The canine chronic atrioventricular block model in cardiovascular preclinical drug research

  2021cites this paper
• Novel Therapeutic Approaches of Ion Channels and Transporters in Cancer.

  2020cites this paper
• Improved cancer survival with use of common antihistamines

  2020cites this paper
• Determination of pKa Values for Some Benzimidazole and Imidazole Group Drugs Using the Reversed-Phase Liquid Chromatography Method

  2020cites this paper
• Torsadogenic potential of a novel remyelinating drug clemastine for multiple sclerosis assessed in the rabbit proarrhythmia model.

  2020cites this paper
• Evaluation of Ionization / Protonation , Lipophilicity and Solubility Constants for Some Heterocyclic Compounds

  2019cites this paper
• Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

  2018cites this paper
• Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking

  2018cites this paper
• Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.

  2018cites this paper
• Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia

  2018cites this paper
• Screening drug-target interactions with positive-unlabeled learning

  2017cites this paper
• Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology.

  2017cites this paper