Abstract
Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKrblockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.
Keywords: mice gestational days, Dofetilide, Teratogenicity, almokalant, Antidepressant Drugs, non-selective monoamine reuptake inhibitors
Current Pharmaceutical Design
Title: New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential
Volume: 13 Issue: 29
Author(s): Miriam Karlsson, Bengt R. Danielsson, Mats F. Nilsson, Christian Danielsson and William S. Webster
Affiliation:
Keywords: mice gestational days, Dofetilide, Teratogenicity, almokalant, Antidepressant Drugs, non-selective monoamine reuptake inhibitors
Abstract: Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKrblockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.
Export Options
About this article
Cite this article as:
Karlsson Miriam, Danielsson R. Bengt, Nilsson F. Mats, Danielsson Christian and Webster S. William, New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential, Current Pharmaceutical Design 2007; 13 (29) . https://dx.doi.org/10.2174/138161207782110471
DOI https://dx.doi.org/10.2174/138161207782110471 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
?Revolutionizing Cancer Treatment: Nano-Therapeutics Targeting Tumor Microenvironment?
This thematic issue explores the forefront of cancer treatment, centering on the groundbreaking potential of nano-therapeutics meticulously designed to target the tumor microenvironment. At its core, the issue aims to unravel the latest advancements in nanotechnology, showcasing innovative materials, formulations, and delivery systems that hold promise for redefining cancer therapeutics. ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Giant Pulmonary Artery Aneurysm Secondary To Patent Ductus Arteriosus: A Case Report
Current Cardiology Reviews MicroRNAs as Biomarkers for Birth Defects
MicroRNA Eisenmenger Syndrome: Recent Advances in Pharmacotherapy
Cardiovascular & Hematological Agents in Medicinal Chemistry Interatrial Block in the Modern Era
Current Cardiology Reviews Surgical Treatment of Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension
Current Pharmaceutical Design Prediction and Prevention of Abnormal Antenatal Lung Growth
Current Respiratory Medicine Reviews The Diagnostic and Prognostic Value of Brain Natriuretic Peptide and Aminoterminal (nt)-pro Brain Natriuretic Peptide
Current Pharmaceutical Design The Coronary Circulation in Cyanotic Congenital Heart Disease
Current Cardiology Reviews Acute Ischemic Cerebrovascular Events on Antiplatelet Therapy: What is the Optimal Prevention Strategy?
Current Pharmaceutical Design Pediatric Heart Failure in the Developing World
Reviews on Recent Clinical Trials The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders
Current Neuropharmacology The Adult Patient with Eisenmenger Syndrome: A Medical Update after Dana Point Part II: Medical Treatment - Study Results
Current Cardiology Reviews Endocarditis Due to Salmonella Enterica Subsp. Arizonae in a Patient with Sickle Cell Disease: A Case Report and Review of the Literature
Cardiovascular & Hematological Disorders-Drug Targets First Comprehensive Analysis of Outcomes in Adult Patients after Percutaneous Closure of Isolated Secundum Atrial Septal Defects
Cardiovascular & Hematological Agents in Medicinal Chemistry Annual Trends in Use of Periconceptional Folic Acid and Birth Prevalence of Major Congenital Malformations
Current Drug Safety Are Retinoids a Promise for Alzheimer’s Disease Management?
Current Medicinal Chemistry Folic Acid Can Contribute to Memory Deficit and Na+, K+- ATPase Failure in the Hippocampus of Adolescent Rats Submitted to Hypoxia- Ischemia
CNS & Neurological Disorders - Drug Targets Right Heart Catheterization Through Persistent Left Superior Vena Cava, an Extremely Rare Procedure and Review of Current Literature
Current Cardiology Reviews Characterization of Supraventricular Tachycardia in Infants: Clinical and Instrumental Diagnosis
Current Pharmaceutical Design Thrombolytic Treatment of Cardiac Myxoma-Induced Ischemic Stroke: A Review
Current Drug Safety