Abstract
Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.
Keywords: cleft lip, hypoxia, bradycardia, Ikr inhibition, HERG inhibitors, Phenytoin
Current Pharmaceutical Design
Title: The Relationship Between Cleft Lip, Maxillary Hypoplasia, Hypoxia and Phenytoin
Volume: 12 Issue: 12
Author(s): William S. Webster, Andrew M. Howe, Dominique Abela and Diana J. Oakes
Affiliation:
Keywords: cleft lip, hypoxia, bradycardia, Ikr inhibition, HERG inhibitors, Phenytoin
Abstract: Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.
Export Options
About this article
Cite this article as:
Webster S. William, Howe M. Andrew, Abela Dominique and Oakes J. Diana, The Relationship Between Cleft Lip, Maxillary Hypoplasia, Hypoxia and Phenytoin, Current Pharmaceutical Design 2006; 12 (12) . https://dx.doi.org/10.2174/138161206776389868
DOI https://dx.doi.org/10.2174/138161206776389868 |
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
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
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Morpho-Functional Features of In-Vitro Cell Death Induced by Physical Agents
Current Pharmaceutical Design Glaucoma Pathogenesis and Neurotrophins: Focus on the Molecular and Genetic Basis for Therapeutic Prospects
Current Neuropharmacology Good, Bad, Mobile Elements: Genome’s Most Successful “Parasites” as Emerging Players in Cell and Organismal Aging
Current Pharmaceutical Design Cell to Cell Spreading of Misfolded Proteins as a Therapeutic Target in Motor Neuron Disease
Current Medicinal Chemistry Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions?
Current Drug Metabolism CD93 and Related Family Members: Their Role in Innate Immunity
Current Drug Targets Resveratrol and Its Analogues: Promising Antitumor Agents
Anti-Cancer Agents in Medicinal Chemistry subject Index To Volume 2
Current Molecular Medicine Protein Interaction Domains: Structural Features and Drug Discovery Applications (Part 2)
Current Medicinal Chemistry HCV Infection by Cell-to-Cell Transmission: Choice or Necessity?
Current Molecular Medicine Exploiting Protein Phosphatase Inhibitors Based on Cantharidin Analogues for Cancer Drug Discovery
Mini-Reviews in Medicinal Chemistry Image-Guided Nanoparticle-Based siRNA Delivery for Cancer Therapy
Current Pharmaceutical Design Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94
Current Topics in Medicinal Chemistry Anticancer Agents: VTA or VDA
Current Bioactive Compounds Selegiline (l-Deprenyl) as a Unique Neuroprotective Agent for Chronic Neurodegenerative Disorders- A Lesson from MAO Inhibition
Current Medicinal Chemistry - Central Nervous System Agents Anticancer Potential of Dietary Natural Products: A Comprehensive Review
Anti-Cancer Agents in Medicinal Chemistry Meridianins: Marine-Derived Potent Kinase Inhibitors
Mini-Reviews in Medicinal Chemistry Novel Metals and Metal Complexes as Platforms for Cancer Therapy
Current Pharmaceutical Design Elucidation of PLK1 Linked Biomarkers in Oesophageal Cancer Cell Lines: A Step Towards Novel Signaling Pathways by p53 and PLK1-Linked Functions Crosstalk
Protein & Peptide Letters Substance P and Alzheimer’s Disease: Emerging Novel Roles
Current Alzheimer Research