Abstract
GPIIb / IIIa receptor antagonists block fibrinogen binding to platelets and as a result inhibit platelet aggregation. They are very potent inhibitors due to the critical role fibrinogen binding plays in platelet aggregation. When given intravenously these drugs have been shown to be very effective as adjuvant therapy in percutaneous coronary intervention and in acute coronary syndromes. However, despite being as potent as their intravenous counterparts, all of the oral inhibitors showed no benefit or even increased mortality in clinical trials. There are a number of reasons for their failure. The target was different, chronic treatment to prevent thrombotic events as opposed to short-term treatment to prevent acute events and as a result, different dosing regimens were used. The acute use aims for a high level of inhibition (80- 90%) while the chronic use produced lower levels of inhibition. Many of the oral inhibitors had low bioavailability that led to a large peak-trough difference. Most GPIIb / IIIa antagonists have the ability to activate platelets through a GPIIb / IIIa-mediated process. This is known as partial agonism. In the presence of high drug levels, such as during an infusion this is not a problem, however combined with the low trough levels with oral inhibitors this can lead to an increase in platelet aggregation. Other problems include drug-induced conformational changes in GPIIb / IIIa (ligandregulated binding sites) and possible pharmacogenomics effects in the response to the drugs, in particular the PlA polymorphism in GPIIb / IIIa. By addressing these issues it is possible for a new generation of oral GPIIb / IIIa antagonist to be developed.
Keywords: gpIIb IIIa antagonists, platelet aggregation, pharmacogenomics
Current Pharmaceutical Design
Title: Oral GPIIb / IIIa Antagonists: What Went Wrong?
Volume: 10 Issue: 14
Author(s): Dermot Cox
Affiliation:
Keywords: gpIIb IIIa antagonists, platelet aggregation, pharmacogenomics
Abstract: GPIIb / IIIa receptor antagonists block fibrinogen binding to platelets and as a result inhibit platelet aggregation. They are very potent inhibitors due to the critical role fibrinogen binding plays in platelet aggregation. When given intravenously these drugs have been shown to be very effective as adjuvant therapy in percutaneous coronary intervention and in acute coronary syndromes. However, despite being as potent as their intravenous counterparts, all of the oral inhibitors showed no benefit or even increased mortality in clinical trials. There are a number of reasons for their failure. The target was different, chronic treatment to prevent thrombotic events as opposed to short-term treatment to prevent acute events and as a result, different dosing regimens were used. The acute use aims for a high level of inhibition (80- 90%) while the chronic use produced lower levels of inhibition. Many of the oral inhibitors had low bioavailability that led to a large peak-trough difference. Most GPIIb / IIIa antagonists have the ability to activate platelets through a GPIIb / IIIa-mediated process. This is known as partial agonism. In the presence of high drug levels, such as during an infusion this is not a problem, however combined with the low trough levels with oral inhibitors this can lead to an increase in platelet aggregation. Other problems include drug-induced conformational changes in GPIIb / IIIa (ligandregulated binding sites) and possible pharmacogenomics effects in the response to the drugs, in particular the PlA polymorphism in GPIIb / IIIa. By addressing these issues it is possible for a new generation of oral GPIIb / IIIa antagonist to be developed.
Export Options
About this article
Cite this article as:
Cox Dermot, Oral GPIIb / IIIa Antagonists: What Went Wrong?, Current Pharmaceutical Design 2004; 10 (14) . https://dx.doi.org/10.2174/1381612043384673
DOI https://dx.doi.org/10.2174/1381612043384673 |
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
-
Nonalcoholic Fatty Liver Disease and Cardiovascular Disease
Current Pharmaceutical Design Resistin: An Inflammatory Cytokine. Role in Cardiovascular Diseases, Diabetes and the Metabolic Syndrome
Current Pharmaceutical Design Management of Hypertension-Journey from Single Drug Therapy to Multitargeted Ligand Therapy: A Clinical Overview
Current Clinical Pharmacology Pharmacological Treatment of Hypertension in Pregnancy
Current Pharmaceutical Design TiO2-Nanowired Delivery of Mesenchymal Stem Cells Thwarts Diabetes- Induced Exacerbation of Brain Pathology in Heat Stroke: An Experimental Study in the Rat Using Morphological and Biochemical Approaches
CNS & Neurological Disorders - Drug Targets The Role of TMP21 in Trafficking and Amyloid-β Precursor Protein (APP) Processing in Alzheimer’s Disease
Current Alzheimer Research Strategies that Target Tight Junctions for Enhanced Drug Delivery
Current Pharmaceutical Design Pharmacogenomics: A Tool to Prevent and Cure Coronary Heart Disease
Current Pharmaceutical Design Editorial [Hot Topic: Oxidative Stress Induced-Metabolic Imbalance, Mitochondrial Failure, And Cellular Hypoperfusion As Primary Pathogenetic Factors For The Development Of Alzheimer Disease Which Can Be Used As An Alternate And Successful Drug Treatment Strategy: Past, Present And Future (Guest Editor: Gjumrakch Aliev)]
CNS & Neurological Disorders - Drug Targets Morphofunctional Aspects of the Blood-Brain Barrier
Current Drug Metabolism CGRP-Receptor Antagonism in Migraine Treatment
CNS & Neurological Disorders - Drug Targets Ginkgolic Acids Confer Potential Anticancer Effects by Targeting Pro- Inflammatory and Oncogenic Signaling Molecules
Current Molecular Pharmacology Translational Methods for Non-Invasive Electrical Stimulation to Facilitate Gait Rehabilitation Following Stroke - The Future Directions
Neuroscience and Biomedical Engineering (Discontinued) Hydrogen Sulfide: A New Tool to Design and Develop Drugs
Clinical Anti-Inflammatory & Anti-Allergy Drugs (Discontinued) Central Nervous System Vasculitis: Still More Questions than Answers
Current Neuropharmacology Catheter Ablation of Lone Atrial Fibrillation
Current Pharmaceutical Design Mononuclear Cell Recruitment and Inflammation in Atherosclerosis
Vascular Disease Prevention (Discontinued) Chronic Kidney Disease - Different Role for HDL?
Current Medicinal Chemistry A Survey of Peptides with Effective Therapeutic Potential in Alzheimer’s Disease Rodent Models or in Human Clinical Studies
Mini-Reviews in Medicinal Chemistry Hepatocyte Growth Factor (HGF): Neurotrophic Functions and Therapeutic Implications for Neuronal Injury/Diseases
Current Signal Transduction Therapy