Abstract
Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC50 (intrinsic oxime AChE inhibitory activity), of tan α (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD50) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC50) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan α) also have a high in vitro AChE inhibitory activity (low IC50) and have a low LD50 in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.
Keywords: organophosphate, aldoxime, DFP, cholinesterase, LogP, relative risk
Mini-Reviews in Medicinal Chemistry
Title: Pyridinium Oxime Reactivators of Cholinesterase Inhibited by Diisopropyl- Fluorophosphate (DFP): Predictive Value of In-Vitro Testing for In-Vivo Efficacy
Volume: 8 Issue: 13
Author(s): G. A. Petroianu and D. E. Lorke
Affiliation:
Keywords: organophosphate, aldoxime, DFP, cholinesterase, LogP, relative risk
Abstract: Poisoning with organophosphorus cholinesterase inhibitors (OPCs) poses a serious global threat. Therapy comprises the use of atropine and pyridinium oximes to reactivate acetylcholinesterase (AChE). Clinical experience with established oximes (pralidoxime and obidoxime) is disappointing and several experimental potential alternatives (K oximes) have been developed. This review summarizes data on these oximes, when used in exposure to the OPC diisopropylfluorophosphate (DFP). In vitro testing includes determination of IC50 (intrinsic oxime AChE inhibitory activity), of tan α (reactivation capacity) and in silico estimation of LogP (lipophilicity/hydrophilicity) of the individual oximes. In vivo approaches encompass determination of toxicity (LD50) and of protective efficacy (reduction of relative risk of death after DFP exposure in rats). Correlations between the different in vitro and in vivo data available reveal that an oxime with a low in vitro AChE inhibitory activity (high IC50) is rather non-toxic and reduces DFP-induced mortality (low cumulative relative risk). Oximes with a high in vitro AChE reactivation potency (high tan α) also have a high in vitro AChE inhibitory activity (low IC50) and have a low LD50 in vivo, implying high toxicity. Less hydrophilic oximes have strong in vitro AChE inhibitory activity, are better in vitro AChE reactivators, but are also more toxic in vivo and are associated with a high cumulative risk of death after DFP exposure in rats, implying low in vivo efficacy. In vitro reactivation capacity of human red blood cell (RBC)-AChE has no predictive value for in vivo (rat) efficacy, at least in the case of DFP exposure.
Export Options
About this article
Cite this article as:
Petroianu A. G. and Lorke E. D., Pyridinium Oxime Reactivators of Cholinesterase Inhibited by Diisopropyl- Fluorophosphate (DFP): Predictive Value of In-Vitro Testing for In-Vivo Efficacy, Mini-Reviews in Medicinal Chemistry 2008; 8 (13) . https://dx.doi.org/10.2174/138955708786369555
DOI https://dx.doi.org/10.2174/138955708786369555 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
Natural Products in Drug Discovery
Natural products have always been one of the important ways of drug discovery due to their novel skeleton and diverse functional group characteristics. According to statistics, between 1981 and 2019, the FDA approved a total of 1,394 small molecule drugs for marketing, of which 930 marketed drugs originated from the ...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
Related Articles
-
Histone Deacetylase Inhibitors in Cancer Treatment: A Review of the Clinical Toxicity and the Modulation of Gene Expression in Cancer Cells
Current Pharmaceutical Biotechnology Significance of Genome-Wide Analysis of Copy Number Alterations and UPD in Myelodysplastic Syndromes using Combined CGH – SNP Arrays
Current Medicinal Chemistry Alzheimers Disease and Oxidative Stress: The Old Problem Remains Unsolved
Current Medicinal Chemistry - Central Nervous System Agents Pyrazolo[1,5-a]pyrimidines: A Close Look into their Synthesis and Applications
Current Organic Chemistry Effects of 900MHz Mobile Phone Radiation on Human Thyroid Hormone Levels
Recent Patents on Biomarkers The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Signaling Proteins Following Sub-Chronic Administration in Rats
Current Molecular Pharmacology Inhibitors of Catechol-O-Methyltransferase
CNS & Neurological Disorders - Drug Targets Neurological Disorders of Purine and Pyrimidine Metabolism
Current Topics in Medicinal Chemistry Preventing Prion Pathogenicity by Targeting the Cellular Prion Protein
Infectious Disorders - Drug Targets The ARRONAX Project
Current Radiopharmaceuticals A Simple, Efficient and Environmentally Benign Synthetic Protocol for the Synthesis of Spirooxindoles Using Choline Chloride-Oxalic Acid Eutectic Mixture as Catalyst/Solvent System
Combinatorial Chemistry & High Throughput Screening Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders
Mini-Reviews in Medicinal Chemistry Chemopreventive Properties of Peptide Lunasin: A Review
Protein & Peptide Letters A New Investigational Perspective for Purines Against Glioblastoma Invasiveness
Current Drug Targets Therapeutic Potential of Alpinia officinarum
Mini-Reviews in Medicinal Chemistry Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach
CNS & Neurological Disorders - Drug Targets Anticancer Evaluation of 3,4,5,4'-trans-tetramethoxystilbene (DMU-212) and Its Analogs Against an Extensive Panel of Human Tumor Cell Lines
Letters in Drug Design & Discovery Nanostructures for Bypassing Blood Brain Barrier
Current Bioactive Compounds Growth Restriction: Etiology, Maternal and Neonatal Outcome. A Review
Current Women`s Health Reviews Nitric Oxide-Derived Oxidants with a Focus on Peroxynitrite: Molecular Targets,Cellular Responses and Therapeutic Implications
Current Pharmaceutical Design