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Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Jeffrey D. Laskin, Ph.D. - Wed, 08/02/2017 - 02:00

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Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Ann N Y Acad Sci. 2016 Aug;1378(1):174-179

Authors: Lacey CJ, Wohlman I, Guillon C, Saxena J, Fianu-Velgus C, Aponte E, Young SC, Heck DE, Joseph LB, Laskin JD, Heindel ND

Abstract
The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

PMID: 27505078 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

Preparedness and response to chemical and biological threats: the role of exposure science.

Jeffrey D. Laskin, Ph.D. - Wed, 08/02/2017 - 02:00

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Preparedness and response to chemical and biological threats: the role of exposure science.

Ann N Y Acad Sci. 2016 Aug;1378(1):108-117

Authors: Lioy PJ, Laskin JD, Georgopoulos PG

Abstract
There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events.

PMID: 27479653 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Jeffrey D. Laskin, Ph.D. - Wed, 08/02/2017 - 02:00

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Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Ann N Y Acad Sci. 2016 Aug;1378(1):80-86

Authors: Jan YH, Richardson JR, Baker AA, Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.

PMID: 27441453 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members