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3. Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques

Author

Rosenberg, Yvonne J, Wang, Jerry, Ooms, Tara, Rajendran, Narayanan, Mao, Lingjun, Jiang, Xiaoming, Lees, Jonathan, Urban, Lori, Momper, Jeremiah D, Sepulveda, Yadira, Shyong, Yan-Jye, and Taylor, Palmer

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Prevention, Biodefense, Vaccine Related, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Acetamides, Acetylcholinesterase, Aerosols, Animals, Butyrylcholinesterase, Chemical Warfare Agents, Cholinesterase Inhibitors, Cholinesterase Reactivators, Female, Inhalation Exposure, Insecticides, Macaca mulatta, Organophosphate Poisoning, Oximes, Paraoxon, Oxime antidote, Nebulized paraoxon, Macaques, AChE, BChE, Reactivation, IM, Ma, OP, Px, Reactivation., acetylcholinesterase, butyrylcholinesterase, intramuscular, macaque, organophosphate, paraoxon, Environmental Science and Management, Toxicology, Pharmacology and pharmaceutical sciences, Pollution and contamination
Abstract

Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40-100% in

Published
2018

4. Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor

Author

Rosenberg, Yvonne J, Mao, Lingjun, Jiang, Xiaoming, Lees, Jonathan, Zhang, Limin, Radic, Zoran, and Taylor, Palmer

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Prevention, Vaccine Related, Biodefense, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Acetamides, Acetylcholinesterase, Animals, Butyrylcholinesterase, Chemical Warfare Agents, Cholinesterase Reactivators, Gases, Inhalation, Macaca, Models, Animal, Oximes, Paraoxon, Recombinant Proteins, Sarin, Toxicology, Biochemistry and cell biology
Abstract

Organophosphate (OP) nerve agents and pesticides trigger a common mechanism of neurotoxicity resulting from critical targeting and inhibition of acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Therapeutic countermeasures have thus focused on either administering an oxime post-exposure, that can rapidly reactivate OP-inhibited AChE, or by preventing OP poisoning through administering pre-exposure treatments that scavenge OPs before they inhibit their physiological AChE targets. While several pyridinium aldoxime antidotes are currently approved, their utility is impaired due to their inability to cross the blood-brain barrier (BBB) efficiently. The present study utilized a macaque (Ma) model to demonstrate the efficacy of a novel zwitterionic and centrally acting oxime RS194B to reactivate sarin- and paraoxon-inhibited macaque AChE and butyrylcholinesterase (BChE) in vitro and to further assess the capacity of RS194B to effect a reversal of clinical symptoms following sarin inhalation in vivo. In vitro, oxime reactivation of MaAChE and MaBChE was shown to be comparable to their human orthologs, while the macaque studies indicated that IM administration of 62.5 mg/kg of RS194B and 0.28 mg/kg atropine after continuous exposure to 49.6 μg/kg sarin vapor, rapidly reactivated the inhibited AChE and BChE in blood and reversed both early and advanced clinical symptoms of sarin-induced toxicity following pulmonary exposure within 1 h. The rapid cessation of autonomic and central symptoms, including convulsions, observed in macaques bodes well for the use of RS194B as an intra- or post-exposure human treatment and validates the macaque model in generating efficacy and toxicology data required for approval under the FDA Animal rule.

Published
2017

5. A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Author

Rosenberg, Yvonne J., Garcia, Kelly, Diener, Justin, Sullivan, Dennis, Donahue, Scott, Mao, Lingjun, Lees, Jonathan, Jiang, Xiaoming, Urban, Lori A., Momper, Jeremiah D., Ho, Kwok‐Yiu, and Taylor, Palmer

Subjects
*OXIMES, *MACAQUES, *INSECTICIDES, *ACETYLCHOLINESTERASE, *NERVE gases, *CHLORPYRIFOS
Abstract

Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP‐inhibited AChE. However, animal model studies and recent clinical trials using insecticide‐poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood–brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP‐inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1–2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non‐invasive treatment, especially in isolated rural settings. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Evidence for the Role of a Second Fc-Binding Receptor in Placental IgG Transfer in Nonhuman Primates

Author

Rosenberg, Yvonne J., primary, Ordonez, Tracy, additional, Khanwalkar, Urjeet S., additional, Barnette, Philip, additional, Pandey, Shilpi, additional, Backes, Iara M., additional, Otero, Claire E., additional, Goldberg, Benjamin S., additional, Crowley, Andrew R., additional, Leib, David A., additional, Shapiro, Mariya B., additional, Jiang, Xiaoming, additional, Urban, Lori A., additional, Lees, Jonathan, additional, Hessell, Ann J., additional, Permar, Sallie, additional, Haigwood, Nancy L., additional, and Ackerman, Margaret E., additional

Published
2023
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8. A single post‐exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Author

Rosenberg, Yvonne J., primary, Garcia, Kelly, additional, Diener, Justin, additional, Sullivan, Dennis, additional, Donahue, Scott, additional, Mao, Lingjun, additional, Lees, Jonathan, additional, Jiang, Xiaoming, additional, Urban, Lori A., additional, Momper, Jeremiah D., additional, Ho, Kwok‐Yiu, additional, and Taylor, Palmer, additional

Published
2023
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10. Protection of Newborn Macaques by Plant-Derived HIV Broadly Neutralizing Antibodies: a Model for Passive Immunotherapy during Breastfeeding

Author

Rosenberg, Yvonne J., primary, Jiang, Xiaoming, additional, Cheever, Tracy, additional, Coulter, Felicity J., additional, Pandey, Shilpi, additional, Sack, Markus, additional, Mao, Lingjun, additional, Urban, Lori, additional, Lees, Jonathan, additional, Fischer, Miranda, additional, Smedley, Jeremy, additional, Sidener, Heather, additional, Stanton, Jeffrey, additional, and Haigwood, Nancy L., additional

Published
2021
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11. Optimization and qualification of a functional anti-drug antibody assay for HIV-1 bnAbs

Author

Seaman, Michael S., primary, Bilska, Miroslawa, additional, Ghantous, Fadi, additional, Eaton, Amanda, additional, LaBranche, Celia C., additional, Greene, Kelli, additional, Gao, Hongmei, additional, Weiner, Joshua A., additional, Ackerman, Margaret E., additional, Garber, David A., additional, Rosenberg, Yvonne J., additional, Sarzotti-Kelsoe, Marcella, additional, and Montefiori, David C., additional

Published
2020
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14. Creation of a protective pulmonary bioshield against inhaled organophosphates using an aerosolized bioscavenger

Author

Rosenberg, Yvonne J. and Fink, James B.

Subjects
Aerosols, Inhalation Exposure, Drug Delivery Systems, Organophosphorus Compounds, Animals, Humans, Protective Agents, Lung, Article
Abstract

In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists (e.g., the recent sarin attack in Syria). These occurrences highlight the need for an effective countermeasure against OP exposure. Human butyrylcholinesterase (HuBChE) is a leading candidate, but injection of the high doses required for protection present pharmacokinetic challenges. An aerosolized recombinant from (aer-rHuBChE) that can neutralize inhaled OPs at their portal of entry has been assessed for its efficacy to protect macaques against respiratory toxicity following inhalation exposure to the pesticide paraoxon (aer-Px). While protection in macaques has been demonstrated using a Microsprayer delivery device, administration to humans will likely employ a vibrating mesh nebulizer (VMN). Compared to the 50–70% lung deposition achieved in adult humans with a VMN, deposition in macaques is < 5%, an initial major obstacle to demonstrating protection. Such problems have been partly overcome by using a more efficient modified VMN and proportionally higher doses, which together generate an effective rHuBChE pulmonary bioshield and protect against high levels of inhaled Px.

Published
2016

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