Pharmacokinetics of Three Oximes in a Guinea Pig Model and Efficacy of Combined Oxime Therapy

Bohnert, Sara; Berg, R.M. van den; Mikler, John; Klaassen, Steven D.; Joosen, Marloes J.A.

doi:10.1016/j.toxlet.2020.01.013

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…The mean PK parameters are presented in Table 2 . Across the four doses studied, the mean apparent distribution half-life (t 1/2α ) ranges from 0.25 to 0.4 h, and the terminal half-life (t 1/2 β ) spans from 9.61 to 21.92 h. The t 1/2α is similar to what has been reported for the current standard of care 2-PAM of 0.31 h 44 whereas, the t 1/2 β is 2–3 times longer than the 4.6 h-5.0 h range that has been observed for 2-PAM (unpublished data). Total clearance of LLNL-02 from plasma (CL) ranges from 167.77 to 335.60 mL/h/kg and the apparent volume of distribution (V d ) is 3747.90 to 5341.0 mL/kg, suggesting rapid and extensive distribution beyond the plasma compartment.…”

Section: Resultssupporting

confidence: 72%

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Bennion

Malfatti

et al. 2021

Sci Rep

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Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.

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Section: Resultssupporting

confidence: 72%

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Bennion

Malfatti

et al. 2021

Sci Rep

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“…In a previous study, we showed the elimination half-life of PRX administered by intravenous route in the rat was 29.4 ± 1.1 min and 54 ± 9.3 min after intramuscular administration [30]. Bohnert et al [31] reported elimination half-life of PRX of 18.9 ± 9.5 min, after intramuscular injection using auto-injector device. Therefore, the values in rats seem to be different from experiments using the guinea pigs.…”

Section: Discussionmentioning

confidence: 91%

“…Although PRX was shown to rapidly and completely reverse paraoxon-induced respiratory toxicity in rats, its antidotal effect lasted only 30 min meanwhile paraoxon toxicity lasted more than 6 h [30]. A pharmacokinetic study in a guinea pig model reported half-life clearance of obidoxime in the range of 30 min meanwhile the clearance of PRX was in the range of 20 min [31]. The route of administration is a major bias when determining the true elimination half-life.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats

et al. 2020

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Background: Oximes are used in addition to atropine to treat organophosphate poisoning. However, the efficiency of oximes is still a matter of debate. In vitro experiments suggested than new oximes are more potent than the commercial oximes. However, the antidotal activity of new oximes has not been assessed in vivo. Methods: The aim of this work was to assess the safety and efficiency of new oximes compared to pralidoxime in a rat model of diethyl paraoxon-induced non-lethal respiratory toxicity. Results: Safety study of oximes showed no adverse effects on ventilation in rats. KO-33, KO-48, KO-74 oximes did not exhibit significant antidotal effect in vivo. In contrast, KO-27 and BI-6 showed evidence of antidotal activity by normalization of respiratory frequency and respiratory times. KO-27 became inefficient only during the last 30 min of the study. In contrast, pralidoxime demonstrated to be inefficient at 30 min post injection. Inversely, the antidotal activity of BI-6 occurred lately, within the last 90 min post injection. Conclusion: This study showed respiratory safety of new oximes. Regarding, the efficiency, KO-27 revealed to be a rapid acting antidote toward diethylparaoxon-induced respiratory toxicity, meanwhile BI-6 was a late-acting antidote. Simultaneous administration of these two oximes might result in a complete and prolonged antidotal efficiency.

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“…The mechanism of action of the reactivation of AChE by oximes can be best described using the FDA-approved drug, 2-pyridine-aldoxime methyl chloride (2-PAM) (also known as pralidoxime), as a classic example (Figure 7). The 2-PAM is the most popular and well-investigated agent, along with HI-6 and obidoxime [4,36,56]. The 2-PAM has a positively charged quaternary nitrogen atom of the pyridinium ion that specifically interacts with the anionic site of the AChE, and, then, the hydroxyl group of the oxime moiety replaces the serine residue by nucleophilic substitution, releasing the free hydroxy (OH)-group of the amino acid (Figure 7) [57][58][59].…”

Section: Detoxification Of Op Poisoning By Pralidoximementioning

confidence: 99%

“…Table 1 is a compilation of a short comparison of the most important pharmacokinetic parameters for oxime-based AChE reactivators that are already in use, and some most promising experimental oximes. Bohnert et al also recently reviewed the pharmacokinetic data of 2-PAM, HI-6 and obidoxime, as parts of OP poisoning treatment (in combination with each other and atropine) [56]. The problem of slow development of this class of compounds is due to their slow transition from clinical trials to real-time applications, as it occurred to HI-6 in the past [52].…”

Section: Computational and Sar Studies Of Ache Reactivatorsmentioning

confidence: 99%

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

2022

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Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.

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Pharmacokinetics of Three Oximes in a Guinea Pig Model and Efficacy of Combined Oxime Therapy

Cited by 14 publications

References 35 publications

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

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