Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a                Single IV Administration

Hong, Sung-Hyeok; Gibbs, Seth; Kobs, Dean J.; Osheroff, Merrill R.; Johnson, Jerry D.; Burback, Brian

doi:10.1177/1091581813488954

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…It is also consistent with the zwitterionic properties of RS194B and the formation of a neutral species that exhibit more sustained residual tissue and plasma levels. The capacity to cross the blood-brain barrier, to be absorbed orally and to remain in the plasma after a single injection offers RS194B a significant advantage over 2-PAM and several pyridinium aldoxime analogs (HI-6, obidoxime and MMB4) that are unable to enter intracellular sites in tissues or the CNS and thus are rapidly cleared (40,41). …”

Section: Discussionmentioning

confidence: 99%

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

Rosenberg¹,

Mao²,

Jiang³

et al. 2017

Chemico-Biological Interactions

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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 62.5mg/kg of RS194B and 0.28mg/kg atropine after continuous exposure to 49.6 ug/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 one hour. 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.

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Section: Discussionmentioning

confidence: 99%

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

Rosenberg¹,

Mao²,

Jiang³

et al. 2017

Chemico-Biological Interactions

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“…The absolute bioavailability after a single IM injection of MMB4 DMS to rats, rabbits, and dogs could be calculated using the experimental data obtained from the current study and a previous study that examined MMB4 pharmacokinetics after a single intravenous (IV) administration. 13 The absolute bioavailability values ranged from 79% to 95% for rats, 124% to 164% for rabbits, and 89% to 95% for dogs. These results suggest that MMB4 is extensively absorbed into the systemic circulation after the IM administration.…”

Section: Discussionmentioning

confidence: 99%

Comparative Toxicokinetics of MMB4 DMS in Rats, Rabbits, Dogs, and Monkeys Following Single and Repeated Intramuscular Administration

et al. 2013

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1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average T max values ranging from 5 to 30 minutes. Although C max values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUC∞) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, C max and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat.

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“…Several pharmacokinetic studies have been reported for 2-PAM and the more extended pyridinium structures such as MMB4 and HI-6 (Sidell and Groff, 1971;Baggot et al, 1993;Hong et al, 2013). Typically, small volumes of distribution (0.3-0.5 l/kg) and short half-lives (approximately 30 minutes) are evident.…”

Section: Discussionmentioning

confidence: 99%

Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure

Sit

Kovarik

Hrvat

et al. 2018

The Journal of Pharmacology and Experimental Therapeutics

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In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes have received primary attention since their early development by I. B. Wilson in the 1950s. Yet these agents, by virtue of their quaternary structure, are limited in rates of crossing the blood-brain barrier, and they require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine in mice to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored as leads or backups for animal studies. We compared oral and parenteral dosing, and we developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote were achieved with sequential administrations out to 10 hours, with brain levels exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime showed substantial protection after gavage, whereas the classic methylpyridinium aldoxime (2-pyridinealdoxime methiodide) was without evident protection. Although further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.

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Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a Single IV Administration

Cited by 6 publications

References 16 publications

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

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

Comparative Toxicokinetics of MMB4 DMS in Rats, Rabbits, Dogs, and Monkeys Following Single and Repeated Intramuscular Administration

Pharmacology, Pharmacokinetics, and Tissue Disposition of Zwitterionic Hydroxyiminoacetamido Alkylamines as Reactivating Antidotes for Organophosphate Exposure

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