Chemical Stability of the Hagedorn Oximes HGG‐12 and HI‐6

Eyer, Peter; Hell, W.

doi:10.1002/ardp.19853181015

Cited by 22 publications

(7 citation statements)

References 16 publications

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“…A temperature‐dependent decrease of oxime concentrations in EDTA plasma was observed for all analytes. At room temperature the peak areas decreased by 5.1% for 2‐PAM, 4.5% for Obi, and 12.1% for HI‐6 after 7 h and by 15.0% for 2‐PAM and 21.0% for Obi after 144 h. At 37°C the peak areas decreased by 6.9% for 2‐PAM, 8.0% for Obi, and 43.4% for HI‐6 after 7 h and by 48.1% for 2‐PAM and 37.1% for Obi after 144 h. In the case of HI‐6 only 6.7% were not degraded after 144 h at RT and no HI‐6 was detecatble after 72 h at 37°C, which is in accordance to previous investigations 62,63 …”

Section: Resultssupporting

confidence: 92%

A novel high‐performance liquid chromatography with diode array detector method for the simultaneous quantification of the enzyme‐reactivating oximes obidoxime, pralidoxime, and HI‐6 in human plasma

Kranawetvogl

Steinritz

Thiermann³

et al. 2020

Drug Testing and Analysis

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Oximes such as pralidoxime (2‐PAM), obidoxime (Obi), and HI‐6 are the only currently available therapeutic agents to reactivate inhibited acetylcholinesterase (AChE) in case of intoxications with organophosphorus (OP) compounds. However, each oxime has characteristic agent‐dependent reactivating efficacy, and therefore the combined administration of complementary oximes might be a promising approach to improve therapy. Accordingly, a new high‐performance liquid chromatography method with diode‐array detection (HPLC‐DAD) was developed and validated allowing for simultaneous or single quantification of 2‐PAM, Obi, and HI‐6 in human plasma. Plasma was precipitated using 5% w/v aqueous zinc sulfate solution and subsequently acetonitrile yielding high recoveries of 94.2%–101.0%. An Atlantis T3 column (150 × 2.1mm I.D., 3 μm) was used for chromatographic separation with a total run time of 15 min. Quantification was possible without interferences within a linear range from 0.12 to 120 μg/mL for all oximes. Excellent intra‐day (accuracy 91.7%–98.6%, precision 0.5%–4.4%) and inter‐day characteristics (accuracy 89.4%–97.4%, precision 0.4%–2.2%) as well as good ruggedness were found. Oximes in processed samples were stable for at least 12 h in the autosampler at 15°C as well as in human plasma for at least four freeze–thaw cycles. Finally, the method was applied to plasma samples of a clinical case of pesticide poisoning.

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Section: Resultssupporting

confidence: 92%

A novel high‐performance liquid chromatography with diode array detector method for the simultaneous quantification of the enzyme‐reactivating oximes obidoxime, pralidoxime, and HI‐6 in human plasma

Kranawetvogl

Steinritz

Thiermann³

et al. 2020

Drug Testing and Analysis

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“…They also cannot cross blood brain barrier and action is mainly peripheral they reduce ageing of AChE by 2-2.5 levels. However they are unstable in aqueous solutions, have to be stored in lyophilized form and have to be administered by auto injector [17]. Subsequently 3rd generation ChR have been developed e.g.…”

Section: Discussionmentioning

confidence: 99%

Regeneration of Red Cell Cholinesterase Activity Following Pralidoxime (2-PAM) Infusion in First 24 h in Organophosphate Poisoned Patients

Goel

Gupta²,

Singh³

et al. 2011

Ind J Clin Biochem

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Oximes such as pralidoxime chloride reactivate acetylcholinesterase. However their role in management of organophosphate poisoning is controversial. The study was carried out to find effectiveness of pralidoxime chloride (2-PAM) in regenerating red cell acetyl cholinesterase in first 24 h following administration of it in dose recommended by WHO. Eight patients with OPP [chlorpyriphos (3), phorate (3), dichlorvos (1) and monocrotophos (1) who fulfilled the criteria for inclusion were investigated. In addition to decontamination and atropine, all these patients were administered 30 mg/kg body wt of 2-PAM as bolus dose followed by 7.5 mg/kg body wt/h with maximum dose being 500 mg/h as continuous infusion till first 24 h. Red cell AChE activity was estimated every 15 min for first 4 h, one hourly for next 4 h and then 2 hourly till 24 h and subsequently without 2-PAM every 12 h till 7 days or discharge or death which ever earlier. In all the patients maximum increase in activity was observed in first 4 h following which rise was very slow despite continued 2-PAM infusion and reaching a steady state in 20 h in all the cases. The increase in red cell AChE activity observed in diethyl group at 24 h of 2-PAM infusion was 154% vs. 81% in dimethyl group. At 7 days the increase in activity was 215% vs. 118% respectively. However on multiple repeated ANOVA, no statistically significant difference was observed between diethyl and dimethyl groups at admission and discharge (P > 0.05). Similarly no significant difference was observed in three groups when patients were categorized according to WHO classification of organophosphates (P > 0.05). The maximum increase in red cell AChE activity occurs in first 4 h of 2-PAM administration followed by a slow increase despite 2-PAM infusion till 24 h.

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“…[5][6][7] The MMB4 salts are generally very stable in solid form, but in aqueous formulations MMB4 is prone to hydrolytic cleavage, leading to poor stability (Figure 1). Elevated temperature is known to accelerate this hydrolytic cleavage reaction, leading to poor field stability and insufficient shelf life at temperatures above 25 C. 8 We report the development of IM autoinjectable formulations of MMB4, which maintain the stability of the solid. These non-Newtonian liquid formulations consist of MMB4 DMS microparticles and/or nanoparticles suspended in biocompatible cottonseed oil (CSO).…”

Section: Introductionmentioning

confidence: 99%

MMB4 DMS Nanoparticle Suspension Formulation With Enhanced Stability for the Treatment of Nerve Agent Intoxication

et al. 2013

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Various oximes are currently fielded or under investigation in the United States and other countries as a component of autoinjector emergency treatment systems for organophosphate nerve agent chemical weapons. Bis-pyridinium oximes in general have greater efficacy against a broad spectrum of nerve agents, but they have poor stability due to hydrolytic degradation at elevated temperatures. 1,1'-Methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) is a leading candidate for next-generation nerve agent treatment systems, because it is more stable than other bis-pyridinium oximes, but it still degrades quickly at temperatures often encountered during storage and field use. The primary goal is to increase the stability and shelf life of MMB4 while maintaining the desirable pharmacokinetic (PK) properties of the aqueous formulation. We have developed a formulation to be used in a phase 1 clinical trial consisting of MMB4 micro/nanoparticles suspended in cottonseed oil, a biocompatible vegetable oil. Through various milling techniques, the average particle size can be controlled from approximately 200 to 6000 nm to produce non-Newtonian formulations that are viscous enough to resist rapid particle sedimentation while remaining injectable at a range of concentrations from 5 to 400 mg/mL. The preliminary accelerated stability test shows that MMB4 in these formulations is stable for at least 2 years at temperatures up to 80°C. Preliminary preclinical in vivo studies have demonstrated that all concentrations and particle sizes have desirable PK properties, including high bioavailability and rapid absorption, which is critical to combat potent and fast-acting nerve agents.

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Chemical Stability of the Hagedorn Oximes HGG‐12 and HI‐6

Cited by 22 publications

References 16 publications

A novel high‐performance liquid chromatography with diode array detector method for the simultaneous quantification of the enzyme‐reactivating oximes obidoxime, pralidoxime, and HI‐6 in human plasma

A novel high‐performance liquid chromatography with diode array detector method for the simultaneous quantification of the enzyme‐reactivating oximes obidoxime, pralidoxime, and HI‐6 in human plasma

Regeneration of Red Cell Cholinesterase Activity Following Pralidoxime (2-PAM) Infusion in First 24 h in Organophosphate Poisoned Patients

MMB4 DMS Nanoparticle Suspension Formulation With Enhanced Stability for the Treatment of Nerve Agent Intoxication

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