Development and validation of a sensitive HPLC method for the quantification of HI-6 in guinea pig plasma and evaluated in domestic swine

Bohnert, Sara; Vair, Cory; Mikler, John

doi:10.1016/j.jchromb.2010.03.018

Cited by 10 publications

(9 citation statements)

References 18 publications

(36 reference statements)

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“…[25,39,40] However, when compared to adult humans, swine are characterized by higher plasma volumes, arterial pH, and extracellular space and lower renal blood flow and glomerular filtration rate. [40] To characterize studies using atropine in the treatment of OP poisoning [24,41,42] we determined hyoscyamine enantiomers in the domestic swine model. [40] To characterize studies using atropine in the treatment of OP poisoning [24,41,42] we determined hyoscyamine enantiomers in the domestic swine model.…”

Section: Discussionmentioning

confidence: 99%

“…[40] Different rates of metabolism in the liver determined by different liver blood flows are probably the most important reason for inter-species variance. [40] To characterize studies using atropine in the treatment of OP poisoning [24,41,42] we determined hyoscyamine enantiomers in the domestic swine model.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we introduced a novel, precise, and accurate enzymatic enantioselective HPLC-MS/MS procedure for sensitive quantification of both hyo variants in plasma, which allows for the stereoselective analysis of concentration-time profiles in in vivo studies. [6,[23][24][25] Therefore this study has applied the recently published enantioselective HPLC-MS/MS procedure to monitor hyoscamine concentrations in swine plasma after i.v. [6,[23][24][25] Therefore this study has applied the recently published enantioselective HPLC-MS/MS procedure to monitor hyoscamine concentrations in swine plasma after i.v.…”

Section: Introductionmentioning

confidence: 99%

“…[21] Since several current concepts on the optimal therapy of organophosphorus (OP) poisoning, in which atropine is administered as the symptomatic antidote, make use of swine, it is important to characterize atropine behaviour in this model. [6,[23][24][25] Therefore this study has applied the recently published enantioselective HPLC-MS/MS procedure to monitor hyoscamine concentrations in swine plasma after i.v. administration of atropine sulfate.…”

Section: Introductionmentioning

confidence: 99%

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Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

John¹,

Mikler

Worek³

et al. 2011

Drug Testing and Analysis

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S-hyoscyamine (S-hyo) is a natural plant tropane alkaloid acting as a muscarinic receptor (MR) antagonist. Its racemic mixture (atropine) is clinically used in pre-anaesthesia, ophthalmology and for the antidotal treatment of organophosphorus (OP) poisoning with nerve agents or pesticides even though R-hyo exhibits no effects on MR. Further investigative research is required to optimize treatment of OP poisoning. Swine are often the animal model utilized due to similarities in physiology and antidote response to humans. However, no studies have been reported that elucidated differences in the kinetics of R- and S-hyo. Therefore, the concentration-time profiles of total hyo as well as both enantiomers were analyzed in plasma after intravenous administration of atropine sulfate (Atr(2) SO(4) , 100 µg/kg) to anaesthetized swine. For quantification plasma samples were incubated separately with human serum (procedure A) and rabbit serum (procedure B). The rabbit serum used contained atropinesterase, which is suitable for stereoselective hydrolysis of S-hyo, while human serum does not hydrolyze either enantiomer. After incubation samples were precipitated and the supernatant was analyzed by RP-HPLC-ESI MS/MS. Procedure A allowed determination of total hyo and procedure B remaining R-hyo concentrations. S-hyo was calculated as the difference of the two procedures. Concentration data were regressed by a two-phase decay according to a two-compartment open model revealing similar kinetics for both enantiomers thus indicating distribution, metabolism and elimination without obvious stereoselective preference in tested swine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

John¹,

Mikler

Worek³

et al. 2011

Drug Testing and Analysis

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“…Similar U or V shaped retention profiles have been observed under the zwitterionic HILIC separation mechanism [21]. The assay of oximes in biological matrices is often based on the RP separation mechanism [13,14,16,22,23]. Gradient elution based on the combination between aqueous volatile buffer solutions (i.e., ammonium formate and acetate) and organic modifiers (acetonitrile, methanol or their mixtures) is more often preferred.…”

mentioning

confidence: 83%

LC–MS/MS Approaches for The Assay of Bis -Quaternary Pyridinium Oximes Used as Ache Reactivators in Biological Matrices

Voicu

Albu²,

Tache

et al. 2013

Bioanalysis

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Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

Becker¹,

Worek²,

John³

2010

Drug Testing and Analysis

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Poisoning with organophosphorus compounds (OP), e.g. pesticides and nerve agents, causes inhibition of acetylcholinesterase (AChE) by phosphylation of the active site serine residue. Consequently, accumulation of stimulating acetylcholine in the synaptic cleft induces cholinergic crisis which ultimately may lead to death. For standard causal therapy, enzyme reactivators are administered representing oxime derivatives of quarternary pyridinium compounds, e.g. pralidoxime (2-PAM), obidoxime and HI 6. The mechanism of action includes removal of the phosphyl moiety by a nucleophilic attack of the oximate molecule substituting the enzyme and forming a phosphylated oxime (POX). POX is produced in stoichiometric amounts of reactivated enzyme and exhibits a significantly enhanced toxicity (inhibition rate constant) when compared to the parent OP. However, stability of POX under physiological conditions appears to be highly limited. Nevertheless, the presence of POX reveals a potential critical issue for both therapeutic efficacy in vivo and pharmacokinetic and pharmacodynamic (PK-PD) modelling based on cholinesterase activity data. Detailed characterization represents an important need for elaboration of the entire oxime pharmacology.Nevertheless, reports on POX toxicity and analysis are quite rare and may therefore be indicative of the challenge of POX analysis. This review provides a concise overview of chromatographic approaches applied to POX separation. Chromatography represents the key technology for POX purification and quantification in kinetic in vitro studies using buffers and biological fluids. Applications based on reversed-phase chromatography (RPC), ion pair chromatography (IPC) and an affinity approach as well as thin layer chromatography (TLC) are discussed and novel applications and data are presented.

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Development and validation of a sensitive HPLC method for the quantification of HI-6 in guinea pig plasma and evaluated in domestic swine

Cited by 10 publications

References 18 publications

Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

Application of an enantioselective LC‐ESI MS/MS procedure to determine R‐ and S‐hyoscyamine following intravenous atropine administration in swine

LC–MS/MS Approaches for The Assay of Bis -Quaternary Pyridinium Oximes Used as Ache Reactivators in Biological Matrices

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

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