Determination of 2-hydroxyiminomethyl-1-methyl-pyridinium methanesulphonate (pralidoxime mesylate, P2S) and its degradation products in solution by liquid chromatography

Utley, D.

doi:10.1016/s0021-9673(01)96726-3

Cited by 16 publications

(11 citation statements)

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“…The Z form of 2-PAM can be prepared by ultraviolet (UV) irradiation of the E form [9]. Under physiological conditions, 2-PAM is observed in the protonated and unprotonated forms, the latter being considered the biologically active form [10]. However, there is recent evidence to support the protonated form as the active one [11].…”

Section: Introductionmentioning

confidence: 99%

DFT conformational studies of the HI‐6 molecule

Silva

Borges

Figueroa‐Villar

2005

Int J of Quantum Chemistry

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ABSTRACT:A systematic study of the oxime HI-6 [1-(2-hydroxyiminomethyl-1-pyridinium)-1-(4-carboxy-aminopyridinium)dimethyl ether] hydrochloride, which is one of the most promising antidotes against soman intoxication, was carried out using density functional theory with the B3LYP (Becke, Lee, Yang, and Parr) method and the 6-31ϩG*, 6-31ϩG*, and 6-31ϩG** basis sets. Rotational barriers, equilibrium geometries, and charge distributions were calculated in order to investigate the role of the side chain for the larger oximes used as antidotes in the treatment of neurotoxic organophosphate poisoning. Also reported is the comparison between HI-6 and pralidoxime (2-PAM), a smaller oxime previously studied in our research group. It is shown that conformation minima for the protonated E isomer do not depend on the size of the side chain; on the other hand, this effect has a pronounced influence on the protonated Z isomer. For the unprotonated isomers, other effects, such as electrostatic interactions and resonance, should be taken into account in their conformational analysis.

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Section: Introductionmentioning

confidence: 99%

DFT conformational studies of the HI‐6 molecule

Silva

Borges

Figueroa‐Villar

2005

Int J of Quantum Chemistry

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“…1), first synthesized in 1955 [6]. X-ray [7,8] and nuclear magnetic resonance (NMR) [9] studies have shown that 2-PAM exists in the E form (the hydroxyl group and the pyridinium ring are in opposite sides of the CAN bond), but the Z form has been prepared by UV irradiation of the E form [9] and shown to be involved in its decomposition process [10]. The pKa of the oxime group hydrogen is 7.68 [11] and in physiological conditions the oxime will exist in both the protonated and unprotonated forms.…”

Section: Introductionmentioning

confidence: 99%

Molecular structure, conformational analysis and charge distribution of pralidoxime: Ab initio and DFT studies

Castro¹,

Figueroa‐Villar²

2002

Int J of Quantum Chemistry

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ABSTRACT:A detailed structural study of pralidoxime (2-PAM), the main antidote against organophosphate intoxication, was performed using Hartree-Fock, Möller-Plesset (MP2), and density functional theory (Becke, Lee, Yang, and Paar [B3LYP]) methods. Rotational barriers, equilibrium geometries, and charge distributions were calculated, showing important differences between the two forms available in physiological conditions, namely with the oxime group protonated or unprotonated. For the protonated form, conjugation between the side chain and the pyridinium ring, although present, has little importance, resulting in a flexible structure. On the other hand, the unprotonated form has a more rigid structure and a smaller charge density on the oxime oxygen. Contrary to the common belief, those results strongly suggest that it may be the protonated form of 2-PAM, instead of the unprotonated form, that is responsible for the antidote activity of this compound.

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“…This maximum is shifted to 336 nm (bathochromic shift) after dissociation of the oximino group (deprotonation) thus generating a zwitterionic betaine structure with a modified Π‐electron system resulting in yellow coloured solutions (ε 336 in 0.1 M NaOH 1.84*10 4 M −1 cm −1 ) (Figure , structures highlighted in blue). The pK a of this group was found to be 7.94 for the syn‐isomer and 8.7 for the anti‐isomer . Therefore, at pH > 8.0 2‐PAM is predominantly present as a zwitterion (Figure , III ) and the chargeless nitroso resonance form (Figure , IV ).…”

Section: Introductionmentioning

confidence: 95%

“…The decomposition rate of 2‐PAM increases with higher pH and elevated oxime concentrations (1–50% w/v ) . In citrate injection solutions, maximum stability was found at pH 3.2 and several products were found especially after exposure to thermal stress (80 °C) . As depicted in Figure , the proposed consecutive decomposition reaction of 2‐PAM (Figure , I ) is an initial OH ‐ ‐catalyzed dehydration to 2‐cyano‐N‐methyl‐pyridinium (Figure , VIII ), which is subsequently hydrolyzed to either N‐methyl‐2‐pyridone (Figure , XIII ) and CN ‐ or to 2‐carbamoyl‐N‐methyl‐pyridinium (Figure , IX ).…”

Section: Introductionmentioning

confidence: 98%

“…With respect to the geometry of the N‐substitution of the oxime‐group, 2‐PAM is found exclusively as its syn‐isomer in fresh preparations (Figure , I ) whereas its anti‐form (Figure , II ) is merely produced under UV irradiation and thermal stress . Therefore, we refer to the syn‐isomer when using the abbreviation 2‐PAM if not stated otherwise.…”

Section: Introductionmentioning

confidence: 99%

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Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

John¹,

Blum

2011

Drug Testing and Analysis

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Pralidoxime (2-PAM) belongs to the class of monopyridinium oximes with reactivating potency on cholinesterases inhibited by phosphylating organophosphorus compounds (OPC), for example, pesticides and nerve agents. 2-PAM represents an established antidote for the therapy of anticholinesterase poisoning since the late 1950s. Quite high therapeutic concentrations in human plasma (about 13 µg/ml) lead to concentrations in urine being about 100 times higher allowing the use of less sensitive analytical techniques that were used especially in the early years after 2-PAM was introduced. In this time (mid-1950s until the end of the 1970s) 2-PAM was most often analyzed by either paper chromatography or simple UV spectroscopic techniques omitting any sample separation step. These methods were displaced completely after the establishment of column liquid chromatography in the early 1980s. Since then, diverse techniques including cation exchange, size-exclusion, reversed-phase, and ligand-exchange chromatography have been introduced. Today, the most popular method for 2-PAM quantification is ion pair chromatography often combined with UV detection representing more than 50% of all column chromatographic procedures published. Furthermore, electrophoretic approaches by paper and capillary zone electrophoresis have been successfully used but are seldom applied. This review provides a commentary and exhaustive summary of analytical techniques applied to detect 2-PAM in pharmaceutical formulations and biological samples to characterize stability and pharmacokinetics as well as decomposition and biotransformation products. Separation techniques as well as diverse detectors are discussed in appropriate detail allowing comparison of individual preferences and limitations. In addition, novel data on mass spectrometric fragmentation of 2-PAM are provided.

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Determination of 2-hydroxyiminomethyl-1-methyl-pyridinium methanesulphonate (pralidoxime mesylate, P2S) and its degradation products in solution by liquid chromatography

Cited by 16 publications

References 11 publications

DFT conformational studies of the HI‐6 molecule

DFT conformational studies of the HI‐6 molecule

Molecular structure, conformational analysis and charge distribution of pralidoxime: Ab initio and DFT studies

Review of UV spectroscopic, chromatographic, and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2‐PAM)

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