Ein neuer Esterase-Reaktivator für die Behandlung von Vergiftungen mit Alkylphosphaten

Erdmann, W. D.; Clarmann, M. v.

doi:10.1055/s-0028-1112348

Cited by 47 publications

(2 citation statements)

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“…Most of these human volunteer studies administered parenteral oxime doses recommended as initial dose for treatment of OP patients, i.e. ~ 2 g 2-PAM (Eddleston et al 2004 ; Newmark 2007 ), 250 mg obidoxime (Erdmann and Clarmann 1963 ) and 500 mg HI-6 (Kusic et al 1991 ). Calesnick et al injected up to 45 mg/kg 2-PAM chloride i.m.…”

Section: The Oxime Conceptmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

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Section: The Oxime Conceptmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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“…This bispyridinium derivative was superior to 2-PAM, particularly in tabun poisoning. Obidoxime ( 3 ) was synthesized by Luttringhaus and Hagedorn in the early 1960s8 and studied in pesticide-poisoned patients by Erdmann and von Clarmann 9. In the following decades, Hagedorn and coworkers synthesized numerous oximes in order to increase the efficacy against soman, resulting in the development of HI-6 ( 4 ) 10–12.…”

Section: Introductionmentioning

confidence: 99%

Bisquaternary pyridinium oximes: Comparison of in vitro reactivation potency of compounds bearing aliphatic linkers and heteroaromatic linkers for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase

Bharate¹,

Guo²,

Reeves³

et al. 2010

Bioorganic & Medicinal Chemistry

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Oxime reactivators are the drugs of choice for the post-treatment of OP (organophosphorus) intoxication and used widely for mechanistic and kinetic studies of OP-inhibited cholinesterases. The purpose of the present study was to evaluate new oxime compounds to reactivate acetylcholinesterase (AChE) inhibited by the OP paraoxon. Several new bisquaternary pyridinium oximes with heterocyclic linkers along with some known bisquaternary pyridinium oximes bearing aliphatic linkers were synthesized and evaluated for their in vitro reactivation potency against paraoxon-inhibited electric eel acetylcholinesterase (EeAChE) and recombinant human acetylcholinesterase (rHuAChE). Results herein indicate that most of the compounds are better reactivators of EeAChE than of rHuAChE. The reactivation potency of two different classes of compounds with varying linker chains was compared and observed that the structure of the connecting chain is an important factor for the activity of the reactivators. At a higher concentration (10 −3 M), compounds bearing aliphatic linker showed better reactivation than compounds with heterocyclic linkers. Interestingly, oximes with a heterocyclic linker inhibited AChE at higher concentration (10 −3 M), whereas their ability to reactivate was increased at lower concentrations (10 −4 M and 10 −5 M). Compounds bearing either a thiophene linker 26, 46 or a furan linker 31 showed 59%, 49% and 52% reactivation of EeAChE, respectively, at 10 −5 M. These compounds showed 14%, 6% and 15% reactivation of rHuAChE at 10 −4 M. Amongst newly synthesized analogs with heterocyclic linkers (26-35 and 45-46), compound 31, bearing furan linker chain, was found to be the most effective reactivator with a k r 0.042 min −1 , which is better than obidoxime (3) for paraoxoninhibited EeAChE. Compound 31 showed a k r 0.0041 min −1 that is near equal to pralidoxime (1) for paraoxon-inhibited rHuAChE.

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Acetylcholin-Esterase

Engelhard¹,

Nenner²,

Prchal³

1967

Angew. Chem.

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Abhangigkeit von deren Zusammensetzung studieren. Auch heterogene Reaktionen in elektrochemischen ZeIlen lassen sich so gut verfolgen. Fragen zur Elektronen-und Raumstruktur gasformiger Molekule konnen rnit der Massenspektrometrie nicht unmittelbar angegangen werden. Allerdings hat die Massenspektrometrie zur Identifizierung von Partikeln bei Molekularstrahlexperimenten im magnetischen oder elektrischen Feld schon vie1 beigetragen [1471. Vielversprechend sind Kombinationen optischer mit massenspektrometrischen Untersuchungen unter Einbeziehnng von Mikrowellen-und Matrix-Techniken [1481, desgleichen Kombinationen mit

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Ein neuer Esterase-Reaktivator für die Behandlung von Vergiftungen mit Alkylphosphaten

Cited by 47 publications

References 0 publications

Organophosphorus compounds and oximes: a critical review

Organophosphorus compounds and oximes: a critical review

Bisquaternary pyridinium oximes: Comparison of in vitro reactivation potency of compounds bearing aliphatic linkers and heteroaromatic linkers for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase

Acetylcholin-Esterase

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