title: Photostability of antidotal oxime HI-6, impact on drug development.
abstract: HI-6 exhibits superior efficacy in the therapy of intoxication by different highly toxic organophosphorus nerve agents. Therefore HI-6 is a promising candidate for the development of new antidotes against nerve agents. For ethical and safety reasons antidotes containing HI-6 should get marketing authorization. Active pharmaceutical ingredients of medicinal products have to fulfil regulatory conditions in terms of purity and stability. Photostability is an essential parameter in this testing strategy. HI-6 was tested under conditions of ICH Q1B 'Photostability testing of new drug substances and products'. The data showed a marked degradation of HI-6 after exposure to daylight. The mechanism of degradation could be detected as photoisomerism. The light burden dependent rate of photoisomerism was followed quantitatively. Based on these quantitative results on the amount of light induced isomeric product a pharmacological qualification was made. A standardized in vitro test showed a decreased ability of light exposed HI-6 to reactivate sarin- and paraoxon-inhibited human acetylcholinesterase. These results have an impact on the further development of antidotes containing HI-6, as light protection will probably be necessary during handling, packaging, storage and application.
authors.affiliation: Central Institute of the Bundeswehr Medical Service Munich, Garching Hochbrück, Germany. ReinhardBogan@bundeswehr.org.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bogan
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Marianne
authors.initials: M
authors.lastname: Koller
authors.forename: Bernd
authors.initials: B
authors.lastname: Klaubert
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000931:Antidotes / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007536:Isomerism; D008027:Light; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology; D010261:Paraoxon / Q000633:toxicity; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D012524:Sarin / Q000633:toxicity
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride; D010261:Paraoxon