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Compared efficacy of diazepam or avizafone to prevent soman-induced electroencephalographic disturbances and neuropathology in primates: relationship to plasmatic benzodiazepine pharmacokinetics.
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- Additional Information
- Source:
Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0417615 Publication Model: Print Cited Medium: Print ISSN: 0340-5761 (Print) Linking ISSN: 03405761 NLM ISO Abbreviation: Arch Toxicol Subsets: MEDLINE
- Publication Information:
Original Publication: Berlin, New York, Springer-Verlag.
- Subject Terms:
- Abstract:
We performed an experiment to characterize the toxicity of soman in cynomolgus monkeys in which organophosphorus intoxication was followed by treatment with either the current three-drug therapy atropine/pralidoxime/diazepam or a combination of atropine/pralidoxime/avizafone, avizafone being the water soluble prodrug of diazepam. Clinical, electrophysiological, and histological approaches were combined. When benzodiazepines were injected at the similar molar dose of 0.7 micromol/kg, the protection against soman toxicity was better with the atropine/ pralidoxime/diazepam combination than with the atropine/pralidoxime/avizafone one. Pharmacokinetic studies demonstrated that this difference of efficacy could be explained by a lower plasmatic load of diazepam obtained after injection of avizafone at 0.7 micromol/kg, compared to the administration of diazepam at the same molar dose. Moreover, after injection of avizafone, plasmatic levels of diazepam were achieved faster and declined more rapidly than after administration of diazepam. Compared to diazepam given at a dose of 0.7 micromol/kg, injection of 1 micromol avizafone/kg gave a similar plasmatic load of benzodiazepine, but with a lower time to maximum plasma concentration (tmax) and a higher maximum plasma concentration (Cmax) for plasmatic diazepam. We therefore went on to demonstrate that administration of the atropine/pralidoxime/avizafone combination at a dose 1 micromol benzodiazepine/kg to intoxicated monkeys afforded electrophysiological and histological protection similar to that obtained after administration of atropine/pralidoxime/diazepam at a dose of 0.7 micromol diazepam/kg. Reflections on the possible incorporation of avizafone in three-drug emergency treatment are presented.
- Accession Number:
0 (Cholinesterase Inhibitors)
0 (Dipeptides)
0 (Pralidoxime Compounds)
65NK71K78P (pro-diazepam)
7C0697DR9I (Atropine)
96-64-0 (Soman)
P7MU9UTP52 (pralidoxime)
Q3JTX2Q7TU (Diazepam)
- Publication Date:
Date Created: 20001130 Date Completed: 20010301 Latest Revision: 20190906
- Publication Date:
20240829
- Accession Number:
10.1007/s002040000146
- Accession Number:
11097386
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