title: Single treatment of VX poisoned guinea pigs with the phosphotriesterase mutant C23AL: Intraosseous versus intravenous injection.
abstract: The recent attacks with the nerve agent sarin in Syria reveal the necessity of effective countermeasures against highly toxic organophosphorus compounds. Multiple studies provide evidence that a rapid onset of antidotal therapy might be life-saving but current standard antidotal protocols comprising reactivators and competitive muscarinic antagonists show a limited efficacy for several nerve agents. We here set out to test the newly developed phosphotriesterase (PTE) mutant C23AL by intravenous (i.v.), intramuscular (i.m.; model for autoinjector) and intraosseous (i.o.; model for intraosseous insertion device) application in an in vivo guinea pig model after VX challenge (∼2LD50). C23AL showed a Cmax of 0.63μmolL(-1) after i.o. and i.v. administration of 2mgkg(-1) providing a stable plasma profile up to 180min experimental duration with 0.41 and 0.37μmolL(-1) respectively. The i.m. application of C23AL did not result in detectable plasma levels. All animals challenged with VX and subsequent i.o. or i.v. C23AL therapy survived although an in part substantial inhibition of erythrocyte, brain and diaphragm AChE was detected. Theoretical calculation of the time required to hydrolyze in vivo 96.75% of the toxic VX enantiomer is consistent with previous studies wherein similar activity of plasma containing catalytic scavengers of OPs resulted in non-lethal protection although accompanied with a variable severity of cholinergic symptoms. The relatively low C23AL plasma level observed immediately after its i.v. or i.o load, point at a possible volume of distribution greater than the guinea pig plasma content, and thus underlines the necessity of in vivo experiments in antidote research. In conclusion the i.o. application of PTE is efficient and resulted in comparable plasma levels to the i.v. application at a given time. Thus, i.o. vascular access systems could improve the post-exposure PTE therapy of nerve agent poisoning.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. Electronic address: timowille@bundeswehr.org.
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Neumaier
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Koller
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ehinger
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Aggarwal
authors.affiliation: Department of Biomolecular Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ashani
authors.affiliation: Department of Biomolecular Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Goldsmith
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
authors.affiliation: Department of Biomolecular Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Tawfik
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000931:Antidotes / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow; D006168:Guinea Pigs; D008658:Inactivation, Metabolic; D015552:Injections, Intralesional; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009154:Mutation; D000067397:Nerve Agents / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D062025:Organophosphate Poisoning / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D044345:Phosphoric Triester Hydrolases / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D059748:Proteolysis; D011549:Pseudomonas / Q000201:enzymology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D066007:Toxicokinetics
chemical_list: D000931:Antidotes; D001426:Bacterial Proteins; D000067397:Nerve Agents; D009946:Organothiophosphorus Compounds; D010446:Peptide Fragments; D044345:Phosphoric Triester Hydrolases; D011994:Recombinant Proteins; C009680:VX-agent
keywords: Bioscavenger; Catalytic; In vivo; Intraosseous; Nerve agents; Phosphotriesterase; Therapy; VX