Abstract:
:Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Zdarova Karasova J,Hepnarova V,Andrys R,Lisa M,Jost P,Muckova L,Pejchal J,Herman D,Jun D,Kassa J,Kuca Kdoi
10.1016/j.toxlet.2019.11.021subject
Has Abstractpub_date
2020-03-01 00:00:00pages
64-72eissn
0378-4274issn
1879-3169pii
S0378-4274(19)30378-9journal_volume
320pub_type
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