Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
31794810
DOI
10.1016/j.toxlet.2019.11.021
PII: S0378-4274(19)30378-9
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, CB[7], CNS targeting, Mouse, Oxime K027, Sarin, cucurbit[7]uril,
- MeSH
- Acetylcholinesterase blood metabolism MeSH
- A549 Cells MeSH
- Hep G2 Cells MeSH
- Erythrocytes drug effects enzymology MeSH
- GPI-Linked Proteins blood metabolism MeSH
- Risk Assessment MeSH
- Imidazoles administration & dosage pharmacokinetics toxicity MeSH
- Injections, Intramuscular MeSH
- Humans MeSH
- Maximum Tolerated Dose MeSH
- Brain drug effects enzymology MeSH
- Mice, Inbred ICR MeSH
- Oximes administration & dosage pharmacokinetics toxicity MeSH
- Bridged-Ring Compounds administration & dosage pharmacokinetics toxicity MeSH
- Pyridinium Compounds administration & dosage pharmacokinetics toxicity MeSH
- Cholinesterase Reactivators administration & dosage pharmacokinetics toxicity MeSH
- Tissue Distribution MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
- Acetylcholinesterase MeSH
- ACHE protein, human MeSH Browser
- Ache protein, mouse MeSH Browser
- cucurbit(7)uril MeSH Browser
- GPI-Linked Proteins MeSH
- Imidazoles MeSH
- Oximes MeSH
- Bridged-Ring Compounds MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
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.
References provided by Crossref.org
Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents
Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
