Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.
Bridged-Ring Compounds/chemistry , Cholinesterase Reactivators/administration & dosage , Drug Carriers/chemistry , Imidazoles/chemistry , Organophosphate Poisoning/drug therapy , Oximes/pharmacokinetics , Pyridinium Compounds/pharmacokinetics , Acetylcholinesterase/metabolism , Animals , Area Under Curve , Blood-Brain Barrier/metabolism , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/toxicity , Cholinesterase Reactivators/pharmacokinetics , Chromatography, High Pressure Liquid , Disease Models, Animal , Enzyme Assays , Humans , Hydrophobic and Hydrophilic Interactions , Mass Spectrometry , Mice , Oximes/administration & dosage , Pyridinium Compounds/administration & dosage , Sarin/administration & dosage , Sarin/toxicity
The neuroprotective effects of newly developed oximes (K156, K203) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery 24 hours after cyclosarin challenge. The results indicate that a newly developed oxime K156 is able to counteract slightly cyclosarin-induced neurotoxicity while another newly developed oxime K203 is completely ineffective in reducing cyclosarin-induced neurotoxic signs and symptoms. The neuroprotective efficacy of K156 is comparable with commonly used obidoxime and oxime HI-6. Thus, none of the newly developed oximes achieves better neuroprotective efficacy than both commonly used oximes. They are therefore not suitable replacements for antidotal treatment of acute poisonings with cyclosarin.
Chemical Warfare Agents/toxicity , Neurotoxicity Syndromes/prevention & control , Organophosphorus Compounds/toxicity , Oximes/therapeutic use , Animals , Male , Oximes/chemistry , Rats , Rats, Wistar
