Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016)

ABSTRACT

Introduction: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function.

Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication.

Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.

KEYWORDS:

• Acetylcholinesterase
• reactivators
• organophosphate
• nerve agents
• catalytic bioscavengers
• methods of detection
• identification

Article highlights

• This review article analyzes patent inventions in the treatment of OP exposure for the recent ten years (2006 – 2016).

• Nowadays pyridinium oxime reactivators are the only used causal antidotes for OP intoxication, even though they fail in several cases.

• Novel strategies are discussed herein in an effort to surpass the limitation of standard oximes.

• AChE reactivators, AChE inhibitors, aged-AChE reactivators, catalytic scavengers and methods of detection are all disclosed.

• In the end we pointed out major concerns associated with introduction of AChE reactivators into the clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The work was supported by the Long-term Development Plan of the Faculty of Medicine, University of Ostrava, by the University of Defence (SV/FVZ201601), by the Grant 17-32801A and the University of Hradec Kralove (Faculty of Science, No. SV2110/2016).