Approaches to the treatment of nerve agent poisoning with oximes - from experimental studies to the intensive care unit.

Abstract

Introduction: Organophosphorus poisoning is still a continuing threat to military forces and the civilian health sector. The therapeutic value of clinically used oxime antidotes is frequently a matter of controversy. In this narrative review, we will focus on nerve agent poisoning in particular and show how experimental results can be integrated into the therapy of patients.

Methods: This narrative review is based primarily on the extensive studies conducted by the authors over many years, supplemented by appropriate literature to provide the reader with currently available knowledge of the effects of different organophosphorus compounds on the inhibition kinetics, the post-inhibitory reactions and oxime-induced reactivation. The importance of species differences for the translation of animal experiments to humans is discussed by means of suitable published studies. The literature that describes tools that enable the monitoring of organophosphorus compound poisoning or the detection of skin exposure to organophosphorus compounds is reviewed.

Organophosphorus compounds: structure and characteristics: Organophosphorus compounds, including nerve agents and pesticides, have a common general formula. In consequence, the variations in the structure and the physicochemical properties result in differences in the intrinsic toxicity of organophosphorus compounds as well as the onset, severity, and duration of clinical symptoms.

Mechanisms of organophosphorus poisoning: The most toxicologically relevant mechanism of organophosphorus compounds is the inhibition of acetylcholinesterase, resulting in the overstimulation of cholinergic synapses in the neuromuscular junction as well as the central and the autonomic nervous system.

Signs and symptoms of organophosphorus poisoning: After exposure by inhalation to nerve agent vapour, symptoms may develop very fast, and death can occur within minutes. The paralysis of respiratory muscles and the medullary respiratory centre, as well as bronchoconstriction and bronchorrhoea, may lead to death rapidly. In contrast, the onset of clinical signs may be delayed after percutaneous exposure.

Treatment of organophosphorus poisoning: Current medical therapy includes atropine, oximes, and benzodiazepines. Oximes act by the reactivation of organophosphorus-inhibited acetylcholinesterase.

Test systems for the investigation of interactions between organophosphorus compounds and acetylcholinesterase: Based on the spectrophotometric Ellman assay, static in vitro test systems for the determination of the inhibitory potency of an organophosphorus compound, post-inhibitory reactions, and oxime-induced reactivation have been developed, and their value is assessed. In addition, several dynamic models (real-time determination of acetylcholinesterase activity, kinetic computer modeling, and modeling for the determination of muscle force) are reviewed.

Innovative: in vitro experimental approaches and promising therapeutic strategies: Studies assessing the potency of positive allosteric modulators to reduce or reverse the desensitization of the nicotinic acetylcholine receptor are reviewed.

Test systems for the laboratory diagnosis of organophosphorus exposure and the therapeutic monitoring of patients poisoned with organophosphorus compounds: A tool to detect toxic inhibitors of acetylcholinesterase on the skin, cholinesterase status as well as the determination of neuromuscular transmission in organophosphorus poisoning are described.

The integration of test systems into the management of cases of organophosphorus poisoning: A clinical study is used to demonstrate the connection between neuromuscular transmission and acetylcholinesterase activity. Case reports of single patients with parathion poisoning are presented, showing the integration of the dynamic computer model and the cholinesterase status into clinical treatment.

Conclusions: The success of oxime therapy depends on various parameters, such as the physicochemical and toxicokinetic properties of organophosphorus compounds, the route of exposure, the dose, skin decontamination, administration of other antidotes, and emergency treatment, including mechanical ventilation. Various test systems at the enzyme level and experiments with complex human and animal tissues are available to obtain a broader knowledge of the effectiveness of oximes and a comprehensive understanding of events occurring during poisoning and oxime therapy.