Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.

Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

New therapeutic approaches and novel alternatives for organophosphate toxicity.

Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.

Over-the-counter medicine use prior to and during hospitalization.

BACKGROUND: In the UK, medicines are being reclassified from prescription-only drugs to allow supply without prescription. This allows faster and easier access to medicines to treat minor ailments and allows patients to take greater responsibility for their health. However, over-the-counter (OTC) drugs may pose risks to patients; thus, it is important to understand patients' OTC medicine use. OBJECTIVE: To assess use of OTC drugs prior to and during hospital stay of inpatients of all ages and specialties. METHODS: Data were collected for 186 randomly selected patients. Patients were interviewed about OTC medicine use. Clinical notes and drug charts were examined for documentation of OTC medicine use. RESULTS: A total of 268 OTC medicines were used by 119 (64.0%) patients, and 117 (43.7%) were taken at least daily. Only 13 (4.9%) OTC drugs were recorded in the drug history taken at admission. Twenty-six (9.7%) OTC agents were still taken during hospitalization, but only 8 (31%) were recorded on drug charts. Patients bought 183 (68.3%) items from pharmacies, 28 (10.4%) in health food shops, and 57 (21.7%) elsewhere including supermarkets, homeopaths, or mail order. Patients had little knowledge of potential adverse effects or contraindications. CONCLUSIONS: Many patients use OTC medication prior to and during hospital stay, but documentation in hospital notes is poor. Healthcare professionals must pay closer attention to patients' use of OTC drugs.