Currently according to Mielke and colleagues drugs with US F
Currently, according to Mielke and colleagues , drugs with US Food and Drug Administration (FDA) approval for Alzheimer therapy include the following: galantamine (Razadyn®, 4aS,6R,8aS-5,6,9,10,11,12- hexahydro- 3-methoxy- 11-methyl- 4aH , benzofuro[3a,3,2-ef]  benzazepin- 6-ol), rivastigmine (Exelon®, [3-[(1S)-1-(dimethylamino)ethyl]phenyl] N-ethyl-N-methylcarbamate) and donepezil (Aricept®, 2-((1-Benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one). In 1993, the cholinesterase inhibitor tacrine (Cognex®, 1,2,3,4-tetrahydroacridin-9-amine) was the first drug with FDA approval to treat Alzheimer’s disease, but its use was limited by short half-life (requiring 4× daily dosing) and evidence of hepatotoxicity. A recent meta-analysis of the efficacy of cholinesterase inhibitors in Alzheimer’s disease reported that donepezil, rivastigmine and galantamine all produced relatively minimal but significant benefits including enhanced cognition and improved behavioral outcomes . Donepezil and galantamine are selective for CNS ChEs, but all three can elicit nausea, diarrhea and other unwanted effects , , , , . Unfortunately, they have little if any impact on disease progression. Interestingly, Tricco and coworkers  reported that galantamine was associated with a decreased odds ratio for death, while pharmacovigilance databases in both the US and Canada detected an increased odds ratio for death with rivastigmine . Thus, while current cholinesterase inhibitors do have minor therapeutic benefits, the search continues for more effective or multi-purpose inhibitors acting on ChEs and other macromolecular targets , , .
Toxicological uses of cholinesterase inhibitors While ChE inhibitors can and have been used to treat a variety of illnesses, the other side of therapy is toxicity. A remarkable number of microorganisms, plants, fungi and animals have developed anti-ChEs , , . As the ChEs are widespread across the animal kingdom and play an important role in neuronal signaling in all higher species of animals, widespread hyPerFUsion™ high-fidelity DNA polymerase of ChE inhibitors by these many organisms has likely evolved as a defense against predation. The toxic potential of ChE inhibitors has been recognized for over 170 years. Robert Christison, a leading toxicologist of the time reported the first results of toxicological testing of the “trial by ordeal” bean . Indigenous people in the Calabar region of West Africa were known to use an “ordeal poison” to determine whether a person was innocent or guilty of a crime, usually “witchcraft.” As we noted earlier herein, extracts of the calabar bean (Physostigma venenosum) contain eserine (physostigmine), subsequently found to be a potent inhibitor of ChEs. The deadly potency of the extract was noted by European missionaries as early as 1840. It has been speculated that this toxicant actually had inherent properties that led to its effective “judicial” use (see review ). Since discovery of eserine’s toxicity, carbamate structure and anti-ChE action, many other carbamate ChE have been synthesized and characterized . A substantial number were introduced as pesticides in the 1960s and some of these continue extensive use throughout the world . Before widespread introduction of the carbamates, starting in the 1940s, many organophosphorus ChE inhibitors were developed as insecticides . Carbamate and organophosphorus ChE inhibitors both covalently modify the active site serine residue in AChE and BChE, thereby inhibiting all choline ester hydrolysis. Cleavage of carbamoyl moieties by an esterase, while far slower than hydrolysis of the acyl group in a choline ester, is still rapid compared to the painfully prolonged reactivation of esterase inhibited by an organophosphorus agent . Organophosphorus cholinesterase inhibitors did not emerge from a natural source: unlike the carbamates, they are all synthetic entities. Tetraethylpyrophosphate was the first organophosphorus inhibitor, synthesized and reported in the 1850s. Further development and characterization of organophosphorus anti-ChEs were not initiated until the mid-1930s in pre-WWII Germany, under the direction of Dr. Gerhard Schrader . Schrader was searching for synthetic insecticides to address the high cost and low availability of common natural insecticides in use at that time. Tabun (N-dimethyl phosphoramidocyanidate), one of Schrader’s most potent inhibitors, subsequently came under German military control to use as a chemical warfare agent . Other organophosphorus compounds to come from that laboratory included parathion (O,O’-diethyl-O-p-nitrophenyl phosphorothioate) and its oxygen analog (O,O’-diethyl-O-p-nitrophenyl phosphate), paraoxon . Since that time, many organophosphorus anti-ChEs have been synthesized. Most were developed for commercial use as pesticides and, in some cases, as drugs in veterinary and human therapeutics (e.g., diisopropylfluorophosphate for glaucoma, trichlorfon as an anthelminth).