From molecular structure to Alzheimer therapy.
Clinical trials in the USA, Japan and Europe have confirmed the hypothesis that a steady state increase of acetylcholine resulting from cholinesterase inhibition in the brain results in an improvement of cognitive function in mild to moderate Alzheimer disease (AD) patients. During the last decade, a systematic effort to develop a pharmacological treatment for AD has resulted in two drugs being registered for the first time in the USA and Europe for this specific indication. Both are cholinesterase inhibitors (ChEI). Based on these first positive results, several second generation ChEI are being developed. An additional effect of certain ChEI is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. It is possible that the drug effect is one of slowing down cognitive deterioration. Comparison of clinical effects of 5 ChEI demonstrates a rather similar magnitude of improvement. For some drugs, this may represent a limit, while for others it may be possible to increase the benefit further. To maximize and prolong positive drug effects, it is important to start early and adjust the dosage during the treatment. Other strategies may involve combinations with other cholinergic drugs such as muscarinic or nicotinic agonists. A second important class of drugs which is being developed is that of muscarinic m1 agonists. However, their clinical use is still limited by side effects. The increased knowledge and recognition of the beta-amyloid molecule as a central focus of AD pathology has strongly stimulated research with the hope of finding ways of influencing its processing and deposition. At this point, no product in this line of development has reached clinical trial level. Other pharmacological approaches are related to preventive and neuroprotective interventions (estrogens, anti-oxidants and anti-inflammatories). In conclusion, given the relatively short time of research in this field, results are encouraging.
Giacobini
E
E
Department of Geriatrics, University Hospitals of Geneva, University of Geneva, Medical School, Switzerland.
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy
D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D002091:Butyrylcholinesterase