INTRODUCTION: Alzheimer's disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD. AREAS COVERED: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options. EXPERT OPINION: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.
- MeSH
- Alzheimerova nemoc farmakoterapie epidemiologie patofyziologie MeSH
- antagonisté excitačních aminokyselin škodlivé účinky farmakologie terapeutické užití MeSH
- cholinesterasové inhibitory škodlivé účinky farmakologie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- memantin škodlivé účinky farmakologie terapeutické užití MeSH
- progrese nemoci MeSH
- racionální návrh léčiv MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.
- MeSH
- acetylcholin metabolismus MeSH
- acetylcholinesterasa metabolismus MeSH
- adsorpce MeSH
- centrální nervový systém účinky léků MeSH
- katalytická doména MeSH
- krysa rodu rattus MeSH
- nervosvalové spojení účinky léků metabolismus MeSH
- organofosfáty chemie metabolismus MeSH
- potkani Wistar MeSH
- reaktivátory cholinesterasy * krev metabolismus farmakokinetika MeSH
- sérový albumin metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
