Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.
- MeSH
- acetylcholinesterasa chemie MeSH
- antidota * farmakologie terapeutické užití chemie MeSH
- cholinesterasové inhibitory toxicita MeSH
- organofosforové sloučeniny MeSH
- oximy terapeutické užití toxicita MeSH
- reaktivátory cholinesterázy * terapeutické užití toxicita MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia. Clinical progress in this pathogenesis field has drawn the attention of researchers, stimulating the investigation of novel treatment methods. Current therapies that deal with cholinesterase inhibitors and/or NMDA antagonists have shown a modest symptomatic potential, increasing the need for research into more efficient therapeutics. The goal of this review is to summarize the advances in, and the potential of, non-conventional therapies in AD treatment. Areas covered: In this review, the authors describe the current status of unusual therapies in AD treatment, evaluating the modern scientific contexts in which these therapies have been developed. The authors also highlight the usage of methylene blue, natural products, organophosphorus compounds, and Chinese medicine, along with the employment of nanotechnology. Expert opinion: The potential therapies discussed in this review will play increasingly important roles in the prevention and treatment of AD, improving disease management and quality of life for AD patients. Given the annual increasing number of people with dementia, it is crucial to invest in the search for novel therapeutics. In addition, more sophisticated diagnosis techniques are also essential, to allow for an early diagnosis and treatment.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- inhibitory enzymů terapeutické užití MeSH
- lidé MeSH
- methylenová modř terapeutické užití MeSH
- nanotechnologie * MeSH
- organofosforové sloučeniny terapeutické užití MeSH
- tradiční čínská medicína * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients' quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.
- MeSH
- amyloid chemie metabolismus MeSH
- amyloidní beta-protein chemie metabolismus MeSH
- chelátory chemie farmakologie terapeutické užití MeSH
- kovy chemie metabolismus MeSH
- lidé MeSH
- neurodegenerativní nemoci farmakoterapie etiologie metabolismus patologie MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vyvíjení léků * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.
INTRODUCTION: Alzheimer's disease is known to be a chronic disease, with an estimated prevalence of about 10-30%, considering the population over 60 years of age. Most patients with this disorder (> 95%) present the sporadic form, being characterized by a late onset (80-90 years of age), and it is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. Significant numbers of genetic risk factors for the sporadic disease have been researched. Some existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease- modifying therapies. In this line, a complementary strategy based on repositioning drugs which are approved for the treatment of other disorders could be interesting. It is noteworthy the fact that some clinical trials indicate that several classes of drugs own potent and beneficial effects on the Alzheimer's disease treatment. In this present work, we present the details and evaluation of these alternative treatments. It has highlighted several compounds with relevant evidence for this purpose, which deserves further investigation to clarify optimal treatment conditions in the clinical trials of patients with Alzheimer's disease.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- antipsychotika terapeutické užití MeSH
- lidé MeSH
- přehodnocení terapeutických indikací léčivého přípravku * MeSH
- senioři nad 80 let MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
