The history of poisoning is one of the greatest chapters of the human history, where curiosity and genius, scientific discoveries and empirical knowledge intertwine with intrigues, crimes, politics, personal tragedies of notabilities, wars and natural disasters. Knowledge of toxic substances is likely as old as the mankind. In the Middle Age, Paracelsus claimed that in the world there is no non-toxic substance that the therapeutic and toxic properties of substances are indistinguishable up to a single parameter-dose. This postulate still belongs among the basic pillars of modern toxicology. Probably, the most ancient way of killing people was poisoning. In addition, the presence of poison in the body of the victim was very difficult to determine, since the symptoms of poisoning were similar to signs of certain diseases. Therefore, the criminals had a big chance to escape the punishment. Nowadays, together with development of toxicology the chance of disclosure of such crimes has increased, however, the progress in the field of design and production of toxic substances has also gone up. Within current contribution we have reviewed the most famous historical cases of poisoning from the antiquity to the present.

• MeSH
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• dějiny starověku MeSH
• dějiny středověku MeSH
• lidé MeSH
• otrava dějiny   MeSH
• Check Tag
• dějiny 15. století MeSH
• dějiny 16. století MeSH
• dějiny 17. století MeSH
• dějiny 18. století MeSH
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• dějiny starověku MeSH
• dějiny středověku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• historické články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.

• MeSH
• acetylcholinesterasa MeSH
• antidota farmakologie   terapeutické užití   MeSH
• nervová bojová látka otrava   MeSH
• obidoxim chlorid MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• simulace molekulového dockingu MeSH
• trimedoxim MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

• MeSH
• Alzheimerova nemoc farmakoterapie   enzymologie   genetika   patologie   MeSH
• butyrylcholinesterasa chemie   účinky léků   genetika   MeSH
• CHO buňky MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• Cricetulus MeSH
• fluoreny chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• počítačová simulace MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.

• MeSH
• alkaloidy chemie   farmakologie   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• lidé MeSH
• Narcissus chemie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH