- Klíčová slova
- aceklofenak,
- MeSH
- antiflogistika nesteroidní farmakologie terapeutické užití MeSH
- diklofenak analogy a deriváty farmakologie terapeutické užití MeSH
- lidé MeSH
- muskuloskeletální nemoci * farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
Revmatická onemocnění jsou v populaci velmi častá. Charakterizována jsou však nejenom vysokou morbiditou, nýbrž často i zhoršenou kvalitou života. Jejich léčba proto vyžaduje maximálně individualizovaný a komplexní přístup, jenž mimo jiné zahrnuje i užívání nesteroidních antiflogistik. Role těchto látek je v širším kontextu předmětem předloženého textu.
Rheumatic diseases are highly prevalent in our population. However, they are characterized not only by high morbidity, but also by a commonly impaired quality of life. Their treatment therefore requires a maximally individualized and comprehensive approach, which includes, among others, the use of non-steroidal anti-inflammatory drugs. The role of these substances in a broader context is the subject of the present text.
- MeSH
- antiflogistika nesteroidní * farmakologie škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- management bolesti MeSH
- revmatické nemoci farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Klíčová slova
- nimesulid,
- MeSH
- antiflogistika nesteroidní * aplikace a dávkování farmakologie MeSH
- bolest farmakoterapie MeSH
- inhibitory cyklooxygenasy 2 * aplikace a dávkování farmakologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- antitumorózní látky * MeSH
- diklofenak farmakologie MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- nádory * MeSH
- organoplatinové sloučeniny farmakologie MeSH
- platina MeSH
- prekurzory léčiv * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bolesť je závažný subjektívny vnem, ktorý hoci má ochranný charakter, pacienta nielen fyzicky, ale aj psychicky vyčerpáva. Farmakologická oblasť vývoja a výskumu liečby a odstraňovania bolesti je od izolovania kyseliny salicylovej stále dynamická a zaujímavá. Po objavení molekulárnej podstaty cyklooxygenázy a jej inhibície sa výskum nasmeroval na selektívne inhibítory COX-2, ktoré však boli veľkým sklamaním. Dnes sa opäť objavuje možnosť ako kombináciou liečiv prispieť pacientovi k bezpečnej a účinnej analgeticko-antiflogistickej liečbe.
Pain is a serious subjective experience, which, although it has a protective nature, it physically and mentally exhausts the patient. The pharmacological field of development and research in the treatment and relief of pain has been dynamic and interesting ever since the isolation of salicylic acid. After discovering the molecular nature of cyclooxygenase and its inhibition, research focused on selective COX-2 inhibitors, but they were a big disappointment. Today, the possibility of contributing to safe and effective analgesic-antiphlogistic treatment for the patient with a combination of drugs is emerging again.
Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.
- MeSH
- antiflogistika nesteroidní * farmakologie MeSH
- cyklooxygenasa 2 metabolismus MeSH
- inhibitory cyklooxygenasy 2 * farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Infectious diseases caused by new or unknown bacteria and viruses, such as anthrax, cholera, tuberculosis and even COVID-19, are a major threat to humanity. Thus, the development of new synthetic compounds with efficient antimicrobial activity is a necessity. Herein, rationally designed novel multifunctional cationic alternating copolymers were directly synthesized through a step-growth polymerization reaction using a bivalent electrophilic cross-linker containing disulfide bonds and a diamine heterocyclic ring. To optimize the activity of these alternating copolymers, several different diamines and cross-linkers were explored to find the highest antibacterial effects. The synthesized nanopolymers not only displayed good to excellent antibacterial activity as judged by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Escherichia coli, but also reduced the number of biofilm cells even at low concentrations, without killing mammalian cells. Furthermore, in vivo experiments using infected burn wounds in mice demonstrated good antibacterial activity and stimulated wound healing, without causing systemic inflammation. These findings suggest that the multifunctional cationic nanopolymers have potential as a novel antibacterial agent for eradication of multidrug resistant bacterial infections.
- MeSH
- aminy chemie MeSH
- antibakteriální látky farmakologie MeSH
- antiflogistika nesteroidní farmakologie MeSH
- Bacteria účinky léků MeSH
- bakteriální infekce farmakoterapie etiologie MeSH
- biofilmy účinky léků MeSH
- COVID-19 MeSH
- HEK293 buňky účinky léků MeSH
- hojení ran účinky léků MeSH
- kationty farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence účinky léků MeSH
- myši MeSH
- polymery chemie farmakologie MeSH
- popálení komplikace MeSH
- reagencia zkříženě vázaná MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antiflogistika nesteroidní farmakologie škodlivé účinky terapeutické užití MeSH
- gastrointestinální nemoci diagnóza patologie prevence a kontrola MeSH
- Helicobacter pylori patogenita MeSH
- infekce vyvolané Helicobacter pylori farmakoterapie MeSH
- inhibitory protonové pumpy * aplikace a dávkování farmakologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
AIMS: Neuroinflammation is a prominent hallmark in several neurodegenerative diseases (NDs). Halting neuroinflammation can slow down the progression of NDs. Improving the efficacy of clinically available non-steroidal anti-inflammatory drugs (NSAIDs) is a promising approach that may lead to fast-track and effective disease-modifying therapies for NDs. Here, we aimed to utilize the L-type amino acid transporter 1 (LAT1) to improve the efficacy of salicylic acid as an example of an NSAID prodrug, for which brain uptake and intracellular localization have been reported earlier. MAIN METHODS: Firstly, we confirmed the improved LAT1 utilization of the salicylic acid prodrug (SA-AA) in freshly isolated primary mouse microglial cells. Secondly, we performed behavioural rotarod, open field, and four-limb hanging tests in mice, and a whole-brain proteome analysis. KEY FINDINGS: The SA-AA prodrug alleviated the lipopolysaccharide (LPS)-induced inflammation in the rotarod and hanging tests. The proteome analysis indicated decreased neuroinflammation at the molecular level. We identified 399 proteins linked to neuroinflammation out of 7416 proteins detected in the mouse brain. Among them, Gps2, Vamp8, Slc6a3, Slc18a2, Slc5a7, Rgs9, Lrrc1, Ppp1r1b, Gnal, and Adcy5/6 were associated with the drug's effects. The SA-AA prodrug attenuated the LPS-induced neuroinflammation through the regulation of critical pathways of neuroinflammation such as the cellular response to stress and transmission across chemical synapses. SIGNIFICANCE: The efficacy of NSAIDs can be improved via the utilization of LAT1 and repurposed for the treatment of neuroinflammation. This improved brain delivery and microglia localisation can be applied to other inflammatory modulators to achieve effective and targeted CNS therapies.
- MeSH
- antiflogistika nesteroidní * farmakologie MeSH
- intracelulární signální peptidy a proteiny metabolismus MeSH
- kyselina salicylová farmakologie MeSH
- lipopolysacharidy MeSH
- mikroglie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neurodegenerativní nemoci * metabolismus MeSH
- neurozánětlivé nemoci * farmakoterapie MeSH
- prekurzory léčiv * farmakologie MeSH
- proteom metabolismus MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
