Radioterapie je jedným ze základních složek léčby pacientů s intrakraniálními metastázami. Součástí nechirurgické léčby mozkových metastáz jsou celomozkové ozáření (whole brain radiotherapy – WBRT) a také stereotaktická radiochirurgie. V éře pokroku onkologické léčby s implikacemi pro dlouhodobé přežití pacientů je diskutovaným tématem toxicita těchto léčebných postupů, u které nemůžeme přehlédnout kognitivní poruchy. Mechanizmů, na jejichž základě kognitivní poruchy vznikají, je několik a jsou stále předmětem výzkumu. Zaměřujeme se na patofyziologické elementy, které se podílí na kognitivních poruchách, a na strategie, jakými jsou hipokampus šetřící (hippocampal avoidance; HA) WBRT pro kandidáty na cílenou léčbu s různými histologickými typy nádorů, která přechází hematoencefalickou bariéru. I když je léčba HA-WBRT plus memantinem jakožto standard stále předmětem diskuzí, v případech mnohočetných mozkových metastáz nebo metastáz, u kterých není vhodná cílená radioterapie, a u pacientů s očekávaným přežitím > 4 měsíce je nutné aplikovat strategii pro prevence poruch kognitivních funkcí. V budoucnu musí být do analýz a studií zařazeny nové studie, které zhodnotí kognitivní funkce u pacientů s dlouhodobým přežitím, ale také další faktory, jako je počet a objem mozkových metastáz, jejich intrakraniální a extrakraniální lokalizace a efekt moderních onkologických terapií.
Radiotherapy is one of the cornerstones for treatment of patients with intracranial metastases. Whole brain radiotherapy (WBRT) as well as stereotactic radiosurgery are part of the non-surgical treatment for brain metastases. The toxicities associated with the treatment, among which we cannot neglect cognitive impairment, represent a current topic in an era marked by advances in oncological treatments with implications for the long-term survival of these patients. The mechanisms that involve the onset of cognitive decline are multiple and are still the subject of research. We propose to highlight the pathophysiological elements involved in cognitive impairment as well as strategies including hippocampal avoidance (HA) WBRT for different histological cancer type candidates for target therapies that cross the blood-brain barrier. Even if the implementation of HA-WBRT plus memantine as standard is still a subject for debate, for cases with multiple brain metastases or metastases unsuitable for targeted radiotherapy and a life expectancy > 4 months, it is necessary to apply a preventive strategy for the impairment of cognitive function. New studies to evaluate cognitive function for long term survivals, but also an evaluation of other factors including the number and volume of brain metastases, their intracranial and extracranial localization and the effect of modern oncological therapies must be included in future analyzes and studies.
- MeSH
- antitumorózní látky klasifikace terapeutické užití MeSH
- cílená molekulární terapie metody MeSH
- dávka záření MeSH
- kognitivní poruchy * chemicky indukované patofyziologie prevence a kontrola MeSH
- kombinovaná terapie metody MeSH
- lidé MeSH
- memantin farmakologie terapeutické užití MeSH
- nádory mozku farmakoterapie komplikace radioterapie MeSH
- radiochirurgie metody MeSH
- radioterapie * metody škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
N-methyl-D-aspartate receptors (NMDARs) play an essential role in excitatory neurotransmission in the mammalian brain, and their physiological importance is underscored by the large number of pathogenic mutations that have been identified in the receptor's GluN subunits and associated with a wide range of diseases and disorders. Here, we characterized the functional and pharmacological effects of the pathogenic N650K variant in the GluN1 subunit, which is associated with developmental delay and seizures. Our microscopy experiments showed that when expressed in HEK293 cells (from ATCC®), the GluN1-N650K subunit increases the surface expression of both GluN1/GluN2A and GluN1/GluN2B receptors, but not GluN1/GluN3A receptors, consistent with increased surface expression of the GluN1-N650K subunit expressed in hippocampal neurons (from embryonic day 18 of Wistar rats of both sexes). Using electrophysiology, we found that the GluN1-N650K variant increases the potency of GluN1/GluN2A receptors to both glutamate and glycine but decreases the receptor's conductance and open probability. In addition, the GluN1-N650K subunit does not form functional GluN1/GluN2B receptors but does form fully functional GluN1/GluN3A receptors. Moreover, in the presence of extracellular Mg2+, GluN1-N650K/GluN2A receptors have a similar and increased response to ketamine and memantine, respectively, while the effect of both drugs had markedly slower onset and offset compared to wild-type GluN1/GluN2A receptors. Finally, we found that expressing the GluN1-N650K subunit in hippocampal neurons reduces excitotoxicity, and memantine shows promising neuroprotective effects in neurons expressing either wild-type GluN1 or the GluN1-N650K subunit. This study provides the functional and pharmacological characterization of NMDARs containing the GluN1-N650K variant.
- MeSH
- HEK293 buňky MeSH
- krysa rodu rattus MeSH
- kyselina glutamová MeSH
- lidé MeSH
- memantin * farmakologie MeSH
- potkani Wistar MeSH
- receptory N-methyl-D-aspartátu * genetika MeSH
- savci MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination - huperzine A and procyclidine - lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota terapeutické užití MeSH
- atropin terapeutické užití farmakologie MeSH
- cholinesterasové inhibitory toxicita MeSH
- jedy * MeSH
- memantin terapeutické užití MeSH
- míra přežití MeSH
- myši MeSH
- oximy terapeutické užití farmakologie MeSH
- procyklidin farmakologie MeSH
- pyridinové sloučeniny farmakologie MeSH
- receptory N-methyl-D-aspartátu MeSH
- soman * toxicita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15-38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.
- MeSH
- adamantan chemie MeSH
- inzulin analogy a deriváty chemická syntéza metabolismus MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- kvarterní struktura proteinů MeSH
- lidé MeSH
- prolin chemie MeSH
- receptor inzulinu chemie metabolismus MeSH
- simulace molekulární dynamiky MeSH
- stabilita proteinů MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.
- MeSH
- adamantan chemie MeSH
- antitumorózní látky chemie farmakologie MeSH
- beta-cyklodextriny chemie MeSH
- buňky K562 MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- puriny chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Léčba demencí klade důraz na komplexní péči a je založena na čtyřech vzájemně provázaných pilířích: psychosociální intervence (nefarmakologické přístupy a podpora pečovatelů), kognitiva (symptomatická farmakoterapie a ovlivnění průběhu nemoci), neuropsychiatrie (léčba behaviorálních a psychologických projevů demence) a paliativní péče (časná paliativní intervence; komplexní paliativní přístup v pokročilém stadiu demence). V článku jsou detailně popisovány jednotlivé terapeutické modality a je kladen důraz na interdisciplinární přístup a těsnou spolupráci s rodinnými příslušníky, a to již od okamžiku stanovení diagnózy.
Therapeutic aspects in dementia are focused on complex approaches and are based on four interlinked columns: psychosocial interventions (nonpharmacological interventions and caregiver support), pharmacotherapy (mainly acetylcholinesterase inhibitors and memantine), neuropsychiatry (management of behavioral and psychologic symptoms of dementia) and palliative care (early palliative interventions; complex palliative approach in advanced stages of dementia). Different therapeutic modalities are described in detail and particular impact is attributed to interdisciplinarity and close cooperation with relatives, since the diagnosis is established.
- MeSH
- arteterapie MeSH
- behaviorální symptomy terapie MeSH
- cholinesterasové inhibitory terapeutické užití MeSH
- činnosti denního života MeSH
- demence * terapie MeSH
- duševně nemocní MeSH
- imunoterapie MeSH
- kognitivní remediace MeSH
- lidé MeSH
- memantin terapeutické užití MeSH
- muzikoterapie MeSH
- narativní terapie MeSH
- nootropní látky terapeutické užití MeSH
- paliativní péče MeSH
- psychosociální intervence MeSH
- senioři MeSH
- zátěž pečovatele MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- práce podpořená grantem MeSH
Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antiparkinsonika aplikace a dávkování MeSH
- cholinesterasové inhibitory aplikace a dávkování toxicita MeSH
- donepezil aplikace a dávkování MeSH
- dopaminové látky aplikace a dávkování MeSH
- kombinovaná farmakoterapie MeSH
- memantin aplikace a dávkování MeSH
- myši MeSH
- preexpoziční profylaxe metody MeSH
- soman toxicita MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.
- MeSH
- 8-hydroxy-2-(di-N-propylamino)tetralin škodlivé účinky farmakologie MeSH
- chování zvířat účinky léků MeSH
- krysa rodu rattus MeSH
- memantin farmakologie MeSH
- modely nemocí na zvířatech MeSH
- obsedantně kompulzivní porucha * chemicky indukované farmakoterapie patofyziologie MeSH
- paměť účinky léků MeSH
- potkani Long-Evans MeSH
- prostorové učení účinky léků MeSH
- riluzol farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Práce se zabývá nejnovějšími pohledy na diagnostiku a léčbu neuroleptického maligního syndromu (NMS). NMS je vzácný antipsychotiky navozený, život ohrožující stav, charakterizovaný hyperpyrexií, svalovou rigiditou, kvalitativní změnou vědomí a deregulací autonomního nervového systému. Prevalence a mortalita se v průběhu posledních 30 let snížila, hlavně zřejmě díky časné diagnostice a vhodné intervenci. Recentní data uvádějí prevalenci 0,02-0,03 % a mortalitu 5,6 %. Léčba zahrnuje vysazení syndrom vyvolávajícího dopaminového antagonisty a podpůrnou léčbu, může dále zahrnovat specifickou farmakoterapii (benzodiazepiny, bromokriptin, amantadin, dantrolen) a elektrokonvulzivní léčbu. Nicméně klinici, a zvláště lékaři v primární péči, kteří často užívají antipsychotika jako přídatnou léčbu, by měli být s tímto syndromem obeznámeni.
The paper deals with recent aspects of diagnosis and treatment of neuroleptic malignant syndrome (NMS). NMS is an antipsychotic-induced, life-threatening condition, characterized by hyperpyrexia, muscle rigidity, qualitative alteration of consciousness and autonomic nervous system dys-regulation. NMS prevalence and mortality rates have declined over the past 30 years, most likely due to early recognition of the syndrome and appropriate intervention. Recent reports suggest a prevalence of 0.02-0.03%, and 5.6% mortality. Treatment includes withdrawal of the offending dopamine antagonist, supportive care and may include the use of specific pharmacotherapies (benzodiazepines, bromocriptine, amentadine, dantrolene) and electroconvulsive therapy. Nonetheless, clinicians, especially primary care clinicians who are using antipsychotics more often for adjunctive treatments, must be cognizant of this syndrome.
- MeSH
- amantadin terapeutické užití MeSH
- antipsychotika škodlivé účinky terapeutické užití MeSH
- benzodiazepiny terapeutické užití MeSH
- bromokriptin terapeutické užití MeSH
- dantrolen terapeutické užití MeSH
- diferenciální diagnóza MeSH
- farmakovigilance MeSH
- incidence MeSH
- lidé MeSH
- maligní neuroleptický syndrom * diagnóza farmakoterapie MeSH
- směrnice pro lékařskou praxi jako téma * MeSH
- Check Tag
- lidé MeSH
