• MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   MeSH
• gemtuzumab MeSH
• lidé MeSH
• staurosporin terapeutické užití   MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• Geografické názvy
• Česká republika MeSH

Low curability of patients diagnosed with acute myeloid leukemia (AML) must be seen as a call for better understanding the disease's mechanisms and improving the treatment strategy. Therapeutic outcome of the crucial anthracycline-based induction therapy often can be compromised by a resistant phenotype associated with overexpression of ABCB1 transporters. Here, we evaluated clinical relevance of ABCB1 in a context of the FMS-like tyrosine kinase 3 (FLT3) inhibitor midostaurin in a set of 28 primary AML samples. ABCB1 gene expression was absolutely quantified, confirming its association with CD34 positivity, adverse cytogenetic risk, and unachieved complete remission (CR). Midostaurin, identified as an ABCB1 inhibitor, increased anthracycline accumulation in peripheral blood mononuclear cells (PBMC) of CD34+ AML patients and those not achieving CR. This effect was independent of FLT3 mutation, indicating even FLT3- AML patients might benefit from midostaurin therapy. In line with these data, midostaurin potentiated proapoptotic processes in ABCB1-overexpressing leukemic cells when combined with anthracyclines. Furthermore, we report a direct linkage of miR-9 to ABCB1 efflux activity in the PBMC and propose miR-9 as a useful prognostic marker in AML. Overall, we highlight the therapeutic value of midostaurin as more than just a FLT3 inhibitor, suggesting its maximal therapeutic outcomes might be very sensitive to proper timing and well-optimized dosage schemes based upon patient's characteristics, such as CD34 positivity and ABCB1 activity. Moreover, we suggest miR-9 as a predictive ABCB1-related biomarker that could be immensely helpful in identifying ABCB1-resistant AML phenotype to enable optimized therapeutic regimen and improved treatment outcome.

• MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   metabolismus   MeSH
• antracykliny farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• leukocyty mononukleární účinky léků   metabolismus   MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• mutace MeSH
• P-glykoproteiny * genetika   metabolismus   MeSH
• staurosporin * analogy a deriváty   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Akútna myeloidná leukémia (AML) je prevažne ochorenie starších pacientov. V poslednom období sa prežívanie tejto skupiny chorých zlepšuje, rovnako ako aj ich kvalita života, na ktorú sa kladie veľký dôraz, s ohľadom na limitujúce aspekty tejto závažnej onkohematologickej choroby. V ére cielenej terapie s novými liečebnými prípravkami sa úspešnosť efektu terapie AML, vynímajúc z tejto skupiny samostatný podtyp akútnej promyelocytárnej leukémie (APL), ktorá má vlastný liečebný režim, výrazne zlepšila. Zároveň umožnila vznik termínu tzv. semi-intenzívny terapeutický prístup, ktorý môže slúžiť ako premostenie k alogénnej transplantácii, tzv. bridge to transplant, a tým dať starším pacientom šancu na vyliečenie pri zníženej chemoterapeutickej toxicite. Najviac diskutovanou skupinou sú pacienti od 60 do 65 rokov, ktorí síce môžu dostať intenzívnu chemoterapiu, ale preto, že na túto skupinu už pripadá viacero pridružených komorbidít a biologický fakt starnutia, niektorí pacienti z intenzívnej chemoterapie s kuratívnym zámerom nemusia profitovať. Zhodnotenie celkového výkonnostného stavu a zvolenie správnej cielenej terapie podľa molekulárnej genetiky, cytogenetiky a z toho plynúcich prognostických skupín AML je kľúčové pre celkový benefit pacienta.

Acute myeloid leukaemia (AML) is predominantly a disease of elderly patients. Recently, the survival rates in this group have improved, as has the quality of life on which great emphasis is placed, given the limiting aspects of this serious haematological malignancy. In the era of targeted therapy with novel medicinal products, the efficacy rate of AML treatment, excluding the distinct subtype of acute promyelocytic leukaemia (APL) which has its own treatment regimen, has improved significantly. At the same time, a new term has been coined - semi-intensive therapeutic approach which can serve as a bridge to allogeneic transplantation (bridge-to-transplant), thus giving elderly patients a chance for a cure with reduced chemotherapeutic toxicity. The most widely discussed group is that of patients aged 60 to 65 years who can receive intensive chemotherapy; however, since this group is burdened with multiple associated comorbidities and with the biological fact of ageing, some patients may not benefit from intensive chemotherapy with a curative intent. An assessment of the overall performance status and choosing the right targeted therapy based on molecular genetics, cytogenetics, and the resulting prognostic AML groups are crucial for the patient's overall benefit.

• Klíčová slova
• midostaurin, gilteritinib, glasdegib,
• MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   MeSH
• aniliny terapeutické užití   MeSH
• antitumorózní látky * terapeutické užití   MeSH
• benzimidazoly terapeutické užití   MeSH
• cytarabin terapeutické užití   MeSH
• daunomycin terapeutické užití   MeSH
• gemtuzumab terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory   MeSH
• senioři MeSH
• staurosporin analogy a deriváty   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH

Midostaurin is an FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor that provides renewed hope for treating acute myeloid leukaemia (AML). The limited efficacy of this compound as a monotherapy contrasts with that of its synergistic combination with standard cytarabine and daunorubicin (Dau), suggesting a therapeutic benefit that is not driven only by FLT3 inhibition. In an AML context, the activity of the enzyme aldo-keto reductase 1C3 (AKR1C3) is a crucial factor in chemotherapy resistance, as it mediates the intracellular transformation of anthracyclines to less active hydroxy metabolites. Here, we report that midostaurin is a potent inhibitor of Dau inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in a transfected cell model. Likewise, in the FLT3- AML cell line KG1a, midostaurin was able to increase the cellular accumulation of Dau and significantly decrease its metabolism by AKR1C3 simultaneously. The combination of those mechanisms increased the nuclear localization of Dau, thus synergizing its cytotoxic effects on KG1a cells. Our results provide new in vitro evidence of how the therapeutic activity of midostaurin could operate beyond targeting the FLT3 receptor.

• MeSH
• akutní myeloidní leukemie farmakoterapie   enzymologie   genetika   patologie   MeSH
• biotransformace MeSH
• daunomycin metabolismus   farmakologie   MeSH
• HCT116 buňky MeSH
• inhibitory enzymů farmakologie   MeSH
• kolorektální nádory farmakoterapie   enzymologie   genetika   patologie   MeSH
• lidé MeSH
• protein AKR1C3 antagonisté a inhibitory   genetika   metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• staurosporin analogy a deriváty   farmakologie   MeSH
• synergismus léků MeSH
• tyrosinkinasa 3 podobná fms antagonisté a inhibitory   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

At present, nuclear condensation and fragmentation have been estimated also using Hoechst probes in fluorescence microscopy and flow cytometry. However, none of the methods used the Hoechst probes for quantitative spectrofluorometric assessment. Therefore, the aim of the present study was to develop a spectrofluorometric assay for detection of nuclear condensation and fragmentation in the intact cells. We used human hepatoma HepG2 and renal HK-2 cells cultured in 96-well plates treated with potent apoptotic inducers (i.e. cisplatin, staurosporine, camptothecin) for 6-48 h. Afterwards, the cells were incubated with Hoechst 33258 (2 µg/mL) and the increase of fluorescence after binding of the dye to DNA was measured. The developed spectrofluorometric assay was capable to detect nuclear changes caused by all tested apoptotic inducers. Then, we compared the outcomes of the spectrofluorometric assay with other methods detecting cell impairment and apoptosis (i.e. WST-1 and glutathione tests, TUNEL, DNA ladder, caspase activity, PARP-1 and JNKs expressions). We found that our developed spectrofluorometric assay provided results of the same sensitivity as the TUNEL assay but with the advantages of being fast processing, low-cost and a high throughput. Because nuclear condensation and fragmentation can be typical markers of cell death, especially in apoptosis, we suppose that the spectrofluorometric assay could become a routinely used method for characterizing cell death processes.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• bisbenzimidazol chemie   MeSH
• buněčná smrt účinky léků   MeSH
• buněčné jádro účinky léků   metabolismus   MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• cisplatina farmakologie   MeSH
• fluorescenční mikroskopie metody   MeSH
• fluorescenční spektrometrie metody   MeSH
• fragmentace DNA účinky léků   MeSH
• kamptothecin farmakologie   MeSH
• lidé MeSH
• průtoková cytometrie metody   MeSH
• reprodukovatelnost výsledků MeSH
• staurosporin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ač je akutní myeloidní leukemie onemocnění s rostoucí incidencí, v posledních desetiletích nedošlo v její léčbě k radikálnímu posunu k lepšímu a prognóza pacientů se zlepšuje pouze pozvolna. V posledních několika letech se však v terapii akutní myeloidní leukemie objevují léčiva, která reprezentují tzv. cílenou léčbu a mají jistou zásluhu na zlepšení. Článek je zaměřen na přehled základních farmakologických vlastností nových léčiv používaných v terapii akutní myeloidní leukemie, zejména na mechanizmus účinku, nejčastější nežádoucí účinky a jejich management či lékové interakce z pohledu klinického farmaceuta.

Although the incidence of acute myeloid leukaemia is on the rise, there has been no radical improvement in its treatment in recent decades and the prognosis of patients is improving only gradually. Drugs for the treatment of acute myeloid leukaemia that have appeared in the past few years and that represent so-called targeted therapy have been responsible for this improvement. This article focuses on an overview of the basic pharmacological properties of new drugs used in the treatment of acute myeloid leukaemia, especially their mechanism of action, their most common adverse reactions and their management or drug interactions from the perspective of the clinical pharmacist.

• Klíčová slova
• midostaurin, gilteritinib, ivosidenib, enasidenib, venetoklax, glasdegib,
• MeSH
• akutní myeloidní leukemie * farmakoterapie   MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• gemtuzumab farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• staurosporin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.

• MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   fyziologie   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály MeSH
• hyperalgezie etiologie   metabolismus   patofyziologie   MeSH
• karagenan farmakologie   toxicita   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• miniaturní postsynaptické potenciály MeSH
• nocicepce MeSH
• potkani Wistar MeSH
• receptor PAR-2 metabolismus   MeSH
• staurosporin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• adrenalin terapeutické užití   MeSH
• antialergika MeSH
• antihistaminika aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• Aspirin aplikace a dávkování   terapeutické užití   MeSH
• bisfosfonáty terapeutické užití   MeSH
• imunologické faktory MeSH
• individualizovaná medicína MeSH
• inhibitory enzymů MeSH
• inhibitory kostní resorpce MeSH
• interferon alfa terapeutické užití   MeSH
• lidé MeSH
• mastocytóza * diagnóza   farmakoterapie   patologie   MeSH
• mastocyty patologie   účinky léků   MeSH
• omalizumab terapeutické užití   MeSH
• staurosporin analogy a deriváty   terapeutické užití   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   MeSH
• antigeny bakteriální terapeutické užití   MeSH
• azepiny chemie   terapeutické užití   MeSH
• bakteriální proteiny terapeutické užití   MeSH
• inhibitory proteinkinas chemie   terapeutické užití   MeSH
• lidé MeSH
• methylenová modř chemie   terapeutické užití   MeSH
• neurony metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• proteiny tau antagonisté a inhibitory   metabolismus   MeSH
• pyrazoly chemie   terapeutické užití   MeSH
• pyridiny chemie   terapeutické užití   MeSH
• pyrroly chemie   terapeutické užití   MeSH
• staurosporin chemie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception.

• MeSH
• alergie metabolismus   patologie   MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   fyziologie   MeSH
• chování zvířat účinky léků   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• hyperalgezie etiologie   prevence a kontrola   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• metoda terčíkového zámku MeSH
• mícha metabolismus   MeSH
• nervový přenos fyziologie   MeSH
• oligopeptidy farmakologie   MeSH
• potkani Wistar MeSH
• receptor PAR-2 agonisté   metabolismus   MeSH
• staurosporin farmakologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH