An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 μM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.
- MeSH
- antikoagulancia * farmakologie MeSH
- arginin * analogy a deriváty MeSH
- dabigatran farmakologie MeSH
- dospělí MeSH
- hemokoagulace * účinky léků MeSH
- index tělesné hmotnosti MeSH
- INR MeSH
- kyseliny pipekolové * farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- parciální tromboplastinový čas MeSH
- protrombinový čas MeSH
- průřezové studie MeSH
- pyrazoly farmakologie MeSH
- pyridony farmakologie farmakokinetika MeSH
- rivaroxaban * farmakologie MeSH
- sulfonamidy farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).
- MeSH
- adenin * analogy a deriváty farmakologie MeSH
- chronická lymfatická leukemie * farmakoterapie metabolismus genetika patologie MeSH
- forkhead box protein O1 * metabolismus genetika MeSH
- fosforylace MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny metabolismus genetika MeSH
- piperidiny * farmakologie MeSH
- protein RICTOR * genetika metabolismus MeSH
- proteinkinasa BTK metabolismus genetika antagonisté a inhibitory MeSH
- protoonkogenní proteiny c-akt * metabolismus genetika MeSH
- pyrazoly * farmakologie MeSH
- pyrimidiny * farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- sulodexid, apixaban,
- MeSH
- antikoagulancia * farmakologie terapeutické užití MeSH
- bércové vředy * farmakoterapie ošetřování MeSH
- chronická obstrukční plicní nemoc MeSH
- diosmin farmakologie terapeutické užití MeSH
- erysipel farmakoterapie MeSH
- glykosaminoglykany farmakologie terapeutické užití MeSH
- hojení ran MeSH
- hyperbarická oxygenace metody MeSH
- infekce dýchací soustavy etiologie farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- penicilin G farmakologie terapeutické užití MeSH
- pyrazoly farmakologie terapeutické užití MeSH
- pyridony farmakologie terapeutické užití MeSH
- rivaroxaban farmakologie terapeutické užití MeSH
- senioři MeSH
- warfarin škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
- MeSH
- B-buněčný lymfom farmakoterapie metabolismus patologie MeSH
- chemorezistence * MeSH
- inhibitory proteinkinas * terapeutické užití farmakologie MeSH
- inhibitory tyrosinkinasy MeSH
- lidé MeSH
- piperidiny * terapeutické užití farmakologie MeSH
- proteinkinasa BTK * antagonisté a inhibitory MeSH
- pyrazoly * terapeutické užití farmakologie MeSH
- pyrimidiny * terapeutické užití farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Klíčová slova
- Baricitinib,
- MeSH
- alopecia areata farmakoterapie imunologie patofyziologie MeSH
- alopecie * farmakoterapie klasifikace patofyziologie MeSH
- azetidiny farmakologie terapeutické užití MeSH
- hormony kůry nadledvin farmakologie terapeutické užití MeSH
- inhibitory 5-alfa-reduktasy farmakologie terapeutické užití MeSH
- kožní lupus erytematodes farmakoterapie patofyziologie MeSH
- lichen planus farmakoterapie patofyziologie MeSH
- lidé MeSH
- puriny farmakologie terapeutické užití MeSH
- pyrazolony farmakologie terapeutické užití MeSH
- pyrazoly farmakologie terapeutické užití MeSH
- sulfonamidy farmakologie terapeutické užití MeSH
- trichotilomanie etiologie psychologie MeSH
- Check Tag
- lidé MeSH
Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.
- MeSH
- aktivinové receptory typu I antagonisté a inhibitory metabolismus MeSH
- aktivinové receptory typu II * metabolismus antagonisté a inhibitory MeSH
- inhibitory proteinkinas farmakologie chemie MeSH
- kostní morfogenetické proteiny metabolismus MeSH
- lidé MeSH
- molekulární sondy chemie MeSH
- myši MeSH
- objevování léků MeSH
- pyrazoly chemie farmakologie chemická syntéza MeSH
- signální transdukce účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Small molecules that exhibit broad-spectrum enteroviral inhibitory activity by targeting viral replication proteins are highly desired in antiviral drug discovery studies. To discover new human rhinovirus (hRV) inhibitors, we performed a high-throughput screening of 100,000 compounds from the Korea Chemical Bank library. This search led to identification of two phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) inhibitors having the pyrazolo-pyrimidine core structure, which display moderate anti-rhinoviral activity along with mild cytotoxicity. The results of a study aimed at optimizing the activity of the hit compounds showed that the pyrazolo-pyrimidine derivative 6f exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 μM). Furthermore, 6f has broad-spectrum activities against various hRVs, coxsackieviruses and other enteroviruses, such as EV-A71, EV-D68. An assessment of kinase inhibition potencies demonstrated that 6f possesses a high and selective kinase inhibition activity against PI4KIIIβ (IC50 value of 0.057 μM) and not against PI4KIIIα (>10 μM). Moreover, 6f exhibits modest hepatic stability (46.9 and 55.3 % remaining after 30 min in mouse and human liver microsomes, respectively). Finally, an in vivo study demonstrated that 6f possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L∙h-1 kg-1) and modest oral bioavailability (52.4 %). Hence, 6f (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.
- MeSH
- antivirové látky * farmakologie chemie chemická syntéza MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
- inhibitory proteinkinas farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- myši MeSH
- pyrazoly farmakologie chemie chemická syntéza MeSH
- pyrimidiny * farmakologie chemie chemická syntéza MeSH
- replikace viru * účinky léků MeSH
- Rhinovirus * účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 μM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.
- MeSH
- fotochemoterapie * MeSH
- fotosenzibilizující látky * farmakologie chemická syntéza chemie MeSH
- indoly * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie patologie MeSH
- palladium chemie farmakologie MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- pyrazoly * farmakologie chemická syntéza chemie MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol farmakologie MeSH
- kognitivní dysfunkce metabolismus farmakoterapie MeSH
- krysa rodu rattus MeSH
- kyselina kynurenová * metabolismus MeSH
- methylazoxymethanolacetát * analogy a deriváty MeSH
- modely nemocí na zvířatech MeSH
- piperidiny farmakologie MeSH
- potkani Sprague-Dawley * MeSH
- prefrontální mozková kůra * metabolismus účinky léků MeSH
- pyrazoly farmakologie MeSH
- receptor kanabinoidní CB1 metabolismus MeSH
- schizofrenie * metabolismus farmakoterapie MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- zanubrutinib,
- MeSH
- chronická lymfatická leukemie * MeSH
- inhibitory tyrosinkinasy farmakologie terapeutické užití MeSH
- lidé MeSH
- piperidiny farmakologie terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- pyrazoly farmakologie terapeutické užití MeSH
- pyrimidiny farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
