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1.
Ren Fail ; 46(2): 2400541, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39248389

RESUMO

AIMS: Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). METHODS: Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. RESULTS: The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300-5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9-11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. CONCLUSIONS: This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.


Assuntos
Nefropatias Diabéticas , Taxa de Filtração Glomerular , Naftiridinas , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Masculino , Feminino , Nefropatias Diabéticas/tratamento farmacológico , China , Pessoa de Meia-Idade , Idoso , Naftiridinas/uso terapêutico , Naftiridinas/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Albuminúria/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Creatinina/sangue , Creatinina/urina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
2.
Biochemistry (Mosc) ; 89(7): 1300-1312, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39218026

RESUMO

To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson's disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due to the dose-dependent effect of mTOR kinase activity inhibition on cellular parameters associated with, PD pathogenesis. The study used peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we have for the first time showed that inhibition of mTOR by Torin1 only at a concentration of 100 nM affects the level of the lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene. Mutations in GBA1 are considered a high-risk factor for PD development. This concentration led a decrease in pathological phosphorylated alpha-synuclein (Ser129), an increase in its stable tetrameric form with no changes in the lysosomal enzyme activities and concentrations of lysosphingolipids. Our findings suggest that inhibition of the mTOR protein kinase could be a promising approach for developing therapies for PD, particularly for GBA1-associated PD.


Assuntos
Lisossomos , Macrófagos , Doença de Parkinson , Serina-Treonina Quinases TOR , alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , Lisossomos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Linhagem Celular Tumoral , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Relação Dose-Resposta a Droga , Glucosilceramidase/metabolismo , Glucosilceramidase/antagonistas & inibidores , Naftiridinas
3.
Nat Commun ; 15(1): 7659, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227370

RESUMO

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.


Assuntos
Antimaláricos , Malária Falciparum , Naftiridinas , Plasmodium falciparum , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia , Naftiridinas/farmacocinética , Quimioterapia Combinada , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos
4.
Cell Commun Signal ; 22(1): 428, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223665

RESUMO

BRAF serves as a gatekeeper of the RAS/RAF/MEK/ERK pathway, which plays a crucial role in homeostasis. Since aberrant signalling of this axis contributes to cancer and other diseases, it is tightly regulated by crosstalk with the PI3K/AKT/mTOR pathway and ERK mediated feedback loops. For example, ERK limits BRAF signalling through phosphorylation of multiple residues. One of these, T401, is widely considered as an ERK substrate following acute pathway activation by growth factors. Here, we demonstrate that prominent T401 phosphorylation (pT401) of endogenous BRAF is already observed in the absence of acute stimulation in various cell lines of murine and human origin. Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation. In contrast, the mTOR inhibitor torin1 and the dual-specific PI3K/mTOR inhibitor dactolisib significantly suppressed pT401 levels in all investigated cell types, in both a time and concentration dependent manner. Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib. We also show that shRNAmir mediated depletion of the mTORC1 complex subunit Raptor significantly enhanced the suppression of T401 phosphorylation by a low torin1 dose, while knockdown of the mTORC2 complex subunit Rictor was less effective. Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401.


Assuntos
Proteínas Proto-Oncogênicas B-raf , Serina-Treonina Quinases TOR , Fosforilação/efeitos dos fármacos , Humanos , Serina-Treonina Quinases TOR/metabolismo , Animais , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Camundongos , Transdução de Sinais/efeitos dos fármacos , Células HEK293 , Pirimidinonas/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Piridonas/farmacologia , Naftiridinas
5.
Neuropeptides ; 107: 102463, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39180799

RESUMO

Studies have indicated that stress-related symptoms can lead to hormonal and neural changes, affecting the pain threshold and nociceptive behaviors. The precise role of orexin receptors (OX1r and OX2r) in stress-induced analgesia (SIA) remains an inquiry yet to be comprehensively elucidated. The current investigation aimed to assess the impact of acute immobilization restraint stress on pain-related behavioral responses after administering antagonists targeting OX1r and OX2r in a rat model using the tail-flick test. After a period of five to seven days post-stereotaxic surgery in CA1, the baseline tail-flick latency (TFL) was recorded for each animal. Subsequently, rats were unilaterally administered varying doses of the OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), the OX2r antagonist (TCS OX2 29; 1, 3, 10, and 30 nmol), or a vehicle (0.5 µl solution containing 12% DMSO) through an implanted cannula. Following a 5-min interval, the animals were subjected to a restraint stress (RS) lasting for 3 h. The tail-flick test was conducted after the stress exposure, and the TFLs were assessed at 60-min intervals. The findings of this study revealed that RS elicits antinociceptive responses in the tail-flick test. Microinjection of OX1r and OX2r antagonists into the CA1 attenuated RS-induced analgesia during the tail-flick test. Furthermore, the results underscored the preeminent role of OX2 receptors in modulating SIA. In conclusion, the orexin system localized within the hippocampal CA1 region may, in part, contribute to the manifestation of SIA in the context of acute pain.


Assuntos
Benzoxazóis , Região CA1 Hipocampal , Naftiridinas , Antagonistas dos Receptores de Orexina , Receptores de Orexina , Restrição Física , Estresse Psicológico , Animais , Receptores de Orexina/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/administração & dosagem , Masculino , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Estresse Psicológico/metabolismo , Ratos , Benzoxazóis/farmacologia , Benzoxazóis/administração & dosagem , Naftiridinas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/administração & dosagem , Isoquinolinas/farmacologia , Isoquinolinas/administração & dosagem , Ratos Sprague-Dawley , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Piridinas/farmacologia , Piridinas/administração & dosagem , Dor/tratamento farmacológico , Dor/metabolismo , Aminopiridinas , Sulfonamidas
6.
Int J Mol Sci ; 25(16)2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39201774

RESUMO

Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.


Assuntos
Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Humanos , Animais , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia , Espironolactona/análogos & derivados , Espironolactona/uso terapêutico , Eplerenona/farmacologia , Eplerenona/uso terapêutico , Naftiridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Sistema Renina-Angiotensina/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo
7.
J Proteomics ; 307: 105269, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39098729

RESUMO

Quantitative phosphoproteomic data has mostly been reported from experiments comparing relative phosphopeptides intensities in two or more different conditions, while the ideal parameter to compare is phosphopeptides occupancies. This term is scarcely used and therefore barely implemented in phosphoproteomics studies, and this should be of concern for the scientific journals. In order to demonstrate the relevance of this issue, here we show how the method of choice affects the interpretation of the data. The phosphoproteomic profile modulated in two AML cell lines after CK2 inhibition with CIGB-300 or CX-4945 is shown. Following the downstream action of CK2 the phosphosite intensity and occupancy results were compared to validate the best approach for quantitative phosphoproteomic studies. Even when the total number of quantified phosphopeptides was higher by using the intensity calculation, in all the cases the percent of CK2 consensus sequences which were down-regulated in response to CK2 inhibition was higher using the phosphosite occupancy quantification. To note, a high number of CK2 consensus sequences was found down-regulated with at least a 10% or 15% of phosphosite occupancy variation illustrating that low thresholds of occupancy modulation might be indicative of biological effect. Additionally, several biological processes only appear significantly over-represented in the phosphoproteome quantified by occupancy. The functional enrichment analysis per ranges of occupancy variations also illustrated clear differences among AML cell lines subjected to CK2 inhibition by CX-4945. A low overlap between the phosphoproteomes quantified by intensity and occupancy was obtained illustrating that new developments in proteomics techniques are needed to improve the performance of the occupancy approach. Even in such context, results indicate that occupancy quantification performs better than phosphorylation quantification based on intensity reinforcing the importance of such quantification approach to describe phosphoproteomic data.


Assuntos
Caseína Quinase II , Fosfopeptídeos , Proteômica , Caseína Quinase II/metabolismo , Caseína Quinase II/antagonistas & inibidores , Humanos , Fosfopeptídeos/análise , Fosfopeptídeos/metabolismo , Proteômica/métodos , Linhagem Celular Tumoral , Fosfoproteínas/metabolismo , Fosfoproteínas/análise , Fosforilação , Naftiridinas/farmacologia , Fenazinas , Proteoma/análise , Proteoma/metabolismo , Leucemia Mieloide Aguda/metabolismo
8.
Clin Transl Sci ; 17(7): e13865, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39020517

RESUMO

The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N-desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in vitro EC50 values against SARS-CoV-2. In the multicompartment permeability-limited PBPK model, the predicted total Cmax in lung mass for pyronaridine was 34.2 µM on Day 3, 30.5-fold greater than in blood (1.12 µM) and for amodiaquine was 0.530 µM, 8.83-fold greater than in plasma (0.060 µM). In the perfusion-limited PBPK model, the DEAQ predicted total Cmax on Day 3 in lung mass (30.2 µM) was 21.4-fold greater than for plasma (1.41 µM). Based on the available in vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS-CoV-2 replication. Simulations indicated standard dosing regimens of pyronaridine-artesunate and artesunate-amodiaquine have potential to treat COVID-19. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID-19. Clinical data for model verification may become available from ongoing clinical studies.


Assuntos
Amodiaquina , Antimaláricos , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos , Pulmão , SARS-CoV-2 , Humanos , Antimaláricos/farmacocinética , Antimaláricos/administração & dosagem , Amodiaquina/farmacocinética , Amodiaquina/administração & dosagem , Amodiaquina/análogos & derivados , SARS-CoV-2/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Naftiridinas/farmacocinética , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia , Modelos Biológicos , COVID-19/virologia , Antivirais/farmacocinética , Antivirais/administração & dosagem , Simulação por Computador
9.
Int J Mol Sci ; 25(13)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-39000107

RESUMO

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.


Assuntos
Artemisininas , Artesunato , Reposicionamento de Medicamentos , Naftiridinas , Artesunato/farmacocinética , Artesunato/farmacologia , Reposicionamento de Medicamentos/métodos , Animais , Ratos , Cães , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Artemisininas/farmacocinética , Especificidade da Espécie , Humanos , Modelos Biológicos , Masculino , Antimaláricos/farmacocinética , Antimaláricos/farmacologia
10.
Biomed Pharmacother ; 178: 117191, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39079263

RESUMO

Casein kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.


Assuntos
Caseína Quinase II , Sepse , Animais , Masculino , Camundongos , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/prevenção & controle , Naftiridinas , Fenazinas , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/farmacologia , Sepse/tratamento farmacológico , Sepse/complicações
11.
Behav Brain Res ; 472: 115133, 2024 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-38960330

RESUMO

The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230-250 g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5 µl DMSO) were microinjected intra-NAc five minutes before exposure to RS (3 hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50 % effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA.


Assuntos
Dor Aguda , Benzoxazóis , Naftiridinas , Núcleo Accumbens , Antagonistas dos Receptores de Orexina , Receptores de Orexina , Ratos Wistar , Restrição Física , Estresse Psicológico , Ureia , Animais , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Masculino , Receptores de Orexina/metabolismo , Benzoxazóis/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/administração & dosagem , Dor Aguda/fisiopatologia , Dor Aguda/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Naftiridinas/farmacologia , Isoquinolinas/farmacologia , Isoquinolinas/administração & dosagem , Ratos , Piridinas/farmacologia , Piridinas/administração & dosagem , Orexinas/farmacologia , Orexinas/metabolismo , Relação Dose-Resposta a Droga , Medição da Dor/efeitos dos fármacos , Aminopiridinas , Sulfonamidas
12.
Antimicrob Agents Chemother ; 68(9): e0004424, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39046237

RESUMO

The emergence and spread of chloroquine-resistant Plasmodium vivax have necessitated the assessment of alternative blood schizonticidal drugs. In Vietnam, chloroquine-resistant P. vivax malaria has been reported. In an open-label, single-arm trial, the safety, tolerability, and efficacy of pyronaridine-artesunate (Pyramax, PA) was evaluated in Dak Nong province, Vietnam. A 3-day course of PA was administered to adults and children (≥20 kg) infected with P. vivax. Patients also received primaquine (0.25 mg/kg daily for 14 days). PA was well tolerated with transient asymptomatic increases in liver transaminases. The per-protocol proportion of patients with day 42 PCR-unadjusted adequate clinical and parasitological response was 96.0% (95% CI, 84.9%-99.0%, n = 48/50). The median parasite clearance time was 12 h (range, 12-36 h), with a median fever clearance time of 24 h (range, 12-60 h). Single nucleotide polymorphisms (SNPs) as potential genetic markers of reduced drug susceptibility were analyzed in three putative drug resistance markers, Pvcrt-o, Pvmdr1, and PvK12. Insertion at position K10 of the Pvcrt-o gene was found in 74.6% (44/59) of isolates. Pvmdr1 SNPs at Y976F and F1076L were present in 61% (36/59) and 78% (46/59), respectively. Amplification of Pvmdr1 gene (two copies) was found in 5.1% (3/59) of parasite samples. Only 5.1% (3/59) of isolates had mutation 552I of the PvK12 gene. Overall, PA rapidly cleared P. vivax blood asexual stages and was highly efficacious in treating vivax malaria, with no evidence of artemisinin resistance found. PA provides an alternative to chloroquine treatment for vivax malaria in Vietnam. CLINICAL TRIALS: This study is registered with the Australian New Zealand Clinical Trials Registry as ACTRN12618001429246.


Assuntos
Antimaláricos , Artemisininas , Artesunato , Malária Vivax , Naftiridinas , Plasmodium vivax , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/parasitologia , Naftiridinas/uso terapêutico , Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Vietnã , Adulto , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/genética , Masculino , Artemisininas/uso terapêutico , Adolescente , Criança , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Primaquina/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Pré-Escolar , Proteínas de Protozoários/genética , Resistência a Medicamentos/genética , Proteínas de Membrana Transportadoras
13.
Food Funct ; 15(17): 8661-8673, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39056112

RESUMO

Background: A high-fat diet (HFD) is generally associated with an increased risk of mental disorders that constitute a sizeable worldwide health. A HFD results in the gut microbiota-brain axis being altered and linked to mental disorders. Hypocretin-1, which can promote appetite, has been previously confirmed to be associated with depression. However, no exact relationship has been found for hypocretin between depression and HFDs. Methods: Adult male SD rats were randomly assigned to either a HFD or a normal diet for eight weeks, followed by behavioral tests and plasma biochemical analyses. Then, we investigated the protein and mRNA levels of inflammation-related factors in the hippocampus. We also observed morphological changes in brain microglia and lipid accumulation. Additionally, metagenomic and metabolomic analyses of gut microbiomes were performed. 3T3-L1 cells were utilized in vitro to investigate the impact of hypocretin receptor 1 antagonists (SB334867) on lipid accumulation. To consider the connection between the brain and adipose tissue, we used a conditioned medium (CM) treated with 3T3-L1 cells to observe the activation and phagocytosis of BV2 cells. Following a 12-week period of feeding a HFD to C57BL/6 mice, a three-week intervention period was initiated during which the administration of SB334867 was observed. This was followed by a series of assessments, including monitoring of body weight changes and emotional problems, as well as attention to plasma biochemical levels and microglial cell phenotypes in the brain. Results: The HFD rats displayed anxiety and depressive-like behaviors. HFD rats exhibited increased plasma HDL, LDL, and TC levels. A HFD also causes an increase in hypocretin-1 and hypocretin-2 in the hypothalamus. Metagenomics and metabolomics revealed that the HFD caused an increase in the relative abundance of associated inflammatory bacteria and decreased the abundance of anti-inflammatory and bile acid metabolites. Compared with the CTR group, hippocampal microglia in the HFD group were significantly activated and accompanied by lipid deposition. At the same time, protein and mRNA expression levels of inflammation-related factors were increased. We found that SB334867 could significantly reduce lipid accumulation in 3T3-L1 cells after differentiation. The expression of inflammatory factors decreased in the SB334867 group. The administration of SB334867 was found to reverse the adverse effects of the HFD on body weight, depressive-like behaviour and anxiety-like mood. Furthermore, this treatment was associated with improvements in plasma biochemical levels and a reduction in the number of microglia in the brain. Conclusions: In summary, our results demonstrated that a HFD induced anxiety and depressive-like behaviors, which may be linked to the increased hypocretin-1 level and lipid accumulation. Supplementation with SB334867 improved the above. These observations highlight the possibility of hypocretin-1 inducing the risk of HFD-associated emotional dysfunctions.


Assuntos
Depressão , Dieta Hiperlipídica , Microbioma Gastrointestinal , Inflamação , Camundongos Endogâmicos C57BL , Receptores de Orexina , Orexinas , Ratos Sprague-Dawley , Animais , Masculino , Camundongos , Ratos , Células 3T3-L1 , Benzoxazóis , Depressão/metabolismo , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Inflamação/metabolismo , Microglia/metabolismo , Microglia/efeitos dos fármacos , Naftiridinas , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Orexinas/metabolismo , Fenótipo , Ureia/análogos & derivados
14.
Int J Mol Sci ; 25(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38999929

RESUMO

The mechanistic target of rapamycin complex (mTORC) regulates protein synthesis and can be activated by branched-chain amino acids (BCAAs). mTORC has also been implicated in the regulation of mitochondrial metabolism and BCAA catabolism. Some speculate that mTORC overactivation by BCAAs may contribute to insulin resistance. The present experiments assessed the effect of mTORC activation on myotube metabolism and insulin sensitivity using the mTORC agonist MHY1485, which does not share structural similarities with BCAAs. METHODS: C2C12 myotubes were treated with MHY1485 or DMSO control both with and without rapamycin. Gene expression was assessed using qRT-PCR and insulin sensitivity and protein expression by western blot. Glycolytic and mitochondrial metabolism were measured by extracellular acidification rate and oxygen consumption. Mitochondrial and lipid content were analyzed by fluorescent staining. Liquid chromatography-mass spectrometry was used to assess extracellular BCAAs. RESULTS: Rapamycin reduced p-mTORC expression, mitochondrial content, and mitochondrial function. Surprisingly, MHY1485 did not alter p-mTORC expression or cell metabolism. Neither treatment altered indicators of BCAA metabolism or extracellular BCAA content. CONCLUSION: Collectively, inhibition of mTORC via rapamycin reduces myotube metabolism and mitochondrial content but not BCAA metabolism. The lack of p-mTORC activation by MHY1485 is a limitation of these experiments and warrants additional investigation.


Assuntos
Mitocôndrias , Fibras Musculares Esqueléticas , Sirolimo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Animais , Camundongos , Sirolimo/farmacologia , Linhagem Celular , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Aminoácidos de Cadeia Ramificada/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Resistência à Insulina , Serina-Treonina Quinases TOR/metabolismo , Naftiridinas
15.
J Med Chem ; 67(13): 11401-11420, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38918002

RESUMO

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of Plasmodium falciparum (Pf) phosphatidylinositol-4-kinase ß (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained Plasmodium PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PfPI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.


Assuntos
1-Fosfatidilinositol 4-Quinase , Antimaláricos , Hemeproteínas , Naftiridinas , Plasmodium falciparum , Peixe-Zebra , Plasmodium falciparum/efeitos dos fármacos , Animais , Naftiridinas/farmacologia , Naftiridinas/química , Naftiridinas/síntese química , Naftiridinas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , 1-Fosfatidilinositol 4-Quinase/metabolismo , Humanos , Relação Estrutura-Atividade , Hemeproteínas/antagonistas & inibidores , Hemeproteínas/metabolismo , Camundongos , Ratos , Malária Falciparum/tratamento farmacológico , Masculino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química
16.
J Am Heart Assoc ; 13(12): e032971, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38842271

RESUMO

BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.


Assuntos
Modelos Animais de Doenças , Fibrose , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Óxido Nítrico Sintase Tipo III , Insuficiência Renal Crônica , Disfunção Ventricular Esquerda , Animais , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Diástole/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Rim/metabolismo , Fosforilação , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Sprague-Dawley , Ratos , Nefrectomia
17.
Adv Ther ; 41(8): 3138-3158, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38880821

RESUMO

INTRODUCTION: Adding finerenone to current standard of care (SoC), as recommended by Chinese guidelines, has shown substantial benefit in delaying chronic kidney disease (CKD) progression and reducing cardiovascular risk in patients with CKD and type 2 diabetes (T2D) in the landmark FIDELIO-DKD trial. This study aimed to evaluate the cost-effectiveness of finerenone + SoC versus SoC alone among Chinese patients with T2D and CKD from a healthcare system perspective. METHODS: A cost-effectiveness model (FINE-CKD) has been developed and published, with health states defined for CKD stages (CKD 1/2, CKD 3, CKD 4, and CKD 5 without renal replacement therapy (RRT), dialysis, or transplant) and cardiovascular event history. Additionally, the model also considered adverse events. Transition probabilities and event risks were derived using patient-level data from Asian population analysis of FIDELIO-DKD. Since the price of finerenone after the national reimbursement drug list (NRDL) inclusion was confidential, the cost of finerenone in the model was assumed to be the same as that of SoC. Other health resource costs were gathered from literature and supplemented by physician interviews. Measured by the EQ-5D-5L questionnaire, quality of life was translated into utilities based on the Chinese EQ-5D-5L value set. RESULTS: Discounted at 5.0% annually, over a lifetime horizon, finerenone + SoC resulted in a quality-adjusted life years (QALYs) gain of 0.321 versus SoC alone (8.660 vs. 8.338 QALYs), due to a reduction in the incidence of cardiovascular events and dialysis. Total costs per patient were lower under finerenone + SoC than SoC alone (381,130 CNY vs. 392,390 CNY). As a result, finerenone + SoC was a dominant treatment strategy compared with SoC alone. Sensitivity analysis has confirmed the robustness of this study. CONCLUSION: Adding finerenone to SoC was likely to be either a dominant or cost-effective treatment option compared with SoC alone in Chinese patients with CKD and T2D.


Assuntos
Análise Custo-Benefício , Diabetes Mellitus Tipo 2 , Naftiridinas , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , China , Insuficiência Renal Crônica/terapia , Masculino , Naftiridinas/uso terapêutico , Naftiridinas/economia , Feminino , Anos de Vida Ajustados por Qualidade de Vida , Padrão de Cuidado , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/economia , Idoso
18.
Int Immunopharmacol ; 137: 112524, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-38909494

RESUMO

Ischemic stroke (IS) is a serious threat to human health. The naturally derived small molecule (E)-5-(2-(quinolin-4-yl) ethenyl) benzene-1,3-diol (RV01) is a quinolinyl analog of resveratrol with great potential in the treatment of IS. The aim of this study was to investigate the potential mechanisms and targets for the protective effect of the RV01 on IS. The mouse middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reperfusion (OGD/R) models were employed to evaluate the effects of RV01 on ischemic injury and neuroprotection. RV01 was found to significantly increase the survival of SH-SY5Y cells and prevent OGD/R-induced apoptosis in SH-SY5Y cells. Furthermore, RV01 reduced oxidative stress and mitochondrial damage by promoting mitophagy in OGD/R-exposed SH-SY5Y cells. Knockdown of CK2α' abolished the RV01-mediated promotion on mitophagy and alleviation on mitochondrial damage as well as neuronal injury after OGD/R. These results were further confirmed by molecular docking, drug affinity responsive target stability and cellular thermal shift assay analysis. Importantly, in vivo study showed that treatment with the CK2α' inhibitor CX-4945 abolished the RV01-mediated alleviation of cerebral infarct volume, brain edema, cerebral blood flow and neurological deficit in MCAO/R mice. These data suggest that RV01 effectively reduces damage caused by acute ischemic stroke by promoting mitophagy through its interaction with CK2α'. These findings offer valuable insights into the underlying mechanisms through which RV01 exerts its therapeutic effects on IS.


Assuntos
Caseína Quinase II , Infarto da Artéria Cerebral Média , AVC Isquêmico , Camundongos Endogâmicos C57BL , Mitofagia , Fármacos Neuroprotetores , Resveratrol , Animais , Mitofagia/efeitos dos fármacos , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Caseína Quinase II/metabolismo , Caseína Quinase II/antagonistas & inibidores , Masculino , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Camundongos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Simulação de Acoplamento Molecular , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Naftiridinas , Fenazinas
19.
Int J Antimicrob Agents ; 64(1): 107196, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38734217

RESUMO

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.


Assuntos
Antimaláricos , Voluntários Saudáveis , Malária Falciparum , Naftiridinas , Parasitemia , Plasmodium falciparum , Humanos , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/administração & dosagem , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/administração & dosagem , Plasmodium falciparum/efeitos dos fármacos , Adulto , Masculino , Adulto Jovem , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Feminino , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Administração Oral , Pessoa de Meia-Idade , Resultado do Tratamento
20.
J Med Chem ; 67(10): 8445-8459, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38706130

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Naftiridinas , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Camundongos , Naftiridinas/farmacologia , Naftiridinas/síntese química , Naftiridinas/química , Naftiridinas/uso terapêutico , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Camundongos Nus , Ensaios de Seleção de Medicamentos Antitumorais
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