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1.
Mol Cancer ; 23(1): 91, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715012

RESUMO

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Receptor IGF Tipo 1 , Transdução de Sinais , Humanos , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Acrilamidas/farmacologia , RNA Circular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Animais , Camundongos , Apoptose , Movimento Celular/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Feminino , Indóis , Pirimidinas
2.
Ther Drug Monit ; 46(3): 321-331, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38723115

RESUMO

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.


Assuntos
Inibidores da Angiogênese , Carcinoma de Células Renais , Monitoramento de Medicamentos , Indazóis , Neoplasias Renais , Pirimidinas , Sarcoma , Sulfonamidas , Indazóis/uso terapêutico , Humanos , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacocinética , Pirimidinas/uso terapêutico , Pirimidinas/farmacocinética , Monitoramento de Medicamentos/métodos , Carcinoma de Células Renais/tratamento farmacológico , Sarcoma/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacocinética
3.
Chem Biol Drug Des ; 103(5): e14530, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38725091

RESUMO

Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure-activity relationships (SAR). We found the correlation between IC50s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC50 of 0.030 µM ± 0.009. This compared to FIV IC50 values of 0.22 ± 0.17 µM, 0.040 ± 0.010 µM and >160 µM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.


Assuntos
Transcriptase Reversa do HIV , Vírus da Imunodeficiência Felina , Inibidores da Transcriptase Reversa , Animais , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/química , Gatos , Vírus da Imunodeficiência Felina/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , Humanos , Relação Estrutura-Atividade , Pirimidinas/química , Pirimidinas/farmacologia , Alcinos/química , Alcinos/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Ciclopropanos/farmacologia , Ciclopropanos/química , Simulação de Acoplamento Molecular , Benzoxazinas/química , Benzoxazinas/farmacologia
4.
Pak J Pharm Sci ; 37(1(Special)): 173-184, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38747267

RESUMO

Hydrazones 1-6, azo-pyrazoles 7-9 and azo-pyrimidines 10-15 are compounds that exhibit antibacterial activity. The mode of action and structures of these derivatives have been previously confirmed as antibacterial. In this investigation, biological screening and molecular docking studies were performed for derivatives 1-15, with compounds 2, 7, 8, 14 and 15 yielding the best energy scores (from -20.7986 to -10.5302 kcal/mol). Drug-likeness and in silico ADME prediction for the most potent derivatives, 2, 7, 8, 14 and 15, were predicted (from 84.46 to 96.85%). The latter compounds showed good recorded physicochemical properties and pharmacokinetics. Compound 8 demonstrated the strongest inhibition, which was similar to the positive control (eflornithine) against Trypanosoma brucei brucei (WT), with an EC50 of 25.12 and 22.52µM, respectively. Moreover, compound 14 exhibited the best activity against Leishmania mexicana promastigotes and Leishmania major promastigotes (EC50 =46.85; 40.78µM, respectively).


Assuntos
Simulação de Acoplamento Molecular , Pirazóis , Pirimidinas , Tripanossomicidas , Trypanosoma brucei brucei , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Leishmania mexicana/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Simulação por Computador , Compostos Azo/farmacologia , Compostos Azo/química , Compostos Azo/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade Parasitária
5.
Molecules ; 29(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38731613

RESUMO

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 µM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.


Assuntos
Fármacos Anti-HIV , Simulação de Acoplamento Molecular , Pirimidinas , Relação Quantitativa Estrutura-Atividade , Pirimidinas/química , Pirimidinas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Humanos , Simulação de Dinâmica Molecular , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/metabolismo , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Estrutura Molecular
7.
J Am Chem Soc ; 146(19): 13317-13325, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700457

RESUMO

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Nitrilas , Pirazóis , Pirimidinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Apoptose/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/síntese química , Rutênio/química , Rutênio/farmacologia , Luz , Estrutura Molecular , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo
8.
BMC Med ; 22(1): 204, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38764059

RESUMO

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease, and its morbidity and mortality are increasing. At present, there is no specific therapy available. An exacerbated IFN-I response and cytokine storm are related to the mortality of patients with SFTS. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that can block proinflammatory cytokines and inhibit the type I IFN pathway. We aimed to explore the use of ruxolitinib plus standard of care for severe SFTS. METHODS: We conducted a prospective, single-arm study of severe SFTS. We recruited participants aged 18 years or older who were admitted to the hospital with laboratory-confirmed severe SFTS and whose clinical score exceeded 8 points within 6 days of symptom onset. Participants received oral ruxolitinib (10 mg twice a day) for up to 10 days. The primary endpoint was 28-day overall survival. The secondary endpoints included the proportion of participants who needed intensive care unit (ICU) admission, total cost, changes in neurologic symptoms and clinical laboratory parameters, and adverse events (AEs) within 28 days. A historical control group (HC group, n = 26) who met the upper criteria for inclusion and hospitalized from April 1, 2021, to September 16, 2022, was selected and 1:1 matched for baseline characteristics by propensity score matching. RESULTS: Between Sep 16, 2022, and Sep 16, 2023, 26 participants were recruited into the ruxolitinib treatment group (RUX group). The 28-day overall mortality was 7.7% in the RUX group and 46.2% in the HC group (P = 0.0017). There was a significantly lower proportion of ICU admissions (15.4% vs 65.4%, p < 0.001) and total hospitalization cost in the RUX group. Substantial improvements in neurologic symptoms, platelet counts, hyperferritinemia, and an absolute decrease in the serum SFTS viral load were observed in all surviving participants. Treatment-related adverse events were developed in 6 patients (23.2%) and worsened in 8 patients (30.8%), and no treatment-related serious adverse events were reported. CONCLUSIONS: Our findings indicate that ruxolitinib has the potential to increase the likelihood of survival as well as reduce the proportion of ICU hospitalization and being tolerated in severe SFTS. Further trials are needed. TRAIL REGISTRATION: ChiCTR2200063759, September 16, 2022.


Assuntos
Nitrilas , Pirazóis , Pirimidinas , Febre Grave com Síndrome de Trombocitopenia , Humanos , Pirazóis/uso terapêutico , Nitrilas/uso terapêutico , Masculino , Feminino , Pirimidinas/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Febre Grave com Síndrome de Trombocitopenia/tratamento farmacológico , Padrão de Cuidado , Adulto , Hospitalização , Resultado do Tratamento
9.
Pharmacol Res Perspect ; 12(3): e1202, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38764241

RESUMO

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.


Assuntos
Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Interações Alimento-Droga , Voluntários Saudáveis , Pirimidinas , Sulfonamidas , Comprimidos , Tadalafila , Equivalência Terapêutica , Humanos , Masculino , Adulto , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Tadalafila/farmacocinética , Tadalafila/administração & dosagem , Tadalafila/sangue , Adulto Jovem , Feminino , Sulfonamidas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Pessoa de Meia-Idade , Administração Oral , Jejum , Adolescente
10.
Anal Chim Acta ; 1309: 342666, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38772654

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors and represent the targets for the therapeutical treatment of type 2 diabetes, dyslipidemia and hyperglycemia associated with metabolic syndrome. Some medicinal plants have been traditionally used to treat this kind of metabolic diseases. Today only few drugs targeting PPARs have been approved and for this reason, the rapid identification of novel ligands and/or chemical scaffolds starting from natural extracts would benefit of a selective affinity ligand fishing assay. RESULTS: In this paper we describe the development of a new ligand fishing assay based on size exclusion chromatography (SEC) coupled to LC-MS for the analysis of complex samples such as botanical extracts. The known PPARα and PPARγ ligands, WY-14643 and rosiglitazone respectively, were used for system development and evaluation. The system has found application on an Allium lusitanicum methanolic extract, containing saponins, a class of chemical compounds which have attracted interest as PPARs ligands because of their hypolipidemic and insulin-like properties. SIGNIFICANCE: A new SEC-AS-MS method has been developed for the affinity screening of PPARα and PPARγ ligands. The system proved to be highly specific and will be used to improve the throughput for the identification of new selective metabolites from natural souces targeting PPARα and PPARγ.


Assuntos
Cromatografia em Gel , PPAR alfa , PPAR gama , Extratos Vegetais , PPAR gama/metabolismo , PPAR gama/química , PPAR alfa/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ligantes , Espectrometria de Massas , Rosiglitazona/farmacologia , Rosiglitazona/química , Humanos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/análise , Pirimidinas
11.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732120

RESUMO

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Corpo Estriado , Modelos Animais de Doenças , Doença de Parkinson , Receptor A2A de Adenosina , Animais , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Ratos , Masculino , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptor A2A de Adenosina/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Triazóis/farmacologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Sprague-Dawley
12.
J Assoc Physicians India ; 72(1): 32-42, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38736072

RESUMO

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.


Assuntos
Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Pioglitazona , Tiazolidinedionas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Metformina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Feminino , Tiazolidinedionas/uso terapêutico , Tiazolidinedionas/administração & dosagem , Hemoglobinas Glicadas/análise , Índia , Pioglitazona/uso terapêutico , Pioglitazona/administração & dosagem , Glicemia/análise , Glicemia/efeitos dos fármacos , Adulto , Resultado do Tratamento , Idoso , Pirimidinas
14.
J Zhejiang Univ Sci B ; 25(5): 410-421, 2024 Mar 12.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38725340

RESUMO

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.


Assuntos
Neoplasias das Glândulas Suprarrenais , Cisteína , Metionina , Feocromocitoma , Pirimidinas , Tirosina , Feocromocitoma/metabolismo , Feocromocitoma/sangue , Humanos , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/sangue , Pirimidinas/metabolismo , Metionina/metabolismo , Tirosina/metabolismo , Tirosina/sangue , Cisteína/metabolismo , Masculino , Metabolômica/métodos , Feminino , Pessoa de Meia-Idade , Adulto , Redes e Vias Metabólicas
15.
BMJ Open Ophthalmol ; 9(1)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702178

RESUMO

BACKGROUND: Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods. METHODS: In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite. RESULTS: The docking results revealed that the compounds are having binding affinity in the range of -5.1 to -8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8-4.8 Å. CONCLUSION: In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria's outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS's binding to TLR4.


Assuntos
Síndromes do Olho Seco , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triterpenos Pentacíclicos , Pirimidinas , Receptor 4 Toll-Like , Síndromes do Olho Seco/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/química , Humanos , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/uso terapêutico , Triterpenos/farmacologia , Triterpenos/química , Simulação por Computador , Ligantes , Aminopiridinas/farmacologia , Aminopiridinas/química , Aminopiridinas/uso terapêutico
16.
BMC Public Health ; 24(1): 1275, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724960

RESUMO

OBJECTIVE: This study aimed to evaluate the cost-utility of the addition of vericiguat for treating chronic heart failure (CHF) in China from the healthcare payer's perspective. METHODS: A Markov model was built to estimate the cost and utility of treating CHF using vericiguat plus standard treatment (vericiguat group) vs. standard treatment alone (standard treatment group). The clinical parameters (mortality of cardiovascular and hospitalization rate of HF) were calculated according to the VICTORIA clinical trial. The HF cost and utility data were obtained from the literature published in China. One-way sensitivity analysis and probability sensitivity analysis were performed. RESULTS: According to the 13-year model, vericiguat was more expensive (155599.07 CNY vs. 259396.83 CNY) and more effective (4.41 QALYs vs. 4.54 QALYs). The incremental cost-utility ratio (ICUR) was 802389.27 CNY per QALY. One-way sensitivity analysis revealed that cardiovascular mortality in the two groups was the parameter that had the greatest impact on the results. The GDP per capita in 2022 in China was 85,700 CNY. The probability sensitivity analysis (PSA) showed that the probability of vericiguat being cost-effective was only 41.7% at the willingness-to-pay (WTP) threshold of 3 times GDP per capita (257,100 CNY). CONCLUSIONS: In China, the treatment of CHF with vericiguat is not cost-effective. The drug price could decrease to 145.8 CNY, which could be considered cost-effective.


Assuntos
Análise Custo-Benefício , Insuficiência Cardíaca , Cadeias de Markov , Pirimidinas , Volume Sistólico , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/economia , China , Pirimidinas/uso terapêutico , Pirimidinas/economia , Doença Crônica/tratamento farmacológico , Quimioterapia Combinada , Anos de Vida Ajustados por Qualidade de Vida , Masculino , Feminino , Compostos Heterocíclicos com 2 Anéis
17.
Sci Rep ; 14(1): 11609, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773214

RESUMO

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.


Assuntos
Biomarcadores Tumorais , Neoplasias Bucais , Pirimidinas , Uracila , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Uracila/metabolismo , Biomarcadores Tumorais/metabolismo , Pirimidinas/metabolismo , Feminino , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral , Idoso , Apirase/metabolismo
18.
J Agric Food Chem ; 72(20): 11331-11340, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38721769

RESUMO

Research on mesoionic structures in pesticide design has gained significant attention in recent years. However, the 1-position of pyridino[1,2-a]pyrimidine is usually designed with 2-chlorothiazole, 2-chloropyridine, or cyano moieties commonly found in neonicotinoid insecticides. In order to enrich the available pharmacophore library, here, we disclose a series of new pyridino[1,2-a]pyrimidine mesoionics bearing indole-containing substituents at the 1-position. Most of these target compounds are confirmed to have good insecticidal activity against aphids through bioevaluation. In addition, a three-dimensional structure-activity relationship model is established to allow access to optimal compound F45 with an LC50 value of 2.97 mg/L. This value is comparable to the property achieved by the positive control triflumezopyrim (LC50 = 2.94 mg/L). Proteomics and molecular docking analysis suggest that compound F45 has the potential to modulate the functioning of the aphid nervous system through its interaction with neuronal nicotinic acetylcholine receptors. This study expands the existing pharmacophore library for the future development of new mesoionic insecticides based on 1-position modifications of the pyridino[1,2-a]pyrimidine scaffold.


Assuntos
Afídeos , Desenho de Fármacos , Indóis , Inseticidas , Simulação de Acoplamento Molecular , Pirimidinas , Inseticidas/química , Inseticidas/síntese química , Inseticidas/farmacologia , Animais , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Afídeos/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/efeitos dos fármacos
19.
Biochim Biophys Acta Rev Cancer ; 1879(3): 189108, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38723697

RESUMO

Non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) are associated with a high mortality rate. Mutations in the V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) proto-oncogene GTPase (KRAS) are frequently observed in these cancers. Owing to its structural attributes, KRAS has traditionally been regarded as an "undruggable" target. However, recent advances have identified a novel mutational regulatory site, KRASG12C switch II, leading to the development of two KRASG12C inhibitors (adagrasib and sotorasib) that are FDA-approved. This groundbreaking discovery has revolutionized our understanding of the KRAS locus and offers treatment options for patients with NSCLC harboring KRAS mutations. Due to the presence of alternative resistance pathways, the use of KRASG12C inhibitors as a standalone treatment for patients with CRC is not considered optimal. However, the combination of KRASG12C inhibitors with other targeted drugs has demonstrated greater efficacy in CRC patients harboring KRAS mutations. Furthermore, NSCLC and CRC patients harboring KRASG12C mutations inevitably develop primary or acquired resistance to drug therapy. By gaining a comprehensive understanding of resistance mechanisms, such as secondary mutations of KRAS, mutations of downstream intermediates, co-mutations with KRAS, receptor tyrosine kinase (RTK) activation, Epithelial-Mesenchymal Transitions (EMTs), and tumor remodeling, the implementation of KRASG12C inhibitor-based combination therapy holds promise as a viable solution. Furthermore, the emergence of protein hydrolysis-targeted chimeras and molecular glue technologies has been facilitated by collaborative efforts in structural science and pharmacology. This paper aims to provide a comprehensive review of the recent advancements in various aspects related to the KRAS gene, including the KRAS signaling pathway, tumor immunity, and immune microenvironment crosstalk, as well as the latest developments in KRASG12C inhibitors and mechanisms of resistance. In addition, this study discusses the strategies used to address drug resistance in light of the crosstalk between these factors. In the coming years, there will likely be advancements in the development of more efficacious pharmaceuticals and targeted therapeutic approaches for treating NSCLC and CRC. Consequently, individuals with KRAS-mutant NSCLC may experience a prolonged response duration and improved treatment outcomes.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Acetonitrilas , Piperazinas , Piridinas , Pirimidinas
20.
Target Oncol ; 19(3): 473-480, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38724820

RESUMO

Futibatinib (LYTGOBI®) is an oral small molecule compound that selectively, irreversibly and potently inhibits the tyrosine kinase activity of fibroblast growth factor receptor (FGFR)1-4. It is approved in the EU, Japan and the USA for the treatment of adults with locally advanced or metastatic cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy. In the phase II part (FOENIX-CCA2) of a multinational phase I/II study in this patient population, monotherapy with futibatinib 20 mg once daily was associated with clinically meaningful and durable responses, sustained health-related quality of life (HR-QOL), and a manageable safety profile with supportive care and as-needed dose modifications. Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.


Cholangiocarcinoma (CCA) is an invasive tumour arising from the biliary tract. In the early stages it presents silently; this, along with its highly aggressive nature, means it is often diagnosed in the later (advanced) stages when surgery is not a treatment option. Up to half of CCAs have genetic aberrations that can be targeted for treatment. One such abnormality (present in 9­15% of CCAs) is found in fibroblast growth factor receptor (FGFR)2. The presence of this aberration promotes tumour survival and development. Futibatinib (LYTGOBI®) is an oral drug that strongly inhibits the activity of FGFR1­4. When given to adults with unresectable or metastatic CCA harbouring an FGFR2 aberration who had disease progression after systemic therapy, futibatinib 20 mg once daily produced clinically meaningful and prolonged responses and sustained health-related quality of life; moreover, with supportive care and as-needed dose modifications, futibatinib had a manageable safety profile. In a patient population that has limited treatment options and poor life expectancy, current evidence indicates that futibatinib is a valuable targeted therapy option.


Assuntos
Colangiocarcinoma , Humanos , Colangiocarcinoma/tratamento farmacológico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Metástase Neoplásica , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirazóis , Pirróis
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