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1.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069042

RESUMO

OBJECTIVES: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. METHODS: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. RESULTS: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. CONCLUSION: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Granulócitos/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Morfolinas/administração & dosagem , Paclitaxel/administração & dosagem , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/administração & dosagem , Resultado do Tratamento , Triazinas/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Clin Neurosci ; 89: 158-160, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119261

RESUMO

Intracranial myeloid sarcoma (IMS) is a rare central nervous system manifestation of hematopoietic neoplasms of myeloid origin. We report the first case of IMS treatment with an isocitrate dehydrogenase-2 (IDH-2) inhibitor, Enasidenib, following surgical resection, whole-brain radiation, and consolidation Etoposide/Cytarabine therapy. A 42-year-old female was diagnosed with IMS after a 10-year remission of her acute myeloid leukemia (AML). She underwent surgical debulking and had postoperative resolution of her visual symptoms. She received adjuvant radiation and medical management, and continues to show no evidence of recurrence or progression at 17 months postoperatively. This case is notable for an isolated IMS presentation in a patient with a very distant history of AML remission, and without evidence of concurrent bone marrow relapse. The goals of neurosurgical intervention should be symptomatic relief of mass effect and pathological diagnosis, due to the sensitivity of IMS to adjuvant radiation and medical management such as IDH-2 inhibitors.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mieloide Aguda/terapia , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/terapia , Adulto , Aminopiridinas/administração & dosagem , Citarabina/administração & dosagem , Feminino , Humanos , Quimioterapia de Indução/métodos , Indução de Remissão/métodos , Triazinas/administração & dosagem
3.
J Plant Physiol ; 261: 153427, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33940557

RESUMO

Metamitron (MET) is a fruitlet thinning compound for apple trees, needing better understanding of its action on leaf energy metabolism, depending on nighttime temperature. A trial under environmental controlled conditions was set with 'Golden Reinders' potted trees, under 25/7.5 and 25/15 °C (diurnal/nighttime temperature), with (MET, 247.5 ppm) or without (CTR) application, and considering the monitoring of photosynthetic and respiration components from day 1 (D1) to 14 (D14). Net photosynthesis (Pn) decline promoted by MET after D1 was not stomatal related. Instead, non-stomatal constraints, reflected on the photosynthetic capacity (Amax), included a clear photosystem (PS) II inhibition (but barely of PSI), as shown by severe reductions in thylakoid electron transport at PSII level, maximal (Fv/Fm) and actual (Fv'/Fm') PSII photochemical efficiencies, estimate of quantum yield of linear electron transport (Y(II)), and the rise in PSII photoinhibition status (Fs/Fm' and PIChr) and uncontrolled energy dissipation (Y(NO)). To Pn inhibition also contributed the impact in RuBisCO along the entire experiment, regardless of night temperature, here reported for the first time. Globally, MET impact on the photosynthetic parameters was usually greater under 7.5 °C, with maximal impacts between D4 and D7, probably associated to a less active metabolism at lower temperature. Cellular energy metabolism was further impaired under 7.5 °C, through moderate inhibition of NADH-dependent malate dehydrogenase (MDH) and pyruvate kinase (PK) enzymes involved in respiration, in contrast with the increase of dark respiration in MET 7.5 until D7. The lower impact on PK and MDH under 15 °C and a likely global higher active metabolism at that temperature would agree with the lowest sucrose levels in MET 15 at D4 and D7. Our findings showed that MET alters the cell energy machinery in a temperature dependent manner, affecting the sucrose balance mainly at 15 °C, justifying the observed greater thinning potential.


Assuntos
Malus/metabolismo , Fotossíntese , Folhas de Planta/metabolismo , Temperatura , Triazinas/metabolismo , Dióxido de Carbono/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Malus/efeitos dos fármacos , Fotoperíodo , Fotossíntese/efeitos dos fármacos , Complexo de Proteína do Fotossistema II/metabolismo , Folhas de Planta/efeitos dos fármacos , Tilacoides/efeitos dos fármacos , Tilacoides/metabolismo , Triazinas/administração & dosagem
4.
Food Chem ; 360: 130054, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34020367

RESUMO

A depletion study of toltrazuril and its metabolites was performed using 20 hens medicated via drinking water for two days in a dosage of 7 mg kg-1 per kg body weight. Afterward, eggs were collected for 42 days. Residues were analyzed in whole eggs and yolk and whites. Toltrazuril sulfone was found to be the most predominant in all matrices, the highest concentration was found in the yolk - 5567 µg kg-1, followed by whole eggs samples - 4767 µg kg-1 and egg whites - 532 µg kg-1. On last day toltrazuril sulfone were still detected - 22.5 µg kg-1. 70 days is required to concentration of toltrazuril sulfone reach zero. Administrating toltrazuril before the laying phase can pose a risk of residues of toltrazuril sulfone in eggs. Setting Maximum Residue Limit could reduce the risk of non-complaint samples and ensure the safety of consumers, but still requires 44 days of the withdrawal period.


Assuntos
Galinhas/metabolismo , Resíduos de Drogas/análise , Ovos/análise , Triazinas/análise , Administração Oral , Animais , Clara de Ovo/análise , Gema de Ovo/química , Feminino , Sulfonas/análise , Triazinas/administração & dosagem , Triazinas/metabolismo
5.
Expert Opin Drug Metab Toxicol ; 17(6): 725-731, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33899649

RESUMO

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have significant clinical efficacy for type 2 diabetes mellitus (T2DM). The combination of fotagliptin (FOT) with metformin (MET) is a promising therapeutic approach in MET-resistant patients. The aim of the present study was to evaluate the pharmacokinetic (PK) interaction between FOT and MET in healthy subjects after multiple-dose administration. METHODS: Eighteen participants received a randomized open-label, three period treatment that included MET 1000 mg alone, co-administration of FOT 24 mg and MET, followed by FOT 24 mg alone. Serial blood samples were collected for PK analysis, which included geometric mean ratios (GMRs) with 90% confidence intervals (CIs), area under the concentration-time curve (AUC), and maximum plasma concentration (Cmax). RESULTS: Analysis results showed that for FOT alone or combination therapy, the 90% CIs of the GMR for AUC0-24,ss and Cmax,ss were 102.08% (98.9%, 105.36%) and 110.65% (102.19%, 119.82%), respectively. For MET, they were 113.41% (100.32%, 128.22%) and 97.11% (83.80%, 112.55%) for AUC0-12,ss and Cmax,ss, respectively. FOT or MET monotherapy and the combination therapy with both drugs were well tolerated. CONCLUSIONS: No PK drug-drug interactions were found in the combination therapy with FOT and MET. Therefore, FOT can be co-administered with MET without dose adjustment. TRIAL REGISTRATION: The trial is registered at http://www.chinadrugtrials.org.cn/(Registration No. CTR20190221).


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Piperidinas/farmacocinética , Triazinas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Interações Medicamentosas , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Adulto Jovem
6.
BMC Cancer ; 21(1): 291, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740926

RESUMO

BACKGROUND: Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). METHODS: This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression. RESULTS: Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. CONCLUSIONS: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. TRIAL REGISTRATION: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirróis/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Estudos Retrospectivos , Triazinas/efeitos adversos
9.
Lancet ; 397(10275): 695-703, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33592176

RESUMO

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.


Assuntos
Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Sunitinibe/administração & dosagem , Idoso , Anilidas/efeitos adversos , Canadá , Carcinoma de Células Renais/mortalidade , Crizotinibe/administração & dosagem , Crizotinibe/efeitos adversos , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/efeitos dos fármacos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Piridinas/efeitos adversos , Sunitinibe/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Estados Unidos
10.
J Pharm Sci ; 110(3): 1316-1322, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33249050

RESUMO

Under pandemic-caused emergency, evaluation of the potential of existing antiviral drugs for the treatment of COVID-19 is relevant. Triazavirin, an antiviral drug developed in Russia for per-oral administration, is involved in clinical trials against SARS-CoV-2 coronavirus. This virus has affinity to epithelial cells in respiratory tract, so drug delivery directly in lungs may enhance therapeutic effect and reduce side effects for stomach, liver, kidneys. We elaborated ultrasonic method of triazavirin aerosol generation and investigated the inhalation delivery of this drug in mice. Mean particle size and number concentration of aerosol used in inhalation experiments are 560 nm and 4 × 105 cm-3, respectively. Aerosol mass concentration is 1.6 × 10-4 mg/cm3. Inhalation for 20 min in a nose-only chamber resulted in 2 mg/kg body delivered dose and 2.6 µg/mL triazavirin concentration in blood plasma. Elimination rate constant determined in aerosol administration experiments was ke = 0.077 min-1, which agrees with the value measured after intravenous delivery, but per-oral administration resulted in considerably lower apparent elimination rate constant of pseudo-first order, probably due to non-linear dependence of absorption rate on triazavirin concentration in gastrointestinal tract. The bioavailability of triazavirin aerosol is found to be 85%, which is about four times higher than for per-oral administration.


Assuntos
Aerossóis/administração & dosagem , Antivirais/administração & dosagem , Azóis/administração & dosagem , Nebulizadores e Vaporizadores , Triazinas/administração & dosagem , Administração por Inalação , Administração Oral , Aerossóis/farmacocinética , Animais , Antivirais/sangue , Antivirais/farmacocinética , Azóis/sangue , Azóis/farmacocinética , Disponibilidade Biológica , COVID-19/tratamento farmacológico , Sistemas de Liberação de Medicamentos/instrumentação , Vias de Eliminação de Fármacos , Desenho de Equipamento , Humanos , Masculino , Camundongos , Triazinas/sangue , Triazinas/farmacocinética
11.
Vet Parasitol ; 289: 109318, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33249303

RESUMO

The treatment effect of ethanamizuril (EZL) to broiler chickens experimentally infected with 8 × 104Eimeria tenella was evaluated. On the third day after infection, the broiler chickens were treated with EZL by gavage at doses of 2, 4, and 8 mg/kg body weight (bw) for once. For double administration, the challenged broiler chickens were administered EZL at doses of 1, 2, 4, and 8 mg/kg bw by gavage continually on the third day and fourth day and once a day. Throughout the experimental period, performance parameters including body weight gain, mortality, cecal lesion score, bloody diarrhoea and oocyst output were recorded. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). Meanwhile, the concentrations of EZL in chicken cecal contents were measured, and the data were analyzed with a non-compartmental model. The results indicated that EZL showed good anticoccidial activity at single dose of 4 mg/kgbw, with the corresponding ACI of 175.73. When the challenged chickens were treated with EZL under double administration, the EZL showed a medium level of anticoccidial activity at a dose of 2 mg/kg bw, with the corresponding ACI of 162.48. The maximum concentrations (Cmax) of EZL in content were 2.43 ±â€¯1.16, 4.28 ±â€¯1.56, and 8.57 ±â€¯1.33 mg/kg after the chickens were administrated at doses of 2, 4, and 8 mg/kg bw, respectively. The respective areas under the curve were 36.93 ±â€¯8.91, 96 ±â€¯16.31, and 262.76 ±â€¯51.52 mg/kg h. The respective half-lives (T1/2) were 10.82 ±â€¯2.02, 10.53 ±â€¯2.23, and 10.60 ±â€¯1.50 h. The results show that when the concentrations of EZL in chicken cecal contents reached 4.28 ±â€¯1.56 mg/kg, there is a significant therapeutic effect on chicken coccidiosis.


Assuntos
Galinhas/parasitologia , Coccidiose/veterinária , Coccidiostáticos/uso terapêutico , Eimeria tenella , Doenças das Aves Domésticas/parasitologia , Triazinas/uso terapêutico , Animais , Área Sob a Curva , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Coccidiostáticos/farmacocinética , Redução da Medicação , Conteúdo Gastrointestinal/química , Meia-Vida , Humanos , Doenças das Aves Domésticas/tratamento farmacológico , Triazinas/administração & dosagem , Triazinas/farmacocinética
12.
Eur J Pharm Sci ; 157: 105631, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115675

RESUMO

BACKGROUND: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients. METHODS: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). RESULTS: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group. CONCLUSIONS: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.


Assuntos
Amidas , COVID-19 , Dibenzotiepinas , Morfolinas , Pirazinas , Piridonas , Triazinas , Amidas/administração & dosagem , Amidas/sangue , Amidas/farmacocinética , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/farmacocinética , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Dibenzotiepinas/administração & dosagem , Dibenzotiepinas/sangue , Dibenzotiepinas/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/sangue , Morfolinas/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/sangue , Pirazinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Piridonas/farmacocinética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Avaliação de Sintomas , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/sangue , Triazinas/farmacocinética , Carga Viral/efeitos dos fármacos
13.
Eur J Pharmacol ; 890: 173611, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33017589

RESUMO

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.


Assuntos
Anti-Inflamatórios/farmacologia , Eosinófilos/metabolismo , Indóis/farmacologia , Receptores Histamínicos H4/antagonistas & inibidores , Triazinas/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Transformada , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Óleo de Cróton/toxicidade , Modelos Animais de Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Células Endoteliais/metabolismo , Eosinófilos/efeitos dos fármacos , Humanos , Indóis/administração & dosagem , Indóis/química , Masculino , Camundongos , Prurido/induzido quimicamente , Prurido/tratamento farmacológico , Triazinas/administração & dosagem , Triazinas/química , Triazinas/metabolismo
14.
Int J Biol Macromol ; 167: 756-765, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33285197

RESUMO

This study was conducted as a plot experiment to investigate the phytotoxicity effects of nano-encapsulated savory essential oil (EO) when it is incorporated separately into carbohydrate and protein natural polymers (Arabic gum-gelatin, apple pectin and gelatin) and two cross-linkers including one poly acid and one enzyme (citric acid and transglutaminase enzyme). Each product was tested as a pre-emergence herbicide against amaranth and tomato. The evaluations also involved determining the stability, morphology, encapsulation efficiency and release properties of the prepared formulations. Coating the savory EO with cross-linked biopolymers enhanced its stability and herbicidal activity, compared to the EO nano-emulsion without any polymer or cross-linker. Among the tested formulations, the strongest inhibitory effect against amaranth germination and growth was caused by Arabic gum-gelatin and apple pectin biopolymers at the concentration of 3 ml/L of EO, when cross-linked with citric acid. These two treatments had slight effects on tomato seedlings, however. The suppressive ability of the formulations was almost similar and comparable to the chemical herbicide metribuzin (1.75 g/L). In conclusion, Arabic gum-gelatin and apple pectin cross-linked by citric acid containing savory EO can be considered as potential, green and safe replacements for metribuzin in organic tomato production.


Assuntos
Gelatina/química , Goma Arábica/química , Herbicidas/química , Malus/química , Nanopartículas/química , Óleos Voláteis/química , Pectinas/química , Reagentes para Ligações Cruzadas/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Cromatografia Gasosa-Espectrometria de Massas , Germinação/efeitos dos fármacos , Química Verde , Herbicidas/administração & dosagem , Herbicidas/farmacologia , Nanopartículas/ultraestrutura , Tamanho da Partícula , Triazinas/administração & dosagem , Triazinas/química , Triazinas/farmacologia
15.
Drugs R D ; 21(1): 65-78, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33331996

RESUMO

BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Sulfonas/administração & dosagem , Triazinas/administração & dosagem , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Apetite/efeitos dos fármacos , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Miosite/enzimologia , Miosite/genética , Náusea/induzido quimicamente , Neoplasias/enzimologia , Neoplasias/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/genética , Sulfonas/efeitos adversos , Sulfonas/sangue , Sulfonas/farmacocinética , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/sangue , Triazinas/farmacocinética
16.
Gene ; 764: 145083, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32860902

RESUMO

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Moringa oleifera/química , Extratos Vegetais/administração & dosagem , Insuficiência Renal/prevenção & controle , Triazinas/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Moléculas de Adesão Celular/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Modelos Animais de Doenças , Poluentes Ambientais/toxicidade , Etanol/química , Contaminação de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Insuficiência Renal/sangue , Insuficiência Renal/induzido quimicamente , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Triazinas/administração & dosagem
17.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33320833

RESUMO

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirimidinonas/administração & dosagem , Pirróis/administração & dosagem , Triazinas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Camundongos , Camundongos SCID , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
18.
BMC Vet Res ; 16(1): 444, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203451

RESUMO

BACKGROUND: Triazine coccidiostats are widely used in chickens and turkeys for coccidiosis control. Ethanamizuril is a novel triazine compound that exhibits anticoccidial activity in poultry. This study was designed to evaluate the subchronic toxicity of ethanamizuril in beagle dogs at doses of 12, 60 or 300 mg/kg/day in diet for 90 days. RESULTS: Ethanamizuril was well tolerated at low and middle dosages in beagle dogs, and no drug-related toxical effects were observaed in terms of survival, clinical observations, organs weight and damage in these dose groups. However, in high dose administration group, food consumption and histologic changes in kidneys were noticed in both sexes of beagle dog, although the renal lesions were finally resolved at the end of 4 weeks exposure of ethanamizuril. CONCLUSIONS: No-observed-adverse-effect level (NOAEL) was considered for ethanamizuril at dose of 60 mg/kg/day in Beagle dog. This result added toxicity effects of ethanamizuril to the safety database, which might guide safely using of ethanamizuril as a novel coccidiostat.


Assuntos
Coccidiostáticos/toxicidade , Triazinas/toxicidade , Administração Oral , Animais , Coccidiostáticos/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Feminino , Rim/efeitos dos fármacos , Masculino , Triazinas/administração & dosagem
19.
PLoS One ; 15(8): e0234166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797098

RESUMO

Response to simultaneous stressors is an important facet of plant ecology and land management. In a greenhouse trial, we studied how eight plant species responded to single and combined effects of three soil concentrations of the phytotoxic munitions constituent RDX and two levels of water-resourcing. In an outdoor trial, we studied the effects of high RDX soil concentration and two levels of water-resourcing in three plant species. Multiple endpoints related to RDX fate, plant health, and plant survival were evaluated in both trials. Starting RDX concentration was the most frequent factor influencing all endpoints. Water-resourcing also had significant impacts, but in fewer cases. For most endpoints, significant interaction effects between RDX concentration and water-resourcing were observed for some species and treatments. Main and interaction effects were typically variable (significant in one treatment, but not in another; associated with increasing endpoint values for one treatment and/or with decreasing endpoint values in another). This complexity has implications for understanding how RDX and water-availability combine to impact plants, as well as for applications like phytoremediation. As an additional product of these greenhouse and outdoor trials, three plants native or naturalized within the southeastern United States were identified as promising species for further study as in situ phytoremediation resources. Plumbago auriculata exhibited relatively strong and markedly consistent among-treatment mean proportional reductions in soil RDX concentrations (112% and 2.5% of the means of corresponding values observed within other species). Likewise, across all treatments, Salvia coccinea exhibited distinctively low variance in mean leaf chlorophyll content index levels (6.5% of the means of corresponding values observed within other species). Both species also exhibited mean wilting and chlorosis levels that were 66% and 35%, and 67% and 84%, of corresponding values observed in all other plants, respectively. Ruellia caroliniensis exhibited at least 43% higher mean survival across all treatments than any other test species in outdoor trials, despite exhibiting similar RDX uptake and bioconcentration levels.


Assuntos
Substâncias Explosivas/toxicidade , Plantas/efeitos dos fármacos , Poluentes do Solo/toxicidade , Triazinas/toxicidade , Acanthaceae/efeitos dos fármacos , Acanthaceae/crescimento & desenvolvimento , Acanthaceae/fisiologia , Biodegradação Ambiental , Substâncias Explosivas/administração & dosagem , Substâncias Explosivas/farmacocinética , Instalações Militares , Desenvolvimento Vegetal/efeitos dos fármacos , Fenômenos Fisiológicos Vegetais/efeitos dos fármacos , Plumbaginaceae/efeitos dos fármacos , Plumbaginaceae/crescimento & desenvolvimento , Plumbaginaceae/fisiologia , Salvia/efeitos dos fármacos , Salvia/crescimento & desenvolvimento , Salvia/fisiologia , Poluentes do Solo/administração & dosagem , Poluentes do Solo/farmacocinética , Sudeste dos Estados Unidos , Estresse Fisiológico/efeitos dos fármacos , Triazinas/administração & dosagem , Poluentes Químicos da Água/administração & dosagem , Poluentes Químicos da Água/farmacocinética , Poluentes Químicos da Água/toxicidade , Recursos Hídricos
20.
N Engl J Med ; 383(4): 309-320, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32640124

RESUMO

BACKGROUND: Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018-2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed. RESULTS: A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out. CONCLUSIONS: Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.).


Assuntos
Antivirais/uso terapêutico , Transmissão de Doença Infecciosa/prevenção & controle , Vírus da Influenza A , Influenza Humana/prevenção & controle , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Criança , Pré-Escolar , Dibenzotiepinas , Método Duplo-Cego , Endonucleases/antagonistas & inibidores , Família , Feminino , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Influenza Humana/transmissão , Influenza Humana/virologia , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Morfolinas , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiepinas/administração & dosagem , Tiepinas/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos
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