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1.
J Med Chem ; 64(3): 1435-1453, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492141

RESUMO

In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cobre/química , Nitrilos/química , Quinolonas/síntese química , Quinolonas/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Animais , Catálise , DNA Topoisomerases Tipo I/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Simulação de Acoplamento Molecular , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Methods Mol Biol ; 2207: 199-220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33113138

RESUMO

Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication.Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.


Assuntos
Antineoplásicos , Portadores de Fármacos , Neoplasias , Polietilenoglicóis/química , Quinolonas , Resinas Vegetais/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Quinolonas/química , Quinolonas/farmacocinética , Quinolonas/farmacologia
3.
Eur J Med Chem ; 197: 112259, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32334267

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and interstitial lung disease with the median survival of only 3-5 years. However, due to the unclear etiology and problems in accurate diagnosis, up to now only two drugs were approved by FDA for the treatment of IPF and their outcome responses are limited. Numerous studies have shown that TGF-ß is the most important cytokine in the development of pulmonary fibrosis and plays a role through its downstream signaling molecule TGF-binding receptor Smads protein. In this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as the most active one and could inhibit TGF-ß-induced collagen deposition of NRK-49F cells and mouse fibroblasts migration with comparable activity and lower cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen Ⅰ by inhibiting the TGF-ß/Smad dependent pathways and ERK1/2 and p38 pathways. Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more effectively alleviated collagen deposition in lung tissue and delayed the destruction of lung tissue structure both in bleomycin-induced prevention and treatment mice pulmonary fibrosis models. The immunohistochemical experiments further showed that 20f could block the expression level of phosphorylated Smad3 in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare with nintedanib) and an appropriate elimination half-life (T1/2 = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Quinolonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Actinas/metabolismo , Animais , Bleomicina , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Desenho de Fármacos , Fibrose Pulmonar Idiopática/induzido quimicamente , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/farmacocinética , Quinolonas/toxicidade , Ratos Sprague-Dawley , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta/metabolismo
4.
J Med Chem ; 63(7): 3577-3595, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32141297

RESUMO

Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57, with EC50 = 145 nM and a solubility of 33 µM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63, with EC50 = 162 nM and a solubility of 9 µM, showed lower clearance and seems better suited for in vivo studies. Using 57, we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.


Assuntos
Quinolonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Regulação Alostérica , Animais , Estabilidade de Medicamentos , Gânglios Espinais/efeitos dos fármacos , Humanos , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/metabolismo , Quinolonas/farmacocinética , Receptores Acoplados a Proteínas-G/genética , Relação Estrutura-Atividade
5.
J Med Chem ; 63(9): 4468-4483, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32023060

RESUMO

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Quinazolinas/uso terapêutico , Quinolonas/uso terapêutico , Regulação Alostérica , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Camundongos Nus , Conformação Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Basic Clin Pharmacol Toxicol ; 126(3): 236-246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31520576

RESUMO

Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic-induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty-one healthy volunteers receiving a 10-mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by HPLC-MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin Cmax and AUC0-12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.


Assuntos
Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Farmacogenética , Prolactina/metabolismo , Adolescente , Adulto , Antipsicóticos/farmacocinética , Aripiprazol/farmacocinética , Ritmo Circadiano , Estudos Cross-Over , Citocromo P-450 CYP2D6/genética , Feminino , Humanos , Ibuprofeno/farmacologia , Masculino , Piperazinas/farmacocinética , Quinolonas/farmacocinética , Receptor 5-HT2C de Serotonina/genética , Receptores de Dopamina D3/genética , Fatores Sexuais , Adulto Jovem
7.
Malar J ; 18(1): 291, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455339

RESUMO

BACKGROUND: The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. METHODS: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. RESULTS: A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM). CONCLUSIONS: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.


Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Plasmodium yoelii/efeitos dos fármacos , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Animais , Feminino , Camundongos , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética
8.
Expert Opin Pharmacother ; 20(16): 1925-1933, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31431092

RESUMO

Introduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as 'depression inadequately responding to the standard antidepressant drug,' carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression. Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology. Expert opinion: Brexpiprazole is a 'third-generation' antipsychotic featuring dopaminergic D2 and serotonergic 5-HT1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of 'inadequate response' to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D2 intrinsic activity, although the latter features a more potent serotonergic 5-HT2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quinolonas/uso terapêutico , Tiofenos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinética
9.
J Med Chem ; 62(14): 6575-6596, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31199148

RESUMO

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Sítio Alostérico/efeitos dos fármacos , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/genética , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Mutação Puntual , Quinolonas/farmacocinética
10.
J Cyst Fibros ; 18(5): 708-713, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31253540

RESUMO

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.


Assuntos
Aminofenóis , Benzodioxóis , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística , Indóis , Quinolonas , Testes de Função Respiratória/métodos , Suor , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminofenóis/farmacocinética , Benzodioxóis/administração & dosagem , Benzodioxóis/efeitos adversos , Benzodioxóis/farmacocinética , Disponibilidade Biológica , Criança , Pré-Escolar , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/efeitos adversos , Agonistas dos Canais de Cloreto/farmacocinética , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada/métodos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Mutação , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Suor/química , Suor/efeitos dos fármacos , Resultado do Tratamento
11.
Rapid Commun Mass Spectrom ; 33(21): 1643-1651, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31240777

RESUMO

RATIONALE: The complexity of central nervous system (CNS) drug delivery is the main obstacle with the blood-brain barrier (BBB) known to restrict access of most pharmaceutical drugs into the brain. Mass spectrometry imaging (MSI) offers possibilities for studying drug deposition into the CNS. METHODS: The deposition and spatial distribution of the two antiretroviral drugs elvitegravir and tenofovir in the brain were investigated in healthy female Sprague-Dawley rats following a single intraperitoneal administration (50 mg/kg). This was achieved by the utilization of quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS) and matrix-assisted laser desorption/ionization (MALDI) MSI. RESULTS: LC/MS/MS showed that elvitegravir has better BBB penetration, reaching maximum concentration in the brain (Cmax brain) of 976.5 ng/g. In contrast, tenofovir displayed relatively lower BBB penetration, reaching Cmax brain of 54.5 ng/g. MALDI-MSI showed the heterogeneous distribution of both drugs in various brain regions including the cerebral cortex. CONCLUSIONS: LC/MS/MS and MALDI-MSI provided valuable information about the relative concentration and the spatial distribution of the two common antiretroviral drugs. This study has also shown the capability of MALDI-MSI for direct visualization of pharmaceutical drugs in situ.


Assuntos
Antirretrovirais/farmacocinética , Encéfalo/metabolismo , Cromatografia Líquida/métodos , Neuroimagem/métodos , Quinolonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Tenofovir/farmacocinética , Animais , Antirretrovirais/química , Encéfalo/diagnóstico por imagem , Química Encefálica , Feminino , Quinolonas/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Tenofovir/química , Distribuição Tecidual
12.
Clin Pharmacol Drug Dev ; 8(7): 952-961, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31173673

RESUMO

Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug-drug interactions. The pharmacokinetic interaction of the HCV fixed-dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed-dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24 ) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0-24 of elbasvir was ∼2 times higher and the AUC0-24 of grazoprevir was ∼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0-24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.


Assuntos
Benzofuranos/farmacocinética , Cobicistat/farmacocinética , Emtricitabina/farmacocinética , Imidazóis/farmacocinética , Quinolonas/farmacocinética , Quinoxalinas/farmacocinética , Tenofovir/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Benzofuranos/administração & dosagem , Cobicistat/administração & dosagem , Esquema de Medicação , Combinação de Medicamentos , Interações Medicamentosas , Emtricitabina/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , Quinoxalinas/administração & dosagem , Tenofovir/administração & dosagem
13.
Am J Nephrol ; 49(6): 470-478, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112954

RESUMO

BACKGROUND: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. METHODS: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. RESULTS: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. CONCLUSION: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).


Assuntos
Anemia/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Quinolonas/administração & dosagem , Insuficiência Renal Crônica/complicações , Administração Oral , Adulto , Anemia/sangue , Anemia/etiologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Eritropoese/efeitos dos fármacos , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Resultado do Tratamento
14.
J Cyst Fibros ; 18(6): 838-843, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31053538

RESUMO

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.


Assuntos
Aminofenóis , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística , Pâncreas/enzimologia , Quinolonas , Suor , Ganho de Peso/efeitos dos fármacos , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminofenóis/farmacocinética , Índice de Massa Corporal , Pré-Escolar , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/efeitos adversos , Agonistas dos Canais de Cloreto/farmacocinética , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Feminino , Humanos , Ativação do Canal Iônico/genética , Testes de Função Hepática/métodos , Testes de Função Hepática/estatística & dados numéricos , Masculino , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Cloreto de Sódio/análise , Suor/química , Suor/efeitos dos fármacos , Transaminases/sangue , Resultado do Tratamento
16.
Clin Ther ; 41(3): 505-517.e0, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30819510

RESUMO

PURPOSE: Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment. METHODS: An open-label, single-dose, parallel group (moderate hepatic impairment group and healthy control group) PK study of nemonoxacin was conducted. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to detect the unchanged nemonoxacin concentration in blood and urine samples. The nonlinear mixed effects modeling tool NONMEN (version 7.3) was used to conduct the population PK analysis. The paired-t test was conducted to compare the PK parameters of the hepatic impairment group and the healthy control group by SPSS (Version 17.0). FINDINGS: Ten subjects for each group were enrolled into the PK study. The PK parameters as well as the plasma concentration-time and logarithmic concentration-time profiles after taking a 500-mg single dose of nemonoxacin showed few differences between the two groups (P > 0.05). The mean areas under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72 h) of the moderate hepatic impairment group and the healthy control group in the nemonoxacin PK study were 58.50 (17.30) mg·h/mL and 49.74 (10.16) mg·h/mL, respectively, giving a mean (SD) AUC0-72 h ratio of 1.15 (0.42) with a 90% CI of 0.91-1.39. A 3- compartment model was considered to be the best model for the data, especially in fitting the plasma point at low drug concentrations. Covariate analysis indicated that weight affected CL/F, V1/F, and V3/F and that eGFR only affected CL/F in the power function model, while gender affected V3/F in the linear model by forward selection and backward deletion. IMPLICATIONS: The population PK parameters of nemonoxacin were evaluated in patients with hepatic impairment. The hepatic function did not have a significant impact on the PK parameters of nemonxacin, but renal function was a meaningful covariate that is consistent with its PK characteristics. In this study, nemonoxacin was well tolerated in the patients with moderate hepatic impairment as well as in the healthy subjects. Based on these data, it is not necessary to consider dose adjustment of nemonoxacin in patients with mild or moderate hepatic impairment. ClinicalTrials.gov identifier: NCT02604498.


Assuntos
Antibacterianos/farmacocinética , Hepatopatias/metabolismo , Modelos Biológicos , Quinolonas/farmacocinética , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/urina , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Quinolonas/sangue , Quinolonas/urina
17.
J Pharm Biomed Anal ; 168: 163-173, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30807921

RESUMO

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is critically involved in cell migration, spreading and proliferation at the early step of various cancers. Small molecule inhibitors of FAK are effective to inhibit its activation in the process of tumor formation in cell. To better understand biotransformation of FAK inhibitors, this work has investigated in vitro phase I metabolism of inhibitors (namely PF-573228, PF-562271 and PF-03814735) by rat liver microsomes model. Using liquid chromatography - quadrupole time of flight mass spectrometry and tandem mass spectrometry (LC/Q-TOF/MS and MS/MS), three metabolites of PF-573228 and PF-562271 were observed and characterized, respectively. These in vitro metabolites were reported for the first time. The structures and fragmentation patterns of these metabolites were elucidated, and phase I metabolic pathways for FAK inhibitors were proposed. The main metabolic pathways of PF-573228 were hydroxylation, dehydrogenation and N-dealkylation. For PF-562271, they were hydroxylation and dehydrogenation. Hydroxylation was observed as the primary metabolism for PF-0381473.


Assuntos
Cromatografia Líquida/métodos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Remoção de Radical Alquila , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Hidroxilação , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Pirimidinas/farmacocinética , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacocinética , Sulfonas/farmacocinética
18.
Eur J Med Chem ; 166: 318-327, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30731400

RESUMO

Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. The compound also significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-ß1 induced MDA-MD-231 breast cancer cells. In addition, 8i demonstrated reasonable pharmacokinetic properties and exhibited extraordinary target selectivity over 468 kinases except for Flt3 (IC50 = 50 nM)), with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 µM, respectively. Compound 8i may serve as a new valuable lead compound for future anticancer drug discovery.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolonas/química , Quinolonas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antibacterianos/farmacocinética , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley
19.
J Psychosoc Nurs Ment Health Serv ; 57(2): 7-11, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703220

RESUMO

When dopamine was identified as a primary target for schizophrenia, the dopamine antagonists, now referred to as first-generation antipsychotics, were added to our pharmacopeia. In the 1990s, with the discovery of risperidone and clozapine, the mechanism of dopamine receptor antagonism was paired with serotonin receptor antagonism to give rise to second-generation antipsychotics. A decade later these mechanisms were further refined to selective dopamine receptors antagonism and serotonin receptors antagonism and agonism to create a modulation or stabilization of dopamine nerve firing in differential ways. This new wave may be referred to as the third generation. The current article reviews the pharmacodynamics and pharmacokinetics of these dopamine modulators. [Journal of Psychosocial Nursing and Mental Health Services, 57(2), 7-11.].


Assuntos
Antipsicóticos , Antagonistas dos Receptores de Dopamina D2 , Antagonistas da Serotonina , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Aripiprazol/farmacocinética , Aripiprazol/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Quinolonas/farmacocinética , Quinolonas/farmacologia , Receptores de Dopamina D2/agonistas , Esquizofrenia/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Tiofenos/farmacocinética , Tiofenos/farmacologia
20.
Ann Pharmacother ; 53(8): 833-844, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30739498

RESUMO

Objective: To synthesize data on the pharmacokinetics and safety of dolutegravir and elvitegravir in pregnant women living with HIV. Data Sources: A PubMed, EMBASE, Web of Science, and Google Scholar literature search (January 2010 to December 2018) was performed using the search terms dolutegravir, elvitegravir, women, pregnant*, and HIV. Additional reports were identified from conference abstracts and review of reference lists. Study Selection and Data Extraction: English-language studies reporting pharmacokinetic and/or safety data in pregnant women receiving dolutegravir or elvitegravir/cobicistat were included. Data Synthesis: A total of 17 studies were selected. Studies demonstrated a modest decrease in dolutegravir concentrations in pregnancy. Preliminary data suggest an increased risk of neural tube defects when dolutegravir is used at the time of conception. Available pharmacokinetic data in pregnant women showed significantly reduced plasma concentrations of elvitegravir/cobicistat which may increase the risk of virological failure. Current guidelines recommend that dolutegravir should not be initiated in women who have the potential to become pregnant or women in their first trimester of pregnancy and elvitegravir/cobicistat should be avoided during pregnancy. Relevance to Patient Care and Clinical Practice: This review highlights pharmacokinetic and safety data for dolutegravir and elvitegravir/cobicistat in pregnant women. Clinicians need to be aware of these data to convey the risks and benefits of using these agents in women of child-bearing potential. Conclusions: Changes in guideline recommendations reflect emerging data regarding the use of dolutegravir and elvitegravir/cobicistat in pregnancy. Until further information is available, raltegravir or other first-line agents are recommended for women with HIV planning to become pregnant.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV , Compostos Heterocíclicos com 3 Anéis , Complicações Infecciosas na Gravidez/tratamento farmacológico , Quinolonas , Feminino , Guias como Assunto , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Oxazinas , Piperazinas , Gravidez , Complicações Infecciosas na Gravidez/virologia , Piridonas , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Quinolonas/uso terapêutico
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