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1.
AAPS PharmSciTech ; 20(5): 210, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161269

RESUMO

Dorzolamide HCl (DRZ) ophthalmic drop is one of the most common glaucoma medications which rapidly eliminates after instillation leading to short residence time of the drug on cornea. The purpose of the present study is to develop a pH-triggered in situ gel system for ophthalmic delivery of DRZ for treatment of ocular hypertension. In this study, a 32 full factorial design was used for preparation of in situ gel formulations using different levels of Carbopol® and hydroxyl propyl methyl cellulose (HPMC). Rheological behavior, in vitro drug release, ex vivo corneal permeability, and IOP-lowering activity were investigated. DRZ solution (2% w/v) containing of 0.1% (w/v) Carbopol® and 0.1% (w/v) HPMC was selected as the optimal formulation considering its free flow under non-physiological conditions (initial pH and 25 ± 2°C) and transition to appropriate gel form under physiological circumstance (pH 7.4 and 34°C). This in situ gel presented the mucoadhesive property. Ex vivo corneal permeability of this combined solution was similar to those of DRZ solution. The developed formulation compared to the marketed drop (Biosopt®) and DRZ 2% solution had a better performance in intraocular pressure activity. The efficiency and long duration of IOP reduction could be due to the prolonged residence time of the in situ gel. The presence of Carbopol® as a pH triggered and mucoadhesive polymer causes to attach to the ocular mucosal surface for a long term.


Assuntos
Resinas Acrílicas/farmacocinética , Anti-Hipertensivos/farmacocinética , Portadores de Fármacos/farmacocinética , Derivados da Hipromelose/farmacocinética , Sulfonamidas/farmacocinética , Tiofenos/farmacocinética , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/síntese química , Administração Oftálmica , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Córnea/efeitos dos fármacos , Córnea/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Glaucoma/tratamento farmacológico , Glaucoma/metabolismo , Concentração de Íons de Hidrogênio , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/síntese química , Pressão Intraocular/efeitos dos fármacos , Pressão Intraocular/fisiologia , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/farmacocinética , Coelhos , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Suínos , Tiofenos/administração & dosagem , Tiofenos/síntese química
2.
Ecotoxicol Environ Saf ; 181: 138-145, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176248

RESUMO

While N-ethyl perfluorooctane sulfonamidoethanol (EtFOSE) is a precursor of perfluorooctane sulfonate (PFOS), its bioaccumulation, transformation and toxicological effects in earthworms (Eisenia fetida) exposed to quartz sands are poorly understood. The present study showed that except for parent EtFOSE, N-ethylperfluorooctane sulfonamide acetate (EtFOSAA), N-ethyl perfluorooctane sulfonamide (EtFOSA), perfluorooctane sulfonamide acetate (FOSAA), perfluorooctane sulfonamide (FOSA) and PFOS were detected in earthworms, with EtFOSAA as the primary biotransformation product. The biota-to-sand accumulation factor (BSAF) and uptake rate coefficient (ku) of EtFOSE were 5.7 and 0.542/d, respectively. The elimination rate constants (ke) decreased in the order EtFOSA (0.167/d) ∼ FOSAA (0.147/d) > FOSA (0.119/d) ∼ EtFOSAA (0.117/d) > EtFOSE (0.095/d) > PFOS (0.069/d). No significant effects were observed in malondialdehyde (MDA) contents and acetylcholinesterase (AChE) activities between EtFOSE treatments and controls. EtFOSE could cause significant accumulation of reactive oxygen species (ROS) in earthworms. Peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) were significantly activated by 41.4-74.3%, 37.2-44.4% and 32.4-52.3% from day 4-10, respectively, while 8-Hydroxy-2-deoxyguanosine (8-OHdG) levels were elevated by 47.7-70.3% from day 8-10, demonstrating that EtFOSE induced oxidative stress and oxidative DNA damage in earthworms. Significant increase of glutathione-S-transferase (GST) with 41.6-62.8% activation (8-10 d) gave indirect evidence on the conjugation of EtFOSE or its corresponding metabolites during phase II of detoxication. This study provides important information on the fate and potential risks of EtFOSE to terrestrial invertebrates.


Assuntos
Hidrocarbonetos Fluorados/toxicidade , Oligoquetos/metabolismo , Quartzo , Sulfonamidas/toxicidade , Animais , Biodegradação Ambiental , Biotransformação , Dano ao DNA , Fluorcarbonetos/metabolismo , Hidrocarbonetos Fluorados/farmacocinética , Estresse Oxidativo , Dióxido de Silício , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
3.
Hematol Oncol ; 37(4): 464-473, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31251400

RESUMO

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Terapia de Alvo Molecular , Indução de Remissão , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento
4.
Eur J Med Chem ; 177: 198-211, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136894

RESUMO

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aß aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Desenho de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Multimerização Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
5.
Chemosphere ; 227: 496-504, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004816

RESUMO

Wetland plants are proven to perform well in water treatment. However, the phytoremediation capability of wetland plants for antibiotics, especially the uptake and metabolism involved in vivo, is poorly understood. In this study, we investigated the removal, uptake, and specific metabolism by Canna indica and Iris pseudacorus of five sulfonamides (SAs) using hydroponic experiments for seven days. The removal of SAs ranged from 15.2% to 98.4% in the planted groups, whereas that in the unplanted control group was much lower (12.6%-39.9%). The accumulation of SAs in plants was in a concentration-dependent manner via an active process and is not a major removal mechanism (constituted 0.31%-3.62% of the total removal load in plant system). The results also showed differences in the removal and accumulation by plant species of SAs. The acetyl conjugates (N-acetyl SA) were formed, which significantly enhanced the uptake of SAs (P < 0.001) except sulfapyridine. The concentrations of N-acetyl SA accounted for only 0.4%-23.8% of the total SAs distribution in plants, suggesting the involvement of other metabolism pathways. Methylation and oxidation metabolites were identified in plant tissues and no SA-induced growth stress occurred, revealing that antibiotic metabolism in vivo should be associated with the ability of wetland plants to accumulate antibiotic and tolerate antibiotic stress.


Assuntos
Biodegradação Ambiental , Plantas/metabolismo , Sulfonamidas/metabolismo , Áreas Alagadas , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Transporte Biológico , Tolerância a Medicamentos , Iris/metabolismo , Estresse Fisiológico , Sulfonamidas/farmacocinética , Purificação da Água
6.
Comput Biol Chem ; 80: 234-243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009872

RESUMO

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R2>0.75) and predictability (Q2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica II/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Conjuntos de Dados como Assunto , Desenho de Drogas , Humanos , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
7.
Drug Des Devel Ther ; 13: 949-964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962677

RESUMO

Background: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. Subjects and methods: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. Results: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Conclusion: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.


Assuntos
Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Adulto Jovem
8.
Anticancer Res ; 39(3): 1309-1316, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842163

RESUMO

BACKGROUND/AIM: Pazopanib is approved for advanced soft tissue sarcoma (STS) patients. The aim of the study was to examine the usefulness of (18F)-Fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) imaging for early evaluation of the response of STS patients to pazopanib, as well as the association between pazopanib pharmacokinetics and early metabolic response. PATIENTS AND METHODS: Twenty STS patients underwent FDG-PET scans at baseline, two- and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks. RESULTS: After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis. CONCLUSION: In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders.


Assuntos
Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Sarcoma , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Adulto , Idoso , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Sarcoma/patologia , Resultado do Tratamento
9.
Pharmazie ; 74(2): 79-82, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782255

RESUMO

IG-105, N-(2, 6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel carbazole sulfonamide, shows a potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In the present study, a rapid and convenient liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and applied to the pharmacokinetic study of IG-105 in rats. Chromatographic separation was accomplished on a C18 column using an isocratic mobile phase of acetonitrile-water-acetic acid (56:44:0.2, v/v/v). The ion transitions of IG-105 and combretastatin A4 (internal standard) in selected reaction monitoring mode were m/z 398→154 and m/z 317→286, respectively. The assay exhibited good linearity over the range of 2-512 ng/mL. Intra- and inter-day precisions were within 8.2 %, and the accuracies ranged from -6.0 to 3.7 %. The extraction recoveries were higher than 90 %, and the matrix effects were negligible. All quality control samples were stable at different storage conditions. The validated LC-MS/MS method was successfully applied to a preclinical pharmacokinetic study of IG-105 in rats after a single oral dose of 100, 250, or 1000 mg/kg which showed tumor growth inhibition activity. The absorption of IG-105 was proved to be rapid but saturated to a certain extent into the blood circulation, from where it was distributed and eliminated gradually.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Carbazóis/sangue , Carbazóis/farmacocinética , Cromatografia Líquida/métodos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Moduladores de Tubulina , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Moduladores de Tubulina/sangue , Moduladores de Tubulina/farmacocinética
10.
Biomed Chromatogr ; 33(5): e4502, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725476

RESUMO

Macitentan is an endothelin receptor antagonist commonly used in the treatment of pulmonary arterial hypertension (PAH). A novel, rapid, simple and sensitive UPLC-MS/MS method was developed and validated for pharmacokinetic study and the determination of macitentan in PAH patients. Macitentan and bosentan, which are used as internal standards, were detected using atmospheric pressure chemical ionization in positive ion and multiple reaction monitoring mode by monitoring the mass transitions m/z 589.1 → 203.3 and 552.6 → 311.5, respectively. Chromatographic separation was performed on a reverse-phase C18 column (5 µm, 4.6 × 150 mm) with an isocratic mobile phase, which consisted of water containing 0.2% acetic acid-acetonitrile (90:10, v/v) at a flow rate of 1 mL/min. Retention times were 1.97 and 1.72 min for macitentan and IS, respectively. The calibration curve with high correlation coefficient (0.9996) was linear in the range 1-500 ng/mL. The lower limit of quantitation and average recovery values were determined as 1 ng/mL and 89.8%, respectively. This method is the first UPLC-MS/MS method developed and validated for the determination of macitentan from human plasma. The developed analytical method was fully validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery according to US Food and Drug Administration guidelines. The developed method was applied successfully for pharmacokinetic study and the determination of macitentan in PAH patients.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Hipertensão Pulmonar/tratamento farmacológico , Pirimidinas/sangue , Sulfonamidas/sangue , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
11.
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
12.
Med Chem ; 15(6): 676-684, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799793

RESUMO

BACKGROUND: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. OBJECTIVE: The goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. METHODS: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. RESULTS: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. CONCLUSION: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.


Assuntos
Agonismo Inverso de Drogas , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Animais , Humanos , Hidrocarbonetos Fluorados/química , Ligantes , Receptores X do Fígado/agonistas , Camundongos , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Ratos , Relação Estrutura-Atividade , Sulfonamidas/agonistas , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Células Th17
13.
Bioorg Med Chem ; 27(1): 216-223, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30528163

RESUMO

The [18F] isotope-labelled CB1 inverse agonist 3 was elaborated and synthesized for positron emission tomography scanning studies. After immediate purification and calibration with its unlabeled counterpart, compound 3 was intravenously injected in mice and revealed that its distribution percentage in brain over 90-min scans among five region of interests, including brain, liver, heart, thigh muscle and kidney was lower than 1%, thus providing direct evidence to justify itself as a peripherally restricted CB1 antagonist.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos de Flúor , Marcação por Isótopo , Masculino , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons/métodos , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Tiofenos/química , Tiofenos/farmacocinética , Distribuição Tecidual
14.
Drugs Today (Barc) ; 54(7): 407-421, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30090878

RESUMO

The fixed-dose combination of glecaprevir (GLE), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (PIB), an NS5A inhibitor, was recently approved for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1-6 (GT-1-6) without cirrhosis or with compensated cirrhosis, and for the treatment of HCV GT-1 patients who have failed treatment with either NS5A inhibitors or NS3/4A protease inhibitors, but not both. This combination, administered over 8 or 12 weeks, has resulted in high cure rates in all six HCV genotypes, including patients with HIV coinfection. GLE/PIB was well tolerated, with the most common adverse events being headache and fatigue. GLE/PIB is recommended to be taken as three tablets (total daily dose: GLE 300 mg and PIB 120 mg) orally once daily with food. No dose adjustment is required in patients with any degree of renal impairment or in patients undergoing hemodialysis. Dose adjustment is also not required in patients with Child-Pugh A liver disease. However, the use of GLE/PIB is not recommended in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Interações de Medicamentos , Farmacorresistência Viral , Humanos , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética
15.
Molecules ; 23(9)2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158432

RESUMO

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animais , Estabilidade de Medicamentos , Humanos , Indóis/química , Masculino , Microssomos Hepáticos/química , Estrutura Molecular , Especificidade de Órgãos , Hiperplasia Prostática/tratamento farmacológico , Ratos , Sulfonamidas/química
16.
Artigo em Inglês | MEDLINE | ID: mdl-29980099

RESUMO

Drugs modulating the metabotropic glutamate type 2 receptor (mGluR2) activity may have therapeutic benefits in treating a large spectrum of neuro-psychiatric disorders, from schizophrenia to Parkinson's disease, both as a symptomatic therapy and potential disease-modifying paradigm. LY-487,379 is a highly selective mGluR2 positive allosteric modulator that is widely used to study mGluR2 function using experimental animal models. The common marmoset is a small primate that has long been used in neuroscience. However, given its small size and small circulating blood volume, conducting studies to determine the PK profile of LY-487,379 is challenging. We developed and validated a sensitive and selective analytical method that enables quantification of LY-487,379 using a limited volume of plasma (10 µL). The analytical method consists of protein precipitation followed by high-performance liquid chromatography with heat assisted electrospray ionization mass spectrometry (HPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of acetonitrile and 0.01% formic acid in water on a Thermo Scientific Aquasil C18 analytical column (100 × 2.1 mm I.D., 5 µm) operating at 40 °C and at a flow rate of 300 µL/min. The method displays a linear relationship ranging from 0.2 to 100 ng/mL. Intra- and inter-day relative standard deviations are <1.4% and 7.9%, respectively and the relative error ranged from -6.9 to 9.7%. The method was used to quantify LY-487,379 in both rat and marmoset plasma, and PK parameters were determined after a single subcutaneous dose of 1.0 mg kg-1 in both species and significant differences in Cmax, AUC and T1/2 were observed.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Piridinas/sangue , Piridinas/farmacocinética , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Callithrix , Limite de Detecção , Modelos Lineares , Piridinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sulfonamidas/química
17.
Expert Opin Drug Metab Toxicol ; 14(6): 649-657, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29855221

RESUMO

INTRODUCTION: Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Administração Oral , Antivirais/farmacocinética , Antivirais/farmacologia , Benzazepinas/administração & dosagem , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Combinação de Medicamentos , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Imidazóis/farmacologia , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/farmacologia , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Japão , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
18.
Drugs Today (Barc) ; 54(4): 255-268, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29869647

RESUMO

Hepatitis C virus (HCV) is a significant public health burden worldwide, owing in large part to ineffective and poorly tolerated treatments. The antivirals have evolved over time to become more effective and better tolerated with cure rates increasing from an average of 50% to a complete virologic response. This article summarizes the latest Food and Drug Administration (FDA)-approved addition to combination treatment for patients with HCV, voxilaprevir plus sofosbuvir/velpatasvir.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Combinação de Medicamentos , Hepacivirus/patogenicidade , Hepatite C/diagnóstico , Hepatite C/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Compostos Macrocíclicos/efeitos adversos , Compostos Macrocíclicos/farmacocinética , Sofosbuvir/efeitos adversos , Sofosbuvir/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento
19.
Drugs R D ; 18(2): 149-159, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29856004

RESUMO

OBJECTIVE: The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist. METHODS: 240 healthy volunteers across eight phase I studies received single (0.1-200 mg) or multiple once- or twice-daily (10-120 mg) oral AZD5069 as solution, suspension, capsules or tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods. RESULTS: AZD5069 was rapidly absorbed (time to maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal delayed and reduced the peak plasma AZD5069 concentration (Cmax) by 50%, but total exposure (AUC) was unchanged (fed:fasting geometric mean ratio 90% confidence interval within 0.80-1.25). The plasma concentration of AZD5069 declined with an initial half-life of 4 h and terminal half-life of 11 h. Steady-state plasma concentrations were achieved within 2-3 days and accumulation was ~ 1.1-fold with twice-daily dosing. Systemic exposure was approximately proportional to dose. Intra- and inter-subject variability in AUC was 3-11 and 29-64%, respectively. Less than 5% of the AZD5069 dose was excreted as parent drug in the urine. Elderly subjects had 39% higher AZD5069 AUC and 21% higher Cmax than younger adults. Japanese subjects had similar or slightly higher exposure to AZD5069 than Caucasian subjects. Co-administration with ketoconazole resulted in 2.1-fold higher AUC and 1.6-fold higher Cmax. All formulations had similar bioavailability. CONCLUSIONS: AZD5069 demonstrated predictive linear pharmacokinetics with low intra- and moderate inter-subject variability and no major influences from ethnicity, age, food or formulation. Half-life data indicated suitability for twice-daily dosing. CLINICALTRIALS. GOV IDENTIFIERS: NCT00953888, NCT01051505, NCT01083238, NCT01100047, NCT01332903, NCT01480739, NCT01735240, NCT01989520.


Assuntos
Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Disponibilidade Biológica , Cápsulas/farmacocinética , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Cetoconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/sangue , Pirimidinas/urina , Soluções/farmacocinética , Sulfonamidas/sangue , Sulfonamidas/urina , Suspensões/farmacocinética , Comprimidos/farmacocinética , Adulto Jovem
20.
Arch Pharm Res ; 41(5): 564-570, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29728928

RESUMO

Tamsulosin, a selective antagonist of the α1-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2 mg oral dose of tamsulosin. After a washout period of 1 week, on day 8, the subjects were given a 60 mg oral dose of diltiazem three times daily for four days. On day 10, 1 h after the morning dose of diltiazem, they received a single 0.2 mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the Cmax and AUCinf of tamsulosin in each CYP2D6 genotype group were significantly increased (p < 0.0001 for all). The CL/F of tamsulosin was also significantly decreased after diltiazem treatment (both p < 0.0001). However, diltiazem did not affect the t1/2 of tamsulosin in each genotype group. In conclusion, diltiazem significantly increases exposure to tamsulosin regardless of the genotype of CYP2D6. Dose adjustment in the daily maintenance dose of tamsulosin may improve tolerability and safety in patients receiving diltiazem.


Assuntos
Citocromo P-450 CYP2D6/genética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Diltiazem/farmacologia , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Diltiazem/administração & dosagem , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Estudos Prospectivos , República da Coreia , Sulfonamidas/administração & dosagem , Tansulosina , Adulto Jovem
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