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1.
J Pharmacol Exp Ther ; 374(2): 342-353, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32487538

RESUMO

Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1α and HIF-2α proteins, leading to an increase in EPO production, even in the presence of EPO-suppressing inflammatory cytokines. Roxadustat administered intermittently to healthy rats and cynomolgus monkeys increased circulating EPO levels, reticulocytes, blood Hb, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after five-sixth nephrectomy and in a rat model of anemia of inflammation with impaired iron metabolism induced by peptidoglycan-polysaccharide (PG-PS). In the PG-PS model, roxadustat significantly decreased hepatic expression of hepcidin, a hormone responsible for iron sequestration and functional iron deficiency, and increased expression of two genes involved in duodenal iron absorption: divalent metal transporter 1 and duodenal cytochrome b. In conclusion, by activating the HIF pathway, roxadustat increased EPO production, elevated Hb, corrected anemia, and improved iron homeostasis. The coordinated erythropoietic response stimulated by roxadustat, involving both EPO production and mobilization of iron stores, makes this compound a promising treatment of anemia of CKD and anemia associated with functional iron deficiency. SIGNIFICANCE STATEMENT: Roxadustat is a novel orally available small-molecule inhibitor of HIF prolyl hydroxylase enzymes that reversibly stabilizes HIF-α, thus activating transcription of HIF-dependent genes, including EPO and regulators of iron homeostasis. Activation of the HIF pathway by roxadustat induces erythropoiesis in healthy rats and monkeys and corrects experimentally induced anemia in rats. The coordinated erythropoietic response that increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of chronic kidney disease and anemia associated with functional iron deficiency.


Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Glicina/análogos & derivados , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/farmacologia , Insuficiência Renal Crônica/complicações , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Eritropoese/efeitos dos fármacos , Eritropoetina/metabolismo , Glicina/farmacocinética , Glicina/farmacologia , Glicina/uso terapêutico , Haplorrinos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoquinolinas/farmacocinética , Isoquinolinas/uso terapêutico , Masculino , Ratos
2.
Cancer Chemother Pharmacol ; 85(5): 959-968, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32296873

RESUMO

PURPOSE: Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). METHODS: Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4ß-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. RESULTS: Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4ß-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib. CONCLUSIONS: Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02074839.


Assuntos
Glicina/análogos & derivados , Neoplasias Hematológicas , Isocitrato Desidrogenase , Piridinas , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Mutação , Estadiamento de Neoplasias , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Resultado do Tratamento
3.
Ecotoxicol Environ Saf ; 196: 110549, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251953

RESUMO

Chemicals used to assure agricultural production and the feasibility of planting sites often end up in bodies of water used for crop irrigation. In a pot study, we investigated the consequences associated with the irrigation of maize with water contaminated by ciprofloxacin (Cipro; 0, 0.2, 0.8, 1.4 and 2.0 µg l-1) and/or glyphosate (0, 5, 25 and 50 mg l-1) on yields and food safety. Glyphosate in concentrations ≥25 mg l-1 prevented plant establishment, regardless of Cipro presence. Evaluations made at the V5 stage of plants reveal that Cipro concentrations ≥0.8 µg l-1 and glyphosate decreased photosynthesis and induced changes in leaf anatomy and stem biophysical properties that may contribute to decreased kernel yields. When those chemicals were applied together, kernel yield reductions were accentuated, evidencing their interactive effects. Irrigation with contaminated water resulted in accumulations of Cipro and glyphosate (as well as its metabolite, aminomethylphosphonic acid) in plant tissues. Accumulation of these chemicals in plant tissues such as leaves and kernels is a problem, since they are used to feed animals and humans. Moreover, these chemicals are of potential toxicological concern, principally due to residue accumulations in the food chain. Specially, the antibiotic residue accumulations in maize tissues can assist the induction of antibiotic resistance in dangerous bacteria. Therefore, we point out the urgency of monitoring the quality of water used for crop irrigation to avoid economic and food-quality losses.


Assuntos
Antibacterianos/toxicidade , Ciprofloxacino/toxicidade , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Zea mays/efeitos dos fármacos , Irrigação Agrícola , Animais , Antibacterianos/farmacocinética , Ciprofloxacino/farmacocinética , Produtos Agrícolas/anatomia & histologia , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/economia , Inocuidade dos Alimentos , Glicina/farmacocinética , Glicina/toxicidade , Humanos , Fotossíntese/efeitos dos fármacos , Folhas de Planta/anatomia & histologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Poluentes Químicos da Água/farmacocinética , Zea mays/anatomia & histologia , Zea mays/metabolismo
4.
Int J Mol Sci ; 21(3)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991850

RESUMO

Microglia are first-line defense antigen-presenting phagocytes in the central nervous system. Activated microglial cells release pro-inflammatory cytokines and can trigger an oxidative burst. The amino acid glycine exerts anti-inflammatory, immunomodulatory and cytoprotective effects and influences cell volume regulation. This study aimed to investigate the role of glycine in the modulation of inflammatory processes in mouse BV-2 microglial cells. Inflammatory stress was induced by lipopolysaccharide/interferon-γ (LPS/IFN-γ) treatment for 24 h in the absence or presence of 1 or 5 mM glycine. Cells were analyzed by flow cytometry for cell volume, side scatter, apoptosis/necrosis and expression of activation-specific surface markers. Apoptosis progression was monitored by life cell imaging. Reduced glutathione/oxidized glutathione (GSH/GSSG) ratios and release of the pro-inflammatory cytokines IL-6 and TNF-α were measured using luminescence-based assays and ELISA, respectively. We found that LPS/IFN-γ-induced apoptosis was decreased and the fraction of living cells was increased by glycine. Expression of the surface markers CD11b, CD54 and CD80 was dose-dependently increased, while IL-6 and TNF-α release was not altered compared to LPS/IFN-γ-treated cells. We showed that in BV-2 microglial cells glycine improves viability and counteracts deleterious responses to LPS/IFN-γ, which might be relevant in neurodegenerative processes associated with inflammation, like Alzheimer's or Parkinson's disease.


Assuntos
Apoptose/efeitos dos fármacos , Glicina/farmacocinética , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antígenos CD/metabolismo , Linhagem Celular Transformada , Glutationa/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos , Microglia/patologia , Oxirredução/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Ocul Pharmacol Ther ; 35(10): 542-550, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31674861

RESUMO

Purpose: Omidenepag isopropyl (OMDI) is a prodrug of OMD, a selective, nonprostaglandin, prostanoid EP2 receptor agonist. This phase I study aimed to investigate the pharmacokinetic properties, safety, and intraocular pressure (IOP)-lowering efficacy of OMDI. Methods: Fourteen healthy male volunteers (7 Japanese and 7 Caucasian) 20-35 years of age received 1 drop of OMDI 0.0025% at 9:00 h in both eyes for 7 days. Blood samples were taken predose and up to 8 h postdose on days 1, 3, and 7. The plasma concentration of OMD was determined using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters measured included the maximum plasma concentration (Cmax) and the half-life (t½) of OMD. IOP, adverse events (AEs), ophthalmic examinations, vital signs, and laboratory values were assessed. Results: Cmax for all subjects was reached after 10-15 min and decreased with a t½ of ∼30 min. Ad hoc statistical analyses found significant differences in some pharmacokinetic parameters between Japanese and Caucasian subjects, likely due to differences in body weight. These differences reduced over 7 days of dosing and were not thought to be clinically meaningful. There was no OMD accumulation after 7 days of repeated dosing. Mean IOP was reduced by ∼4-5 mmHg between baseline and 2 h postdose, remaining stable from day 3 onward. All AEs were mild and considered treatment related. Conclusions: Pharmacokinetic parameters of OMD were similar between Japanese and Caucasian subjects. There was no accumulation of OMD after 7 days of dosing. OMDI was well tolerated and demonstrated clinically significant IOP reductions.


Assuntos
Glicina/análogos & derivados , Pressão Intraocular/efeitos dos fármacos , Soluções Oftálmicas/farmacocinética , Pirazóis/farmacocinética , Piridinas/farmacocinética , Receptores de Prostaglandina E Subtipo EP2/agonistas , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Grupo com Ancestrais do Continente Europeu , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Voluntários Saudáveis , Humanos , Japão , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Adulto Jovem
6.
BMC Nephrol ; 20(1): 372, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619187

RESUMO

BACKGROUND: Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. METHODS: 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. RESULTS: Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. CONCLUSIONS: These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.


Assuntos
Anemia/sangue , Anemia/tratamento farmacológico , Barbitúricos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Hemoglobinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Barbitúricos/efeitos adversos , Barbitúricos/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Eritropoetina/sangue , Eritropoetina/uso terapêutico , Feminino , Ferritinas/sangue , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Hematínicos/uso terapêutico , Hematopoese/efeitos dos fármacos , Hepcidinas/sangue , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Transferrina/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue
7.
Nucl Med Biol ; 76-77: 21-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648134

RESUMO

OBJECTIVE: Given the requirements of high sensitivity and spatial resolution, the development of new positron emission tomography (PET) agents is required for PET renography. The objective of this study was to investigate a new fluorine-18 labeled hippurate analogue of picolinamide, N-(6-[18F]Fluoropyridin-3-yl)glycine, as a new renal PET agent for evaluating renal function. METHODS: N-(6-[18F]Fluoropyridin-3-yl)glycine was prepared via a two-step reaction, including the nucleophilic substitution reaction of Br with 18F using methyl 2-(6-bromonicotinamido)acetate as a precursor followed the hydrolysis with sodium hydroxide and purification by preparative-HPLC. The in vitro and in vivo stability were determined using HPLC, and the plasma protein binding (PPB) and erythrocyte uptake of N-(6-[18F]Fluoropyridin-3-yl)glycine were determined using blood collected from healthy rats at 5 min post-injection. Biodistribution and dynamic micro-PET/CT imaging studies were conducted in healthy rats. RESULTS: N-(6-[18F]Fluoropyridin-3-yl)glycine was prepared within 45 min with an uncorrected radiochemical yield of 24.5 ±â€¯6.7% (n = 6, based on [18F]F-) and a radiochemical purity of >98%. N-(6-[18F]Fluoropyridin-3-yl)glycine demonstrated good stability both in vitro and in vivo. The results of the biodistribution and dynamic micro-PET/CT imaging studies in normal rats indicated that N-(6-[18F]Fluoropyridin-3-yl)glycine was rapidly and exclusively excreted via the renal-urinary pathway. CONCLUSION: N-(6-[18F]Fluoropyridin-3-yl)glycine is has been shown to be a promising renal PET agent and warrants further evaluation of renal function.


Assuntos
Glicina/síntese química , Rim/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Animais , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Técnicas de Química Sintética , Eritrócitos/metabolismo , Feminino , Glicina/química , Glicina/metabolismo , Glicina/farmacocinética , Radioquímica , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
8.
J Environ Sci Health B ; 54(8): 681-692, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403392

RESUMO

Although there are many reports on the dangers posed by glyphosate, this herbicide is still one of the most popular and widely used total weed killers. Therefore, great effort should be made to minimize exposure to this herbicide and limit its losses into the environment. The aim of this study was to prepare a new formulation consisted of various molecular weight chitosans with glyphosate and their evaluation toward active substance release, phytotoxicity, and preliminary herbicidal efficiency. The phytotoxicity study of the obtained chitosan/glyphosate formulations was determined based on the Organisation for Economic Co-operation and Development 208 guideline. Among all tested formulations evaluated for phytotoxicity, that containing the highest molecular weight of chitosan was found to be the least toxic, showing simultaneously the most effective herbicidal activity against selected weeds. The release rate of glyphosate from the obtained formulations was dependent on the molecular weight and viscosity of chitosan.


Assuntos
Quitosana/química , Glicina/análogos & derivados , Herbicidas/química , Herbicidas/farmacologia , Quitosana/farmacologia , Glicina/química , Glicina/farmacocinética , Glicina/farmacologia , Herbicidas/farmacocinética , Peso Molecular , Plantas Daninhas/efeitos dos fármacos
9.
Biomed Chromatogr ; 33(11): e4658, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325170

RESUMO

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinética
10.
Mol Pharm ; 16(8): 3711-3719, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31299161

RESUMO

The unbiased cytotoxicity and blood-brain barrier (BBB) impermeability render common chemotherapeutics nonviable for treating glioblastoma (GBM) patients. Although rigosertib (RGS), a RAS effector protein inhibitor, has shown low toxicity to healthy cells and high efficacy toward various cancer cells by inactivating PI3K-Akt, it hardly overcomes the BBB barricade. Here, we report that RGS loaded in apolipoprotein E derived peptide (ApoE)-targeted chimaeric polymersomes (ApoE-CP) is safe and highly potent against human GBM in vivo. ApoE-CP exhibited stable loading of RGS in its lumen, giving RGS nanoformulations (ApoE-CP-RGS) with a size of 60 nm and reduction-triggered drug release behavior. Notably, ApoE-CP-RGS induction markedly enhanced the G2/M cell cycle arrest and inhibitory effect in U-87 MG glioblastoma cells compared with the nontargeted CP-RGS and free RGS. The therapeutic outcomes in orthotopic U-87 MG GBM models demonstrated that ApoE-CP-RGS brought about effective GBM inhibition, greatly prolonged survival time, and depleted adverse effects. Rigosertib formulated in ApoE-targeted chimaeric polymersomes has emerged as a novel, highly specific, efficacious, and nontoxic treatment for glioblastoma.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Glicina/análogos & derivados , Sulfonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Apolipoproteínas E/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Glioblastoma/patologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Humanos , Camundongos , Nanopartículas/química , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/metabolismo , Fragmentos de Peptídeos/química , Polímeros/química , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nutrients ; 11(6)2019 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-31208147

RESUMO

Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency-especially in obesity and associated metabolic disorders-and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glicina/farmacocinética , Doenças Metabólicas/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade/sangue , Disponibilidade Biológica , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Microbioma Gastrointestinal , Humanos , Fígado/metabolismo , Doenças Metabólicas/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações
12.
PLoS One ; 14(4): e0215466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30990837

RESUMO

The honeybee (Apis mellifera) has to cope with multiple environmental stressors, especially pesticides. Among those, the herbicide glyphosate and its main metabolite, the aminomethylphosphonic acid (AMPA), are among the most abundant and ubiquitous contaminant in the environment. Through the foraging and storing of contaminated resources, honeybees are exposed to these xenobiotics. As ingested glyphosate and AMPA are directly in contact with the honeybee gut microbiota, we used quantitative PCR to test whether they could induce significant changes in the relative abundance of the major gut bacterial taxa. Glyphosate induced a strong decrease in Snodgrassella alvi, a partial decrease of a Gilliamella apicola and an increase in Lactobacillus spp. abundances. In vitro, glyphosate reduced the growth of S. alvi and G. apicola but not Lactobacillus kunkeei. Although being no bee killer, we confirmed that glyphosate can have sublethal effects on the honeybee microbiota. To test whether such imbalanced microbiota could favor pathogen development, honeybees were exposed to glyphosate and to spores of the intestinal parasite Nosema ceranae. Glyphosate did not significantly enhance the effect of the parasite infection. Concerning AMPA, while it could reduce the growth of G. apicola in vitro, it did not induce any significant change in the honeybee microbiota, suggesting that glyphosate is the active component modifying the gut communities.


Assuntos
Bactérias/crescimento & desenvolvimento , Abelhas/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glicina/análogos & derivados , Isoxazóis/metabolismo , Tetrazóis/metabolismo , Animais , Bactérias/classificação , Glicina/farmacocinética , Glicina/toxicidade
13.
Nutrients ; 11(4)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31009990

RESUMO

BACKGROUND: Celiac disease (CD) is an immunologically-mediated disorder characterized by duodenal mucosa villi atrophy. Iron absorption is usually reduced in celiac patients making every kind of oral iron treatment unhelpful because of malasorption. Feralgine™ is a new product that has been demonstrated to be more bioavailable. As such, the aim of our study was to evaluate the absorption of Feralgine™ in adult patients with CD. METHODS: Twenty-six adults affected by Iron Deficiency Anemia (IDA), of which 14 were also affected by CD and 12 were not affected by CD, were enrolled. An oral iron absorption test (OIAT) was performed in each patient by administrating Feralgine™, and serum iron was evaluated at baseline (T0) and after 2 h (T1) from the oral iron ingestion. RESULTS: The OIAT was well tolerated in all patients, and, surprisingly, an equivalent statistically significant improvement in serum iron occurred in the two groups of patients (IDA plus CD: T0 = 28.21 µg/dL vs. T1 = 94.14 µg/dL p = 0.004 and IDA without CD: T0 = 34.91 µg/dL vs. T1 = 118.83 µg/dL, p = 0.0003). CONCLUSIONS: These results demonstrated the high absorption of Feralgine™ in celiac patients, confirming our previous data obtained with Ferrous Bysglicinate in children with CD.


Assuntos
Alginatos/uso terapêutico , Anemia Ferropriva/tratamento farmacológico , Doença Celíaca/complicações , Compostos Ferrosos/uso terapêutico , Glicina/uso terapêutico , Absorção Intestinal , Ferro/deficiência , Administração Oral , Adulto , Alginatos/farmacocinética , Anemia Ferropriva/complicações , Disponibilidade Biológica , Feminino , Compostos Ferrosos/farmacocinética , Glicina/farmacocinética , Humanos , Ferro/administração & dosagem , Ferro/sangue , Masculino
14.
Eur J Clin Pharmacol ; 75(8): 1099-1108, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31011758

RESUMO

PURPOSE: To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. METHODS: Three phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1-18, plus 250 mg ivosidenib on day 5 (NCT02831972). RESULTS: Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145-195) but had no effect on ivosidenib Cmax. CONCLUSIONS: No ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered. CLINICALTRIALS.GOV : NCT03071770, NCT02579707, and NCT02831972.


Assuntos
Antineoplásicos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Glicina/análogos & derivados , Itraconazol/farmacologia , Síndrome do QT Longo/epidemiologia , Piridinas/farmacocinética , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas/etnologia , Feminino , Interações Alimento-Droga/etnologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/etiologia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos
15.
Drug Res (Stuttg) ; 69(9): 505-511, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30822797

RESUMO

Ivosidenib is an approved drug for relapsed or refractory IDH1 mutant AML patients. The goal of the present work is to develop and validate an LC-MS/MS method for the quantitation of ivosidenib in mice dried blood spots (DBS) as per regulatory guideline in the linearity range of 1.10-3293 ng/mL. To date there is no bioanalytical method reported for quantitation of ivosidenib. The chromatographic resolution of ivosidenib and internal standard (warfarin) was achieved on a C18 column with an isocratic mobile phase. All validation parameters met the acceptance criteria. The intra- and inter-day precision was in the range of 2.79-10.5 and 5.76-9.02%, respectively. Ivosidenib was stable for 3 freeze/thaw cycles, up to 7 days at room temperature and for one month at -80°C. The applicability of the validated method is shown in a mice pharmacokinetic study. Ivosidenib was quantifiable up to 24 and 36 h following intravenous and oral administration to mice, respectively. The oral bioavailability was 48%. Comparison of DBS vs. plasma concentrations of ivosidenib showed excellent correlation, indicating DBS can be used as an alternative for plasma for pharmacokinetic analysis.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Piridinas/farmacocinética , Animais , Disponibilidade Biológica , Calibragem , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Glicina/sangue , Glicina/farmacocinética , Isocitrato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
16.
Drugs ; 79(5): 563-572, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805897

RESUMO

Roxadustat (Ai Rui Zhuo® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Isoquinolinas/farmacocinética , Inibidores de Prolil-Hidrolase/farmacocinética , Anemia/metabolismo , China , Aprovação de Drogas , Eritropoese/efeitos dos fármacos , Eritropoetina/metabolismo , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Hepcidinas/metabolismo , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/uso terapêutico , Inibidores de Prolil-Hidrolase/administração & dosagem , Inibidores de Prolil-Hidrolase/efeitos adversos , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal
17.
Cancer Chemother Pharmacol ; 83(5): 837-848, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758648

RESUMO

PURPOSE: Pharmacokinetics, absorption, metabolism, and excretion of ivosidenib, a mutant isocitrate dehydrogenase-1 inhibitor, were determined in healthy male subjects. METHODS: In this open-label phase I study, a single dose of [14C]ivosidenib (500 mg, 200 µCi/subject) was orally administered to eight subjects (CYP2D6 extensive, intermediate, or poor metabolizers) under fasted conditions. Blood, plasma, urine, and fecal samples were assayed for radioactivity and profiled for metabolites. Ivosidenib plasma concentrations were determined using LC-MS/MS. Metabolites were separated using reverse-phase HPLC and analyzed using high-resolution LC-MS and LC-MS/MS. RESULTS: Ivosidenib was readily absorbed and slowly eliminated from plasma. Median Tmax of both unchanged ivosidenib and radioactivity in plasma was 4 h. Plasma t½ values for total radioactivity and ivosidenib were 71.7 and 53.4 h, respectively. The mean AUC0-72 blood-to-plasma total radioactivity concentration ratio was 0.565, indicating minimal partitioning to red blood cells. CYP2D6 genotype had no effect on ivosidenib exposure. The mean recovery of radioactivity in excreta was 94.3% over 360 h post-dose; the majority was excreted in feces (77.4 ± 9.62%) with a low percentage recovered in urine (16.9 ± 5.62%), suggesting fecal excretion is the primary route of elimination. Unchanged [14C]ivosidenib accounted for 67.4% of the administered radioactivity in feces. Only [14C]ivosidenib was detected in plasma, representing 92.4% of the total plasma radioactivity. Thirteen metabolites were structurally identified in excreta. CONCLUSION: Ivosidenib was well-absorbed, slowly metabolized to multiple oxidative metabolites, and eliminated by fecal excretion, with no CYP2D6 effect observed. Unchanged ivosidenib was the only circulating species in plasma.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Radioisótopos de Carbono , Cromatografia Líquida , Fezes/química , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacocinética , Glicina/urina , Voluntários Saudáveis , Humanos , Limite de Detecção , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/urina , Espectrometria de Massas em Tandem , Distribuição Tecidual
18.
Clin Pharmacol Drug Dev ; 8(6): 765-778, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30720931

RESUMO

Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard-of-care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.


Assuntos
Barbitúricos/administração & dosagem , Barbitúricos/farmacocinética , Pé Diabético/tratamento farmacológico , Glicina/análogos & derivados , Administração Tópica , Adulto , Idoso , Barbitúricos/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Padrão de Cuidado
19.
J Biosci Bioeng ; 128(1): 80-87, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30782422

RESUMO

This study explored the characteristics of a newly isolated glyphosate (GLYP)-degrading bacterium Providencia rettgeri GDB 1, for GLYP bioremediation. Due to the serial selection pressure of high GLYP concentrations for enriched isolation, this highly tolerant GLYP biodegrader shows very promising capabilities for GLYP removal (approximately 71.4% degradation efficiency) compared to previously reported strains. High performance liquid chromatography analyses showed aminomethylphosphonic acid (AMPA) rather than sarcosine (SAR) to be the sole intermediate of GLYP decomposition via the AMPA formation pathway. Moreover, GLYP biodegradation was biochemically favorable in aerobic cultures due to its strong growth-associated characteristics. To the best of our knowledge, this is the first report to indicate that bacterial strains in the Providencia genus could demonstrate highly promising GLYP-degrading characteristics in environments with high GLYP contents.


Assuntos
Glicina/análogos & derivados , Herbicidas/farmacocinética , Providencia/metabolismo , Poluentes Químicos da Água/farmacocinética , Adaptação Biológica , Agricultura/métodos , Agroquímicos/isolamento & purificação , Agroquímicos/farmacocinética , Agroquímicos/toxicidade , Biodegradação Ambiental , Cromatografia Líquida de Alta Pressão/métodos , Glicina/isolamento & purificação , Glicina/farmacocinética , Glicina/toxicidade , Herbicidas/isolamento & purificação , Herbicidas/toxicidade , Humanos , Isoxazóis/química , Isoxazóis/metabolismo , Redes e Vias Metabólicas , Providencia/efeitos dos fármacos , Providencia/enzimologia , Providencia/crescimento & desenvolvimento , Sarcosina/química , Sarcosina/metabolismo , Tetrazóis/química , Tetrazóis/metabolismo , Poluentes Químicos da Água/isolamento & purificação , Poluentes Químicos da Água/toxicidade , Purificação da Água/métodos
20.
Minerva Pediatr ; 71(2): 139-143, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27830928

RESUMO

BACKGROUND: Celiac disease (CD) is an immunologically-mediated enteropathy resulting in small-bowel mucosal villous atrophy with crypt hyperplasia. Iron malabsorption is usually observed in CD. Only few studies investigated oral iron absorption in subjects with gastrointestinal diseases and Iron Deficiency Anemia (IDA), using the oral iron absorption test (OIAT). We considered useful to investigate the OIAT, using ferrous bisglycinate chelate (FBC), in patients with CD at diagnosis or on gluten free diet (GFD) from at least 1 year. METHODS: A total of 25 patients with CD (3-18 years old) and iron depletion, at diagnosis of CD (N.=12) or on GFD from at least 12 months (N.=13), were considered. Serum iron was evaluated at baseline (T0) and after 3 hours (T1) from the oral iron ingestion. Statistical analyses were conducted using SPSS 21.0 software for Mac. RESULTS: OIAT was well tolerated by all patients. An important increase of the serum iron at T1, of at least twice the baseline values, occurred in all patients except in one (P value <0.0005). CONCLUSIONS: These results demonstrated good efficacy of the FBC, not only in patients with CD on GFD but also in children with newly diagnosed CD with the characteristic intestinal lesions.


Assuntos
Anemia Ferropriva/etiologia , Doença Celíaca/fisiopatologia , Dieta Livre de Glúten , Compostos Ferrosos/administração & dosagem , Glicina/administração & dosagem , Administração Oral , Adolescente , Doença Celíaca/complicações , Doença Celíaca/dietoterapia , Criança , Pré-Escolar , Feminino , Compostos Ferrosos/farmacocinética , Glicina/farmacocinética , Humanos , Masculino
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