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1.
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
2.
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
3.
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
4.
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
5.
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 de Medicamentos/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
6.
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
7.
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
8.
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
9.
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
10.
Clin Pharmacol Ther ; 105(2): 376-387, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29446068

RESUMO

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.


Assuntos
Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Inibidores de Proteassoma/uso terapêutico , Animais , Disponibilidade Biológica , Compostos de Boro/farmacocinética , Compostos de Boro/farmacologia , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Glicina/farmacocinética , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Modelos Teóricos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/farmacologia
11.
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
12.
J Clin Pharm Ther ; 43(5): 633-639, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29981285

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. METHODS: This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ), and maximum concentration (Cmax ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax . Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram. RESULTS AND DISCUSSION: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred. WHAT IS NEW AND CONCLUSIONS: Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non-elderly healthy adult male Japanese subjects.


Assuntos
Glicina/análogos & derivados , Isoquinolinas/farmacocinética , Lantânio/efeitos adversos , Administração Oral , Adulto , Anemia/tratamento farmacológico , Anemia/etiologia , Área Sob a Curva , Estudos Cross-Over , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Isoquinolinas/uso terapêutico , Masculino , Insuficiência Renal Crônica/complicações , Adulto Jovem
13.
Br J Haematol ; 182(2): 231-244, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29938772

RESUMO

Weekly ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib-Rd in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/farmacocinética , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/análogos & derivados , Glicina/farmacocinética , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Lenalidomida/farmacocinética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
14.
N Engl J Med ; 378(25): 2386-2398, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29860938

RESUMO

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).


Assuntos
Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Seguimentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Hemoglobinas/análise , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piridinas/efeitos adversos , Piridinas/farmacocinética , Recidiva , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
15.
Eur J Drug Metab Pharmacokinet ; 43(6): 685-692, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29752643

RESUMO

BACKGROUND AND OBJECTIVES: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat. METHODS: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat. After a ≥ 7-day washout, subjects started Period 2 and received daily oral doses of 40 mg omeprazole on Days 1-9, and a single oral dose of 100 mg roxadustat on Day 7. Roxadustat pharmacokinetics were assessed on Days 1-4 in Period 1 and on Days 7-10 in Period 2. Primary endpoints were area under the concentration-time profile from the time of dosing extrapolated to infinity (AUCinf) and maximum concentration (Cmax). Safety was assessed by vital signs, laboratory tests, electrocardiograms, and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). RESULTS: Eighteen subjects were enrolled. The geometric least squares mean ratio for both AUCinf and Cmax of roxadustat (with omeprazole/alone) was 104.5%; 90% confidence intervals were within the no-effect boundaries of 80.0 and 125.0%, indicating no significant effect of omeprazole on the pharmacokinetics of roxadustat. No serious TEAEs were reported. CONCLUSION: Multiple daily oral doses of 40 mg omeprazole had no significant effect on the pharmacokinetics of a single oral dose of 100 mg roxadustat. Roxadustat was considered safe and well tolerated when administered alone or in combination with multiple daily oral doses of 40 mg omeprazole in healthy subjects.


Assuntos
Glicina/análogos & derivados , Isoquinolinas/administração & dosagem , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações de Medicamentos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia
16.
J Environ Sci Health B ; 53(8): 519-525, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-29708830

RESUMO

In this study, the innocuousness of different biomixtures employed for glyphosate degradation was tested through Eisenia fetida earthworms. Eight biomixtures were prepared with local materials: alfalfa straw (AS), wheat stubble (WS), river waste (RW) and two different soils (A and B). Each biomixture was divided into two equal portions: one without glyphosate application (control substrate) and the other was sprayed with a commercial glyphosate formulation of 1,000 mg glyphosate a.i. kg-1 biomixture (applied substrate). The bioassay started when all sprayed biomixtures reached high percentages of glyphosate degradation (spent biomixtures). Three parameters were studied: survival, adults and juveniles biomass and reproduction. The results allowed the identification of three biomixtures (AWS, BWS and BWSRW) for good maintenance and development of E. fetida. In addition, at the end of the bioassay two of the viable biomixtures (AWS and BWS) showed the highest performance of juvenile earthworms compared to a reference soil. The Principal Component Analysis (PCA) indicated that the biomixtures containing high silt and clay percentages and minor density renders higher values of earthworm growth and reproduction. Therefore, these innocuous biomixtures can be used as organic amendments or recycled materials for new treatments on biobeds.


Assuntos
Glicina/análogos & derivados , Oligoquetos/fisiologia , Poluentes do Solo/farmacocinética , Animais , Biodegradação Ambiental , Biomassa , Glicina/farmacocinética , Medicago sativa , Oligoquetos/efeitos dos fármacos , Caules de Planta , Análise de Componente Principal , Solo/química , Testes de Toxicidade Crônica , Triticum
17.
Anticancer Agents Med Chem ; 18(9): 1295-1302, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29521248

RESUMO

BACKGROUND: Breast cancer is a malignant disease with high mortality rate among women in the world. It is necessary to diagnose breast cancer at the early stage before it metastasizes in patients. OBJECTIVE: The aim of this study is the evaluation of 99mTc-(tricine)-HYNIC-Lys-FROP for breast tumor imaging. METHOD: Lys-FROP peptide was labeled with 99mTc using HYNIC as chelator and tricine as co-ligand. Specific binding of this radiolabeled peptide on breast cancerous cell was assessed in different cell lines as well as in tumor-bearing mice. RESULTS: HYNIC-Lys-FROP peptide was labeled with 99mTc at radiochemical purity more than 99%. It was observed high stability in normal saline and serum about 95%. The highest cellular uptake was observed in MCF-7 breast tumor cells treated with 99mTc-(tricine)-HYNIC-Lys-FROP as compared to other cell lines (lung, ovarian, T47D breast cancer cell lines). Biodistribution results in female MCF-7 tumor-bearing mice showed the relatively high tumor uptake and tumor-muscle ratio as 3.82 ± 0.66 after 15 min post-injection of 99mTc-(tricine)- HYNIC-Lys-FROP. Tumor uptake was reduced in mice that were co-injected with excess of unlabeled peptide to be 0.91 ± 0.08. CONCLUSION: Findings showed this radiolabeled peptide is a promising candidate for tumor targeting and molecular imaging of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Glicina/análogos & derivados , Hidrazinas/química , Niacinamida/análogos & derivados , Oligopeptídeos/química , Tecnécio/química , Animais , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacocinética , Feminino , Glicina/química , Glicina/farmacocinética , Humanos , Hidrazinas/farmacocinética , Células MCF-7 , Camundongos Nus , Niacinamida/química , Niacinamida/farmacocinética , Oligopeptídeos/farmacocinética , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética
18.
Eur J Med Chem ; 144: 767-773, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29291444

RESUMO

Overexpression of human epidermal receptor 2 (HER2) has given the opportunity for targeting and delivering of imaging radiotracers. The aim of this study was to evaluate the 99mTc-HYNIC-(EDDA/tricine)-(Ser)3-LTVSPWY peptide for tumor targeting and imaging of tumor with overexpression of HER2. The HYNIC-(Ser)3-LTVSPWY was labeled with 99mTc in presence of EDDA/tricine mixture as co-ligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular specific binding and tumor targeting. The high radiochemical purity of 99mTc-HYNIC (EDDA/tricine)-(Ser)3-LTVSPWY was obtained to be 99%. It exhibited high stability in normal saline and human serum. In HER2 binding affinity study, a significant reduction in uptake of radiolabeled peptide (7.7 fold) was observed by blocking SKOV-3 cells receptors with unlabeled peptide. The KD and Bmax values for this radiolabeled peptide were determined as 3.3 ±â€¯1.0 nM and 2.9 ±â€¯0.3 × 106 CPM/pMol, respectively. Biodistribution study revealed tumor to blood and tumor to muscle ratios about 6.9 and 4 respectively after 4 h. Tumor imaging by gamma camera demonstrated considerable high contrast tumor uptake. This developed 99mTc-HYNIC-(Ser)3-LTVSPWY peptide selectively targeted on HER2 tumor and exhibited a high target uptake combined with acceptable low background activity for tumor imaging in mice. The results of this study and its comparison with another study showed that 99mTc-HYNIC-(EDDA/tricine)-(Ser)3-LTVSPWY is much better than previously reported radiolabeled peptide as 99mTc-CSSS-LTVSPWY for HER2 overexpression tumor targeting and imaging.


Assuntos
Glicina/análogos & derivados , Neoplasias/diagnóstico , Oligopeptídeos/farmacocinética , Compostos de Organotecnécio/farmacocinética , Receptor ErbB-2/biossíntese , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Glicina/química , Glicina/farmacocinética , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/química , Relação Estrutura-Atividade , Distribuição Tecidual
19.
Invest New Drugs ; 36(3): 407-415, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28932928

RESUMO

This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783.


Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Radioisótopos de Carbono/farmacocinética , Glicina/análogos & derivados , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteassoma/farmacocinética , Inibidores de Proteassoma/uso terapêutico , Administração Oral , Idoso , Compostos de Boro/administração & dosagem , Compostos de Boro/sangue , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/sangue , Fezes , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/sangue , Radioatividade , Resultado do Tratamento , Urina
20.
Expert Opin Drug Metab Toxicol ; 14(1): 91-99, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29235380

RESUMO

INTRODUCTION: multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies. Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting.


Assuntos
Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteases/administração & dosagem , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Disponibilidade Biológica , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacocinética , Dexametasona/administração & dosagem , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Meia-Vida , Humanos , Lenalidomida , Mieloma Múltiplo/patologia , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Terapia de Salvação , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Distribuição Tecidual
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