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1.
Expert Opin Investig Drugs ; 30(4): 301-307, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33683991

RESUMO

Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line; and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukemia and has been studied in patients with advanced cholangiocarcinoma.Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches.Expert opinion: Ivosidenib is well tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p < 0.0001); it has also demonstrated a trend toward increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Glicina/análogos & derivados , Piridinas/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias do Sistema Biliar/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacologia , Humanos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacologia , Taxa de Sobrevida
2.
J Environ Sci Health B ; 56(2): 150-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33571041

RESUMO

Plant growth can be stimulated by low doses of glyphosate. The objective of this work was to evaluate the effect of low doses of glyphosate and sowing season on the growth of the early cycle common bean. Two experiments were conducted in the field, the first in the winter and the second in the wet season, with the early cycle common bean cultivar IAC Imperador. The experimental design was a randomized complete block design, consisting of low doses of glyphosate applied on phenological stage V4, with four replications. Environmental conditions, such as air temperature, interfered in the early cycle common bean response to low doses of glyphosate. In the winter season, a dose of 36 g a.e. ha-1 promoted growth in the common bean, and a dose of 7.2 g a.e. ha-1 improved the harvest index. In the wet season, there was no growth stimulus, and the harvest index increased with a dose of 36 g a.e. ha-1. The harvest index was the only characteristic improved in both seasons, but with different doses. Our study indicates that growth characteristics of early cycle common bean are stimulated by low doses of glyphosate, but this response is dependent on the growing environment.


Assuntos
Glicina/análogos & derivados , Herbicidas/administração & dosagem , Hormese , Phaseolus/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Phaseolus/efeitos dos fármacos , Estações do Ano
3.
J Nutr ; 151(3): 531-539, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33437999

RESUMO

BACKGROUND: Suckling piglets synthesize most of their creatine requirement, which consumes substantial amounts of arginine in order to synthesize guanidinoacetic acid (GAA) and methionine in order to transmethylate GAA to creatine. OBJECTIVES: To determine whether supplemental GAA or creatine spare arginine and/or methionine for protein synthesis and, if GAA is supplemented, whether excess methionine is needed for conversion to creatine. METHODS: Yucatan miniature piglets (9-11 days old; both sexes) were fed 1 of 5 elemental diets for 5 days: 1) low arginine (0.3 g·kg-1·d-1) and low methionine (0.20 g·kg-1·d-1; Base); 2) Base plus GAA (0.093 g·kg-1·d-1; +GAA); 3) Base plus GAA plus excess methionine (0.5 g·kg-1·d-1; +GAA/Met); 4) Base plus creatine (0.12 g·kg-1·d-1; +Cre); or 5) excess arginine (1.8 g·kg-1·d-1) and excess methionine (+Arg/Met). Isotope tracers were infused to determine whole-body GAA, creatine, and protein synthesis; tissues were analyzed for creatine synthesis enzymes and metabolite concentrations. Data were analyzed by 1-way ANOVA. RESULTS: : GAA and creatine syntheses were 115% and 32% higher, respectively, with the +Arg/Met diet (P < 0.0001), in spite of 33% lower renal L-arginine: glycine amidinotransferase activity (P < 0.0001) compared to Base, suggesting substrate availability dictates synthesis rather than enzyme capacity. GAA or creatine supplementation reduced arginine conversion to creatine by 46% and 43%, respectively (P < 0.01), but did not spare amino acids for whole-body protein synthesis, suggesting that limited amino acids were diverted to protein at the expense of creatine synthesis. The +GAA/Met diet led to higher creatine concentrations in the kidney (2.6-fold) and liver (7.6-fold) than the +GAA diet (P < 0.01), suggesting excess methionine is needed for GAA conversion to creatine. CONCLUSIONS: Piglets are capable of synthesizing sufficient creatine from the precursor amino acids arginine and methionine, or from GAA plus methionine.


Assuntos
Animais Recém-Nascidos/metabolismo , Arginina/administração & dosagem , Creatina/biossíntese , Glicina/análogos & derivados , Metionina/administração & dosagem , Suínos/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Arginina/metabolismo , Dieta/veterinária , Feminino , Glicina/administração & dosagem , Glicina/metabolismo , Marcação por Isótopo , Masculino , Metionina/metabolismo , Fenilalanina/metabolismo , Tirosina/metabolismo
4.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
5.
Life Sci ; 261: 118348, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860803

RESUMO

AIMS: 3,3'-Diindolylmethane (DIM) has limited anti-cancer effects in gastric cancer. Hydrogen sulfide (H2S) plays an important role in the tumor development and therapy, cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE), two key endogenous H2S biosynthesis enzymes, can affect endogenous H2S levels and alter cancer treatment. Our main objective was to investigate whether the aminooxyacetic acid (AOAA) and DL-Propargylglycine (PAG), two specific inhibitors of CBS and CSE, could assist DIM to exert a stronger anti-cancer effects in gastric cancer BGC-823 and SGC-7901 cells. MATERIALS AND METHODS: Cell proliferation was assayed by MTT and cell colony-forming assay. Apoptosis and migration were detected by Hoechst staining and scratch test respectively. Western blot was used to evaluate the expression of proteins related to proliferation, apoptosis and migration. KEY FINDINGS: Combination of AOAA or PAG with DIM synergistically inhibited proliferation and migration, increased apoptosis in gastric cancer cells. The p38-p53 axis was also further activated by the combination of AOAA or PAG with DIM. Exogenous H2S from sodium hydrosulfide, attenuated the efficacy of DIM in cancer cells by reducing the activation level of p38-p53 axis. Taken together, AOAA or PAG inhibited the expression of endogenous H2S biosynthesis enzymes and effectively enhanced susceptibility of gastric cancer to DIM through activating p38-p53 axis. SIGNIFICANCE: The current study highlight more precise requirements for the clinical application of sulfur-containing anti-cancer drugs, and open a new way to enhance the sensitivity of DIM in chemotherapy of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Indóis/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Alcinos/administração & dosagem , Alcinos/farmacologia , Ácido Amino-Oxiacético/administração & dosagem , Ácido Amino-Oxiacético/farmacologia , Anticarcinógenos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Sinergismo Farmacológico , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Indóis/administração & dosagem , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Ann Hematol ; 99(8): 1793-1804, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32613281

RESUMO

The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study (NCT02181413) demonstrated improved progression-free survival with ixazomib maintenance versus placebo post autologous stem cell transplant (ASCT) in multiple myeloma patients. We report additional safety data from TOURMALINE-MM3 to inform adverse event (AE) management recommendations. Patients were randomized 3:2 to receive ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for ~ 2 years or until progressive disease/toxicity. The initial 3-mg ixazomib dose was escalated to 4 mg in cycle 5, if tolerated in cycles 1-4. Safety was a secondary endpoint assessed in all treated patients; AEs were graded using Common Terminology Criteria for AEs v4.03. The rate of grade ≥ 3 AEs was higher in the ixazomib arm (19%) than in the placebo arm (5%), but the rate of discontinuation due to AEs was similar (7% vs. 5%). For AEs of clinical interest, rates were higher with ixazomib versus placebo: nausea 39% versus 15%, vomiting 27% versus 11%, diarrhea 35% versus 24%, thrombocytopenia 13% versus 3%, and peripheral neuropathy 19% versus 15%. However, the majority of events were low-grade, manageable with supportive therapy or dose reduction, and reversible, and did not result in discontinuation. There was no evidence of cumulative, long-term, or late-onset toxicity with ixazomib maintenance. Ixazomib is an efficacious and tolerable option for post-ASCT maintenance. AEs associated with ixazomib maintenance can be managed in the context of routine post-ASCT supportive care due to the limited additional toxicity. ClinicalTrials.gov NCT02181413.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo , Transplante de Células-Tronco , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Silicatos/administração & dosagem , Silicatos/efeitos adversos , Taxa de Sobrevida
7.
J Anim Sci ; 98(5)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386296

RESUMO

Thirty five barrows (initial body weight [BW]: 15.1 ± 1.0 kg) were used to determine the effect of partially replacing Gly + Ser with Thr in reduced crude protein (CP) diets on growth performance, protein deposition in carcass and viscera, and skin collagen abundance during the late nursery phase to 25 kg BW. Pigs were individually fed one of five iso-nitrogenous diets (n = 7) for 21 d. The basal diet met estimated essential amino acids (AA) requirements by using all essential AA plus Gly and Ser in free form (CON; 12.1% CP; as-fed, analyzed contents). The remaining four diets were formulated by reducing total Gly and Ser concentrations to 60% or 20% of the CON diet. The N removed with Gly and Ser was replaced with either crystalline Thr or Glu. Total analyzed Thr made up either 1.59% (T1; 12.5% CP) or 2.34% (T2; 12.2% CP) of the Thr-supplemented diets, and total analyzed Glu made up either 3.47% (G1; 12.7% CP) or 4.64% (G2; 12.9% CP) of the Glu-supplemented diets. Pigs were slaughtered on day 21 to determine body composition and skin collagen abundance via bright field microscopy. Overall, average daily gain (ADG) and G:F and final carcass weights were greater for pigs fed diets supplemented with Glu (G1 + G2) vs. those fed diets supplemented with Thr (T1 + T2; P < 0.05, P = 0.060, and P = 0.050 for ADG, G:F, and final carcass weight, respectively); intermediate values were observed for CON. Nitrogen retention in carcass plus viscera and the AA profile of deposited protein in the carcass were not influenced by dietary treatment. Pigs fed the T2 and G2 diets had greater retention of Thr (vs. CON and G2) and Glu (vs. CON and T2) in the viscera protein, respectively (P < 0.05). The apparent utilization efficiency of standardized ileal digestible Thr for protein deposition in carcass plus viscera was less for pigs fed T2 (15.1%) vs. those fed CON (56.7%) or G2 (58.6% ± 2.9%) diets (P < 0.001). Only pigs fed T1 had skin collagen abundance not different from CON; pigs fed G1, G2, and T2 had reduced skin collagen abundance compared with CON and T1 (P < 0.01). Using Glu as an N source when Gly and Ser were reduced to 60% and 20% of CON in reduced CP diets maintained ADG for pigs between 15 and 25 kg BW, whereas supplying Thr as a N source reduced ADG and carcass weight. When dietary Gly and Ser were supplied at 60% of CON, only Thr supplementation rescued skin collagen abundance. Therefore, supplemental Thr at excess levels is not sufficient to replace N from Gly and Ser in reduced CP diets fed to late nursery pigs, despite supporting skin collagen abundance as a secondary indicator of Gly status.


Assuntos
Composição Corporal/efeitos dos fármacos , Colágeno/metabolismo , Glicina/farmacologia , Serina/farmacologia , Suínos/fisiologia , Treonina/farmacologia , Ração Animal/análise , Animais , Dieta , Dieta com Restrição de Proteínas , Proteínas na Dieta/administração & dosagem , Proteínas na Dieta/farmacologia , Suplementos Nutricionais , Glicina/administração & dosagem , Masculino , Serina/administração & dosagem , Pele/química , Fenômenos Fisiológicos da Pele , Treonina/administração & dosagem , Vísceras , Ganho de Peso/efeitos dos fármacos
8.
Leuk Res ; 94: 106369, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442785

RESUMO

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.


Assuntos
Azacitidina/administração & dosagem , Glicina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Sulfonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Sulfonas/efeitos adversos
9.
Lancet Oncol ; 21(6): 796-807, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32416072

RESUMO

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Mutação , Piridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Europa (Continente) , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridinas/efeitos adversos , República da Coreia , Fatores de Tempo , Estados Unidos
10.
Leukemia ; 34(11): 3019-3027, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32327729

RESUMO

In the TOURMALINE-MM3 study, post-autologous stem cell transplantation maintenance therapy with the oral proteasome inhibitor ixazomib versus placebo significantly improved progression-free survival (PFS), with a favorable safety profile. With ixazomib versus placebo maintenance, deepening responses occurred in 139/302 (46%) versus 60/187 (32%) patients with very good partial response or partial response (VGPR/PR) at study entry (relative risk 1.41, P = 0.004), and median time to best confirmed deepened response was 19.9 versus 30.8 months (24-month rate: 54.2 versus 41.4%; hazard ratio (HR): 1.384; P = 0.0342). Median PFS in patients with VGPR/PR at study entry was 26.2 versus 18.5 months (HR: 0.636, P < 0.001) with ixazomib versus placebo; in a pooled analysis across arms, in patients with versus without deepening responses, the median PFS was not reached versus 15.9 months (HR: 0.245, P < 0.001). In patients with deepening responses, 24-month PFS rate was 77.4 versus 68.3% with ixazomib versus placebo (HR: 0.831; P = 0.466); in patients without deepening responses, median PFS was 17.9 versus 14.1 months (HR: 0.741; P = 0.028). These analyses demonstrate the significantly higher rate of deepening responses with ixazomib versus placebo maintenance and the association between deepening response and prolonged PFS.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Terapia Combinada , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Cuidados Pós-Operatórios , Resultado do Tratamento , Adulto Jovem
11.
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
12.
Ann Hematol ; 99(5): 1049-1061, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32236735

RESUMO

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/análogos & derivados , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida
13.
Poult Sci ; 99(3): 1551-1563, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32111322

RESUMO

Reducing dietary CP can reduce N pollution. Much research has been reported in corn-based diets; however, the amino acid (AA) profiles of wheat-based diets differ. Poor performance as a result of reduced protein (RP) has been overcome in corn-based diets with essential AA and glycine (Gly) supplementation. The current study examined RP levels and Gly in wheat-based diets. An industry standard protein (SP) diet plus 3 RP diets with and without Gly supplementation, to match the SP treatment at 0.713 and 0.648% digestible Gly for the grower and finisher periods respectively, were fed to male broilers from day 10 of age. Grower CP included 22.5, 20.6, 18.3, and 17.7% (days 10-21) and finisher CP included 19.7, 17.8, 16.2, and 15.5% (days 21-35). Performance, meat yield, N efficiency, water intake, and apparent ileal digestibility of N and AA were measured. No difference in body weight gain (BWG), feed intake, or feed conversion ratio (FCR) were observed at 20% CP compared to the SP treatment. However, further reducing protein reduced BWG (P < 0.001), feed intake (P < 0.001), and increased FCR (P < 0.001). Supplementation of 0.713% Gly in the grower period increased BWG (P < 0.001) and reduced FCR (P < 0.001). Relative meat yield was not affected by dietary protein, however reducing CP increased relative fat pad weight (P < 0.001). Nitrogen efficiency increased with decreased CP in both grower (R2 = 0.69) and finisher (R2 = 0.80) treatments. Water intake decreased (R2 = 0.83) with decreasing CP intake. Apparent ileal digestibility of AA and N were higher in RP diets (P < 0.05). The benefits of reduced water intake and increased N efficiency and the disadvantages of poor performance and increased body fat in RP corn-based diets have been identified in RP wheat-based diets. Furthermore, at 18.5% CP the supplementation of crystalline AA and Gly can maintain BWG and FCR observed in SP diets.


Assuntos
Galinhas/fisiologia , Dieta com Restrição de Proteínas/veterinária , Proteínas na Dieta/análise , Digestão/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Glicina/metabolismo , Nitrogênio/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Íleo/fisiologia , Masculino , Carne/análise , Distribuição Aleatória , Triticum/química
14.
Ann Hematol ; 99(6): 1273-1281, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193630

RESUMO

Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22 months. Median age was 68 (range 38-90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24 months (95% CI 17-30). PFS was 77% and 47% at 12 and 24 months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24 months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24 m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24 months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24 months after a bortezomib induction and for those who have a more indolent disease phenotype.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Pragmáticos como Assunto/métodos , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Dados , Feminino , Seguimentos , Glicina/administração & dosagem , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Ensaios Clínicos Pragmáticos como Assunto/estatística & dados numéricos , Recidiva , Resultado do Tratamento
15.
PLoS One ; 15(1): e0226806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31905208

RESUMO

The emergence of creatine as a potential cognitive enhancement supplement for humans prompted an investigation as to whether supplemental creatine could enhance spatial memory in young swine. We assessed memory performance and brain concentrations of creatine and its precursor guanidinoacetic acid (GAA) in 14-16-week-old male Yucatan miniature pigs supplemented for 2 weeks with either 200 mg/kg∙d creatine (+Cr; n = 7) or equimolar GAA (157 mg/kg∙d) (+GAA; n = 8) compared to controls (n = 14). Spatial memory tests had pigs explore distinct sets of objects for 5 min. Objects were spatially controlled, and we assessed exploration times of previously viewed objects relative to novel objects in familiar or novel locations. There was no effect of either supplementation on memory performance, but pigs successfully identified novel objects after 10 (p < 0.01) and 20 min (p < 0.01) retention intervals. Moreover, pigs recognized spatial transfers after 65 min (p < 0.05). Regression analyses identified associations between the ability to identify novel objects in memory tests and concentrations of creatine and GAA in cerebellum, and GAA in prefrontal cortex (p < 0.05). The concentration of creatine in brain regions was not influenced by creatine supplementation, but GAA supplementation increased GAA concentration in cerebellum (p < 0.05), and the prefrontal cortex of +GAA pigs had more creatine/g and less GAA/g compared to +Cr pigs (p < 0.05). Creatine kinase activity and maximal reaction velocity were also higher with GAA supplementation in prefrontal cortex (p < 0.05). In conclusion, there appears to be a relationship between memory performance and guanidino compounds in the cerebellum and prefrontal cortex, but the effects were unrelated to dietary supplementation. The cerebellum is identified as a target site for GAA accretion.


Assuntos
Ração Animal/análise , Encéfalo/fisiologia , Creatina/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais , Glicina/análogos & derivados , Memória Espacial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Glicina/administração & dosagem , Masculino , Memória Espacial/efeitos dos fármacos , Suínos , Porco Miniatura , Desmame
16.
J Anim Sci ; 98(2)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31965147

RESUMO

A total of 96 newly weaned barrows (initial body weight [BW]: 6.3 ± 0.5 kg) were used to determine the effect of a low crude protein (CP) diet supplemented with Gly and Ser on growth and skin collagen abundance. Barrows were assigned to one of three experimental diets in a three-phase feeding program fed for 35 days (n = 8; pen was the experimental unit): 1) corn-soybean meal diet (CON; 20.3% to 23.1% CP; as-fed, analyzed contents); 2) low CP diet (14.8% to 21.4% CP) supplemented with Gly and Ser (G + S) to the same concentrations as CON; 3) low CP diet supplemented with Glu to maintain the same CP concentration as the G + S diet (GLU; 15.0% to 22.1% CP). On days 21 and 35, eight pigs per treatment were euthanized for the determination of physical and chemical body composition and skin collagen abundance. Pigs fed the CON diet had greater overall ADG and final BW compared to pigs fed GLU and G + S (P < 0.01). Over the entire 35-day experimental period, ADFI was not influenced by dietary treatment but G:F tended to be greater for pigs fed CON than G + S (P = 0.084), while intermediate values were observed for GLU. Carcass weights on days 21 and 35 were greater for pigs fed CON than G + S or GLU (P < 0.01). Viscera weights on day 21 were greater for CON than G + S and GLU (P < 0.05) and on day 35 were greater for CON than G + S (P < 0.05) with intermediate values observed for GLU. The N intake (g/d) between days 0 and 35 was greater for CON than G + S or GLU (P < 0.05) and N retention in combined carcass and viscera was greater for CON than G + S (P < 0.01) with intermediate values observed for GLU. No treatment effects were observed for efficiency of N utilization. Between days 0 and 21 however, the efficiency of using dietary N for N retention in carcass and viscera tended to be less for pigs fed CON vs. GLU (73.8% vs. 91.6%), while intermediate values were observed for G + S (84.3%; P = 0.095). Pigs fed CON and G + S diets had greater skin collagen abundance than pigs fed GLU on days 21 and 35 (P < 0.01). Supplementing low CP diets with Glu or with Gly and Ser at the levels used in the current study did not maintain ADG or combined carcass and viscera N retention and only the G + S diet supported skin collagen abundance not different from pigs fed CON. The importance of meeting essential AA requirements for growth are well accepted, but supplementing specific NEAA may be needed when feeding reduced CP diets to newly weaned pigs to support secondary indicators of AA status, such as skin collagen abundance.


Assuntos
Colágeno/metabolismo , Dieta com Restrição de Proteínas/veterinária , Suplementos Nutricionais , Glicina/farmacologia , Serina/farmacologia , Suínos/crescimento & desenvolvimento , Ração Animal/análise , Animais , Composição Corporal , Dieta/veterinária , Glicina/administração & dosagem , Masculino , Serina/administração & dosagem , Pele/metabolismo , Soja , Suínos/fisiologia
17.
Int J Oral Maxillofac Implants ; 35(35): 197-206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923303

RESUMO

PURPOSE: Numerous approaches have been proposed for the treatment of peri-implantitis, but to date, none has been identified as the most effective. This study compared the efficacy of implantoplasty and glycine air polishing for the surgical treatment of peri-implantitis. MATERIALS AND METHODS: This prospective, randomized, parallel-group trial included 31 patients presenting with 42 implants with peri-implantitis. Patients underwent surgical treatment by implantoplasty (test group, n = 22) or glycine air polishing (control group, n = 20). Clinical parameters (Plaque Index), bleeding on probing (BOP), suppuration on probing (SOP), probing pocket depth (PPD), relative attachment level (RAL), and mucosal recession were assessed before surgery (baseline), and at 3 months and 6 months after surgery. Bone loss was recorded at baseline and 6 months. Two composite outcomes were also evaluated, according to the following definitions: (1) mean PPD reduction ≥ 0.5 mm + no further loss of bone; (2) PPD ≤ 5 mm, absence of BOP/SOP, and no additional mean bone loss ≥ 0.5 mm. RESULTS: Plaque Index remained low (< 0.5) in both groups for the duration of the study. Mean BOP, SOP, PPD, and RAL were greatly reduced at 3 months in both groups, and remained low between 3 months and 6 months. Bone loss was stable in the implantoplasty group, and slight bone gain (0.5 mm) was observed in the glycine air-polishing group. There were no significant differences between the two groups in any parameter, and composite treatment outcomes were similar in both groups, irrespective of the definition. CONCLUSION: Within the limitations of this 6-month follow-up study, implantoplasty is as effective as glycine air polishing for the surgical treatment of peri-implantitis.


Assuntos
Abrasão Dental por Ar , Glicina , Peri-Implantite , Seguimentos , Glicina/administração & dosagem , Humanos , Peri-Implantite/cirurgia , Índice Periodontal , Estudos Prospectivos , Resultado do Tratamento
18.
Appl Environ Microbiol ; 86(5)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-31836576

RESUMO

Despite glyphosate's wide use for weed control in agriculture, questions remain about the herbicide's effect on soil microbial communities. The existing scientific literature contains conflicting results, from no observable effect of glyphosate to the enrichment of agricultural pathogens such as Fusarium spp. We conducted a comprehensive field-based study to compare the microbial communities on the roots of plants that received a foliar application of glyphosate to adjacent plants that did not. The 2-year study was conducted in Beltsville, MD, and Stoneville, MS, with corn and soybean crops grown in a variety of organic and conventional farming systems. By sequencing environmental metabarcode amplicons, the prokaryotic and fungal communities were described, along with chemical and physical properties of the soil. Sections of corn and soybean roots were plated to screen for the presence of plant pathogens. Geography, farming system, and season were significant factors determining the composition of fungal and prokaryotic communities. Plots treated with glyphosate did not differ from untreated plots in overall microbial community composition after controlling for other factors. We did not detect an effect of glyphosate treatment on the relative abundance of organisms such as Fusarium spp.IMPORTANCE Increasing the efficiency of food production systems while reducing negative environmental effects remains a key societal challenge to successfully meet the needs of a growing global population. The herbicide glyphosate has become a nearly ubiquitous component of agricultural production across the globe, enabling an increasing adoption of no-till agriculture. Despite this widespread use, there remains considerable debate on the consequences of glyphosate exposure. In this paper, we examine the effect of glyphosate on soil microbial communities associated with the roots of glyphosate-resistant crops. Using metabarcoding techniques, we evaluated prokaryotic and fungal communities from agricultural soil samples (n = 768). No effects of glyphosate were found on soil microbial communities associated with glyphosate-resistant corn and soybean varieties across diverse farming systems.


Assuntos
Bactérias/isolamento & purificação , Fungos/isolamento & purificação , Glicina/análogos & derivados , Herbicidas/administração & dosagem , Microbiota , Raízes de Plantas/microbiologia , Microbiologia do Solo , Glicina/administração & dosagem , Maryland , Microbiota/efeitos dos fármacos , Mississippi , Micobioma , Soja/crescimento & desenvolvimento , Zea mays/crescimento & desenvolvimento
19.
Andrologia ; 52(2): e13496, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31793716

RESUMO

The main aim of this study was to assay the testicular H2 S levels in the varicocele rat model and then to investigate the protective effects of NaHS on morphometric changes, sperm parameters, oxidative stress and apoptosis markers in rat's testis. D,L-propargylglycine (PAG) was administrated to show the effects of cystathionine γ-lyase enzyme (CSE) inhibition in the varicocele. Rats were assigned to four groups: (a) Sham, (b) varicocele, (c) varicocele + PAG and (d) varicocele + NaHS. Animals in varicocele + NaHS group received 30 µmol/L NaHS in drinking water for 56 days. In the varicocele + PAG group, animals received PAG 19 mg/kg twice a week. Morphometric assessment, oxidative stress markers, testicular H2 S levels, sperm parameters, TUNEL assay and expression of Bax/Bcl2 were evaluated at the end of experiment. Testicular H2 S levels were significantly decreased in varicocele group. NaHS significantly improved sperm parameters, morphometric characteristics and oxidative stress compared to varicocele group. Oxidative stress status deteriorated in the PAG group compared to the varicocele group. This study showed that a low testicular H2 S level might play a critical role in male infertility. Thus, NaHS administration may be a promising treatment strategy for male infertility in varicocele. In addition, CSE may not be the only important enzyme in testicular H2 S production.


Assuntos
Alcinos/administração & dosagem , Glicina/análogos & derivados , Sulfetos/administração & dosagem , Testículo/efeitos dos fármacos , Varicocele/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicina/administração & dosagem , Sulfeto de Hidrogênio/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espermatozoides/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Varicocele/patologia
20.
J Pharmacol Sci ; 142(3): 93-100, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31866051

RESUMO

Orally active hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors that stabilize HIF protein and stimulate the production of erythropoietin have been approved to treat renal anemia. Our previous report suggested that HIF-1α dependent fibrogenic mechanisms are operating at the early onset of renal fibrosis and its contribution declines with the progression in mouse unilateral ureteral obstruction (UUO) model. The aim of the study is to evaluate the renal fibrogenic potential of FG4592, a recently approved orally active HIF prolyl hydroxylase inhibitor in mouse UUO model. Male C57BL/6J mice orally given FG-4592 (12.5 mg/kg/day and 50 mg/kg/day) were subjected to UUO. Neither dose of FG-4592 affected renal fibrosis or macrophage infiltration. FG-4592 had no effects on increased mRNA of collagen I, collagen III or transforming growth factor-ß1. At 3 days after UUO, higher dose of FG-4592 potentiated the increased mRNA expression of profibrogenic molecules, plasminogen activator inhibitor 1 (Pai-1) and connective tissue growth factor (Ctgf) but such potentiation disappeared at 7 days after UUO. It is suggested that FG-4592 used in the present study had little effects on renal fibrosis even though high dose of FG-4592 used in the present study transiently potentiated gene expression of Pai-1 and Ctgf in the UUO kidney.


Assuntos
Glicina/análogos & derivados , Isoquinolinas/administração & dosagem , Rim/patologia , Inibidores de Prolil-Hidrolase/administração & dosagem , Obstrução Ureteral/patologia , Administração Oral , Animais , Fibrose , Glicina/administração & dosagem , Glicina/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Isoquinolinas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Inibidores de Prolil-Hidrolase/farmacologia
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