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1.
Ann Pharmacother ; 54(1): 29-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31416331

RESUMO

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.


Assuntos
Monitoramento de Medicamentos/métodos , Metotrexato/administração & dosagem , Metotrexato/sangue , Cisteína/administração & dosagem , Cisteína/sangue , Cisteína/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Glicina/administração & dosagem , Glicina/sangue , Glicina/uso terapêutico , Ácido Glicirretínico/administração & dosagem , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/sangue , Ácido Glicirretínico/uso terapêutico , Humanos , Leucemia/sangue , Leucemia/tratamento farmacológico , Modelos Logísticos , Linfoma/sangue , Linfoma/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Metotrexato/uso terapêutico , Osteossarcoma/sangue , Osteossarcoma/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Vincristina/administração & dosagem , Vincristina/sangue , Vincristina/uso terapêutico
2.
Respir Res ; 20(1): 254, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718676

RESUMO

BACKGROUND: Pulmonary and systemic inflammation are central features of chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated relationships between biologically active extracellular matrix components, or matrikines, and COPD pathogenesis. We studied the relationships between the matrikine acetyl-proline-glycine-proline (AcPGP) in sputum and plasma and clinical features of COPD. METHODS: Sputum and plasma samples were obtained from COPD participants in the SPIROMICS cohort at enrollment. AcPGP was isolated using solid phase extraction and measured by mass spectrometry. Demographics, spirometry, quality of life questionnaires, and quantitative computed tomography (CT) imaging with parametric response mapping (PRM) were obtained at baseline. Severe COPD exacerbations were recorded at 1-year of prospective follow-up. We used linear and logistic regression models to measure associations between AcPGP and features of COPD, and Kaplan-Meier analyses to measure time-to-first severe exacerbation. RESULTS: The 182 COPD participants in the analysis were 66 ± 8 years old, 62% male, 84% White race, and 39% were current smokers. AcPGP concentrations were 0.61 ± 1.89 ng/mL (mean ± SD) in sputum and 0.60 ± 1.13 ng/mL in plasma. In adjusted linear regression models, sputum AcPGP was associated with FEV1/FVC, spirometric GOLD stage, PRM-small airways disease, and PRM-emphysema. Sputum AcPGP also correlated with severe AECOPD, and elevated sputum AcPGP was associated with shorter time-to-first severe COPD exacerbation. In contrast, plasma AcPGP was not associated with symptoms, pulmonary function, or severe exacerbation risk. CONCLUSIONS: In COPD, sputum but not plasma AcPGP concentrations are associated with the severity of airflow limitation, small airways disease, emphysema, and risk for severe AECOPD at 1-year of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS).


Assuntos
Glicina/sangue , Prolina/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Espirometria/métodos , Escarro/metabolismo , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escarro/química
3.
PLoS One ; 14(11): e0224274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697702

RESUMO

Glycated hemoglobin (HbA1c) is an indicator of the average blood glucose concentration. Failing to control HbA1c levels can accelerate the development of complications in patients with diabetes. Although metabolite profiles associated with HbA1c level in diabetes patients have been characterized using different platforms, more studies using high-throughput technology will be helpful to identify additional metabolites related to diabetes. Type 2 diabetes (T2D) patients were divided into two groups based on the HbA1c level: normal (HbA1c ≤6%) and high (HbA1c ≥9%) in both discovery and replication sets. A targeted metabolomics approach was used to quantify serum metabolites and multivariate logistic regression was used to identify significant differences between groups. The concentrations of 22 metabolites differed significantly between the two groups in the discovery set. In the replication set, the levels of 21 metabolites, including 16 metabolites identified in the discovery set, differed between groups. Among these, concentrations of eleven amino acids and one phosphatidylcholine (PC), lysoPC a C16:1, were higher and four metabolites, including three PCs (PC ae C36:1, PC aa C26:0, PC aa C34:2) and hexose, were lower in the group with normal HbA1c group than in the group with high HbA1c. Metabolites with high concentrations in the normal HbA1c group, such as glycine, valine, and PCs, may contribute to reducing HbA1c levels in patients with T2D. The metabolite signatures identified in this study provide insight into the mechanisms underlying changes in HbA1c levels in T2D.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Metabolômica , Idoso , Aminoácidos/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Glicina/sangue , Hexoses/sangue , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fosfatidilcolinas/sangue , Valina/sangue
4.
Amino Acids ; 51(10-12): 1485-1499, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31535220

RESUMO

L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.


Assuntos
Doenças Cardiovasculares/mortalidade , Glicina/análogos & derivados , Homoarginina/sangue , Transplante de Rim/mortalidade , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Causas de Morte , Estudos Transversais , Feminino , Seguimentos , Glicina/sangue , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fatores de Risco
5.
Clin Chim Acta ; 498: 116-121, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442447

RESUMO

BACKGROUND: Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China. METHODS: Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined. RESULTS: The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and "dirty sock" odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study). CONCLUSIONS: We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Grupo com Ancestrais do Continente Asiático/genética , Isovaleril-CoA Desidrogenase/deficiência , Mutação , Alelos , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Carnitina/sangue , China/epidemiologia , Feminino , Glicina/sangue , Humanos , Recém-Nascido , Isovaleril-CoA Desidrogenase/genética , Masculino , Fenótipo
6.
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
7.
J Pharm Biomed Anal ; 174: 175-181, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31170631

RESUMO

Glufosinate and glyphosate, which are non-selective herbicides that include an amino acid moiety in their structures, are frequently used worldwide to control unwanted vegetation. Unfortunately, these readily available herbicides are also used by people to commit suicide, and thus represent important chemicals of interest in the fields of clinical medicine and forensics. Because of the high water solubility of these herbicides, most analytical methods for their detection require a derivatization step, which results in longer analysis times. Therefore, derivatization-based methods do not currently contribute to judgements on treatment decisions in emergency medicine. In this study, we addressed this limiting factor by developing an ultra-rapid and simple analytical technique using a combination of probe electrospray ionization (PESI) and tandem mass spectrometry (MS/MS), which gives quantitative results within 0.3 min. Herbicide standards were added to human serum that was then subjected to analysis (N = 5 per concentration). The analysis was repeated daily over eight consecutive days. The limit of detection (LOD) was 0.59 µg/mL for glufosinate and 0.20 µg/mL for glyphosate. The limit of quantitation (LOQ), i.e., the lowest point on the calibration curves, was 1.56 µg/mL for both the herbicides. The matrix effects were observed at three different concentrations (between 95.7%-104% for glufosinate, and between 90.7%-95.7% for glyphosate). When applied to samples taken from actual poisoning cases (six samples for each herbicide), the present method gave almost the same quantitative values as those obtained by conventional high-performance liquid chromatography with fluorescence detection. Thus, we believe that PESI-MS/MS could emerge as a rapid diagnosis method in the clinical emergency field.


Assuntos
Aminobutiratos/sangue , Glicina/análogos & derivados , Herbicidas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Aminobutiratos/envenenamento , Calibragem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Glicina/sangue , Glicina/envenenamento , Herbicidas/envenenamento , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Extração em Fase Sólida
8.
Metab Brain Dis ; 34(5): 1467-1472, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31230217

RESUMO

Nonketotic hyperglycinemia (NKH) is a neuro-metabolic disorder caused by a deficiency in the glycine cleavage system (GCS) and glycine transporter 1 (GlyT1). A case of atypical late onset of NKH has been reported in a colony of captive-bred Vervet monkeys. The purpose of this study was to evaluate the effect of sodium benzoate and dextromethorphan in reducing glycine levels in hyperglycinemic monkeys. Twelve captive-bred Vervet monkeys were assigned into three groups consisting of four animals (control, valproate induced and cataract with spontaneous hyperglycinemia). Valproate was used to elevate glycine levels and the induced group was then treated with sodium benzoate and dextromethorphan together with group three to normalise glycine levels in cerebrospinal fluid (CSF) and plasma. Valproate induction elicited changes in phosphate, alkaline phosphatase and platelet count, however, no significant changes in the glycine levels were observed, and this might be due to the individual variability within the group. The treatment intervention was only obtained in the spontaneous group whereby the glycine levels were normalised in CSF and plasma. Therefore, it can be concluded that sodium benzoate and dextromethorphan treatment was effective and beneficial to the hyperglycinemic group.


Assuntos
Dextrometorfano/uso terapêutico , Glicina/sangue , Hiperglicinemia não Cetótica/tratamento farmacológico , Benzoato de Sódio/uso terapêutico , Animais , Chlorocebus aethiops , Hiperglicinemia não Cetótica/sangue , Resultado do Tratamento
9.
Am J Emerg Med ; 37(8): 1600.e5-1600.e6, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31053371

RESUMO

INTRODUCTION: This report describes changes in blood and urine concentrations of glyphosate potassium over time and their correlations with clinical symptoms in a patient with acute glyphosate potassium poisoning. CASE REPORT: A 67-year-old man visited the emergency center after ingesting 250 mL of a glyphosate potassium-based herbicide 5 h before. He was alert but presented with nausea, vomiting, and bradyarrhythmia with atrial fibrillation (tall T waves). Laboratory findings revealed a serum potassium level of 6.52 mEq/L. After treatment with an injection of calcium gluconate, insulin with glucose, bicarbonate, and an enema with polystyrene sulfonate, the patient's serum potassium level normalized and the bradyarrhythmia converted to a normal sinus rhythm. During admission, the blood and urine concentration of glyphosate and urine aminomethylphosphonic acid (AMPA, a glyphosate metabolite) was measured at regular time intervals. The patient's glyphosate blood concentration on admission was 11.48 mg/L, and it had decreased rapidly by 16 h and maintained about 1mgl/L by 70 h after admission. Urine glyphosate and AMPA levels had also decreased rapidly by 6 h after admission. DISCUSSION: Glyphosate potassium poisoning causes hyperkalemia. Blood concentrations of glyphosate were decreased rapidly by 16 h after admission, and urine concentrations were also decreased by 6 h after admission.


Assuntos
Glicina/análogos & derivados , Herbicidas/sangue , Herbicidas/envenenamento , Hiperpotassemia/induzido quimicamente , Idoso , Arritmias Cardíacas/induzido quimicamente , Glicina/sangue , Glicina/envenenamento , Glicina/urina , Herbicidas/urina , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/tratamento farmacológico , Masculino , Náusea/induzido quimicamente , Potássio/sangue , Tentativa de Suicídio , Resultado do Tratamento , Vômito/induzido quimicamente
10.
J Pharm Biomed Anal ; 173: 1-17, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31100508

RESUMO

An ultrahigh performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) was developed for the determination of 41 target and 8 additional bile acids isomers (BAs) in biological fluids. BAs were analysed by solid-phase extraction on 50 µL biofluid-aliquots, followed by a properly optimised 27 min-chromatographic run. The method provided high sensitivity (limits of detection 0.0002-0.03 µM, limits of quantitation 0.0007-0.11 µM), linearity (R2>0.99) and precision (relative standard deviations ≤16%). A strategy of scheduled/ unscheduled injections of real samples together with neutral loss (80 Da and 176 Da) scans allowed us to find additional bile acid isomers not a priori included in the method, while high resolution full scan and MS/MS fragmentation analysis confirmed their structural adherence to the bile acid family. Moreover this is the first study quantifying four sulfate glycine conjugated-dihydroxy bile acid isomers, independently of the diet and postprandial time. Application to a dietary intervention kinetic study confirmed the existence of possible metabotypes amongst the study population (n = 20). A trend differentiating males from females was observed suggesting that serum samples from women contained smaller amounts of certain bile acids.


Assuntos
Ácidos e Sais Biliares/sangue , Glucuronídeos/sangue , Glicina/sangue , Técnica de Diluição de Radioisótopos , Ácidos e Sais Biliares/química , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão/métodos , Jejum/sangue , Feminino , Glucuronídeos/química , Glicina/química , Humanos , Limite de Detecção , Masculino , Período Pós-Prandial , Reprodutibilidade dos Testes , Fatores Sexuais , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
11.
Ann Clin Transl Neurol ; 6(4): 669-677, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019991

RESUMO

Objective: Many stroke patients make a partial recovery in function during the first 3 months, partially through promoting insulin-like growth factor-1 (IGF-1) function. A prognostic biomarker that associates with IGF-1 function may predict clinical outcome and recovery of stroke. This study evaluated plasma concentrations of IGF-1, IGF binding protein (IGFBP)-3 and cyclic-glycine-proline (cGP) and their associations with clinical outcome in stroke patients. Methods: Thirty-four patients were recruited within 3 days of stroke. Clinical assessments included the National Institutes of Health Stroke Scale (NIHSS) within 3 days (baseline), and at days 7 and 90; the modified Rankin Scale (mRS) and Fugl-Meyer Upper-Limb Assessment Scale (FM-UL) at days 7 and 90. Plasma samples were collected from the patients at the baseline, days 7 and 90. Fifty age-matched control participants with no history of stroke were also recruited and provided plasma samples. IGF-1, IGFBP-3, and cGP concentrations were analyzed using ELISA or HPLC-MS. Results: Baseline concentrations of IGFBP-3, cGP, and cGP/IGF-1 ratio were lower in stroke patients than the control group. The neurological scores of stroke patients were improved and plasma cGP and cGP/IGF-1 ratio increased over time. Baseline cGP/IGF-1 ratio was correlated with the NIHSS scores at day 90 and the changes in NIHSS scores from the baseline to 90 days. Interpretation: Low cGP concentrations and cGP/IGF-1 ratio in stroke patients suggest an impaired IGF-1 function. The cGP/IGF-1 ratio at admission maybe further developed as a prognostic biomarker for stroke recovery.


Assuntos
Glicina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Peptídeos Cíclicos/sangue , Acidente Vascular Cerebral/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Feminino , Humanos , Fator de Crescimento Insulin-Like I/biossíntese , Masculino , Pessoa de Meia-Idade , Plasma/metabolismo , Prolina/sangue , Adulto Jovem
12.
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
13.
Nat Commun ; 10(1): 1060, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837465

RESUMO

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Glicina/sangue , Hiperinsulinismo/genética , Redes e Vias Metabólicas/genética , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicina/metabolismo , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/epidemiologia , Incidência , Polimorfismo de Nucleotídeo Único
14.
J Steroid Biochem Mol Biol ; 189: 171-175, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30849463

RESUMO

Polycystic ovary syndrome (PCOS) is a common metabolic disorder with hyperandrogenism as the core pathophysiologic feature. Increased bile acids and altered bile acid pool composition have been implicated in the pathogenesis of several metabolic diseases. Thus, this study aimed to clarify the specific alterations in circulating bile acids in patients with PCOS and investigate its associations with hyperandrogenism. We recruited 37 patients with PCOS and 35 age- and BMI-matched control subjects. Serum bile acids and androgen profiles were assessed by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Compared with control subjects, glycine- and taurine-conjugated primary bile acids were significantly elevated in patients with PCOS (P = 0.001 and P < 0.001). In addition, these conjugated primary bile acids were significantly and positively associated with serum concentrations of total testosterone and androstenedione in the PCOS group. In conclusion, increased circulating conjugated primary bile acids are positively associated with hyperandrogenism in women with PCOS. Further studies are warranted to explore the underlying mechanism.


Assuntos
Ácidos e Sais Biliares/sangue , Hiperandrogenismo/sangue , Síndrome do Ovário Policístico/sangue , Adulto , Ácidos e Sais Biliares/análise , Cromatografia Líquida , Feminino , Glicina/análogos & derivados , Glicina/sangue , Humanos , Hiperandrogenismo/complicações , Síndrome do Ovário Policístico/complicações , Espectrometria de Massas em Tandem , Taurina/análogos & derivados , Taurina/sangue , Adulto Jovem
15.
PLoS One ; 14(2): e0211698, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30721263

RESUMO

Atypical myopathy (AM) in horses is caused by ingestion of seeds of the Acer species (Sapindaceae family). Methylenecyclopropylacetyl-CoA (MCPA-CoA), derived from hypoglycin A (HGA), is currently the only active toxin in Acer pseudoplatanus or Acer negundo seeds related to AM outbreaks. However, seeds or arils of various Sapindaceae (e.g., ackee, lychee, mamoncillo, longan fruit) also contain methylenecyclopropylglycine (MCPG), which is a structural analogue of HGA that can cause hypoglycaemic encephalopathy in humans. The active poison formed from MCPG is methylenecyclopropylformyl-CoA (MCPF-CoA). MCPF-CoA and MCPA-CoA strongly inhibit enzymes that participate in ß-oxidation and energy production from fat. The aim of our study was to investigate if MCPG is involved in Acer seed poisoning in horses. MCPG, as well as glycine and carnitine conjugates (MCPF-glycine, MCPF-carnitine), were quantified using high-performance liquid chromatography-tandem mass spectrometry of serum and urine from horses that had ingested Acer pseudoplatanus seeds and developed typical AM symptoms. The results were compared to those of healthy control horses. For comparison, HGA and its glycine and carnitine derivatives were also measured. Additionally, to assess the degree of enzyme inhibition of ß-oxidation, several acyl glycines and acyl carnitines were included in the analysis. In addition to HGA and the specific toxic metabolites (MCPA-carnitine and MCPA-glycine), MCPG, MCPF-glycine and MCPF-carnitine were detected in the serum and urine of affected horses. Strong inhibition of ß-oxidation was demonstrated by elevated concentrations of all acyl glycines and carnitines, but the highest correlations were observed between MCPF-carnitine and isobutyryl-carnitine (r = 0.93) as well as between MCPA- (and MCPF-) glycine and valeryl-glycine with r = 0.96 (and r = 0.87). As shown here, for biochemical analysis of atypical myopathy of horses, it is necessary to take MCPG and the corresponding metabolites into consideration.


Assuntos
Acer/efeitos adversos , Ciclopropanos/metabolismo , Glicina/análogos & derivados , Doenças dos Cavalos/metabolismo , Doenças Musculares/veterinária , Intoxicação por Plantas/veterinária , Animais , Cromatografia Líquida de Alta Pressão , Ciclopropanos/sangue , Ciclopropanos/urina , Feminino , Glicina/sangue , Glicina/metabolismo , Glicina/urina , Doenças dos Cavalos/sangue , Doenças dos Cavalos/etiologia , Doenças dos Cavalos/urina , Cavalos/sangue , Cavalos/urina , Masculino , Redes e Vias Metabólicas , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Intoxicação por Plantas/etiologia , Intoxicação por Plantas/metabolismo , Sementes/efeitos adversos , Espectrometria de Massas em Tandem
16.
Cancer Chemother Pharmacol ; 83(5): 837-848, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758648

RESUMO

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


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Radioisótopos de Carbono , Cromatografia Líquida , Fezes/química , Glicina/administração & dosagem , Glicina/sangue , Glicina/farmacocinética , Glicina/urina , Voluntários Saudáveis , Humanos , Limite de Detecção , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/urina , Espectrometria de Massas em Tandem , Distribuição Tecidual
17.
PLoS One ; 14(1): e0209910, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30608977

RESUMO

Seminal plasma is a key biological fluid that modulates sperm function in the reproduction process. However, its role in sperm biotechnologies is scarce in poultry. The aims of the present study were to study the amino acids profile and total proteins of seminal plasma in 12 Spanish chicken breeds and to investigate the role of seminal plasma on cryoresistance of rooster sperm. To investigate the role of seminal plasma on cryoresistance, diluted pooled semen samples were cryopreserved in the presence and absence of seminal plasma. Glutamic acid was the most abundant free amino acid in seminal plasma, followed by alanine, serine, valine, and glycine. There was an influence of breed (P<0.05) on the percentage of viable sperm after freezing-thawing of samples with seminal plasma. Cluster analysis revealed that White Prat, Black Castellana, Blue Andaluza, Quail Castellana, and Red-Barred Vasca returned the best freezing-thawing response (good freezers). There was a positive correlation between seminal plasma concentrations of valine, isoleucine lysine, leucine and post thaw viability. The evaluation of fertilization capacity of frozen-thawed semen from the breeds White Prat ('good freezer') and Black-Red Andaluza ('bad freezer') showed that good freezer had higher fertility (20/68, 29.4%) compared to bad freezer breed (14/76, 18.4%), even if the difference was not significant (P = 0.08). The TUNEL assay revealed that freezing/thawing procedures in presence of seminal plasma provoked higher DNA fragmentation in most of the breeds, with a positive correlation between seminal alanine, valine, isoleucine, methionine, leucine, tyrosine, phenylalanine concentrations and DNA integrity. DNA fragmentation was lower in absence of seminal plasma and the breed effect on sperm viability was highly reduced. It is concluded that specific seminal plasma amino acids were associated with post-thaw percentage of viable sperm and DNA integrity. The removal of seminal plasma decreases the variability of the results and DNA fragmentation damages.


Assuntos
Aminoácidos/sangue , Sêmen/fisiologia , Espermatozoides/fisiologia , Alanina/sangue , Animais , Galinhas , Criopreservação/métodos , Fragmentação do DNA , Ácido Glutâmico/sangue , Glicina/sangue , Marcação In Situ das Extremidades Cortadas , Masculino , Serina/sangue , Valina/sangue
18.
Med Hypotheses ; 123: 125-129, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30696582

RESUMO

Receptor-mediated activation of NADPH oxidase complexes commonly occurs in endosomes; the hydrogen peroxide produced by the dismutation of superoxide generated within the endosomes often functions to boost receptor function by reversibly inhibiting protein tyrosine phosphatases or by promoting formation of signaling complexes. NADPH oxidase-mediated formation of superoxide entails transfer of two electrons (provided by NADPH) from the cytosol to the endosomal lumen, where two molecules of superoxide are generated. This charge transfer must be balanced if NADPH oxidase activity is to be sustained. In many cells, this balance is achieved by ClC-3, a chloride-proton antiporter which can extrude two chlorides from the endosome to balance the importation of two electrons. The efficiency of this chloride extrusion will evidently be contingent on the cytosolic chloride level. Pro-inflammatory hormones which stimulate NADPH oxidase activity in endosomes have been shown to promote chloride extrusion from the cell, thereby expediting endosomal chloride export. Conversely, high cytosolic chloride could potentially slow endosomal NADPH oxidase activity by impeding ClC-3-mediated chloride export. Glycine-activated, strychnine-inhibitable chloride channels, which boost intracellular chloride in cells which maintain intracellular chloride levels lower than that of plasma, have shown anti-inflammatory and anti-angiogenic activity in cell culture and rodent studies. It is proposed that many of these effects may be attributable to glycine-mediated suppression of endosomal NADPH oxidase activity. This model suggests that supplemental glycine may have utility for prevention and control of atherosclerosis, heart failure, angiogenesis associated with cancer or retinal disorders, and a range of inflammation-driven syndromes - including metabolic syndrome; and it might complement the suppression of NADPH oxidase activity achievable with phycocyanobilin-enriched spirulina extracts.


Assuntos
Canais de Cloreto/metabolismo , Cloretos/metabolismo , Endossomos/metabolismo , NADPH Oxidases/metabolismo , Receptores da Glicina/metabolismo , Adipócitos/citologia , Animais , Anti-Inflamatórios/farmacologia , Eritrócitos/metabolismo , Glicina/administração & dosagem , Glicina/sangue , Humanos , Transporte de Íons , Oxirredução , Ratos , Transdução de Sinais , Superóxidos/metabolismo
19.
J Pharm Biomed Anal ; 162: 82-90, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30227356

RESUMO

Systemic Sclerosis (SSc) is a chronic autoimmune disease whose origin and pathogenesis are not yet well known. Recent studies are allowing a better definition of the disease. However, few studies have been performed based on metabolomics. In this way, this study aims to find altered metabolites in SSc patients in order to improve their diagnosis, prognosis and treatment. For that, 59 SSc patients and 28 healthy volunteers participated in this study. Urine and plasma samples were analysed by a fingerprinting metabolomic approach based on HPLC-ESI-QTOF-MS. We observed larger differences in urine than plasma metabolites. The main deregulated metabolic families in urine were acylcarnitines, acylglycines and metabolites derived from amino acids, specifically from proline, histidine and glutamine. These results indicate perturbations in fatty acid beta oxidation and amino acid pathways in scleroderma patients. On the other hand, the main plasma biomarker candidate was 2-arachidonoylglycerol, which is involved in the endocannabinoid system with potential implications in the induction and propagation of systemic sclerosis and autoimmunity.


Assuntos
Biomarcadores/sangue , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Metabolômica/métodos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/urina , Espectrometria de Massas por Ionização por Electrospray , Acilação , Adulto , Idoso , Ácidos Araquidônicos/sangue , Ácidos Araquidônicos/urina , Carnitina/análogos & derivados , Carnitina/sangue , Carnitina/urina , Estudos de Casos e Controles , Endocanabinoides/sangue , Endocanabinoides/urina , Feminino , Glicerídeos/sangue , Glicerídeos/urina , Glicina/sangue , Glicina/urina , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Escleroderma Sistêmico/diagnóstico , Urinálise
20.
Biol Psychiatry ; 85(4): 345-354, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30446206

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. METHODS: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. RESULTS: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. CONCLUSIONS: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.


Assuntos
Transtorno do Espectro Autista/sangue , Glutamina/sangue , Glicina/sangue , Ornitina/sangue , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Biologia Computacional , Feminino , Humanos , Lactente , Masculino , Metabolômica , Valor Preditivo dos Testes , Sensibilidade e Especificidade
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