RESUMO
The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.
Assuntos
Aminobutiratos , Compostos Benzidrílicos , Compostos de Bifenilo , Combinação de Medicamentos , Interações Medicamentosas , Glucosídeos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Tetrazóis , Valsartana , Espectrometria de Massas em Tandem/métodos , Glucosídeos/farmacocinética , Glucosídeos/sangue , Animais , Humanos , Células CACO-2 , Ratos , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/análise , Valsartana/farmacocinética , Tetrazóis/farmacocinética , Cromatografia Líquida/métodos , Masculino , Compostos de Bifenilo/farmacocinética , Aminobutiratos/farmacocinética , Aminobutiratos/análise , Aminobutiratos/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massa com Cromatografia LíquidaRESUMO
This study focuses on the purification and detection of glufosinate (GLUF) and its metabolites N-acetyl GLUF and MPP in plasma samples. A Dikma Polyamino HILIC column was used for the effective retention and separation of GLUF and its metabolites, and the innovative addition of a low concentration of ammonium fluoride solution to the mobile phase effectively improved the detection sensitivity of the target analytes. Monodisperse core-shell weak cation exchange (WCX)/C18 bifunctional magnetic polymer composites (Fe3O4@WCX/C18) were prepared in a controllable manner, and their morphology and composition were fully characterized. The Fe3O4@WCX/C18 microspheres were used as a magnetic solid-phase extraction (MSPE) adsorbent for the sample purification and detection of GLUF and its metabolites in plasma samples combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The purification conditions of Fe3O4@WCX/C18 microspheres for GLUF and its metabolites in spiked plasma samples were optimized to achieve the best MSPE efficiency. The purification mechanisms of the target analytes in plasma samples include electrostatic attraction and hydrophobic interactions. Furthermore, the effect of the molar ratio of the two functional monomers 4-VBA and 1-octadecene in the adsorbent was optimized and it shows that the bifunctional components WCX/C18 have a synergistic effect on the determination of GLUF and its metabolites in plasma samples. In addition, the present study compared the purification performance of the Fe3O4@WCX/C18 microsphere-based MSPE method with that of the commercial Oasis WCX SPE method, and the results showed that the Fe3O4@WCX/C18 microsphere-based MSPE method established in this work had a stronger ability to remove matrix interferences. Under optimal purification conditions, the recoveries of GLUF and its metabolites in plasma were 87.6-111 % with relative standard deviations (RSDs) ranging from 0.2 % to 4.8 %. The limits of detection (LODs, S/N≥3) and limits of quantification (LOQs, S/N≥10) were 0.10-0.18 µg/L and 0.30-0.54 µg/L, respectively. The MSPE-LC-MS/MS method developed in this study is fast, simple, accurate and sensitive and can be used to confirm GLUF intoxication based not only on the detection of the GLUF prototype but also on the detection of its two metabolites.
Assuntos
Aminobutiratos , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Aminobutiratos/sangue , Aminobutiratos/química , Cromatografia Líquida/métodos , Limite de Detecção , Polímeros/química , Animais , Microesferas , Adsorção , Ratos , Cromatografia por Troca Iônica/métodosRESUMO
In forensic science, glyphosate (GLYP) and glufosinate (GLUF), a class of non-selective broad-spectrum herbicides, have been frequently encountered in many fatal poisoning and suicide cases due to their widespread availability. Therefore, it is essential to develop an effective method for detecting these compounds. Some conventional methods, such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), have been reported to detect these compounds. However, these methods are not ideal for their time-consuming and non-sensitive feature. Herein, probe electrospray ionization (PESI) tandem mass spectrometry (MS/MS), a fast and sensitive technique, was applied for the determination of GLYP and GLUF in human blood, which can obtain analytical results within 0.5 min without derivatization and chromatographic separation. After protein precipitation of blood samples, the supernatant was mixed with isopropanol and ultra-pure water (1:1 v/v). Then, 8 µL of the mixture was introduced into the plastic sample plate for PESI-MS/MS analysis. The limits of detection (LODs) of the method were 0.50 µg/mL and 0.25 µg/mL for two analytes, and the limits of quantitation (LOQs) were both 1.00 µg/mL, which are higher than the concentration of reported poisoning and fatal cases. In the linear range of 1-500 µg/mL, the regression coefficients (r2) for GLYP and GLUF were over 0.99. The matrix effects ranged from 94.8 % to 119.5 %, and the biases were below 4.3 %. The recoveries ranged between 84.8 % and 107.4 %, and the biases were below 7.6 %. Meanwhile, the method was effectively utilized to detect and quantify the blood, urine, and other samples. Consequently, the results suggest that PESI-MS/MS is a straightforward, fast, and sensitive method for detecting GLUF and GLYP in forensics. In the future, PESI-MS/MS will become an indispensable technique for polar substances in grassroots units of public security where rapid detection is essential.
Assuntos
Aminobutiratos , Glicina , Glifosato , Herbicidas , Limite de Detecção , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Humanos , Glicina/análogos & derivados , Glicina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Aminobutiratos/sangue , Espectrometria de Massas em Tandem/métodos , Herbicidas/sangue , Herbicidas/intoxicação , Reprodutibilidade dos TestesRESUMO
Diquat (DQ), paraquat (PQ), glufosinate (GLU), and glyphosate (GLYP) are commonly used herbicides that have been confirmed to be toxic to humans. Rapid and accurate measurements of these toxicants in clinical practice are beneficial for the correct diagnosis and timely treatment of herbicide-poisoned patients. The present study aimed to establish an efficient, convenient, and reliable method to achieve the simultaneous quantification of DQ, PQ, GLU, and GLYP in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS) without using derivatization or ion-pairing reagents. DQ, PQ, GLU, and GLYP were extracted by the rapid protein precipitation and liquid-liquid extraction method and then separated and detected by LC-MS/MS. Subsequently, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, extraction recovery, matrix effect, dilution integrity, and stability were evaluated to validate the method based on the FDA criteria. Finally, the validated method was applied to real plasma samples collected from 166 Chinese patients with herbicide poisoning. The results showed satisfactory linearity with low LOD (1 ng/mL for DQ and PQ, 5 ng/mL for GLU, and 10 ng/mL for GLYP, respectively) and low LOQ (5 ng/mL for DQ and PQ, 25 ng/mL for GLU and GLYP, respectively). In addition, the precision, accuracy, extraction recovery, and stability of the method were acceptable. The matrix effect was not observed in the analyzed samples. Moreover, the developed method was successfully applied to determine the target compounds in real plasma samples. These data provided reliable evidence for the application of this LC-MS/MS method for clinical poisoning detection.
Assuntos
Aminobutiratos , Diquat , Glicina , Glifosato , Herbicidas , Limite de Detecção , Paraquat , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Glicina/análogos & derivados , Glicina/sangue , Aminobutiratos/sangue , Diquat/sangue , Diquat/intoxicação , Paraquat/sangue , Paraquat/intoxicação , Herbicidas/sangue , Herbicidas/intoxicação , Cromatografia Líquida/métodos , Reprodutibilidade dos TestesRESUMO
Red meat (RM) consumption is correlated with multiple health outcomes. This study aims to identify potential biomarkers of RM consumption in the Chinese population and evaluate their predictive ability. We selected 500 adults who participated in the 2015 China Health and Nutrition Survey and examined their overall metabolome differences by RM consumption by using elastic-net regression, then evaluate the predictivity of a combination of filtered metabolites; 1108 metabolites were detected. In the long-term RM consumption analysis 12,13-DiHOME, androstenediol (3α, 17α) monosulfate 2, and gamma-Glutamyl-2-aminobutyrate were positively associated, 2-naphthol sulfate and S-methylcysteine were negatively associated with long-term high RM consumption, the combination of metabolites prediction model evaluated by area under the receiver operating characteristic curve (AUC) was 70.4% (95% CI: 59.9-80.9%). In the short-term RM consumption analysis, asparagine, 4-hydroxyproline, and 3-hydroxyisobutyrate were positively associated, behenoyl sphingomyelin (d18:1/22:0) was negatively associated with short-term high RM consumption. Combination prediction model AUC was 75.6% (95% CI: 65.5-85.6%). We identified 10 and 11 serum metabolites that differed according to LT and ST RM consumption which mainly involved branch-chained amino acids, arginine and proline, urea cycle and polyunsaturated fatty acid metabolism. These metabolites may become a mediator of some chronic diseases among high RM consumers and provide new evidence for RM biomarkers.
Assuntos
Aminoácidos/sangue , Lipídeos/sangue , Metabolômica/métodos , Carne Vermelha/estatística & dados numéricos , Adulto , Aminobutiratos/sangue , Androstenodióis/sangue , Povo Asiático , Biomarcadores/sangue , China/epidemiologia , Cisteína/análogos & derivados , Cisteína/sangue , Dieta/métodos , Ácidos Graxos Insaturados/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Carne Vermelha/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Inquéritos e QuestionáriosRESUMO
An accurate and sensitive UPLC-MS/MS method was developed and validated for the simultaneous estimation of the newly developed combination of sacubitril and valsartan and the co-administered drugs nebivolol, chlorthalidone and esomeprazole in human plasma. Solid-phase extraction was conducted for the purification and extraction of the drugs from human plasma. Chromatographic separation was carried out on an Agilent SB-C18 (1.8 µm, 2.1 × 50 mm) column using losartan as internal standard. Isocratic elution was applied using acetonitrile-0.1% formic acid in water (85: 15, v/v) as mobile phase. Detection was carried out using a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring, at positive mode at m/z 412.23 â 266.19 for sacubitril, m/z 436.29 â 235.19 for valsartan, m/z 405.8 â 150.98 for nebivolol, m/z 346.09 â 198 for esomeprazole and a selected combination of two fragments m/z 423.19 â 207.14 and 423.19 â 192.2 for losartan (internal standard), and in negative ionization mode at m/z 337.02 â 190.12 for chlorthalidone. The method was linear over the concentration ranges 30-2,000 ng/ml for sacubitril, 70-2,000 ng/ml for valsartan, esomeprazole and chlorthalidone and 70-5,000 pg/ml for nebivolol. The developed method is sensitive and selective and could be applied for dose adjustment, bioavailability and drug-drug interaction studies.
Assuntos
Aminobutiratos/sangue , Compostos de Bifenilo/sangue , Cromatografia Líquida de Alta Pressão/métodos , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Valsartana/sangue , Aminobutiratos/administração & dosagem , Aminobutiratos/isolamento & purificação , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/isolamento & purificação , Clortalidona/administração & dosagem , Clortalidona/sangue , Clortalidona/isolamento & purificação , Combinação de Medicamentos , Estabilidade de Medicamentos , Esomeprazol/administração & dosagem , Esomeprazol/sangue , Esomeprazol/isolamento & purificação , Humanos , Limite de Detecção , Modelos Lineares , Nebivolol/administração & dosagem , Nebivolol/sangue , Nebivolol/isolamento & purificação , Reprodutibilidade dos Testes , Valsartana/administração & dosagem , Valsartana/isolamento & purificaçãoRESUMO
An LC-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of fimasartan and sacubitrilat using positive ion mode. The protein precipitation method was employed for the extraction of fimasartan, sacubitrilat and alprazolam (internal standard) from rat heparinized plasma. Baseline separation of the analytes was accomplished using an ACE-5, C18 (4.6 × 50 mm) column and gradient elution of mobile phase A (5 mm ammonium formate and 0.1% formic acid in purified water) and B (acetonitrile:methanol, 80:20; v/v). All peaks of interest were eluted within a 5-min runtime. The quantitation was achieved in the selected reaction monitoring mode. The developed method was validated as per US Food and Drug Administration guidelines and met the pre-defined acceptance criteria. The method showed linearity from 5 to 10,000 ng/mL. The accuracy/precision of intra- and inter-batch assays was 96.64%/2.05% to 109.17%/13.70% and 100.74%/3.76% to 106.39%/9.75% for fimasartan and 100.02%/1.49% to 113.80%/9.38% and 100.75%/2.31% to 108.40%/7.74% for sacubitrilat, respectively, in rat plasma. Fimasartan and sacubitrilat remained stable in rat plasma at different experimental conditions up to 21 days. The developed method was sensitive, selective and applied successfully to monitor plasma concentrations of fimasartan and sacubitrilat in an oral rat pharmacokinetic study.
Assuntos
Aminobutiratos/sangue , Compostos de Bifenilo/sangue , Cromatografia Líquida/métodos , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Tetrazóis/sangue , Aminobutiratos/química , Aminobutiratos/farmacocinética , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Modelos Lineares , Masculino , Pró-Fármacos , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/métodos , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
PURPOSE: Metabolomics is an emerging field in cancer research. Plasma free amino acid profiles (PFAAs) have shown different features in various cancers, but the characteristic in advanced sarcoma remains unclear. We aimed to uncover the specific PFAAs in advanced sarcoma and to find the relationship between the altering of PFAAs and response to chemotherapy. PATIENTS AND METHODS: We analyzed the differences in PFAAs between 23 sarcoma patients and 30 healthy subjects basing on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, we compared the dynamics of PFAAs after chemotherapy between improvement group and deterioration group. RESULTS: We identified seven biological differential amino acids and four pathways which were perturbed in the sarcoma patients compared with healthy subjects. After one cycle chemotherapy, the levels of γ-aminobutyric acid (GABA) and carnosine (Car) decreased significantly in the improvement group but not in deterioration group. The levels of α-aminobutyric acid (Abu) increased significantly in the deterioration group but not in the improvement group. CONCLUSION: Our study suggests the potential specific PFAAs in sarcoma patients. The unusual amino acids and metabolic pathways may provide ideas for clinical drugs targeting therapy. Three amino acids including Car, GABA and Abu may be metabolic biomarkers playing a role in dynamic monitoring of the therapeutic effect.
Assuntos
Aminobutiratos/sangue , Biomarcadores Tumorais/sangue , Carnosina/sangue , Sarcoma/tratamento farmacológico , Ácido gama-Aminobutírico/sangue , Adulto , Idoso , Aminoácidos/sangue , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Sarcoma/sangue , Sarcoma/patologia , Espectrometria de Massas em Tandem , Resultado do Tratamento , Adulto JovemRESUMO
Osteoporosis is a highly prevalent chronic aging-related disease that frequently is only detected after fracture. We hypothesized that aminobutyric acids could serve as biomarkers for osteoporosis. We developed a quick, accurate, and sensitive screening method for aminobutyric acid isomers and enantiomers yielding correlations with bone mineral density (BMD) and osteoporotic fracture. In serum, γ-aminobutyric acid (GABA) and (R)-3-aminoisobutyric acid (D-BAIBA) have positive associations with physical activity in young lean women. D-BAIBA positively associated with hip BMD in older individuals without osteoporosis/osteopenia. Lower levels of GABA were observed in 60-80 year old women with osteoporotic fractures. Single nucleotide polymorphisms in seven genes related to these metabolites associated with BMD and osteoporosis. In peripheral blood monocytes, dihydropyrimidine dehydrogenase, an enzyme essential to D-BAIBA generation, exhibited positive association with physical activity and hip BMD. Along with their signaling roles, BAIBA and GABA might serve as biomarkers for diagnosis and treatments of osteoporosis.
Assuntos
Aminobutiratos/sangue , Biomarcadores , Metabolômica , Osteoporose/sangue , Osteoporose/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Animais , Líquidos Corporais/metabolismo , Cromatografia Líquida , Feminino , Perfilação da Expressão Gênica , Humanos , Metaboloma , Metabolômica/métodos , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Osteoporose/etiologia , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Transdução de Sinais , Espectrometria de Massas em TandemRESUMO
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 0.3â¯min. Herbicide standards were added to human serum that was then subjected to analysis (Nâ¯=â¯5 per concentration). The analysis was repeated daily over eight consecutive days. The limit of detection (LOD) was 0.59⯵g/mL for glufosinate and 0.20⯵g/mL for glyphosate. The limit of quantitation (LOQ), i.e., the lowest point on the calibration curves, was 1.56⯵g/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/intoxicação , Calibragem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Glicina/sangue , Glicina/intoxicação , Herbicidas/intoxicação , Humanos , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Extração em Fase Sólida , GlifosatoRESUMO
AIM: To examine the association between depressive symptoms and plasma amino acid related metaboli in older adults. METHODS: A total of 152 older adults aged ≥65 years, residing in Niigata, Japan, were used for analysis. We evaluated depressive symptoms using the Geriatric Depression Scale-15, which has been validated in older community-dwelling individuals, and used a cut off score of ≥5 to classify participants as having depressive symptoms. We used high-performance liquid chromatography-electrospray ionization mass spectrometry to measure the concentrations of plasma amino acid-related metabolites, and carried out logistic regression analysis to assess the association between depressive symptoms and plasma amino acid-related metabolites. RESULTS: Of the 119 older adults (mean age 76.3 years) included in the analysis, 22 were classified as having depressive symptoms (depressive group). There were no significant differences in physical and cognitive impairments between participants in the depressive and non-depressive groups. The plasma α-aminobutyric acid (AABA) level was significantly lower in the depressive group than in the non-depressive group (P < 0.001). Logistic regression analysis showed the best-fit model, which included AABA, leucine, threonine, hydroxyl proline and histidine levels (area under the receiver operating characteristic curve 0.8346; 95% confidence interval 0.7365-0.9326). In particular, the plasma AABA level was strongly associated with depressive symptoms. CONCLUSIONS: Plasma AABA level is significantly associated with depression symptoms in older community-dwelling adults in Japan. Thus, plasma AABA might serve as a potential marker of depression in older adults aged ≥65 years. Geriatr Gerontol Int 2019; 19: 254-258.
Assuntos
Aminobutiratos/sangue , Depressão/sangue , Vida Independente , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Depressão/diagnóstico , Feminino , Avaliação Geriátrica , Humanos , Japão , Modelos Logísticos , MasculinoRESUMO
AIMS: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. METHODS: All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. RESULTS: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan reduced plasma Cmax and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
Assuntos
Aminobutiratos/farmacologia , Aminobutiratos/farmacocinética , Interações Medicamentosas , Furosemida/farmacologia , Furosemida/farmacocinética , Tetrazóis/farmacologia , Tetrazóis/farmacocinética , Adolescente , Adulto , Aminobutiratos/sangue , Aminobutiratos/urina , Antagonistas de Receptores de Angiotensina/sangue , Antagonistas de Receptores de Angiotensina/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/urina , Compostos de Bifenilo , Ensaios Clínicos como Assunto/estatística & dados numéricos , Diurese/efeitos dos fármacos , Diuréticos/sangue , Diuréticos/farmacocinética , Diuréticos/farmacologia , Diuréticos/urina , Combinação de Medicamentos , Feminino , Furosemida/sangue , Furosemida/urina , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Tetrazóis/sangue , Tetrazóis/urina , Valsartana , Adulto JovemRESUMO
BACKGROUND: Central nervous system (CNS) complications such as seizures and reduced consciousness are important in glufosinate and may occur in severe glyphosate poisoning. The aim of this study was to assess the possible role of serum S100B protein as a biochemical marker of CNS complications associated with glyphosate or glufosinate poisoning. METHODS: The study enrolled 40 patients (23 glyphosate poisoning and 17 glufosinate poisoning). Altered consciousness and seizure were observed during hospitalization. S100B level was measured with fully automated modular analytic E170 system using electrochemoluminometric immunoassay. RESULTS: Among 40 patients, neurologic features were observed in 12 patients with a median time to onset of 21.5 (IQR 8.25-24.75) h. Serum S100B concentrations measured on admission were higher in the group with neurologic features than in the group without neurologic features [0.148 µg/L (IQR 0.128-0.248) vs. 0.072 µg/L (IQR 0.047-0.084), p < .001]. Univariate analysis of measured patient raw parameters using a ROC curve showed that S100B was a significant predictor of neurologic features in glyphosate and glufosinate poisoning. The area under the ROC curve was 0.894 (95% confidential interval 0.791-0.998). When S100B was set at 0.0965, its sensitivity and specificity for predicting neurologic features in glyphosate and glufosinate poisoning were 92% and 82%, respectively. CONCLUSIONS: In our pilot study, S100B was a significant predictor of neurologic complications in patients with glyphosate and glufosinate poisoning. Large prospective cohorts are needed to confirm this finding.
Assuntos
Aminobutiratos/intoxicação , Estado de Consciência/efeitos dos fármacos , Glicina/análogos & derivados , Doenças do Sistema Nervoso/diagnóstico , Intoxicação/sangue , Proteínas S100/sangue , Adulto , Idoso , Aminobutiratos/sangue , Biomarcadores/sangue , Glicina/sangue , Glicina/intoxicação , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/induzido quimicamente , Projetos Piloto , Intoxicação/complicações , Estudos Prospectivos , Curva ROC , Convulsões/sangue , Convulsões/induzido quimicamente , Convulsões/diagnóstico , Sensibilidade e Especificidade , GlifosatoRESUMO
BACKGROUND AND OBJECTIVE: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. METHODS: In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. RESULTS: Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. CONCLUSION: The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects.
Assuntos
Aminobutiratos/efeitos adversos , Aminobutiratos/farmacocinética , Povo Asiático , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Adolescente , Adulto , Aminobutiratos/administração & dosagem , Aminobutiratos/sangue , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacocinética , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/sangue , Valsartana , Adulto JovemRESUMO
Isomeric molecules present a challenge for analytical resolution and quantification, even with MS-based detection. The eight aminobutyric acid (ABA) isomers are of interest for their various biological activities, particularly γ-aminobutyric acid (GABA) and the d- and l-isomers of ß-aminoisobutyric acid (ß-AIBA; BAIBA). This study aimed to investigate LC-MS/MS-based resolution of these ABA isomers as their Marfey's (Mar) reagent derivatives. HPLC was able to separate three Mar-ABA isomers l-ß-ABA (l-BABA), and l- and d-α-ABA (AABA) completely, with three isomers (GABA, and d/l-BAIBA) in one chromatographic cluster, and two isomers (α-AIBA (AAIBA) and d-BABA) in a second cluster. Partially separated cluster components were deconvoluted using Gaussian peak fitting except for GABA and d-BAIBA. MS/MS detection of Marfey's derivatized ABA isomers provided six MS/MS fragments, with substantially different intensity profiles between structural isomers. This allowed linear deconvolution of ABA isomer peaks. Combining HPLC separation with linear and Gaussian deconvolution allowed resolution of all eight ABA isomers. Application to human serum found a substantial level of l-AABA (13 µM), an intermediate level of l-BAIBA (0.8 µM), and low but detectable levels (<0.2 µM) of GABA, l-BABA, AAIBA, d-BAIBA, and d-AABA. This approach should be useful for LC-MS/MS deconvolution of other challenging groups of isomeric molecules.
Assuntos
Aminobutiratos/sangue , Espectrometria de Massas/métodos , Cromatografia Líquida/métodos , HumanosRESUMO
A simple method, incorporating protein-precipitation/organic backwashing and liquid chromatography-tandem mass spectrometry (LC-MS-MS), has been successfully developed for the simultaneous analysis of four highly water-soluble and less volatile herbicides (paraquat, diquat, glufosinate and glyphosate) in ante- and postmortem blood, urine and gastric content samples. Respective isotopically labeled analogs of these analytes were adopted as internal standards. Acetonitrile and dichloromethane were used for protein precipitation and organic solvent backwashing, respectively, followed by injecting the upper aqueous phase into the LC-MS-MS system. Chromatographic separation was achieved using an Agilent Zorbax SB-Aq analytical column, with gradient elution of 15 mM heptafluorobutyric acid and acetonitrile. Mass spectrometric analysis was performed under electrospray ionization in positive-ion multiple reaction monitoring mode. The precursor ions and the two transition ions (m/z) adopted for each of these four analytes were paraquat (185; 169 and 115), diquat (183; 157 and 78), glufosinate (182; 136 and 119) and glyphosate (170; 88 and 60), respectively. Analyte-free blood and urine samples, fortified with the analytes of interest, were used for method development/validation and yielded acceptable recoveries of the analytes; interday and intraday precision and accuracy data; calibration linearity and limits of detection and quantitation. This method was successfully incorporated into an overall analytical scheme, designed for the analysis of a broad range of compounds present in postmortem samples, helpful to medical examiners' efforts to determine victims' causes of death.
Assuntos
Herbicidas/metabolismo , Aminobutiratos/sangue , Aminobutiratos/metabolismo , Aminobutiratos/urina , Autopsia , Cromatografia Líquida , Médicos Legistas , Morte , Diquat/sangue , Diquat/metabolismo , Diquat/urina , Toxicologia Forense , Glicina/análogos & derivados , Glicina/sangue , Glicina/metabolismo , Glicina/urina , Herbicidas/sangue , Herbicidas/urina , Paraquat/sangue , Paraquat/metabolismo , Paraquat/urina , Espectrometria de Massas em Tandem , GlifosatoRESUMO
PURPOSE: LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and sacubitril (a prodrug), and its metabolite sacubitrilat (the active neprilysin inhibitor, formerly named as LBQ657), which is eliminated primarily via renal route. Since renal dysfunction is a common comorbidity in patients with HF, two open-label studies assessing the effect of mild, moderate, and severe renal impairment were conducted. METHODS: Patients with mild (N = 8; creatinine clearance [CrCl] 50 to ≤80 mL/min), moderate (N = 8; CrCl 30 to <50 mL/min), and severe (N = 6; CrCl <30 mL/min) renal impairment and matching healthy subjects (CrCl >80 mL/min) for each severity group were enrolled to assess the pharmacokinetics of LCZ696 analytes following administration of LCZ696 400 mg once daily (QD) on days 1 and 5. RESULTS: The steady-state Cmax and AUC0-24h of sacubitril and valsartan were unchanged in patients with renal impairment compared with healthy subjects. However, the steady-state Cmax of sacubitrilat was increased by â¼60 % in patients irrespective of degree of renal impairment; half-life increased from 12 h (in healthy subjects) to 21.1, 23.7, and 38.5 h, respectively; and AUC0-24h was increased 2.10-, 2.24-, and 2.70-fold, respectively, in patients with mild, moderate, and severe renal impairment. CONCLUSION: Renal dysfunction increases exposure to sacubitrilat while not impacting sacubitril and valsartan exposure. LCZ696 was generally well tolerated in patients with renal impairment.
Assuntos
Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Insuficiência Renal/metabolismo , Tetrazóis/farmacocinética , Adulto , Aminobutiratos/efeitos adversos , Aminobutiratos/sangue , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/sangue , Compostos de Bifenilo , Combinação de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/fisiopatologia , Tetrazóis/efeitos adversos , Tetrazóis/sangue , ValsartanaRESUMO
PURPOSE: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. METHOD: This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. RESULTS: Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. CONCLUSION: Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.
Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Adolescente , Adulto , Aminobutiratos/efeitos adversos , Aminobutiratos/sangue , Aminobutiratos/farmacocinética , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacologia , Compostos de Bifenilo/sangue , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , Valsartana/efeitos adversos , Valsartana/farmacocinética , Valsartana/farmacologia , Adulto JovemRESUMO
A selective, sensitive and rapid liquid chromatographic method with electrospray ionization tandem mass spectrometric detection has been developed and validated for simultaneous quantification of sacubitril and valsartan in rat plasma using telmisartan as internal standard (IS). The analytes were extracted by deprotenization of 50 µL of plasma sample using 200 µL of acetonitrile. In a short chromatographic run of 1.50 min run time, separation was achieved on a Hypersil Gold C18 column using a mobile phase composed of 0.1% formic acid in Milli-Q water-0.1% formic acid in acetonitrile in gradient elution mode. The quantification of target compounds was performed in a positive electrospray ionization mode and multiple reaction monitoring. Response was a linear function of concentration in the ranges of 0.5-20,000 ng/mL for both analytes, with r(2) > 0.9997. The intra- and inter-day precision and accuracy results were <15% and acceptable as per US Food and Drug Administration guidelines. Stability of compounds were established in a battery of stability studies, i.e. bench-top, autosampler and long-term storage stability as well as freeze-thaw cycles. The validated method can be used as a routine method to support pharmacokinetic studies. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Aminobutiratos/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Antagonistas de Receptores de Angiotensina/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tetrazóis/sangue , Valsartana/sangue , Aminobutiratos/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Animais , Compostos de Bifenilo , Combinação de Medicamentos , Limite de Detecção , Masculino , Ratos , Ratos Sprague-Dawley , Tetrazóis/farmacocinética , Valsartana/farmacocinéticaRESUMO
LCZ696, a novel angiotensin receptor neprilysin inhibitor, is in development for the treatment of heart failure. Administration of LCZ696 results in systemic exposure to sacubitril (inactive prodrug of LBQ657), LBQ657 (neprilysin inhibitor), and valsartan (angiotensin II receptor blocker). We investigated the potential effects of age and sex on the pharmacokinetics of LCZ696 analytes (LBQ657 and valsartan) in an open-label, single oral dose (400 mg), parallel-group study in healthy subjects. Among 36 enrolled subjects, there were 19 male and 17 female subjects; 18 subjects were 18-45 years old (young), and 18 subjects were 65 years of age or older (elderly). Compared with young subjects, the AUCinf and T1/2 for LBQ657 were 42% and 30% greater, respectively, in elderly subjects. The Cmax for LBQ657 was similar between age groups. The AUCinf, Cmax, and T1/2 for valsartan were 30%, 24% greater, and 3.35 hours longer, respectively, in the elderly when compared with young subjects. All pharmacokinetic parameters of LCZ696 analytes (LBQ657 and valsartan) were similar between male and female subjects, indicating no effect on the pharmacokinetics of LCZ696 analytes based on sex. Considering the magnitude of change and its clinical significance, dose adjustment based on age or sex is not considered necessary.