RESUMEN
We aimed to explore the proteomic profiles of mid-trimester amniotic fluid in pregnant women with systemic lupus erythematosus (SLE) according to the occurrence of adverse pregnancy outcome (APO). The study population included 35 pregnant women with SLE who underwent clinically indicated amniocentesis at 15-24 weeks of gestation. Patients were divided into two groups according to pregnancy outcomes: SLE patients without APO (Group 1) and SLE patients with APO (Group 2). Stored samples of amniotic fluid were analyzed using mass spectrometry (MS)-based proteomics with two-step approach, consisting of discovery and verification phase. In the discovery phase, 44 proteins were differentially expressed between Group 1 and Group 2. In the verification phase, differentially expressed proteins (DEPs) were verified in independent samples using DIA method. Four proteins including filamin A (FLNA), sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1), lecithin-cholesterol acyltransferase (LCAT), and transglutaminase 2 (TGM2) were differentially expressed both in discovery and verification phase. To select the best combination of proteins for discriminating two groups, three-fold cross validation (CV) with repetition of one hundred times was performed. The multi-marker model with three biomarkers (SVEP1, LCAT, TGM2) had a high discriminatory power to distinguish between the two groups (the area under the receiver operating characteristic, AUROC = 0.946, p <0.001). Our results indicate that the expression of FLNA, SVEP1, LCAT, and TGM2 in mid-trimester amniotic fluid was increased in SLE patients with APO (Group 2). A large-scale prospective study is warranted to verify this finding.
Asunto(s)
Líquido Amniótico/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Proteínas/análisis , Adulto , Amniocentesis , Biomarcadores/análisis , Biomarcadores/metabolismo , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Embarazo , Resultado del Embarazo , Trimestres del Embarazo , Pronóstico , Proteínas/metabolismo , Proteómica , Estudios RetrospectivosRESUMEN
Patients with systemic lupus erythematosus (SLE) are at increased risk for adverse pregnancy outcome (APO). Accurate prediction of APO is critical to identify, counsel, and manage these high-risk patients. We undertook this study to identify novel biomarkers in mid-trimester maternal plasma to identify pregnant patients with SLE at increased risk of APOs. The study population consisted of pregnant women whose plasma was taken in mid-trimester and available for metabolic signature: (1) SLE and normal pregnancy outcome (Group 1, n = 21); (2) SLE with APO (Group 2, n = 12); and (3) healthy pregnant controls (Group 3, n = 10). Mid-trimester maternal plasma was analyzed for integrative profiles of primary metabolite and phospholipid using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography Orbitrap mass spectrometry (LC-Orbitrap MS). For performance comparison and validation, plasma samples were analyzed for sFlt-1/PlGF ratio. In the study population, APO developed in 12 of 33 women with SLE (36%). Metabolite profiling of mid-trimester maternal plasma samples identified a total of 327 metabolites using GC-TOF MS and LC-Orbitrap MS. Partial least squares discriminant analysis (PLS-DA) showed clear discrimination among the profiles of SLE groups and healthy pregnant controls (Groups 1/2 vs. 3). Moreover, direct comparison between Groups 1 and 2 demonstrated that 4 primary metabolites and 13 lipid molecules were significantly different. Binary logistic regression analysis suggested a potential metabolic biomarker model that could discriminate Groups 1 and 2. Receiver operating characteristic (ROC) analysis revealed the best predictability for APO with the combination model of two metabolites (LysoPC C22:5 and tryptophan) with AUC of 0.944, comparable to the AUC of sFlt-1/PlGF (AUC 0.857). In conclusion, metabolic biomarkers in mid-trimester maternal plasma can accurately predict APO in patients with SLE.
Asunto(s)
Biomarcadores/sangre , Lupus Eritematoso Sistémico/sangre , Resultado del Embarazo , Segundo Trimestre del Embarazo/sangre , Adulto , Inductores de la Angiogénesis/sangre , Análisis Discriminante , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Metaboloma , Análisis Multivariante , Embarazo , Curva ROCRESUMEN
BACKGROUND: Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer's disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. METHODS: Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), or 175 mg/50 cm(2). Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. RESULTS: The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74-76 hours (~2-4 hours after patch removal), and mean t1/2ß was ~63.77-93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%-86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. CONCLUSION: The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics.
Asunto(s)
Indanos/farmacocinética , Piperidinas/farmacocinética , Parche Transdérmico , Administración Cutánea , Adulto , Cromatografía Liquida , Donepezilo , Tolerancia a Medicamentos , Voluntarios Sanos , Humanos , Indanos/administración & dosificación , Indanos/sangre , Masculino , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/sangre , Método Simple Ciego , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: "Udenafil" is a phosphodiesterase-5 inhibitor indicated for erectile dysfunction. "Dapoxetine" is a serotonin transport inhibitor indicated for premature ejaculation. The aim of the study reported here was to investigate the pharmacokinetic drug interaction between udenafil and dapoxetine in healthy male subjects. METHODS: An open-label, three-treatment, six-sequence, three-period crossover study was performed in healthy male subjects. In varying sequences, each subjects received single oral doses of udenafil 200 mg, dapoxetine 60 mg, and both treatments. The periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 hours after dosing. The plasma concentrations of udenafil and dapoxetine were determined using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed throughout the study. RESULTS: Twenty-three healthy subjects completed the study. The geometric mean ratios of the area under the plasma concentration-time curve from time 0 to last measurable time point and measured peak plasma concentration for udenafil were 0.923 (90% confidence interval [CI]: 0.863-0.987) and 0.864 (90% CI: 0.789-0.947), respectively. The geometric mean ratios of the area under the plasma concentration-time curve from time 0 to last measurable time point and measured peak plasma concentration for dapoxetine were 1.125 (90% CI: 1.044-1.213) and 0.837 (90% CI: 0.758-0.925), respectively. There were no serious adverse events reported, and none of the subjects dropped out due to adverse events. CONCLUSION: Udenafil was found to have no clinically significant pharmacokinetic interactions with dapoxetine. The concurrent administration of udenafil and dapoxetine was generally well tolerated.
Asunto(s)
Bencilaminas/farmacocinética , Naftalenos/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Bencilaminas/administración & dosificación , Bencilaminas/química , Estudios Cruzados , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Naftalenos/administración & dosificación , Naftalenos/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Sulfonamidas/administración & dosificación , Sulfonamidas/química , Adulto JovenRESUMEN
PURPOSE: A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. METHODS: Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 µmol/L of adenosine diphosphate. FINDINGS: Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. IMPLICATIONS: Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268.
Asunto(s)
Adenosina/análogos & derivados , Inhibidores de Agregación Plaquetaria/administración & dosificación , Agregación Plaquetaria/efectos de los fármacos , Clorhidrato de Prasugrel/administración & dosificación , Adenosina/administración & dosificación , Adenosina/farmacocinética , Adenosina/farmacología , Adulto , Pueblo Asiatico , Plaquetas/efectos de los fármacos , Estudios Cruzados , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Pruebas de Función Plaquetaria , Clorhidrato de Prasugrel/farmacocinética , Clorhidrato de Prasugrel/farmacología , Espectrometría de Masas en Tándem , Ticagrelor , Adulto JovenRESUMEN
OBJECTIVE: Gemigliptin is a selective DPP4 inhibitor used to treat type 2 diabetes. The objective of this study was to evaluate the pharmacokinetics (PKs) of gemigliptin, rosuvastatin, and irbesartan monotherapies and combination therapies. RESEARCH DESIGN AND METHODS: Randomized, open-label, three-treatment, six-sequence, three-period, crossover studies were performed on healthy male volunteers. The three treatments were: 50 mg gemigliptin alone; 20 mg rosuvastatin (part A) or 300 mg irbesartan alone (part B); and rosuvastatin or irbesartan with concomitant gemigliptin. Each drug was administered as part of once daily, 7 day, repeated dosing regimens with a 14 day washout period. CLINICAL TRIAL REGISTRATION: NCT01823133 (part A) and NCT01825850 (part B). MAIN OUTCOME MEASURES: The primary PK parameters - Cmax and AUCτ - were compared to the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) that were determined for the combination therapies and monotherapies. RESULTS: A total of 60 participants were administered the study drugs, and 52 participants (27 participants in part A; 25 participants in part B) were analyzed as part of the PK dataset. In part A, the GMRs (gemigliptin + rosuvastatin/gemigliptin) of the Cmax and AUCτ values of gemigliptin were 0.955 (90% CI = 0.874-1.044) and 1.023 (90% CI = 0.991-1.057), and those of rosuvastatin were 1.012 (90% CI = 0.946-1.084) and 1.086 (90% CI = 1.032-1.142), respectively. In part B, the GMRs of the Cmax and AUCτ values of gemigliptin were 1.046 (90% CI = 0.964-1.134) and 1.035 (90% CI = 1.005-1.065), and those of irbesartan were 0.966 (90% CI = 0.897-1.040) and 1.050 (90% CI = 0.993-1.111), respectively. The limitations of this study include its relatively short treatment period and small sample size, as only healthy participants were included. CONCLUSIONS: Gemigliptin does not affect the PK properties of rosuvastatin or irbesartan; also, rosuvastatin and irbesartan do not affect the PKs of gemigliptin.