RESUMEN
Mineralocorticoid receptor antagonists (MRAs) decrease morbidity and mortality in patients with heart failure (HF). However, spironolactone, a non-selective MRA, has been shown to exert a harmful effect on glucose homeostasis. The objective of this multicenter, randomized, controlled, double-blind trial was to compare the effects of spironolactone to those of the selective MRA eplerenone on glucose homeostasis among 62 HF patients with glucose intolerance or type II diabetes. Trial registration number:NCT01586442.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Eplerenona/uso terapéutico , Intolerancia a la Glucosa/complicaciones , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Homeostasis , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Espironolactona/uso terapéutico , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Método Doble Ciego , Eplerenona/efectos adversos , Femenino , Hemoglobina Glucada/metabolismo , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Estudios Prospectivos , Espironolactona/efectos adversos , Volumen SistólicoAsunto(s)
Canrenona/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Cumplimiento de la Medicación , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Espironolactona/uso terapéutico , Canadá , Ensayos Clínicos como Asunto , Humanos , Antagonistas de Receptores de Mineralocorticoides/metabolismo , Federación de Rusia , Espironolactona/metabolismo , Estados UnidosRESUMEN
Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.
RESUMEN
Background: Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are available on the transfer of this drug into breast milk. Case Report: We report the case of a woman diagnosed with myotonia congenita who breastfed two children after two consecutive pregnancies. During the breastfeeding of the first and the second infant, she collected, respectively, five and seven samples at 0, 2, 4, 6, and 8 hours and 0, 1, 2, 3, 4, 6, and 8 hours after taking 200 mg of mexiletine thrice daily for seven doses. One week after the collection, samples were analyzed with a validated liquid chromatography tandem mass spectrometry method. No side effect was observed in either child according to the mother. Results: Using the mean milk concentrations, it is estimated that an exclusively breastfed infant would receive a maximum of 5.14% of the initial pediatric mexiletine dosage. We calculated a maximum of 2.67% for the first infant in our case, considering a nonexclusive breastfeeding. Maximal concentrations were observed 1-2 hours after the dose of mexiletine. Results seem to be in accordance with the two cases previously published. Conclusions: Mexiletine transfers into breast milk in low levels. However, results are obtained from only one woman. Therefore, caution should be used when mexiletine is prescribed to breastfeeding women. More cases are needed to evaluate the interindividual variability and to guide women regarding breastfeeding with mexiletine.
Asunto(s)
Lactancia Materna , Leche Humana , Lactante , Embarazo , Femenino , Niño , Humanos , Leche Humana/química , Lactancia Materna/efectos adversos , Mexiletine/análisis , Mexiletine/uso terapéutico , MadresRESUMEN
Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.
Asunto(s)
Alopurinol , Oxipurinol , Masculino , Femenino , Animales , Metoprolol , Estudios Prospectivos , Estudios Transversales , Relación Dosis-Respuesta a DrogaRESUMEN
Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ß-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
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Amiodarona , Adulto , Humanos , Frecuencia Cardíaca , Estudios Transversales , Metoprolol , Bradicardia , Citocromo P-450 CYP2D6RESUMEN
Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.
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Estudio de Asociación del Genoma Completo , Metoprolol , Humanos , Metoprolol/uso terapéutico , Metoprolol/farmacocinética , Citocromo P-450 CYP2D6/genética , Farmacogenética , Estudios TransversalesRESUMEN
Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kp(liver)) were calculated from liver to plasma exposure ratios. In vitro hepatocyte partition coefficients (Kp(hep)) were determined by the ratio of cellular to medium drug concentrations. Human Kp(liver) was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp(liver) multiplied by the ratio of human Kp(hep) over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kp(liver). Our results demonstrated that the in vitro-in vivo proportionality approach provided the best human Kp(liver) prediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r(2) of 0.48) with maximum viral load reduction and led to a corresponding 50% effective dose (ED(50)) IQ of 42, with a 95% confidence interval (CI) of 0.1 to 148534. In contrast, the LCIQ-maximum VLR relationship fit into a typical sigmoidal curve with an r(2) value of 0.95 and an ED(50) LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kp(liver) prediction model, and the LCIQ correlated well with the viral load reductions observed in short-term HCV monotherapy of different DAAs and provides a valuable tool to guide HCV drug discovery.
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Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Hígado/metabolismo , Animales , Células Cultivadas , Digoxina/farmacocinética , Doxorrubicina/farmacocinética , Hepatocitos/virología , Humanos , Imipramina/farmacocinética , Masculino , Ratones , Quinidina/farmacocinética , Ratas , Ratas Sprague-Dawley , Verapamilo/farmacocinéticaRESUMEN
The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).
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Antivirales/farmacocinética , Oligopéptidos/farmacocinética , Inhibidores de Proteasas/farmacocinética , Tiazoles/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Absorción , Ácidos Aminoisobutíricos , Animales , Disponibilidad Biológica , Células CACO-2 , Perros , Evaluación Preclínica de Medicamentos , Hepacivirus/enzimología , Humanos , Leucina/análogos & derivados , Macaca mulatta , Masculino , Microsomas Hepáticos , Oligopéptidos/química , Prolina/análogos & derivados , Quinolinas , Ratas , Ratas Sprague-Dawley , Tiazoles/química , Distribución TisularRESUMEN
Aquatic organisms are continuously exposed to emerging contaminants coming from urban effluents of wastewater treatment plants. The contamination of surface water by those effluents poses a number of environmental risks, and pharmaceuticals are part of this class of effluent contaminants. Various classes of pharmaceuticals are not treated by wastewater treatment plants and anticancer drugs are part of them. The chemotherapy drug methotrexate (MTX) is an emerging contaminant and its growing use with the increase in cancer cases worldwide raises potential risk to aquatic organisms exposed to effluent discharges. However, chemical analyses in exposed freshwater aquatic organisms for ecotoxicological studies are rarely available and no studies have been done yet to accompany ecotoxicological data of exposed filter-feeding organisms. The purpose of this study was to develop a specific and sensitive analytical LC-MS/MS method for the quantification of methotrexate uptake in mussels exposed at different concentrations of the drug. A solid/liquid extraction followed by solid phase extraction (SPE) using an MCX phase purification scheme was optimized. The optimal recovery of 65% and matrix effect of 38% allowed to achieve a limit of quantification of 0.25 ng g-1, with an accuracy of 99-106%, a precision of no more than 3% RSD, and linearity ranging from 0.25 to 25 ng g-1. This methodology was tested with mussels exposed for 96 h at different concentrations (4 to 100 µg L-1) of MTX. The data revealed tissue uptake at concentrations ranging from 0 to 2.53 ng g-1. This suggests that this drug has low uptake potential and this methodology could be used to examine tissue levels of this drug in organisms continuously exposed to urban pollution.
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Bivalvos , Citostáticos , Unionidae , Contaminantes Químicos del Agua , Animales , Cromatografía Liquida/métodos , Citostáticos/análisis , Metotrexato/análisis , Preparaciones Farmacéuticas , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Aguas Residuales/química , Contaminantes Químicos del Agua/análisisRESUMEN
ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Alopurinol , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Alopurinol/análogos & derivados , Alopurinol/sangre , Alopurinol/metabolismo , Alopurinol/farmacocinética , Estudios Transversales , Humanos , Oxipurinol/sangre , Oxipurinol/metabolismo , Oxipurinol/farmacocinética , Ribonucleósidos/sangre , Ribonucleósidos/metabolismo , Ribonucleósidos/farmacocinética , Ácido Úrico/sangreRESUMEN
Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10-14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.
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Citocromo P-450 CYP2D6 , Metoprolol , Estudios Transversales , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Genotipo , Humanos , Metoprolol/farmacocinética , FenotipoRESUMEN
A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the quantification of (S)-metoprolol (MET) and its main metabolite, (S)-α-hydroxymetoprolol (OH-MET). Human plasma samples (50 µL) were spiked with both analytes and their deuterated internal standards (IS) (S)-MET-(d7) and α-OH-MET-(d5). Phospholipid removal microelution-solid phase extraction (PRM-SPE) was performed using a 4-step protocol with Oasis PRiME MCX µElution 96-well cartridges. The eluates were reconstituted in 100 µL of acetonitrile with 50 µg/mL (S)-α-methylbenzyl isocyanate (MBIC) for chiral derivatization. After 60 min at room temperature, the reaction was quenched using 100 µL of water 2 % formic acid. Chromatographic separation of the derivatized analytes was performed on a Kinetex phenyl-hexyl core-shell stationary phase with an elution gradient. Mobile phases were composed of a mixture of water and methanol, with ammonium formate and formic acid as buffers. Total runtime was 15 min. Analyte detection was performed by an AB/SCIEX 4000 QTRAP mass spectrometer with multiple reaction monitoring. Chromatograms showed MBIC successfully reacted with racemic MET, α-OH-MET, and their respective IS. Detection by positive electrospray ionization did not reveal derivatized by-products. Quantification ranges were validated for (S)-MET and (S)-α-OH-MET between 0.5-500 and 1.25-500 ng/mL, respectively, with correlation coefficients (r2) >0.9906. The PRM-SPE assay showed low matrix effects (86.9-104.0 %) and reproducible recoveries (69.4-78.7 %) at low, medium, and high quality control (QC) levels. Precision and accuracy were all comprised between 85-115 % for all three QCs, and between 80-120 % for the lower limit of quantification, for intra- and inter-day values (n = 6, 3 consecutive days). Non-derivatized analytes were stable at room temperature, after 3 freeze-thaw cycles, and stored for 30 days at -80 °C (n = 4). Reinjection reproducibility of a previously validated batch was achieved after 8 days under auto-sampler conditions, indicating the stability of (S)-MET and (S)-α-OH-MET derivatives. Its clinical use was established in a cohort of 50 patients and could be used to further investigate the clinical impact of (S)-MET concentrations.
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Metoprolol , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Humanos , Isocianatos , Metoprolol/análogos & derivados , Fosfolípidos , Reproducibilidad de los Resultados , Extracción en Fase SólidaRESUMEN
A bioanalytical method by high performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS) for the simultaneous quantification of 17 drugs and 2 major active metabolites in breast milk was developed and validated. Breast milk samples (100 µL) were submitted to a simple protein precipitation for the extraction of the analytes after the addition of deuterated internal standards (10 µL). A Kinetex C8 column was used for the separation of analytes with mobile phases composed of acetonitrile with 0.1 % formic acid and water with 0.1 % formic acid in gradient elution mode. Analytes were detected using an AB/SCIEX 4000 QTRAP instrument with positive electrospray ionization and operating in scheduled multiple reaction monitoring mode. Validation covered a large range of concentrations (0.5-500 ng/mL) for most of the analytes except bisoprolol, lacosamide, vilazodone (1-500 ng/mL), acid mycophenolic, letrozole, clomiphene (2-500 ng/mL) and hydroxy-melatonin (10-500 ng/mL). Within-run and between-run accuracy and precision for 4 levels of quality controls (QC) spiked at the lower limit of quantification (LLOQ), at 3 times the LLOQ, 50 % of the upper limit of quantification (ULOQ) and 80 % of the ULOQ were in agreement with the criteria from international guidelines. Matrix effect and extraction recovery ranged from 40.7 to 106.5 % and 87.3 to 110.8 %, respectively with relative standard deviations less than 15 %. Furthermore, all analytes were stable in breast milk at room temperature for 24 h, at -20 °C for two weeks, at -80 °C for 1 month, and after 3 freeze-thaw cycles. Finally, the method was successfully applied to nursing women samples collected from an ongoing feasibility study on drug quantification in breast milk.
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Leche Humana , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Femenino , Humanos , Reproducibilidad de los ResultadosRESUMEN
A sensitive and selective high-performance liquid chromatographic method coupled to tandem mass spectrometry was developed and validated for the quantification of morphine, hydromorphone, fentanyl, midazolam and propofol and their metabolites morphine-3-ß-d-glucuronide, morphine-6-ß-d-glucuronide, hydromorphone-3-ß-d-glucuronide, 1'-hydroxymidazolam-ß-d-glucuronide, α-hydroxymidazolam and 4-hydroxymidazolam in human plasma using potassium oxalate/sodium fluoride mixture as anticoagulant. Human plasma samples (0.4 mL) to which were added a mixture of eleven deuterated internal standards were subjected to solid phase extraction using a mixed-mode polymeric Oasis PRiME MCX in 96-well format. Propofol was selectively eluted and further derivatized using 2-Fluoro-1-methylpyridinium p-toluenesulfonate, whereas the remaining 10 analytes were eluted separately and further concentrated. The derivatized propofol was analyzed separately in a second injection. The analytes were chromatographically separated on a Kinetex phenyl-hexyl analytical column in gradient elution mode, using a mobile phase consisting of aqueous ammonium formate/formic acid buffer and methanol. The overall run time was 8 min. Detection was performed using an AB/SCIEX 4000 QTRAP instrument with positive electrospray ionization employing scheduled multiple reaction monitoring mode. The lower limits of quantification ranged from 0.02 to 5 ng/mL depending on the analyte. Calibration curves covered a concentration range of 1000× in all cases but 1'-hydroxymidazolam-ß-d-glucuronide where it covered a range of 500 × . The validated method was accurate and precise, the intra-day accuracy and precision of quality control samples (4 concentration levels, n = 6 each) being within 91.5-112 % and 1.3-13.2 % (coefficient of variation), respectively, and inter-day (n = 24; 4 days) accuracy and precision of quality control samples (3 concentration levels) being within 94.8-103.5 % and 3.2-11.2 % (coefficient of variation). Mean absolute extraction recoveries were above 60 % for all compounds, except for hydromorphone-3-ß-d-glucuronide (44 %) and for 1'-hydroxymidazolam-ß-d-glucuronide (33 %). Internal standard corrected matrix effect ranged from -4.8 to 3.8 % in normal plasma and in plasma containing 1 % hemolyzed blood. Analytes were stable (above 90 %) in plasma and blood for 19 h at 22 °C, in blood for 90 h at 5 °C, in plasma for 60 days at -20 °C, for 4 months at -70 °C and after three freeze-thaw cycles, and in the injection solvent for at least 3 days in the autosampler. The present method is successfully being applied in a multicenter clinical study for the analysis of plasma samples from patients in intensive care units from a number of Canadian hospitals.
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Hipnóticos y Sedantes , Espectrometría de Masas en Tándem , Analgésicos , Canadá , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Humanos , Unidades de Cuidados Intensivos , Reproducibilidad de los ResultadosRESUMEN
The authors wish to make the following corrections to this paper [...].
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AIMS: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. METHODS AND RESULTS: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints. CONCLUSIONS: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.
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Insuficiencia Cardíaca , Anciano , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides , Espironolactona , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell® monolayer models were further characterized in terms of tightness and integrity. The in vitro in vivo correlation (IVIVC) was obtained by the correlation of the in vitro permeability data with log BB values obtained in mice for seven drugs. The mouse primary model showed higher monolayer integrity and levels of mRNA expression of BBB tight junction (TJ) proteins and membrane transporters (MBRT), especially for the efflux transporter Pgp. The IVIVC and drug ranking underlined the superiority of the primary model (r2 = 0.765) when compared to the PAMPA-BBB (r2 = 0.391) and bEnd.3 cell line (r2 = 0.019) models. The primary monolayer mouse model came out as a simple and reliable candidate for the prediction of drug permeability across the BBB. This model encompasses a rapid set-up, a fair reproduction of BBB tissue characteristics, and an accurate drug screening.
RESUMEN
BACKGROUND: Duloxetine and methylphenidate are commonly prescribed for the management of depression and attention-deficit/hyperactivity disorder (ADHD), respectively. However, little information is available concerning their safety during lactation. The purpose of this case series was to provide additional information to the medical literature concerning infant exposure to methylphenidate and duloxetine through breast milk. METHOD: Bioanalytical method (liquid chromatography coupled to mass spectrometry) was developed and validated before its use to determine the concentrations of both medications in breast milk samples. CASES: Case 1: A 30-year-old woman with depression and ADHD took duloxetine 90 mg daily and methylphenidate 36 mg daily during pregnancy and breastfeeding. The newborn was found to have a congenital pulmonary airway malformation. The breastfeeding status was nonexclusive. At week 4 postpartum, the concentration found in the milk was 32.8 ng/mL of duloxetine and 7.9 ng/mL of methylphenidate (estimated relative infant dose [RID] of 0.3% and 0.2%, respectively). Case 2: A 41-year-old women with depression took duloxetine 60 mg daily during pregnancy and lactation. She gave birth to a healthy child. The breastfeeding status was nonexclusive. Cord to maternal plasma concentration ratio was 0.4. At day 6 postpartum, the concentration of duloxetine was 23.6 ng/mL in the foremilk and 14.3 ng/mL in the hindmilk (RID of 0.4% and 0.2%, respectively). At week 6 postpartum, the concentration was 25.2 ng/mL in the foremilk and 29.3 ng/mL in the hindmilk (RID of 0.4% and 0.4%, respectively). CONCLUSION: In accordance with previously published data, this case series suggests a minimal exposure to duloxetine and methylphenidate through breast milk. Thus, these drugs are likely compatible with lactation. However, large cohort studies are necessary to evaluate their long-term impact on the exposed infants.