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1.
Nat Commun ; 11(1): 5997, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244003

RESUMO

The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith's Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH)2D level explains 5% of variance in α-diversity. In ß-diversity analyses using unweighted UniFrac, 1,25(OH)2D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH)2D and/or the hormone-to-prohormone [1,25(OH)2D/25(OH)D] "activation ratio." Men with higher levels of 1,25(OH)2D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health.

2.
Afr J Lab Med ; 9(2): 1041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32934915

RESUMO

Background: Past and recent outbreaks have highlighted the vulnerability of humans to infectious diseases, which represent serious economic and health security threats. A paradigm shift in the management of sanitary crises is urgently needed. Based on lessons from the 2014 Ebola outbreak, the Praesens Foundation has developed an all-terrain mobile biosafety laboratory (MBS-Lab) for effective field diagnostics capabilities. Objective: The aim of the study was to train African teams and run a field evaluation of the MBS-Lab, including robustness, technical and operational sustainability, biosafety, connectivity, turn-around times for testing and result delivery. Methods: The MBS-Lab was deployed in Senegal in October 2017 for a six-month field assessment under various ecological conditions and was mobilised during the dengue outbreaks in 2017 and 2018. Results: The MBS-Lab can be considered an off-grid solution that addresses field challenges with regard to working conditions, mobility, deployment, environment and personnel safety. Blood (n = 398) and nasal swab (n = 113) samples were collected from 460 study participants for molecular screening for acute febrile illnesses and respiratory infections. The results showed that malaria (particularly in Kédougou) and upper respiratory tract infections remain problematic. Suspected dengue samples were tested on board during the dengue outbreaks in 2017 (882 tests; 128 confirmed cases) and 2018 (1736 tests; 202 confirmed cases). Conclusion: The MBS-Lab is an innovative solution for outbreak response, even in remote areas. The study demonstrated successful local ownership and community engagement. The MBS-Lab can also be considered an open mobile healthcare platform that offers various opportunities for field-deployable, point-of-care technologies for surveillance programmes.

3.
Biochem Med (Zagreb) ; 30(1): 010802, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839727

RESUMO

Introduction: Hypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning, but the exact mechanism is not known. Case description: An ambulance crew was dispatched to an unconscious 46-year old man. A glucometer point-of-care measurement revealed a profound hypoglycaemia (1.9 mmol/L). Treatment with intravenous glucose was started and the patient was transported to the hospital. The patient had several episodes of pulseless electrical activity requiring cardiopulmonary resuscitation in the ambulance and upon arrival in the hospital. Despite continuous glucose infusion the hypoglycaemia was difficult to correct during the next few hours and the patient developed hypokalaemia. Further investigation to identify the cause of hypoglycaemia revealed that insulin and C-peptide were inappropriately raised. A toxicological investigation revealed the presence of tramadol and its metabolites in lethal concentrations. Also acetaminophen, ibuprofen and lormetazepam were present. Ethanol screening was negative (< 0.1 g/L) and no sulfonylurea were detected. The patient developed multiple organ failure, but eventually recovered. What happened: The hypoglycaemia was caused by inappropriate stimulation of insulin secretion in a patient intoxicated with tramadol. The sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose. Main lesson: To our knowledge, we are the first to document a significant rise in endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication. Our observation suggests that hyperinsulinemia could be the cause of the hypoglycaemia associated with tramadol use.


Assuntos
Analgésicos Opioides/efeitos adversos , Hipoglicemia/diagnóstico , Tramadol/efeitos adversos , Analgésicos Opioides/uso terapêutico , Glicemia/análise , Peptídeo C/sangue , Glucose/administração & dosagem , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/etiologia , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Tramadol/uso terapêutico
4.
Diagnosis (Berl) ; 6(1): 57-68, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808156

RESUMO

Background Dried blood spots (DBSs) could allow patients to prepare their own samples at home and send them to the laboratory for therapeutic drug monitoring (TDM) of immunosuppressants. The purpose of this review is to provide an overview of the current knowledge about the impact of DBS-related preanalytical factors on TDM of tacrolimus, sirolimus and everolimus. Content Blood spot volume, blood spot inhomogeneity, stability of analytes in DBS and hematocrit (Hct) effects are considered important DBS-related preanalytical factors. In addition, the influence of drying time has recently been identified as a noteworthy preanalytical factor. Tacrolimus is not significantly influenced by these factors. Sirolimus and everolimus are more prone to heat degradation and exhibited variations in recovery which were dependent on Hct and drying time. Summary and outlook DBS-related preanalytical factors can have a significant impact on TDM for immunosuppressants. Tacrolimus is not significantly influenced by the studied preanalytical factors and is a viable candidate for DBS sampling. For sirolimus and everolimus more validation of preanalytical factors is needed. In particular, drying conditions need to be examined further, as current protocols may mask Hct-dependent effects on recovery. Further validation is also necessary for home-based self-sampling of immunosuppressants as the sampling quality is variable.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Hematócrito , Imunossupressores/sangue , Fase Pré-Analítica , Everolimo/sangue , Humanos , Sirolimo/sangue , Tacrolimo/sangue
5.
Eur J Clin Microbiol Infect Dis ; 37(8): 1503-1510, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29770901

RESUMO

Vancomycin pharmacokinetic (PK) and pharmacodynamic (PD) data in neonates are based on total concentrations. However, only unbound vancomycin is pharmacologically active. The objective was to determine vancomycin protein binding and the covariates impacting unbound vancomycin concentration in neonates and young infants. In neonates and young infants to whom vancomycin was administered intermittently for medical indications, total and unbound vancomycin plasma concentrations were determined using LC-MS/MS. Sampling occurred randomly during vancomycin exposure, covering a broad range of concentrations. Impact of covariates on unbound vancomycin concentration was determined using linear regression. Significant results of the univariate regressions were entered in a stepwise multiple regression. Passing-Bablok regression and Bland-Altman were used to assess the difference between measured and calculated unbound vancomycin concentration. Thirty-seven samples in 33 patients (median (interquartile range) gestational age 35 (29-39) weeks) were collected. Median total and unbound vancomycin concentrations were 14.2 (7.4-20.6) and 13.6 (7.2-22.5) mg/L, respectively. Median unbound fraction was 0.90 (0.77-0.98). Multiple regression revealed total vancomycin concentration (ß = 0.884, p < 0.001) and albumin (ß = - 0.323, p = 0.007) as most important covariates of unbound vancomycin concentrations, with an R2 adjusted of 0.953 (p < 0.0001). Mean absolute difference between calculated and measured unbound vancomycin was - 0.008 (95% CI - 0.92-0.91) mg/L. The unbound vancomycin fraction in neonates is higher compared to that in children and adults, and total vancomycin concentration and albumin were the most important covariates of unbound vancomycin concentration. Integration of protein binding in future PK/PD analyses is appropriate to optimize vancomycin dosing and to determine population-specific vancomycin PD targets for neonates.


Assuntos
Antibacterianos/farmacocinética , Vancomicina/farmacocinética , Fatores Etários , Antibacterianos/administração & dosagem , Biomarcadores , Cromatografia Líquida , Monitoramento de Medicamentos , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Ligação Proteica , Fatores de Risco , Espectrometria de Massas em Tandem , Vancomicina/administração & dosagem
6.
Data Brief ; 14: 763-772, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28932781

RESUMO

The data presented in this article are related to the research article entitled "The Diagnostic Value of Rescaled Renal Biomarkers Serum Creatinine and Serum Cystatin C and their Relation with Measured Glomerular Filtration Rate" (Pottel et al. (2017) [1]). Data are presented demonstrating the rationale for the normalization or rescaling of serum cystatin C, equivalent to the rescaling of serum creatinine. Rescaling biomarkers brings them to a notionally common scale with reference interval [0.67-1.33]. This article illustrates the correlation between rescaled biomarkers serum creatinine and serum cystatin C by plotting them in a 2-dimensional graph. The diagnostic value in terms of sensitivity and specificity with measured Glomerular Filtration Rate as the reference method is calculated per age-decade for both rescaled biomarkers. Finally, the interchangeability between detecting impaired kidney function from renal biomarkers and from the Full Age Spectrum FAS-estimating GFR-equation and measured GFR using a fixed and an age-dependent threshold is shown.

7.
Clin Chim Acta ; 471: 164-170, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28601669

RESUMO

BACKGROUND: Serum creatinine (Scr) is the major contributing variable in glomerular filtration rate (GFR) estimating equations. Serum cystatin C (ScysC) based GFR estimating (eGFR)-equations have also been developed. The present study investigates the relation between 'rescaled' levels of these renal biomarkers (with reference interval of [0.67-1.33]) and measured GFR (mGFR). METHODS: We evaluated the diagnostic ability to detect impaired kidney function of the rescaled renal biomarkers in 8584 subjects from 12 cohorts with measured GFR, standardized Scr and ScysC. We calculated sensitivity and specificity of the rescaled biomarkers to identify kidney disease, with reference to a fixed (60mL/min/1.73m2) as well as an age-dependent threshold for mGFR. RESULTS: The upper reference limit of 1.33 for rescaled renal biomarkers is closely related to the age-dependent threshold for defining kidney status by mGFR with sensitivity and specificity for the rescaled biomarkers close to 90% for all ages. If the fixed threshold of 60mL/min/1.73m2 for mGFR is used, then lower specificity in children and sensitivity in older adults are observed. CONCLUSIONS: Impaired kidney function can be diagnosed by rescaled renal biomarkers instead of eGFR-equations using the fixed threshold of 1.33 for all ages, consistent with an age-dependent threshold of mGFR.


Assuntos
Cistatina C/sangue , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Estudos de Coortes , Humanos , Testes de Função Renal , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Estudos Retrospectivos , Adulto Jovem
8.
J Steroid Biochem Mol Biol ; 173: 341-348, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28193495

RESUMO

BACKGROUND: The measurement of 1α,25(OH)2D3 in human serum poses a true challenge as concentrations are very low and structurally similar metabolites can interfere. MATERIALS AND METHODS: During optimization of our in-house LC-MSMS method for serum 1α,25(OH)2D3 a previously co-eluting isobaric interference was separated. The isobar was identified as 1ß,25(OH)2D3 by comparing retention time and fragmentation spectra to standards (other isobaric dihydroxylated vitamin D3 analogs). 1ß,25(OH)2D3 showed specific cluster formation (water), not present in 1α,25(OH)2D3. 1ß,25(OH)2D3 was measured in serum of apparently healthy human volunteers (n=20), patients with high serum 25-hydroxyvitamin D [25(OH)D] concentrations (>50ng/mL) (n=33 among which 4 with very high levels (>150ng/mL)) and patients with kidney failure (n=68; 39 stage 1-3, 29 stage 4-5). Pearson's r was calculated for correlations and Mann-Whitney statistic to compare group medians. RESULTS: Median serum 1ß,25(OH)2D3 was 11pg/mL in apparently healthy volunteers and increased to 20pg/mL for serum 25(OH)D concentrations above 80ng/mL (n=22) (p<0.0001). 1ß,25(OH)2D3 concentrations were significantly correlated to serum 25(OH)D concentrations (r=0.85) for the combined results from healthy volunteers and patient sera (n=53) (p<0.0001). For patients with kidney failure, median serum 1ß,25(OH)2D3 was 7pg/mL and not different from the median level in healthy volunteers (p=0.06). The median concentration did not vary with different stages. CONCLUSIONS: We present evidence for the widespread presence of 1ß,25(OH)2D3, a new vitamin D metabolite, in human serum. The level increases with rising serum 25(OH)D concentrations and is particularly high in patients with very high 25(OH)D levels. We previously demonstrated that 1ß,25(OH)2D3 is a poor genomic agonist but a potent non-genomic antagonist of 1α,25(OH)2D3. The clinical implications of the presence of this analog therefore require further exploration.


Assuntos
Calcitriol/sangue , Espectrometria de Massas em Tandem/métodos , Vitaminas/sangue , Adulto , Calcitriol/metabolismo , Cromatografia Líquida/métodos , Humanos , Limite de Detecção , Pessoa de Meia-Idade , Vitaminas/metabolismo , Adulto Jovem
9.
Hypertension ; 69(3): 443-449, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28115515

RESUMO

Low birth weight and prematurity are risk factors for hypertension in adulthood. Few studies in preterm or full-term born children reported on plasma renin activity (PRA). We tested the hypothesis that renin might modulate the incidence of hypertension associated with prematurity. We enrolled 93 prematurely born children with birth weight <1000 g and 87 healthy controls born at term, who were all examined at ≈11 years. Renal length and glomerular filtration rate derived from serum cystatin C were 0.28 cm (95% confidence interval, 0.09-0.47) and 11.5 mL/min per 1.73 m2 (6.4-16.6) lower in cases, whereas their systolic/diastolic blood pressure (BP) was 7.5 mm Hg (4.8-10.3)/4.0 mm Hg (2.1-5.8) higher (P<0.001 for all). The odds of having systolic prehypertension or systolic hypertension associated with extreme low birth weight were 6.43 (2.52-16.4; P<0.001) and 10.9 (2.46-48.4; P=0.002). Twenty-four hours of urinary sodium excretion was similar in cases and controls (102.1 versus 106.8 mmol; P=0.47). Sodium load per nephron was estimated as sodium excretion divided by kidney length (mmol/cm). PRA was 0.54 ng/mL per hour (0.23-0.85; P=0.001) lower in cases. PRA, systolic BP, and sodium load were available in 43 cases and 56 controls. PRA decreased with systolic BP (slope -0.022 ng/mL per hour/-mm Hg; P=0.048), but was unrelated to sodium load (slope +0.13 mmol/cm-mm Hg; P=0.54). The slope of PRA on systolic BP was similar (P=0.17) in cases and controls. In conclusion, extremely low birth weight predisposes young adolescents to low-renin hypertension, but does not affect the inverse association between PRA and BP. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147457.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Recém-Nascido de Baixo Peso , Renina/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Hipertensão/sangue , Lactente , Rim/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Estudos Retrospectivos
10.
Nephrol Dial Transplant ; 32(3): 497-507, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28089986

RESUMO

Background: We recently published and validated the new serum creatinine (Scr)-based full-age-spectrum equation (FAS crea ) for estimating the glomerular filtration rate (GFR) for healthy and kidney-diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults. Methods: Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC ( Q cysC = 0.82 mg/L for ages <70 years and Q cysC = 0.95 mg/L for ages ≥70 years). By replacing Scr/ Q crea in the FAS crea equation with ScysC/ Q cysC , or with the average of both normalized biomarkers, we obtained new ScysC-based (FAS cysC ) and combined Scr-/ScysC-based FAS equations (FAS combi ). To validate the new FAS cysC and FAS combi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n = 6132 unique white subjects (368 children, aged ≤18 years, 4295 adults and 1469 older adults, aged ≥70 years). Results: In children and adolescents, the new FAS cysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC-based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAS combi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAS cysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI cysC ) (P30 = 80.4%) and the FAS combi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAS cysC was superior (P30 = 88.2%) to CKD-EPI cysC (P30 = 84.4%; P < 0.0001) and the FAS combi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001). Conclusion: The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations.


Assuntos
Creatinina/sangue , Cistatina C/sangue , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Lactente , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Adulto Jovem
12.
J Clin Endocrinol Metab ; 101(5): 2226-34, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27007693

RESUMO

CONTEXT: Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD. OBJECTIVES: Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD. DESIGN: This study used a cross-sectional design. SETTING: The general community in the United States, United Kingdom, and The Gambia were included in this study. PARTICIPANTS: Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included. EXPOSURES: Total 25OHD concentration, race, and DBP (GC) genotype exposures were included. OUTCOME MEASURES: Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures. RESULTS: Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80-0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites. CONCLUSIONS: Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.


Assuntos
Proteína de Ligação a Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Estudos Transversais , Grupo com Ancestrais do Continente Europeu , Humanos , Masculino , Vitamina D/sangue
14.
Arch Dis Child ; 101(4): 377-81, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26803050

RESUMO

Therapeutic drug monitoring (TDM) aims to integrate drug measurement results into clinical decision making. The basic rules apply when using TDM in neonates (aminoglycosides, vancomycin, phenobarbital, digoxin), but additional factors should also be taken into account. First, due to both pharmacokinetic variability and non-pharmacokinetic factors, the correlation between dosage and concentration is poor in neonates, but can be overcome with the use of more complex, validated dosing regimens. Second, the time to reach steady state is prolonged, especially when no loading dose is used. Consequently, the timing of TDM sampling is important in this population. Third, the target concentration may be uncertain (vancomycin) or depend on specific factors (phenobarbital during whole body cooling). Finally, because of differences in matrix composition (eg, protein, bilirubin), assay-related inaccuracies may be different in neonates. We anticipate that complex validated dosing regimens, with subsequent TDM sampling and Bayesian forecasting, are the next step in tailoring pharmacotherapy to individual neonates.


Assuntos
Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Antibacterianos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Teorema de Bayes , Humanos , Recém-Nascido , Fenobarbital/administração & dosagem , Vancomicina/administração & dosagem
16.
J Steroid Biochem Mol Biol ; 164: 127-133, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26690787

RESUMO

BACKGROUND: To assess a patient's vitamin D status the precursor metabolite 25-hydroxyvitamin D can be determined. However, measurement of 1,25-dihydroxyvitamin D is required when disorders of 1a-hydroxylation, extrarenal 1a-hydroxylation, or vitamin D receptor defects are suspected. METHODS: The aim of this study was to determine reference values for 1,25-dihydroxyvitamin D3 and D2 using a 2D ID-UPLC-MS/MS method. RESULTS: The LC-MS/MS method, able to measure picomolar concentrations of both 1,25-dihydroxyvitamin D3 and D2 in human serum, was extensively validated. Intra-assay variations were <5% and 8.5% and <7.5% and 11%, for 1,25-dihydroxyvitamin D3 and D2, respectively, over the whole dynamic range (3.1-376 and 3.1-652pmol/L). Limit of quantitation was 3.4pmol/L for both compounds. Our method correlated well with a published LC-MS/MS method (r=0.87) and with the average 1,25-dihydroxyvitamin D3 results of the vitamin D External Quality Assessment Scheme (DEQAS) determined with LC-MS/MS (r=0.93). Reference ranges, determined in 96 plasma samples of healthy volunteers were 59-159pmol/L and <17pmol/L for respectively 1,25-dihydroxyvitamin D3 and D2. The female part of the reference group showed a statistically significant decrease of 1,25-dihydroxyvitamin D3 concentrations with age. The presence of significantly higher average 1,25-dihydroxyvitamin D3 levels in premenopausal women taking oral contraceptive pills compared to postmenopausal women suggests that this effect is estrogen-related, as estrogens lead to a higher vitamin D binding protein. CONCLUSIONS: The major finding of the present study is a reference interval of 59-159pmol/L for 1,25-dihydroxyvitamin D3 determined with a highly sensitive and precise LC-MS/MS method.


Assuntos
Calcitriol/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ergocalciferóis/sangue , Espectrometria de Massas em Tandem/métodos , Vitaminas/sangue , Adulto , Idoso , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Pré-Menopausa/sangue , Valores de Referência , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto Jovem
17.
Antimicrob Agents Chemother ; 59(11): 7073-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26349820

RESUMO

The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [n = 33 samples], intensive care unit [ICU] [n = 51], orthopedics [n = 44], and pediatrics [age range, 6 months to 14 years; n = 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (P < 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], -1.3 to 0.7 mg/liter; R(2) = 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.


Assuntos
Vancomicina/sangue , Vancomicina/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Bilirrubina/sangue , Bilirrubina/metabolismo , Cromatografia Líquida , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/metabolismo , Imunoglobulina M/sangue , Imunoglobulina M/metabolismo , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Espectrometria de Massas em Tandem , Adulto Jovem
19.
Anal Bioanal Chem ; 407(20): 6191-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26072209

RESUMO

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the method of choice for quantifying small molecules in research and clinical setting. Although there is a large toolkit to increase quantification levels for LC-MS/MS, these techniques are sometimes insufficient to attain the needed limits of quantification (LOQs) or the method becomes too impractical for routine use. We examined the possibilities and limitations of signal summing, an under-utilized, easy-to-apply practice to increase LOQs for an immunosuppressant LC-MS/MS method. The limits of signal summing for everolimus were tested by running samples of everolimus at three concentrations in triplicate programming, increasing amounts of identical transitions in a constant cycle time up to the maximum number the software permitted to sum. The increase in peak area and the signal-to-noise ratio were determined. The effect on imprecision of peak areas and response ratios was evaluated by injection of a low concentration of everolimus tenfold using respectively one and five identical transitions, retaining an identical ion counting time. We compared the imprecision, LOQ, and recovery for our routine everolimus method (using one transition for everolimus and one for d3-everolimus) and an adapted method summing three identical transitions for everolimus (and one for d3-everolimus). The increase in signal was close to the theoretically expected one with a larger experimental spread for everolimus once more than five transitions were used. There was no clear beneficial effect of summing on imprecision. The adapted everolimus method showed a lower LOQ, but comparable imprecision and recovery as the routine method. Quantification levels can be improved by signal summing. No clear effect on imprecision was observed.


Assuntos
Cromatografia Líquida/métodos , Everolimo/sangue , Imunossupressores/sangue , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos/métodos , Everolimo/análise , Humanos , Imunossupressores/análise , Limite de Detecção , Reprodutibilidade dos Testes , Razão Sinal-Ruído , Software
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