LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population

2020 ◽  
Vol 58 (5) ◽  
pp. 798-809 ◽  
Author(s):  
Pilar Irún ◽  
Jorge J. Cebolla ◽  
Laura López de Frutos ◽  
Isabel De Castro-Orós ◽  
Mercedes Roca-Espiau ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Plasma Concentrations ◽  
Liver Volume ◽  
Diagnostic Value ◽  
Treatment Monitoring ◽  
Resonance Imaging ◽  
Chromatography Tandem Mass Spectrometry ◽  
Specificity And Sensitivity ◽  
Liquid Chromatography Tandem Mass

AbstractBackgroundGaucher disease (GD), caused by a deficiency in acid β-glucosidase, leads to the accumulation of glucosylsphingosine (GluSph), which has been used as a powerful biomarker for the diagnosis and follow-up of GD. Our aim was to perform the first retrospective study of GluSph in Spanish patients, analyzing its relationship with classical biomarkers and other parameters of disease and its utility regarding treatment monitoring.MethodsClassical biomarkers were evaluated retrospectively by standard methods in a total of 145 subjects, including 47 GD patients, carriers, healthy controls and patients suffering from other lysosomal lipidoses. GluSph was also measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed as part of the present study.ResultsThe optimized method presented intra- and inter-assay variations of 3.1 and 11.5%, respectively, overall recovery higher than 96% and linearity up to plasma concentrations of 1000 ng/mL with 100% specificity and sensitivity. Only GD patients displayed GluSph levels above 5.4 ng/mL at diagnosis and this was significantly correlated with the classical biomarkers chitotriosidase (r = 0.560) and the chemokine CCL18/PARC (CCL18/PARC) (ρ = 0.515), as well as with the Spanish magnetic resonance imaging index (S-MRI, r = 0.364), whereas chitotriosidase correlated with liver volume (r = 0.372) and CCL18/PARC increased in patients with bone manifestations (p = 0.005). GluSph levels decreased with treatment in naïve patients.ConclusionsPlasma GluSph is the most disease-specific biomarker for GD with demonstrated diagnostic value and responsiveness to therapy. GluSph in the present series of patients failed to demonstrate better correlations with clinical characteristics at onset than classical biomarkers.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

scholarly journals Evaluation of diagnostic value of ultrasound and magnetic resonance imaging for malignant and benign breast lesions

2018 ◽  
Vol 2 (5) ◽  
Author(s):  
Yanni Zeng ◽  
Hongwei Zhang ◽  
Jiuxia Zhang ◽  
Yan Yu ◽  
Liangjin Liu
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Statistical Significance ◽  
Diagnostic Value ◽  
Breast Lesions ◽  
Resonance Imaging ◽  
Benign Lesions ◽  
Specificity And Sensitivity ◽  
Treatment Data ◽  
Benign Breast Lesions

[Abstract] Objectives: To investigate diagnostic value of ultrasound and magnetic resonance imaging (MRI) for malignant and benign breast lesions. Methods: Retrospective analysis of treatment data of 48 patients diagnosed with malignant and benign breast lesions in our hospital, collected from December 2017 to November 2018. A total number of 56 breast masses were examined by both ultrasound and MRI, and were compared with postoperative pathological biopsy results. Results: Postoperative pathological biopsy results showed that there were 26 and 30 malignant and benign lesions respectively. Comparison of MRI curve type of malignant and benign lesions showed statistical significance (P<0.05). By comparison with pathological biopsy results, specificity and sensitivity of ultrasound diagnosis were 83.33% (25/30) and 84.61% (22/26) respectively; specificity and sensitivity of MRI diagnosis were 96.66% (29/30) and 92.30% (24/26) respectively. Conclusions: Ultrasonographic examination of malignant and benign breast lesions is straight-forward, simple and inexpensive. Accuracy, specificity and sensitivity of MRI are significantly higher than ultrasound in examining malignant and benign breast lesions, this can reduce misdiagnosis.

Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography–tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening

2020 ◽  
pp. 096914132093772
Author(s):  
Zhenzhen Hu ◽  
Jianbin Yang ◽  
Yiming Lin ◽  
Junjuan Wang ◽  
Lingwei Hu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Methylmalonic Acid ◽  
Dried Blood Spots ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Total Homocysteine

Objectives Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography–tandem mass spectrometry has usually been used as a second-tier test to improve performance of newborn screening for propionylcarnitine-related disorders. However, factors that potentially affect its detection results have not been investigated, and we aimed to evaluate these influencing factors and explore their potential utility in newborn screening and initial follow-up for propionylcarnitine-related disorders. Methods This study comprised a prospective group (1998 healthy infants, to establish cutoff values and investigate the influencing factors) and a retrospective group (804 suspected positive cases screened from 381, 399 newborns for propionylcarnitine-related disorders by tandem mass spectrometry, to evaluate the performance of newborn screening and initial follow-up). Results Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively. Concentration of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots is not impacted by sex, age, birth weight, gestational age, or dried blood spot storage time. A total of 75 of 804 cases were screened positive by combined tandem mass spectrometry and liquid chromatography–tandem mass spectrometry, thus eliminating 90% of the false positives without compromising sensitivity. Eighteen propionylcarnitine-related disorders were successfully identified, including one CblX case missed in the initial follow-up by tandem mass spectrometry. Conclusions Methylmalonic acid, 2-methylcitric acid, and total homocysteine detected in dried blood spots by liquid chromatography–tandem mass spectrometry is a reliable, specific, and sensitive approach for identifying propionylcarnitine-related disorders. We recommend this assay should be performed rather than tandem mass spectrometry in follow-up for propionylcarnitine-related disorders besides second-tier tests in newborn screening.

scholarly journals Effects of a non-steroidal aromatase inhibitor on ovarian function in cattle

2012 ◽  
Vol 24 (4) ◽  
pp. 631 ◽  
Author(s):  
M. Jimena Yapura ◽  
Reuben J. Mapletoft ◽  
Jaswant Singh ◽  
Roger Pierson ◽  
Jonathan Naile ◽  
...  
Keyword(s):  
Aromatase Inhibitor ◽  
High Performance ◽  
Ovarian Function ◽  
Plasma Concentrations ◽  
Dominant Follicle ◽  
Follicular Wave ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Arrest Growth ◽  
Phosphate Buffered Saline

Effects of the non-steroidal aromatase inhibitor letrozole on ovarian function in cattle were determined. The hypothesis that letrozole would arrest growth of the dominant follicle, resulting in emergence of a new follicular wave at a predictable post-treatment interval, was tested. Heifers were assigned randomly to four groups 4 days after follicular ablation (~2½ days after wave emergence) and given intravenous doses of 500 (n = 9), 250 (n = 10), or 125 µg kg–1 (n = 10) letrozole or phosphate-buffered saline (controls; n = 10). Blood was collected and ovarian structures were monitored daily by transrectal ultrasonography. Plasma concentrations of LH and FSH were measured by radioimmunoassay; plasma concentrations of letrozole were determined by high-performance liquid chromatography tandem mass spectrometry. A single intravenous dose of letrozole did not induce regression of the dominant follicle present at the time of treatment, nor did it directly affect FSH release. Conversely, treatment with letrozole increased endogenous concentrations of LH and extended the lifespan of the dominant follicle, which delayed the next FSH surge and subsequent follicular wave emergence. Letrozole continues to have potential as a non-steroidal treatment for controlling ovarian function in cattle.

scholarly journals 32. TREATMENT MONITORING OF IMMUNOTHERAPY AND TARGETED THERAPY USING AMINO ACID PET IN PATIENTS WITH BRAIN METASTASES

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii5-ii6
Author(s):  
Norbert Galldiks ◽  
Diana Abdulla ◽  
Matthias Scheffler ◽  
Fabian Wolpert ◽  
Jan-Michael Werner ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Amino Acid ◽  
Brain Metastases ◽  
Response Assessment ◽  
Diagnostic Value ◽  
Treatment Monitoring ◽  
Fet Pet ◽  
Time To Peak ◽  
Amino Acid Pet

Abstract PURPOSE Recently, the RANO group has analyzed the additional diagnostic value of amino acid PET in patients with primary and secondary brain tumors and recommended the use of this imaging technique in addition to conventional MRI. Here, we investigated the value of PET using the radiolabled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive. METHODS We retrospectively identified 40 patients with 107 BM secondary to melanoma (n=29 with 75 BM) or non-small cell lung cancer (n=11 with 32 BM) treated with ICI or TT who had FET PET (n=60 scans) for treatment monitoring from 2015–2019. The majority of patients (n=37; 92.5%) had radiotherapy during the course of disease. In 27 patients, FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic FET PET parameters were obtained (i.e., mean tumour-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference. RESULTS A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P=0.003). Metabolic Responders to ICI or TT on FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P=0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P=0.019). CONCLUSIONS FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.

scholarly journals Contribution of N-Glucuronidation to Efavirenz EliminationIn Vivoin the Basal and Rifampin-Induced Metabolism of Efavirenz

2011 ◽  
Vol 55 (4) ◽  
pp. 1504-1509 ◽  
Author(s):  
Doo-Yeoun Cho ◽  
Evan T. Ogburn ◽  
David Jones ◽  
Zeruesenay Desta
Keyword(s):  
Enzymatic Hydrolysis ◽  
Crossover Trial ◽  
Plasma Concentrations ◽  
Treated Group ◽  
Pharmacokinetic Parameters ◽  
Treatment Groups ◽  
Chromatography Tandem Mass Spectrometry ◽  
Significant Difference ◽  
Liquid Chromatography Tandem Mass

ABSTRACTIn this study, the contribution of efavirenz N-glucuronidation to efavirenz eliminationin vivowas assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n= 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with β-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P> 0.05; pairedttest, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P= 0.007) and rifampin (P= 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P< 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenzN-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal.

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