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Background: Although adherence to inhaled medication is critically important for treatment efficiency, around half of patients taking these drugs are non-adherent or make critical errors when using their delivery device. Segmental hair analysis might be a valuable tool for therapeutic monitoring because hair concentrations reflect exposure from month to month. The objective of the present proof-ofconcept study was to establish the feasibility of segmental hair analysis of inhaled budesonide and formoterol in asthma patients. Methods: We conducted a prospective, open-label, interventional study of adult patients being treated with budesonide/formoterol for controlled, moderate-tosevere asthma (CorticHair, NCT03691961). Asthma control, lung function, and medication adherence were recorded. Hair samples were taken 4 months after enrolment and cut into four 1 cm segments. Results: Samples were available from 21 patients (20 women; median age: 53; median budesonide dose: 600 µg/d). Budesonide and formoterol were detected in samples from 18 to 13 patients, respectively. The median hair concentrations were 6.25 pg/mg for budesonide and 0.9 pg/mg for formoterol. The intrapatient coefficient of variation between hair segments was 21% for budesonide and 40% for formoterol. Pearson's coefficients for the correlations between the hair concentration and the self-reported drug dose and the prescribed drug dose were respectively 0.42 (p = 0.08) and 0.29 (p = 0.25) for budesonide and 0.24 (p = 0.44) and 0.17 (p = 0.57) for formoterol. Conclusion: Segmental hair analysis of inhaled medications was feasible, with low intrapatient variability. This innovative, non-invasive means of assessing monthly drug exposure might help physicians to personalize drug regimens for patients with difficult-to-treat asthma. [ABSTRACT FROM AUTHOR]

Objective: To examine the safety, efficacy and pharmacology of intravenous (IV), intramuscular (IM) and oral tranexamic acid (TXA) use in pregnant women. Design: Randomised, open‐label trial. Setting: Hospitals in Pakistan and Zambia. Population: Women giving birth by caesarean section. Methods: Women were randomised to receive 1 g IV, 1 g IM, 4 g oral TXA or no TXA. Adverse events in women and neonates were recorded. TXA concentration in whole blood was measured and the concentrations over time were examined with population pharmacokinetics. The relationship between drug exposure and D‐dimer was explored. The trial registration is NCT04274335. Main outcome measures: Concentration of TXA in maternal blood. Results: Of the 120 women included in the randomised safety study, there were no serious maternal or neonatal adverse events. TXA concentrations in 755 maternal blood and 87 cord blood samples were described by a two‐compartment model with one effect compartment linked by rate transfer constants. Maximum maternal concentrations were 46.9, 21.6 and 18.1 mg/L for IV, IM and oral administration, respectively, and 9.5, 7.9 and 9.1 mg/L in the neonates. The TXA response was modelled as an inhibitory effect on the D‐dimer production rate. The half‐maximal inhibitory concentration (IC50) was 7.5 mg/L and was achieved after 2.6, 6.4 and 47 minutes with IV, IM and oral administration of TXA, respectively. Conclusions: Both IM and oral TXA are well tolerated. Oral TXA took about 1 hour to reach minimum therapeutic concentrations and would not be suitable for emergency treatment. Intramuscular TXA inhibits fibrinolysis within 10 minutes and may be a suitable alternative to IV. This article includes Author Insights, a video abstract available at: https://vimeo.com/798431697/87065a2fac. [ABSTRACT FROM AUTHOR]

The objective of the present study was to investigate the putative correlation between the saliva concentration and free serum concentration for 10 uremic toxins (UTs; eight protein-bound solutes: 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid (HA), indole-3-acetic acid (3-IAA), indoxyl sulfate (I3S), kynurenic acid (KA), kynurenine (KYN), p-cresyl glucuronide (pCG), and p-cresyl sulfate (pCS); two free, water-soluble, low-molecular weight solutes: phenylacetylglutamine (PAGN) and trimethylamine N-oxide (TMAO); and three precursors: tyrosine (Tyr), phenylalanine, and tryptophan). Saliva samples and blood samples were collected simultaneously from 18 healthy volunteers. After the addition of internal standards, 50 µL of saliva or serum were precipitated with methanol. UTs and precursors were quantified using a validated LC-MS/MS method. The saliva–serum correlation was statistically significant (according to Spearman's coefficient) for six UTs (TMAO, HA, I3S, pCS, 3-IAA, and CMPF). Tyr presented a weak saliva-serum correlation (p = 0.08), whereas the other two precursors did not show a saliva–serum correlation. For three UTs (KYN, KA and pCG), we were unable to test the correlation since the saliva or serum levels were too low in many of the volunteers. The present study is the first to report on the saliva concentrations of TMAO, KYN, HA, PAGN, pCG, and 3-IAA. [ABSTRACT FROM AUTHOR]

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition. [ABSTRACT FROM AUTHOR]

Context: Maternal obesity has a significant impact on placental development. However, this impact on the placenta's structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject.Objective: We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta.Design: We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions.Setting: Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye.Patients: The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18-25 kg/m2 for the nonobese (control) group and 30-40 kg/m2 for the obese group.Results: In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production.Conclusion: These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity. [ABSTRACT FROM AUTHOR]

Background: Ropivacaine is a widely used local anaesthetic drug, highly bound to plasma proteins with a free plasma fraction of about 5%. Therefore, the monitoring of free drug concentration is most relevant to perform pharmacokinetic studies and to understand the drug pharmacokinetic/pharmacodynamic (PK/PD) relationship. Methods: A high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using reverse-phase LC and electrospray ionisation mass spectrometry with multiple reaction monitoring (MRM) is described for the quantitation of both free and total ropivacaine in human plasma. Ropivacaine-d7 was used as an internal standard (IS). Results: The method was validated in the range 0.5–3000 ng/mL, with five levels of QC samples and according to the European Medicine Agency and Food and Drug Administration guidelines. The performance of the method was excellent with a precision in the range 6.2%–14.7%, an accuracy between 93.6% and 113.7% and a coefficient of variation (CV) of the IS-normalised matrix factor below 15%. This suitability of the method for the quantification of free and total ropivacaine in clinical samples was demonstrated with the analysis of samples from patients undergoing knee arthroplasty and receiving a local ropivacaine infiltration. Conclusions: A method was developed and validated for the quantification of free and total ropivacaine in human plasma and was shown suitable for the analysis of clinical samples. [ABSTRACT FROM AUTHOR]

Lung macrophages (LM) are in the first line of defense against inhaled pathogens and can undergo phenotypic polarization to the proinflammatory M1 after stimulation with Toll-like receptor agonists. The objective of the present work was to characterize the metabolic alterations occurring during the experimental M1 LM polarization. Human LM were obtained from resected lungs and cultured for 24 hrs in medium alone or with 10 ng.mL-1 lipopolysaccharide. Cells and culture supernatants were subjected to extraction for metabolomic analysis with high-resolution LC-MS (HILIC and reverse phase -RP- chromatography in both negative and positive ionization modes) and GC-MS. The data were analyzed with R and the Worklow4Metabolomics and MetaboAnalyst online infrastructures. A total of 8,741 and 4,356 features were detected in the intracellular and extracellular content, respectively, after the filtering steps. Pathway analysis showed involvement of arachidonic acid metabolism, tryptophan metabolism and Krebs cycle in the response of LM to LPS, which was confirmed by the specific quantitation of selected compounds. This refined analysis highlighted a regulation of the kynurenin pathway as well as the serotonin biosynthesis pathway, and an involvement of aspartate-arginosuccinate shunt in the malate production. Macrophages M1 polarization is accompanied by changes in the cell metabolome, with the differential expression of metabolites involved in the promotion and regulation of inflammation and antimicrobial activity. The analysis of this macrophage immunometabolome may be of interest for the understanding of the pathophysiology of lung inflammatory disesases. [ABSTRACT FROM AUTHOR]

Non‐tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus, are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis, the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus. Structure‐activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD‐88 as a new promising active analogue against M. abscessus. Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half‐life of 3.2 hours. [ABSTRACT FROM AUTHOR]

Objective Drug coated balloons (DCB) improve the patency of femoropopliteal angioplasty but their use in infrapopliteal lesions is debateable as paclitaxel (PTX) particle embolisation has been suspected in some trials. The aim of this study was to compare experimentally five DCBs in terms of distal embolism of PTX. Methods Twenty-five New Zealand rabbits were divided into five groups according to the DCB used: Lutonix (Bard), In.Pact (Medtronic), Passeo-18 Lux (Biotronik), Ranger (Boston Scientific), and Stellarex (Spectranetics) (n = 5 in each group). After ligation of the right common iliac artery, a 4 × 40 mm DCB was inflated in the infrarenal aorta for 180 seconds. Rabbits were euthanised two hours after inflation of the DCB. The infrarenal aorta, a blood sample and three left hind leg muscles (tensor fasciae latae [TFL], vastus lateralis [VL], and tibialis anterior [TA] muscles) were harvested for blind measurement of PTX concentrations and histological analysis (PTX emboli count). Results In the TA muscle (the most distal), concentrations of PTX were significantly lower for the Ranger (0.067 ng/mg) than for the Lutonix (0.342 ng/mg; p =.008), In.Pact (0.370 ng/mg; p =.012), and Passeo-18-Lux (0.160 ng/mg; p =.021) DCBs. Similarly, concentrations of PTX were significantly lower for the Passeo-18-Lux than for the In.Pact (p =.028). Concentrations of PTX were not significantly different between DCBs in the TFL and VL muscles. Concentrations of PTX were found to be significantly higher in the plasma and lower in the aorta and on the DCBs after use of Lutonix compared with the four other DCBs. Histological analysis revealed evidence of embolised PTX crystals in small arterioles of all muscle tissue samples without any significant difference between the DCBs. Conclusions This study suggests some differences regarding distal embolisation profiles between the five assessed DCBs. Although clinical implications remain to be demonstrated, the present results may have implications when choosing a DCB, especially in a critical limb ischaemia setting. [ABSTRACT FROM AUTHOR]

• A LC–MS/MS method was developed for the quantification of inhaled drugs in hair. • The sensitivity was excellent, allowing to quantify 13 drugs in the pg/mg range. • Validation was performed according to established guidelines. • The suitability to analyse patient hair was shown with clinical samples. Pharmacological treatments of asthma and chronic obstructive pulmonary disease include medications such as inhaled corticosteroids, long- or short-acting β 2 -adrenoreceptor agonists and anticholinergics. There is an unmet need for the monitoring of adherence and drug exposure to those therapies since poor adherence and/or inhalation technique may impact the control of the disease and the pharmacological strategy. Since plasma therapeutic drug monitoring only reflects the body exposure in the last few hours, the measurement of hair drug concentrations may be of great interest to assess the chronic exposure. A liquid chromatography – tandem mass spectrometry method was therefore developed for the quantification of corticosteroids, β 2 -adrenoreceptor agonists and anticholinergics in human hair. The method was validated according to the European Medicines Agency and Food and Drug Administration guidelines. Sensitivity, accuracy and precision were excellent, allowing the quantification of drugs in the pg/mg range. The method was shown suitable for the analysis of clinical hair samples, demonstrating that it could be used for hair therapeutic drug monitoring in asthma or chronic obstructive pulmonary disease patients. [ABSTRACT FROM AUTHOR]

Background: The triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) translates into major respiratory improvements in adults; yet current clinical endpoints may prove insufficiently sensitive in young children. We hypothesised that ETI rapidly modifies the lungs' metabolism, resulting in changes in breath composition., Methods: Eleven children with CF were enrolled in a longitudinal pilot study at the paediatric Necker hospital. Breath was collected on sorbent tubes using a ReCIVA® device before, after one week and one month of ETI. Samples were analysed by 2D-gas chromatography-mass spectrometry (2D-GC-MS). A linear mixed-effect model, corrected for clinical confounding factors, identified exhaled metabolites differentially expressed throughout the visits. Correlations were calculated between these and clinical indicators., Results: Breath collection was successful in all children from six years old. They presented a decreased sweat chloride and improved lung function as early as within one week of ETI. Breath composition gradually evolved over the visits. ETI induced significant modifications in the level of 12 breath metabolites. Amongst those, dimethyl sulphide and tetradecene changes correlated with improvements in forced expiratory volume in one second (FEV 1 ) and forced expiratory flow (FEF 25-75 ), whilst 3-methyldecane and 3-(chloromethyl)-heptane were predictive of changes in lung clearance index (LCI 2.5 )., Conclusions: ETI impacts the breath profile from the first week of treatment. Not only could "breathomics" bring mechanistic insights into the metabolic impact of ETI, but it may also offer novel non-invasive options to monitor CF disease and predict therapeutic response., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isabelle Sermet-Gaudelus reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory, funding grants, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although adherence to inhaled medication is critically important for treatment efficiency, around half of patients taking these drugs are non-adherent or make critical errors when using their delivery device. Segmental hair analysis might be a valuable tool for therapeutic monitoring because hair concentrations reflect exposure from month to month. The objective of the present proof-of-concept study was to establish the feasibility of segmental hair analysis of inhaled budesonide and formoterol in asthma patients. Methods: We conducted a prospective, open-label, interventional study of adult patients being treated with budesonide/formoterol for controlled, moderate-to-severe asthma (CorticHair, NCT03691961). Asthma control, lung function, and medication adherence were recorded. Hair samples were taken 4 months after enrolment and cut into four 1 cm segments. Results: Samples were available from 21 patients (20 women; median age: 53; median budesonide dose: 600 μg/d). Budesonide and formoterol were detected in samples from 18 to 13 patients, respectively. The median hair concentrations were 6.25 pg/mg for budesonide and 0.9 pg/mg for formoterol. The intrapatient coefficient of variation between hair segments was 21% for budesonide and 40% for formoterol. Pearson's coefficients for the correlations between the hair concentration and the self-reported drug dose and the prescribed drug dose were respectively 0.42 ( p = 0.08) and 0.29 ( p = 0.25) for budesonide and 0.24 ( p = 0.44) and 0.17 ( p = 0.57) for formoterol. Conclusion: Segmental hair analysis of inhaled medications was feasible, with low intrapatient variability. This innovative, non-invasive means of assessing monthly drug exposure might help physicians to personalize drug regimens for patients with difficult-to-treat asthma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Salvator, Lamy, Roquencourt, Bardin, Devillier and Grassin-Delyle.)

Volatilomics is the branch of metabolomics dedicated to the analysis of volatile organic compounds in exhaled breath for medical diagnostic or therapeutic monitoring purposes. Real-time mass spectrometry (MS) technologies such as proton transfer reaction (PTR) MS are commonly used, and data normalisation is an important step to discard unwanted variation from non-biological sources, as batch effects and loss of sensitivity over time may be observed. As normalisation methods for real-time breath analysis have been poorly investigated, we aimed to benchmark known metabolomic data normalisation methods and apply them to PTR-MS data analysis. We compared seven normalisation methods, five statistically based and two using multiple standard metabolites, on two datasets from clinical trials for COVID-19 diagnosis in patients from the emergency department or intensive care unit. We evaluated different means of feature selection to select the standard metabolites, as well as the use of multiple repeat measurements of ambient air to train the normalisation methods. We show that the normalisation tools can correct for time-dependent drift. The methods that provided the best corrections for both cohorts were probabilistic quotient normalisation and normalisation using optimal selection of multiple internal standards. Normalisation also improved the diagnostic performance of the machine learning models, significantly increasing sensitivity, specificity and area under the receiver operating characteristic (ROC) curve for the diagnosis of COVID-19. Our results highlight the importance of adding an appropriate normalisation step during the processing of PTR-MS data, which allows significant improvements in the predictive performance of statistical models. Clinical trials : VOC-COVID-Diag (EudraCT 2020-A02682-37); RECORDS trial (EudraCT 2020-000296-21)., (© 2023 IOP Publishing Ltd.)