Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), with a clinical outcome ranging from mild to severe, including death. To date, it is unclear ...why some patients develop severe symptoms. Many authors have suggested the involvement of vitamin D in reducing the risk of infections; thus, we retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (
= 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years. On the basis of this preliminary observation, vitamin D supplementation might be a useful measure to reduce the risk of infection. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations and to confirm our preliminary observation.
Abstract
Background
Remdesivir has received significant attention for its potential application in the treatment of COVID-19, caused by SARS-CoV-2. Remdesivir has already been tested for Ebola virus ...disease treatment and found to have activity against SARS and MERS coronaviruses. The remdesivir core contains GS-441524, which interferes with RNA-dependent RNA polymerases alone. In non-human primates, following IV administration, remdesivir is rapidly distributed into PBMCs and converted within 2 h to the active nucleoside triphosphate form, while GS-441524 is detectable in plasma for up to 24 h. Nevertheless, remdesivir pharmacokinetics and pharmacodynamics in humans are still unexplored, highlighting the need for a precise analytical method for remdesivir and GS-441524 quantification.
Objectives
The validation of a reliable UHPLC-MS/MS method for remdesivir and GS-441524 quantification in human plasma.
Methods
Remdesivir and GS-441524 standards and quality controls were prepared in plasma from healthy donors. Sample preparation consisted of protein precipitation, followed by dilution and injection into the QSight 220 UHPLC-MS/MS system. Chromatographic separation was obtained through an Acquity HSS T3 1.8 μm, 2.1 × 50 mm column, with a gradient of water and acetonitrile with 0.05% formic acid. The method was validated using EMA and FDA guidelines.
Results
Analyte stability has been evaluated and described in detail. The method successfully fulfilled the validation process and it was demonstrated that, when possible, sample thermal inactivation could be a good choice in order to improve biosafety.
Conclusions
This method represents a useful tool for studying remdesivir and GS-441524 clinical pharmacokinetics, particularly during the current COVID-19 outbreak.
Objective(s)
This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection during the first trimester of ...pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients.
Study Design
Seromolecular testing for SARS‐CoV‐2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first‐trimester SARS‐CoV‐2‐positive (case) group and a SARS‐CoV‐2‐negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1‐ and 5‐min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed.
Results
A total of 17 of 164 women tested positive for SARS‐CoV‐2 (10.3%) in the first trimester. One SARS‐CoV‐2‐positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS‐CoV‐2‐positive and 10.5% (11/105) SARS‐CoV‐2‐negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS‐CoV‐2.
No maternal pneumonia or hospital admission due to coronavirus disease‐19 were recorded.
Conclusion
Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS‐CoV‐2‐negative women.
Therapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by guiding dosage adjustments. The ...comparison of TDM results with drug-specific pharmacokinetic/pharmacodynamic (PK/PD) parameters, based on killing dynamics and bacterial susceptibility, increases the probability of therapeutic success.
The aim of this study was the analytical validation of a new UHPLC-MS/MS assay for the quantification of 19 antibiotics divided in two different sets considering their chemical/pharmacological properties. This method has been implemented in an analytical LC-MS/MS Kit System by CoQua Lab s.r.l (Turin).
The analytical validation is developed in accordance with “ICH Harmonized Guideline M10 on bioanalytical method validation and study sample analysis” and “Guidelines for regulatory auditing of quality management system of medical device manufacturers". Method suitability in the clinical context was tested by analysing clinical samples from patients treated with antibiotic drugs.
This method allows for simultaneous TDM of the following molecules: dalbavancin, daptomycin, linezolid, tedizolid, levofloxacin, moxifloxacin, meropenem, ertapenem, vaborbactam, avibactam, sulbactam, tazobactam, ceftazidime, ceftriaxone, ceftolozane, ceftobiprole, cefiderocol, ceftaroline and piperacillin. These drugs were quantified showing analytical performance parameters compliant with guidelines in terms of repeatability, reproducibility, robustness, bias, LOD, LOQ and linearity. The method was capable to successfully monitor drug concentrations in 65 samples from 52 patients undergoing treatment.
The UHPLC-MS/MS method described in this work can be useful for TDM of the reported antimicrobial agents. The analytical protocol is rapid and suitable to be used in routine analysis.
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•Multiresidual method for simultaneous determination of 19 antibiotics in human plasma.•Fast and reproducible procedure, suitable for routinely context of Therapeutic Drug Monitoring.•Method compliance to guidelines for matrix effect, robustness, imprecision and inaccuracy.•Analytical method validation and application on real human samples.
Voriconazole therapeutic drug monitoring is not consistently recommended due to its high interpatient and intrapatient variability. Here, we aimed to describe our experience with voriconazole for ...treatment and prophylaxis of invasive fungal infections in paediatric patients. A fully validated high‐performance liquid chromatography–mass spectrometry method was used to quantify voriconazole concentration in plasma, at the end of dosing interval. A high interindividual variability was shown. We enrolled 237 children, 83 receiving intravenous and 154 oral voriconazole. A positive correlation between drug dose and drug plasma exposure was observed. Considering intravenous route, patients with higher serum creatinine had higher voriconazole concentrations; a positive correlation was found among drug exposure and age. Sex significantly influenced drug levels: males had higher median drug concentrations than females (P < 0.001). Close voriconazole pharmacokinetics monitoring should help individualize antifungal therapy for children.
Vitamin D (VD) is a calcium- and phosphate-controlling hormone used to treat bone disorders; yet, several other effects are progressively emerging. VD deficiency is highly prevalent worldwide, with ...suboptimal exposure to sunlight listed among the leading causes: oral supplementation with either cholecalciferol or calcitriol is used. However, there is a scarcity of clinical studies investigating how quickly VD concentrations can increase after supplementation. In this pilot study, the commercial supplement ImmuD3 (by
) was chosen as the source of VD and 2000 IU/day was administered for one month to 21 healthy volunteers that had not taken any other VD supplements in the previous 30 days. Plasma VD levels were measured through liquid chromatography coupled to tandem mass spectrometry after 7, 14, and 28 days of supplementation. We found that 95% of the participants had insufficient VD levels at baseline (<30 ng/mL; median 23.72 ng/mL; IQR 18.10-26.15), but after 28 days of supplementation, this percentage dropped to 62% (median 28.35 ng/mL; IQR 25.78-35.20). The median increase in VD level was 3.09 ng/mL (IQR 1.60-5.68) after 7 days and 8.85 ng/mL (IQR 2.85-13.97F) after 28 days. This study suggests the need for continuing VD supplementation and for measuring target level attainment.
Evidence for the real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on preterm birth is unclear, as available series report composite pregnancy outcomes and/or do ...not stratify patients according to disease severity. The purpose of the research was to determine the real impact of asymptomatic/mild SARS-CoV-2 infection on preterm birth not due to maternal respiratory failure. This case-control study involved women admitted to Sant Anna Hospital, Turin, for delivery between 20 September 2020 and 9 January 2021. The cumulative incidence of Coronavirus disease-19 was compared between preterm birth (case group, n = 102) and full-term delivery (control group, n = 127). Only women with spontaneous or medically-indicated preterm birth because of placental vascular malperfusion (pregnancy-related hypertension and its complications) were included. Current or past SARS-CoV-2 infection was determined by nasopharyngeal swab testing and detection of IgM/IgG antibodies in blood samples. A significant difference in the cumulative incidence of Coronavirus disease-19 between the case (21/102, 20.5%) and the control group (32/127, 25.1%) (P= 0.50) was not observed, although the case group was burdened by a higher prevalence of three known risk factors (body mass index > 24.9, asthma, chronic hypertension) for severe Coronavirus disease-19. Logistic regression analysis showed that asymptomatic/mild SARS-CoV-2 infection was not an independent predictor of spontaneous and medically-indicated preterm birth due to pregnancy-related hypertension and its complications (0.77; 95% confidence interval, 0.41-1.43). Pregnant patients without comorbidities need to be reassured that asymptomatic/mild SARS-CoV-2 infection does not increase the risk of preterm delivery. Preterm birth and severe Coronavirus disease-19 share common risk factors (i.e., body mass index > 24.9, asthma, chronic hypertension), which may explain the high rate of indicated preterm birth due to maternal conditions reported in the literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity.
Medical ...Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety.
Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation.
In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively.
Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method.
Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers.
For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.
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•Cannabis shows different pharmacological applications, in particular in the management of pain.•Cannabinoids pharmacokinetics description in patients with chronic and neuropathic pain.•Differences in cannabinoids plasma exposure between route of administration.
Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and ...Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11–Hydroxy–Δ9–tetrahydrocannabinol, 11–Nor–9carboxy–Δ9–tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.
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•Fast and robust method for the simultaneous quantification of 10 cannabinoids in human plasma.•Fast and reproducible UHPLC separation.•Optimal separation between Δ9-tetrahydrocannabinol and Δ8-tetrahydrocannabinol (Δ8-THC) and in a few minutes.•Thorough evaluation of method ruggedness in terms on matrix effect and recovery.•Full method validation and application of real human samples.
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