Pre- and Postnatal Maturation are Important for Fentanyl Exposure in Preterm and Term Newborns : A Pooled Population Pharmacokinetic Study

Publisher Copyright: © 2021, The Author(s).Background and Objective Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. Methods We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 mu g/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 mu g/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM(R) 7.4. Results Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. Conclusions As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.Peer reviewe

Pharmacokinetics of the most commonly used antihypertensive drugs throughout pregnancy methyldopa, labetalol, and nifedipine:a systematic review

Purpose Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and are therefore recommended in international guidelines for treatment of hypertension. In this review, we provide a complete overview of what is known on the pharmacokinetics (PK) of the antihypertensive drugs methyldopa, labetalol, and nifedipine throughout pregnancy. Methods A systematic search was performed to retrieve studies on the PK of methyldopa, labetalol, and nifedipine used throughout pregnancy. The search was restricted to English and original studies. The systematic search was conducted on July 27, 2021, in Embase, Medline Ovid, Web of Science, Cochrane Library, and Google Scholar. Keywords were methyldopa, labetalol, nifedipine, pharmacokinetics, pregnancy, and placenta. Results A total of 1459 unique references were identified of which title and abstract were screened. Based on this screening, 67 full-text papers were assessed, to retain 30 PK studies of which 2 described methyldopa, 12 labetalol, and 16 nifedipine. No fetal accumulation is found for any of the antihypertensive drugs studied. Conclusion We conclude that despite decades of prescribing methyldopa, labetalol, and nifedipine throughout pregnancy, descriptions of their PK during pregnancy are hampered by a large heterogeneity in the low number of available studies. Aiming for evidence-based and personalized dosing of antihypertensive medication in the future, further studies on the relationship of both PK and pharmacodynamics (including the optimal blood pressure targeting) during pregnancy and pregnancy-related pathology are urgently needed to prevent undertreatment, overtreatment, and side effects

Dried blood spot analysis for the quantification of vancomycin and creatinine using liquid chromatography – tandem mass spectrometry:Method development and validation

Background: Vancomycin is a widely used antibiotic for the treatment of gram-positive bacterial infections, especially for methicillin-resistant Staphylococcus aureus (MRSA) infections. Due to a small therapeutic range and large inter-patient variability, therapeutic drug monitoring (TDM) of vancomycin is required to minimize toxicity and maximize treatment efficacy. Venous blood sampling is mostly applied for TDM of vancomycin, although this widely used sampling method is more invasive compared to less painful alternatives, such as the dried blood spot (DBS) method, which can be performed at home. Method: We developed an UPLC-MS/MS method for the quantification of vancomycin and creatinine in DBS. A fast sample preparation and short analysis run time of 5.2 min were applied, which makes this method highly suitable for clinical settings. Validation was performed according to international (FDA and EMA) guidelines. Results: The validated concentration range was found linear for creatinine from 41.8 µmol/L to 722 µmol/L and for vancomycin from 3.8 mg/L to 76.6 mg/L (r2 &gt; 0.990) and the inaccuracies, imprecisions, hematocrit effects, and recoveries were &lt; 15 % for both compounds. No significant carryover effect was observed. Conclusion: Hence, we successfully validated a quantification method for the simultaneous determination of creatinine and vancomycin in DBS.</p

Pharmacological characterization of the αvβ6 integrin binding and internalization kinetics of the foot-and-mouth disease virus derived peptide A20FMDV2

A20FMDV2 is a peptide derived from the foot-and-mouth disease virus with a high affinity and selectivity for the alphav beta-6 (αvβ6) arginyl-glycinyl-aspartic acid (RGD)-binding integrin. It has been shown to be an informative tool ligand in pre-clinical imaging studies for selective labelling of the αvβ6 integrin in a number of disease models. In a radioligand- binding assay using a radiolabelled form of the peptide ([3H]A20FMDV2), its high affinity (KD:0.22nmol/l) and selectivity (at least 85-fold) for αvβ6 over the other members of the RGD integrin family was confirmed. [3H]A20FMDV2 αvβ6 binding could be fully reversed only in the presence of EDTA, whereas a partial reversal was observed in the presence of excess concentrations of an RGD-mimetic small molecule (SC-68448) or unlabelled A20FMDV2. Using flow cytometry on bronchial epithelial cells, the ligand-induced internalization of αvβ6 by A20FMDV2 and LAP1 was shown to be fast (t1/2:1.5and 3.1 min, respectively), concentration-dependent (EC50:values 1.1 and 3.6nmol/l, respectively) and was followed by a moderately slow return of integrin to the surface. The results of the radioligand-binding studies suggest that the binding of A20FMDV2 to the RGD-binding site on αvβ6 is required to maintain its engagement with the hypothesised A20FMDV2 synergy site on the integrin. In addition, there is evidence from flow cytometric studies that the RGD-ligand engagement of αvβ6 post-internalization plays a role in delaying recycling of the integrin to the cell surface. This mechanism may act as a homeostatic control of membrane αvβ6 following RGD ligand engagement

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation

Purpose: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. Methods: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. Results: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. Conclusion: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.</p

Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients

Rationale: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients. Objectives: To characterize the course of FEV1 over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV1. Methods: FEV1% predicted (FEV1%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models. Measurements and Main Results: FEV1%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV1%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV1%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV1 greater than 20% in the 6 months preceding BOS (termed “rapid onset”) was associated with shorter time to BOS onset (p = 0.01), lower FEV1%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV1%pred at 2 years after onset (p = 0.0002). Conclusions: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.Supported in part by National Institutes of Health grants K23 HL077719 (V.N.L.) and K24 HL04212 (F.J.M.), and by a grant from the American Society of Transplantation/ Chest Foundation (V.N.L.).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91969/1/2007 AJRCCM Course of FEV1 after Onset of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients.pd

In-Flight Water Quality Monitoring on the International Space Station (ISS): Measuring Biocide Concentrations with Colorimetric Solid Phase Extraction (CSPE)

The colorimetric water quality monitoring kit (CWQMK) was delivered to the International Space Station (ISS) on STS-128/17A and was initially deployed in September 2009. The kit was flown as a station development test objective (SDTO) experiment to evaluate the acceptability of colorimetric solid phase extraction (CSPE) technology for routine water quality monitoring on the ISS. During the SDTO experiment, water samples from the U.S. water processor assembly (WPA), the U.S. potable water dispenser (PWD), and the Russian system for dispensing ground-supplied water (SVO-ZV) were collected and analyzed with the CWQMK. Samples from the U.S. segment of the ISS were analyzed for molecular iodine, which is the biocide added to water in the WPA. Samples from the SVOZV system were analyzed for ionic silver, the biocide used on the Russian segment of the ISS. In all, thirteen in-flight analysis sessions were completed as part of the SDTO experiment. This paper provides an overview of the experiment and reports the results obtained with the CWQMK. The forward plan for certifying the CWQMK as operational hardware and expanding the capabilities of the kit are also discussed

Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke.

Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; &lt;4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation