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Influenza and Other Respiratory Viruses Jul 2023Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.
METHODS
This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In Part 1, patients ( = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients ( = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.
RESULTS
No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group.
CONCLUSIONS
AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.
CLINICAL TRIALS REGISTRATION
NCT02654171.
Topics: Child; Infant; Humans; Child, Preschool; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Sulfones; Quinazolines
PubMed: 37502622
DOI: 10.1111/irv.13176 -
Molecules (Basel, Switzerland) Dec 2019Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine...
Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron-dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.
Topics: Boron Compounds; Chemistry Techniques, Synthetic; Enzyme Inhibitors; Methanol; Molecular Structure; Phosphotransferases (Alcohol Group Acceptor); Pyrrolidines; Spectrum Analysis; Structure-Activity Relationship; Sulfones
PubMed: 31810327
DOI: 10.3390/molecules24234408 -
Ecotoxicology and Environmental Safety Dec 2022Per- and polyfluoroalkyl substances (PFASs) are common environmental contaminants and are widely detected in humans. Previous studies have linked PFASs exposure to...
BACKGROUND
Per- and polyfluoroalkyl substances (PFASs) are common environmental contaminants and are widely detected in humans. Previous studies have linked PFASs exposure to adverse birth outcomes. However, the association between maternal exposure to PFASs and hemoglobin (Hb) and hematocrit (HCT) remains unclear.
OBJECTIVES
We aimed to explore the relationship between PFASs exposure with Hb and HCT during pregnancy.
METHODS
The present birth cohort study included 1044 pregnant women from Wuhan, China. Maternal HCT and Hb were measured in the first, second and third trimesters, and 13 PFASs were detected in the cord sera. Mixed linear models and general linear regression were applied to analyze the association between each single PFASs and Hb and HCT. Weighted quantile sum (WQS) regressions were used to investigate the association between PFASs mixture and Hb and HCT during pregnancy.
RESULTS
In single-PFAS models, 10 PFASs were positively associated with HCT and Hb across pregnancy (a 10-fold increase in PFASs was associated with 1.47-3.54 % change in HCT and 1.46-3.20 % change in Hb (All P-FDR < 0.05). In addition, Hb and HCT were more positively related to PFASs in the second and third trimesters rather than the first trimester. The association between PFASs exposure and maternal HCT and Hb was not significant in the iron supplementation group, whereas significant in the non-iron supplementation group. A significant interaction between iron supplementation and non-iron supplementation was also detected. WQS regressions showed that perfluorononanoic acid (PFNA) and perfluorohexane sulfonate (PFHxS) contributed most to the association between PFASs and HCT and Hb in the second and third trimesters, respectively.
CONCLUSION
Maternal PFASs exposure was positive with serum Hb and HCT. Moreover, maternal iron supplementation may play a modifying effect in influencing the relationship between PFASs and HCT and Hb.
Topics: Pregnancy; Female; Humans; Hematocrit; Fluorocarbons; Cohort Studies; Hemoglobins; Alkanesulfonates
PubMed: 36423372
DOI: 10.1016/j.ecoenv.2022.114319 -
Clinics in Orthopedic Surgery Jun 2022The aim of this study was to evaluate clinical outcomes of sodium tetradecyl sulphate (STS) sclerotherapy for conservative treatment of lateral malleolar bursitis of the...
BACKGROUND
The aim of this study was to evaluate clinical outcomes of sodium tetradecyl sulphate (STS) sclerotherapy for conservative treatment of lateral malleolar bursitis of the ankle.
METHODS
We reviewed data from 20 consecutive patients (20 ankles) who underwent STS sclerotherapy between August 2018 and June 2019. After aspiration of fluid from the lateral malleolar bursal sac, 2 mL (20 mg) STS was injected into the sac. Clinical outcomes and side effects and complications were evaluated at 2 weeks, 3 months, 1 year, and 2 years after sclerotherapy. Responses to treatment were assessed according to degree of fluctuation, shrinkage of the bursal sac, and soft-tissue swelling. The 36-item short form survey (SF-36) was completed for each patient before and after therapy.
RESULTS
Complete response was observed in 17 patients (85%), and partial response was observed in 3 patients (15%) after STS sclerotherapy. SF-36 physical component scores improved from 62.2 (interquartile range, 5.2) before therapy to 70.0 (interquartile range, 7.9) at last follow-up ( < 0.05). One patient (5%) experienced transient hyperpigmentation at the injection site. No major complications occurred.
CONCLUSIONS
STS sclerotherapy was an effective and safe treatment for patients with lateral malleolar bursitis of the ankle.
Topics: Ankle; Bursitis; Humans; Sclerosing Solutions; Sclerotherapy; Sodium Tetradecyl Sulfate
PubMed: 35685968
DOI: 10.4055/cios21182 -
Journal of the American Chemical Society Mar 2020Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable...
Photoactivation of bioactive molecules allows manipulation of cellular processes with high spatiotemporal precision. The recent emergence of visible-light excitable photoprotecting groups has the potential to further expand the established utility of the photoactivation strategy in biological applications by offering higher tissue penetration, diminished phototoxicity, and compatibility with other light-dependent techniques. Nevertheless, a critical barrier to such applications remains the significant hydrophobicity of most visible-light excitable photocaging groups. Here, we find that applying the conventional 2,6-sulfonation to -methyl BODIPY photocages is incompatible with their photoreaction due to an increase in the excited state barrier for photorelease. We present a simple, remote sulfonation solution to BODIPY photocages that imparts water solubility and provides control over cellular permeability while retaining their favorable spectroscopic and photoreaction properties. Peripherally disulfonated BODIPY photocages are cell impermeable, making them useful for modulation of cell-surface receptors, while monosulfonated BODIPY retains the ability to cross the cellular membrane and can modulate intracellular targets. This new approach is generalizable for controlling BODIPY localization and was validated by sensitization of mammalian cells and neurons by visible-light photoactivation of signaling molecules.
Topics: Alkanesulfonates; Animals; Boron Compounds; Cell Membrane; Dopamine; Drug Carriers; Fluorescent Dyes; HEK293 Cells; Hippocampus; Histamine; Humans; Light; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Structure; Neurons; Rats; Solubility
PubMed: 32115942
DOI: 10.1021/jacs.9b13219 -
BMC Pediatrics May 2022Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation - no study has been done in the past to compare the two forms. Each has its own benefits - but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension.
METHODS
An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects.
RESULTS
Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00-8.00) and 9.00 (8.00-9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group.
CONCLUSION
Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate.
TRIAL REGISTRATION
Trial was registered in the clinical trials registry of India [ CTRI/2019/04/018781 ][25/04/2019].
Topics: Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents
PubMed: 35624452
DOI: 10.1186/s12887-022-03366-3 -
Advanced Science (Weinheim,... Jul 2023Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term...
Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non-specific anti-proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3-inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad-spectrum anti-inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non-specific anti-proliferative effects of PTX and SMS. Using an in vitro model of NLRP3-mediated inflammation in murine macrophages, MCC950 reduced IL-1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re-endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti-inflammatory drug-elution strategy with significant implications for cardiovascular device intervention.
Topics: Animals; Humans; Mice; Anti-Inflammatory Agents; Endothelial Cells; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfonamides; Sulfones
PubMed: 37150865
DOI: 10.1002/advs.202300521 -
Environment International Mar 2023Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS...
Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS provided that quantitative in vitro to in vivo extrapolation (QIVIVE) can be developed. The QIVIVE ratio is the ratio of nominal (C) or freely dissolved concentration (C) in human blood to C or C in the bioassays. Considering that the concentrations of PFAS in human plasma and in vitro bioassays may vary by orders of magnitude, we tested the hypothesis that anionic PFAS bind to proteins concentration-dependently and therefore the binding differs substantially between human plasma and bioassays, which has an impact on QIVIVE. Solid phase microextraction (SPME) with C18-coated fibers served to quantify the C of four anionic PFAS (perfluorobutanoate (PFBA), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS)) in the presence of proteins and lipid, medium components, cells and human plasma over five orders of magnitude in concentrations. The C18-SPME method was used to quantify the non-linear binding to proteins, human plasma and medium, and the partition constants to cells. These binding parameters were used to predict C of PFAS in cell bioassays and human plasma by a concentration-dependent mass balance model (MBM). The approach was illustrated with a reporter gene assay indicating activation of the peroxisome proliferator-activated receptor gamma (PPARγ-GeneBLAzer). Blood plasma levels were collected from literature for occupational exposure and the general population. The QIVIVE ratios were higher than the QIVIVE ratios due to the strong affinity to proteins and large differences in protein contents between human blood and bioassays. For human health risk assessment, the QIVIVE ratios of many in vitro assays need to be combined to cover all health relevant endpoints. If C cannot be measured, they can be estimated with the MBM and concentration-dependent distribution ratios.
Topics: Humans; Biological Availability; Protein Binding; Fluorocarbons; Alkanesulfonic Acids; Alkanesulfonates; Biological Assay; Environmental Pollutants
PubMed: 36881956
DOI: 10.1016/j.envint.2023.107857 -
Journal of Analytical Toxicology Mar 2022Bisphenol S (BPS) has been detected in personal care products, water, food and indoor house dust, demonstrating the potential for human exposure. Due to limited data to...
Bisphenol S (BPS) has been detected in personal care products, water, food and indoor house dust, demonstrating the potential for human exposure. Due to limited data to characterize the hazard of BPS, the National Toxicology Program (NTP) is investigating the toxicity of BPS in rodent models. Generating systemic exposure data is integral to putting toxicological findings into context. The objective of this work was to develop and validate a method to quantitate free (unconjugated parent) and total (free and all conjugated forms of) BPS in rodent plasma, amniotic fluid and fetal homogenate in support of NTP studies. The method used incubation with (total BPS) and without (free BPS) deconjugating enzyme and then protein precipitation followed by ultra-performance liquid chromatography-tandem mass spectrometry. In Sprague Dawley rat plasma, the method was linear (r ≥ 0.99) over the range 5-1,000 ng/mL, accurate (mean relative error (RE) ≤ ±10.5%) and precise (relative standard deviation (RSD) ≤ 7.7%). Mean recoveries were ≥93.1% for both free and total analyses. The limits of detection were 1.15 ng/mL (free) and 0.862 ng/mL (total) in plasma. The method was evaluated in the following study matrices: (i) male Hsd:Sprague Dawley®SD® (HSD) rat plasma, (ii) female HSD rat plasma, (iii) male B6C3F1 mouse plasma, (iv) female B6C3F1 mouse plasma, (v) HSD rat gestational day (GD) 18 dam plasma, (vi) HSD rat GD 18 amniotic fluid, (vii) HSD rat GD 18 fetal homogenate and (viii) HSD rat postnatal day 4 pup plasma (mean %RE ≤ ±8.2 and %RSD ≤ 8.7). Stability of BPS in extracted samples was demonstrated for up to 7 days at various temperatures, and freeze-thaw stability was demonstrated after three cycles over 7 days. BPS in various matrices stored at -80°C for at least 60 days was within 92.1-115% of Day 0 concentrations, demonstrating its stability in these matrices. These data demonstrate that this simple method is suitable for determination of free and total BPS in plasma, amniotic fluid and fetuses following exposure of rodents to BPS.
Topics: Amniotic Fluid; Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Female; Male; Mice; Phenols; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Rodentia; Sulfones; Tandem Mass Spectrometry
PubMed: 33512500
DOI: 10.1093/jat/bkab008 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2020Bioactive small molecules containing α-fluoro sulfur motifs [RS(O) CH F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors....
Bioactive small molecules containing α-fluoro sulfur motifs [RS(O) CH F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors. Prominent examples include the anti-asthma drug Flovent and the phenylpyrazole insecticide pyrafluprole. Given the popularity of these structural units in bioactive small molecule design, together with the varying oxidation states of sulfur, a conformational analysis of α-fluoro sulfides, sulfoxides, and sulfones, would be instructive in order to delineate the non-covalent interactions that manifest themselves in structure. A combined crystallographic and computational analysis demonstrates the importance of hyperconjugative donor-acceptor interactions in achieving acyclic conformational control. The conformational disparity in the syn- and anti-diastereoisomers of α-fluorosulfoxides is particularly noteworthy.
Topics: Hydrocarbons, Fluorinated; Molecular Conformation; Sulfides; Sulfones; Sulfoxides; Sulfur; Sulfur Compounds
PubMed: 32735052
DOI: 10.1002/chem.202003361