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Drug Metabolism and Disposition: the... Nov 2020The eastern woodchuck () is a hibernating species extensively used as an in vivo efficacy model for chronic human hepatitis B virus infection. Under laboratory...
The eastern woodchuck () is a hibernating species extensively used as an in vivo efficacy model for chronic human hepatitis B virus infection. Under laboratory conditions, woodchucks develop a pseudohibernation condition; thus, the pharmacokinetics (PK) of small-molecule therapeutics may be affected by the seasonal change. The seasonal PK of four probe compounds were characterized over 12 months in seven male and nine female laboratory-maintained woodchucks. These compounds were selected to study changes in oxidative metabolism [antipyrine (AP)], glucuronidation [raltegravir (RTG)], renal clearance [lamivudine (3TC)], and hepatic function [indocyanine green (ICG)]. Seasonal changes in physiologic parameters and PK were determined. Seasonal body weight increases were ≥30%. Seasonal changes in body temperature and heart rate were <10%. The mean AP exposure remained unchanged from April to August 2017, followed by a significant increase (≥1.0-fold) from August to December and subsequent decrease to baseline at the end of study. A similar trend was observed in RTG and 3TC exposures. The ICG exposure remained unchanged. No significant sex difference in PK was observed, although female woodchucks appeared to be less susceptible to seasonal PK and body weight changes. Significant seasonal PK changes for AP, RTG, and 3TC indicate decreases in oxidative metabolism, phase II glucuronidation, and renal clearance during pseudohibernation. The lack of seasonal change in ICG exposure suggests there are no significant changes in hepatic function. This information can be used to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK. SIGNIFICANCE STATEMENT: Woodchuck is a hibernating species and is commonly used as a nonclinical model of hepatitis B infection. Investigation of seasonal PK changes is perhaps of greater interest to pharmaceutical industry scientists, who use the woodchuck model to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK and/or toxicity. This information is also valuable to drug metabolism and veterinary scientists in understanding woodchuck's seasonal metabolism and behavior under the pseudohibernation condition.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Hepatitis B, Chronic; Hibernation; Humans; Male; Marmota; Metabolic Clearance Rate; Seasons
PubMed: 32892154
DOI: 10.1124/dmd.120.000140 -
Brain Stimulation 2023Although amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to...
BACKGROUND
Although amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to targeting the health of corticospinal motor neurons. Focused ultrasound combined with systemically circulating microbubbles (FUS/MB) is an emerging modality capable of site-specific molecular delivery temporarily and noninvasively within a range of appropriate parameters.
OBJECTIVE
To investigate the effect of FUS/MB-enhanced delivery of therapeutics to the motor cortex on the disease progression by using a transgenic mouse model of ALS.
METHODS
Multiple FUS/MB-enhanced deliveries of Edaravone (Eda) to the motor cortex were performed on the SOD1 mouse model of ALS. The motor function of the animals was evaluated by gait analysis, grip strength and wire hanging tests. Corticospinal and spinal motor neuronal health, misfolded SOD1 protein and neuroinflammation after treatments were evaluated by histological examination.
RESULTS
Ultrasound-enhanced delivery of Eda in the targeted motor cortex was achieved by a two-fold increase without gross tissue damage. Compared with the ALS mice administered Eda treatments only, the animals given additionally FUS/MB-enhanced brain delivery of Eda (FUS/MB + Eda) exhibited further improvements in neuromuscular functions characterized by gait patterns, muscular strength, and motor coordination along with rescued muscle atrophy. FUS/MB + Eda treatments conferred remarkable neuroprotection to both upper and lower motor neurons revealed by normalized neuronal morphology with increasing cell body size and profoundly alleviated neuroinflammation and misfolded SOD1 protein in the brains and lumbar spinal cords.
CONCLUSION
We report a pilot study that non-invasive ultrasound-enhanced brain delivery of Eda provides additive amelioration on disease progression of ALS and suggest that broadening the target from spinal to cortical network functions using the FUS/MB-enhanced delivery can be a rational therapeutic strategy of this debilitating disorder.
Topics: Mice; Animals; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Edaravone; Neuroinflammatory Diseases; Neurodegenerative Diseases; Pilot Projects; Superoxide Dismutase; Motor Neurons; Mice, Transgenic; Brain; Disease Progression; Disease Models, Animal
PubMed: 36931463
DOI: 10.1016/j.brs.2023.03.006 -
Muscle & Nerve Feb 2020
Topics: Amyotrophic Lateral Sclerosis; Edaravone; Humans; Neuroprotective Agents
PubMed: 31778230
DOI: 10.1002/mus.26770 -
ACS Nano Sep 2023Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used...
Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used as an antioxidant but shows poor liver distribution. Herein, we report on the design of a Kupffer cell-oriented nanoantioxidant based on a disulfide cross-linked albumin nanoparticle containing encapsulated edaravone (EeNA) as a therapeutic for the treatment of hepatitis. Since the edaravone is bound to albumin, this results in a soluble and stable form of edaravone in water. Exchanging the intramolecular disulfide bonds to intermolecular disulfide bridges of albumin molecules allowed the preparation of a redox responsive albumin nanoparticle that is stable in the blood circulation but can release drugs into cells. Consequently, EeNA was fabricated by the nanoscale self-assembly of edaravone and albumin nanoparticles without the additives that are contained in commercially available edaravone preparations. EeNA retained its nanostructure under serum conditions, but the encapsulated edaravone was released efficiently under intracellular reducing conditions in macrophages. The EeNA was largely distributed in the liver and subsequently internalized into Kupffer cells within 60 min after injection in a concanavalin-A-induced hepatitis mouse. The survival rate of the hepatitis mice was significantly improved by EeNA due to the suppression of liver necrosis and oxidative stress by scavenging excessive ROS. Moreover, even through the postadministration, EeNA showed an excellent hepatoprotective action as well. In conclusion, EeNA has the potential for use as a nanotherapeutic against various types of hepatitis because of its Kupffer cell targeting ability and redox characteristics.
Topics: Animals; Mice; Antioxidants; Reactive Oxygen Species; Edaravone; Hepatitis; Albumins; Oxidation-Reduction; Nanoparticles; Disulfides
PubMed: 37579503
DOI: 10.1021/acsnano.3c02877 -
Toxicology Letters Jun 2020In addition to the transfer across the placenta, placenta displays hormonal and xenobiotic metabolism, as well as enzymatic defense against oxidative stress. We analyzed...
In addition to the transfer across the placenta, placenta displays hormonal and xenobiotic metabolism, as well as enzymatic defense against oxidative stress. We analyzed aromatase (CYP19A1), uridine 5'-diphospho-glucuronyltransferase (UGT), glutathione-S-transferase (GST) and catalase (CAT) activities in over 70 placentas from nonsmokers stored at -80 °C from former perfusion studies. A wide interindividual variation in all activities was found. Longterm storage at -80 °C did not affect the activities. Ethoxyresorufin-O-deethylase (EROD, CYP1A1) was not detected in any of the studied placentas perfused with chemicals. Several compounds in placental perfusion changed statistically significantly the enzyme activities in placental tissue. Melamine and nicotine increased CYP19A1, melamine increased UGT and GST, PhIP with ethanol decreased CYP19A1 and increased GST, and PhIP with buprenorphine decreased CAT. Antipyrine in 100 μg/ml also changed the studied enzyme activities, but not statistically significantly. Because antipyrine is a reference compound in placental perfusions, its potential effects must be taken into account in human placental perfusion. Enzyme activities deserve further studies as biomarkers of placental toxicity. Finally, enzyme activities deserve further studies as biomarkers of placental toxicity.
Topics: Adult; Antipyrine; Aromatase; Catalase; Cytochrome P-450 CYP1A1; Female; Glucuronosyltransferase; Glutathione Transferase; Humans; Placenta; Pregnancy
PubMed: 32113805
DOI: 10.1016/j.toxlet.2020.02.014 -
CNS Neuroscience & Therapeutics Sep 2023Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared...
INTRODUCTION
Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient-derived cell-based models.
METHODS
To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics.
RESULTS
Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes.
CONCLUSION
This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.
Topics: Humans; Astrocytes; Edaravone; Eukaryotic Initiation Factor-2; Leukoencephalopathies; Mitochondria; White Matter
PubMed: 36971196
DOI: 10.1111/cns.14190 -
Sorption and biodegradation parameters of selected pharmaceuticals in laboratory column experiments.Journal of Contaminant Hydrology Jan 2021Pharmaceutically active compounds have increasingly been detected in groundwater worldwide. Despite constituting a risk for human health and ecosystems, their fate in...
Pharmaceutically active compounds have increasingly been detected in groundwater worldwide. Despite constituting a risk for human health and ecosystems, their fate in the environment has still not been exhaustively investigated. This study characterizes the transport behavior of five selected pharmaceutically active compounds (antipyrine, atenolol, caffeine, carbamazepine and sulfamethoxazole) in two sediments (coarse quartz sand and sandy loam) using column experiments with long-term injection of spiked groundwater. Transport parameters were estimated using an analytical reactive transport model. When five selected compounds were injected simultaneously, transport behavior of antipyrine, carbamazepine and the antibiotic sulfamethoxazole were similar to the conservative tracer in both sediments and under varying redox conditions. Atenolol and caffeine were retarded significantly stronger in the sandy loam sediment than in the coarse quartz sand. Biodegradation of caffeine was observed in both sediments after an adaption period and depended on dissolved oxygen. The identification of biodegradation processes was supported by monitoring of intracellular adenosine triphosphate (ATP) as a measure for microbial activity. ATP was present in varying concentrations in all sediments and was highest when biodegradation of pharmaceuticals, especially caffeine, was observed. When only caffeine and sulfamethoxazole were injected simultaneously, sulfamethoxazole was degraded while caffeine degradation was reduced. The latter seemed to be influenced by low concentrations in dissolved oxygen rather than the presence of the antibiotic sulfamethoxazole. Results of these experiments emphasize the impact on pharmaceutical sorption and (bio)degradation of sediment type and redox conditions, as well as available time for microbial adaption and the combination of pharmaceuticals that are released together into groundwater.
Topics: Biodegradation, Environmental; Ecosystem; Humans; Laboratories; Pharmaceutical Preparations; Water Pollutants, Chemical
PubMed: 33310632
DOI: 10.1016/j.jconhyd.2020.103738 -
Scientific Reports Apr 2024The etiopathogenesis of severe acute pancreatitis (SAP) remains poorly understood. We aim to investigate the role of immune cells Infiltration Characteristics during SAP...
The etiopathogenesis of severe acute pancreatitis (SAP) remains poorly understood. We aim to investigate the role of immune cells Infiltration Characteristics during SAP progression. Gene expression profiles of the GSE194331 dataset were retrieved from the GEO. Lasso regression and random forest algorithms were employed to select feature genes from genes related to SAP progression and immune responses. CIBERSORT was utilized to estimate differences in immune cell types and proportions and the relationship between immune cells and gene expression. We performed pathway enrichment analysis using GSEA to examine disparities in KEGG signaling pathways when comparing the two groups. Additionally, CMap analysis was executed to identify prospective small molecular compounds. The three hub genes (CBLB, JADE2, RNF144A) were identified that can predict SAP progression. Analysis of CIBERSORT and TISIDB databases has shown that there are significant differences in immune cell expression levels between the normal and SAP groups, and three hub genes (CBLB, JADE2, RNF144A) were highly correlated with multiple immune cells, regulating the characteristics of immune cell infiltration in the microenvironment. Finally, drug prediction through the Connectivity Map database suggested that compounds such as Entecavir, KU-0063794, Y-27632, and Antipyrine have certain effects as potential targeted drugs for the treatment of SAP. CBLB, JADE2, and RNF144A are hub genes in SAP, potentially playing important roles in SAP progression. This finding further broadens the understanding of the etiopathogenesis of SAP and provides a feasible basis for future research on diagnostic and immunotherapeutic targets for SAP.
Topics: Humans; Acute Disease; Prospective Studies; Pancreatitis; Drug Delivery Systems; Computational Biology
PubMed: 38622245
DOI: 10.1038/s41598-024-59205-1 -
Muscle & Nerve Feb 2023An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension...
INTRODUCTION/AIMS
An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone.
METHODS
This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone.
RESULTS
The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug.
DISCUSSION
This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.
Topics: Female; Humans; Male; Middle Aged; Administration, Oral; Amyotrophic Lateral Sclerosis; Constipation; Edaravone
PubMed: 36504406
DOI: 10.1002/mus.27768 -
Stroke and Vascular Neurology Sep 2019Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic... (Comparative Study)
Comparative Study Randomized Controlled Trial
Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial.
BACKGROUND
Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic stroke models. This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke (AIS).
METHODS
In this multicentre, randomised, double-blind, multiple-dose, active-controlled, phase II clinical trial, patients with AIS within 48 hours after stroke onset were randomly assigned (1:1:1:1) to low-dose (12.5 mg), medium-dose (37.5 mg) or high-dose (62.5 mg) Edaravone Dexborneol groups, and an active control group with edaravone (30 mg) by 30 min intravenous infusion every 12 hours, for 14 consecutive days. The primary efficacy outcome was the proportion of modified Rankin Scale (mRS)score ≤1 at 90 days and National Institutes of Health Stroke Scale (NIHSS) score change from baseline to 14 days after randomisation. The safety outcome included any adverse event during 90 days after treatment.
RESULTS
Of 385 patients included in the efficacy analysis, 94 were randomised to low-dose group, 97 to medium-dose group, 98 to high-dose group and 96 to the control group. No significant difference was observed among the four groups on mRS score (mRS ≤1, p=0.4054) at 90 days or NIHSS score change at 14 days (p=0.6799). However, a numerically higher percentage of patients with mRSscore ≤1 at 90 days in the medium-dose (69.39%) and high-dose (65.63%) groups was observed than in the control group (60.64%). No significant difference in severe adverse events was found among the four groups (p=0.3815).
CONCLUSIONS
Compared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed at 90days.
TRIAL REGISTRATION NUMBER
NCT01929096.
Topics: Aged; China; Double-Blind Method; Drug Administration Schedule; Edaravone; Female; Functional Status; Humans; Infusions, Intravenous; Ischemic Stroke; Male; Middle Aged; Neuroprotective Agents; Recovery of Function; Time Factors; Treatment Outcome
PubMed: 31709115
DOI: 10.1136/svn-2018-000221