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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 -
Frontiers in Pharmacology 2023Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John's wort and valerian are valid candidates, but safety data in pregnancy...
Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John's wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John's wort), and valerenic acid (from valerian) was evaluated using the cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin - but not to valerenic acid - is likely to be minimal.
PubMed: 37063288
DOI: 10.3389/fphar.2023.1123194 -
Free Radical Research May 2020Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying...
Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the JAK2/STAT3 signaling pathway. AMI in rats was established by left anterior descending coronary artery ligation. Two hours after AMI model established rats were treated with edaravone, edaravone plus AG490, physiological saline, respectively. We detected antioxidant effects by reduced glutathione (GSH), glutathione S-transferase (GST), and Glutathione Peroxidase (GSHPx) Activity. The expressions of t-JAK2, p-JAK2, t-STAT3, p-STAT3 and cleaved caspase-3 were examined by western blot. The mRNA levels for Bcl-2, Bax, Fas, and FasL were measured by RT-PCR and apoptosis was assessed by TUNEL. Edaravone significantly improved hemodynamics after AMI ( < 0.05) and reduced the total infarct volumes ( < 0.05). Compared with Sham rats, the mRNA of Bax, Fas, and FasL increased in different degrees in the AMI group, however, the mRNA of Bcl-2 and the ratio of Bcl-2/Bax decreased, especially the myocardial apoptosis index significantly increased in AMI hearts (all < 0.05). After treatment with edaravone, the mRNA levels of Bcl-2 and the ratio of Bcl-2/Bax significantly upregulated whereas Bax, Fas, FasL apparently decreased, and the protein expressions of p-JAK2 and p-STAT3 dramatically increased ( < 0.05). In addition, cotreatment with JAK2 inhibitor AG490 abolished the effects of edaravone. We conclude that edaravone attenuated myocardial apoptosis induced by AMI JAK2/STAT3 signaling pathway.
Topics: Acute Disease; Animals; Apoptosis; Edaravone; Janus Kinase 2; Male; Muscle Cells; Myocardial Infarction; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Signal Transduction
PubMed: 32543312
DOI: 10.1080/10715762.2020.1772469 -
Journal of Biomolecular Structure &... Feb 2023Herein, a series of novel antipyrine based α-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for...
Herein, a series of novel antipyrine based α-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for cholinesterase inhibition, enzyme kinetic studies, protein denaturation assay, proteinase inhibitory assay and cell viability assay. For cholinesterase inhibition, the results inferred that the test compounds possess better AChE activity (0.46 to 6.67 µM) than BuChE (2.395 to 12.47 µM). Compound inhibited both AChE and BuChE (IC = 0.475 ± 0.12 µM and 2.95 ± 0.16 µM, respectively), implying that it serves as a dual AChE/BuChE inhibitor. Also, kinetic studies revealed that compound exhibits mixed-type inhibition against both AChE and BuChE, with K values of 3.003 µM and 5.750 µM, respectively. Further, protein denaturation and proteinase inhibitory assays were used to test anti-inflammatory potential. It was found that compound exhibited highest activity against protein denaturation (IC = 42.64 ± 0.19 µM) and proteinase inhibition (IC = 37.57 ± 0.19 µM) when compared to diclofenac. In addition, cell viability assay revealed that active compounds possess no cytotoxicity against N2a cell and RAW 264.7 macrophages. Finally, molecular docking experiments for AChE, BuChE, and COX-2 were conducted to better understand the binding modes of active compounds.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Molecular Docking Simulation; Cholinesterase Inhibitors; Alzheimer Disease; Antipyrine; Kinetics; Acetylcholinesterase; Anti-Inflammatory Agents; Peptide Hydrolases; Structure-Activity Relationship; Molecular Structure
PubMed: 34878960
DOI: 10.1080/07391102.2021.2006088 -
Journal of Veterinary Pharmacology and... Nov 2021Metamizole sodium (MT) is an analgesic and antipyretic drug molecule used in humans, horses, cattle, swine, and dogs. Metamizole rapidly hydrolyzes and turns into...
Metamizole sodium (MT) is an analgesic and antipyretic drug molecule used in humans, horses, cattle, swine, and dogs. Metamizole rapidly hydrolyzes and turns into methylamino antipyrine (MAA), an active primary metabolite of MT. The present study aims to determine the pharmacokinetic (PK) profiles of MT metabolites after intravenous (IV) and intramuscular (IM) administration into sex of Arabian horses (Equus ferus caballus) using a cross-over study design. The plasma samples were extracted by solid-phase extraction (SPE) method, and plasma concentrations of MT metabolites were analyzed by high-performance liquid chromatography (HPLC). After administrations of MT, plasma concentrations of methylamino antipyrine (MAA), amino antipyrone (AA), and acetylamino antipyrone (AAA) were determined within range of 15 min-12 h. Plasma concentrations of AA and AAA were lower than the plasma concentrations of major metabolite MAA at each sampling point. The PK parameters were statistically evaluated for MT's metabolites between male and female horses and also between IM and IV administrations of PK parameters such as C , t , t , AUC , AUC , λz, Cl and V (p < .05). The AUC /AUC ratio in female and male horses for MAA was 1.19 and 1.13, respectively. The AUC /AUC ratio for AA was lower than those found for MAA. AUC /AUC ratio was statistically significantly different between male and female horses for AA (p < .05). According to these results, some PK parameters such as Cmax, AUC, and MRT, MAA and AA concentrations have shown statistically significant differences by MT administrations.
Topics: Administration, Intravenous; Analgesics; Animals; Antipyrine; Area Under Curve; Cross-Over Studies; Dipyrone; Female; Horses; Male
PubMed: 34431528
DOI: 10.1111/jvp.13003 -
The Journal of Maternal-fetal &... Sep 2019Reports relating to maternal-fetal transport kinetics of chromium, an essential trace element in the human pregnancies are scanty. Hence, we thought it interesting to...
Reports relating to maternal-fetal transport kinetics of chromium, an essential trace element in the human pregnancies are scanty. Hence, we thought it interesting to investigate the transport kinetics of this trace element in the human placenta in late gestation . Human placentae were collected immediately after delivery from normal uncomplicated pregnancies. Chromium chloride solution (GFS Chem Inc, Ohio, USA) at 10 times the physiological concentrations and antipyrine (Sigma Chem Co., St. Louis, USA) as internal reference marker was injected as a single bolus (100 µl) into the maternal arterial circulation of perfused placental lobules and perfusate samples were collected from maternal and fetal circulations over a study period of 5 minutes. National culture and Tissue collection medium, diluted with Earle's buffered salt solution was used as the perfusate. Serial perfusate samples were collected from fetal venous perfusate for a period of 30 minutes. Chromium concentration in perfusate samples was determined using atomic absorption spectrophotometry and the concentration of reference marker, antipyrine was measured by spectrophotometry. Transport kinetics and transport parameters of study and reference markers were assessed using well-established parameters. Differential transport rates of chromium and antipyrine in 10 perfusions differed significantly for 10 and 50% efflux fractions (ANOVA test, < .05) while those of 25, 75, and 90% efflux fractions were not significantly different between the study and reference substances. Chromium transport fraction (TF) averaged 54.9% of bolus dose in 10 perfusions while that of antipyrine averaged 89% of bolus dose, representing 61.80% of reference marker TF. The difference observed in TF values of chromium and antipyrine was statistically significant (Student's -test, < .05). Pharmacokinetic parameters such as area under the curve, clearance, absorption rate, elimination rate of chromium compared to reference marker was significantly different (ANOVA test, < .05) between the study and reference substances. Our studies report for the first time maternal-fetal transport kinetics of chromium in human placenta . Considering the restricted transfer of this essential trace element from maternal to fetal circulation despite its small molecular weight, we hypothesize an active transport of chromium across the human placental membrane. Further studies relating to placental transport kinetics of this trace element in various pregnancy-related disease states are in progress.
Topics: Adult; Antipyrine; Biological Transport; Chromium; Female; Humans; Maternal-Fetal Exchange; Placenta; Pregnancy
PubMed: 29621925
DOI: 10.1080/14767058.2018.1454425 -
Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials.Expert Opinion on Emerging Drugs Jun 2020Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing... (Review)
Review
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3-5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need.
AREAS COVERED
Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed.
EXPERT OPINION
This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a 'fertile ground' for drug development for this devastating disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Progression; Drug Development; Drug Discovery; Edaravone; Humans; Neuroprotective Agents; Oxidative Stress; Riluzole
PubMed: 32456491
DOI: 10.1080/14728214.2020.1769067 -
Journal of the Neurological Sciences Oct 2022Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based...
Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-β oligomers (AβO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AβO was established to simulate an AD cell model. Exposure to AβO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AβO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AβO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 μM) and resveratrol (20 μM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Curcumin; Edaravone; Free Radical Scavengers; Humans; Neuroblastoma; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Reactive Oxygen Species; Resveratrol
PubMed: 35963200
DOI: 10.1016/j.jns.2022.120356 -
American Journal of Obstetrics and... Dec 2021Pregnant women have an increased risk of infections, and early and decisive treatment is preferred to prevent complications. Although ciprofloxacin is very commonly...
BACKGROUND
Pregnant women have an increased risk of infections, and early and decisive treatment is preferred to prevent complications. Although ciprofloxacin is very commonly used, safety aspects of maternal treatment during pregnancy are limited, and avoidance of its use during late pregnancy is recommended.
OBJECTIVE
The aim is to estimate maternal-to-fetal transfer clearance of ciprofloxacin at a therapeutic concentration and to determine fetal exposure to maternally administered ciprofloxacin.
STUDY DESIGN
Transplacental pharmacokinetics were determined with an ex vivo placental model, which is a reliable experimental model for estimating fetal drug exposure. Human placentas from uncomplicated term pregnancies were collected after delivery and a suitable cotyledon was cannulated. Ciprofloxacin was added at a therapeutic concentration (1.6 μg/mL) to the maternal compartment, and antipyrine was included as a reference drug (10.0 μg/mL). Samples were collected from the maternal and fetal compartment at 12 time points (-2 to 180 minutes), and the integrity and metabolic parameters were measured consecutively. Drug concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry.
RESULTS
A total of 5 human placentas from healthy term pregnancies were collected after delivery and cannulated with success. Ciprofloxacin crossed the placenta; its mean concentration in the fetal compartment was 0.3 μg/mL, accounting for 22% (0.29/1.30; range, 15%-31%) of the maternal concentration after 3 hours. The fetal/maternal ciprofloxacin concentration ratio increased gradually over time and reached 0.53. The transfer clearance for ciprofloxacin was 0.28 mL/min (range, 0.21-0.41 mL/min) during the first hour and 0.21 mL/min (range, 0.14-0.26 mL/min) during the following 2 hours. After end perfusion, the mean tissue concentration and proportion of ciprofloxacin were 0.7 μg/g and 11% (14/130; range, 7%-14%), respectively.
CONCLUSION
Ciprofloxacin crossed the placenta at a slow, constant rate, indicating moderate fetal exposure. This study verifies an accumulation of ciprofloxacin in the placenta that may lengthen the duration of fetal exposure. These results are an essential element of fetal risk assessment, but further studies are needed to estimate fetal safety.
Topics: Adult; Anti-Bacterial Agents; Ciprofloxacin; Female; Humans; Models, Biological; Placenta; Pregnancy
PubMed: 34058171
DOI: 10.1016/j.ajog.2021.05.032