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Current Research in Toxicology 2024Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis...
Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.
PubMed: 38292667
DOI: 10.1016/j.crtox.2024.100149 -
Biomedicine & Pharmacotherapy =... Feb 2024Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational...
Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational and type 2 diabetes in pregnancy are still limited. Empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) are three sodium glucose co-transporter 2 (SGLT2) inhibitors, a newer group of oral antidiabetics that are well established in the treatment of type 2 diabetes mellitus in non-pregnant patients. To date, no data regarding their placental transfer and safety in pregnant women are available. We performed ex vivo human placental perfusions (n = 4, term placentas, creatinine and antipyrine as connectivity controls) to evaluate the transplacental transfer of EMPA, DAPA and CANA across the placental barrier and assessed their influence on the secretion of two placental peptide hormones, leptin and β-human chorionic gonadotropin (β-hCG). We discovered that all three SGLT2 inhibitors cross the placental barrier and attained maximal foetal to maternal concentration ratios of 0.38 ± 0.09 (EMPA), 0.67 ± 0.05 (DAPA) and 0.62 ± 0.05 (CANA) within the tested 360 min. A moderate but statistically significant decrease in placental leptin - but not β-hCG - secretion was observed during perfusions with SGLT2 inhibitors, which was confirmed in experiments performed with human placental BeWo cells. SGLT2 inhibitors are able to cross the human placental barrier and seem to interfere with placental leptin production. These observations should be considered in the ongoing discussion on the optimal treatment for gestational diabetes and type 2 diabetes mellitus in pregnancy.
Topics: Humans; Female; Pregnancy; Canagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Leptin; Placenta; Benzhydryl Compounds; Hypoglycemic Agents; Perfusion; Glucosides
PubMed: 38262151
DOI: 10.1016/j.biopha.2024.116177 -
Molecules (Basel, Switzerland) Jan 2024The long-term presence of PPCPs in the aqueous environment poses a potentially significant threat to human life and physical health and the safety of the water...
Elimination of Pharmaceutical Compounds from Aqueous Solution through Novel Functionalized Pitch-Based Porous Adsorbents: Kinetic, Isotherm, Thermodynamic Studies and Mechanism Analysis.
The long-term presence of PPCPs in the aqueous environment poses a potentially significant threat to human life and physical health and the safety of the water environment. In our previous work, we investigated low-cost pitch-based HCP adsorbents with an excellent adsorption capacity and magnetic responsiveness through a simple one-step Friedel-Crafts reaction. In this work, we further investigated the adsorption behavior of the prepared pitch-based adsorbents onto three PPCP molecules (DFS, AMP, and antipyrine) in detail. The maximum adsorption capacity of P-MPHCP for DFS was 444.93 mg g. The adsorption equilibrium and kinetic processes were well described through the Langmuir model and the proposed secondary kinetic model. The negative changes in Gibbs free energy and enthalpy reflected that the adsorption of HCPs onto PPCPs was a spontaneous exothermic process. The recoverability results showed that the adsorption of MPHCP and P-MPHCP onto DFS remained above 95% after 10 adsorption-desorption cycles. The present work further demonstrates that these pitch-based adsorbents can be used for multiple applications, which have a very extensive practical application prospect.
PubMed: 38257376
DOI: 10.3390/molecules29020463 -
Molecules (Basel, Switzerland) Dec 2023This study compared the neuroprotective efficacy of three antioxidants-the plant-derived carnosic acid (CA), and two synthetic free radical scavengers: edaravone (ED)...
This study compared the neuroprotective efficacy of three antioxidants-the plant-derived carnosic acid (CA), and two synthetic free radical scavengers: edaravone (ED) and ebselen (EB)-in in vitro models of neuronal cell damage. Results showed that CA protected mouse primary neuronal cell cultures against hydrogen peroxide-induced damage more efficiently than ED or EB. The neuroprotective effects of CA were associated with attenuation of reactive oxygen species level and increased mitochondrial membrane potential but not with a reduction in caspase-3 activity. None of the tested substances was protective against glutamate or oxygen-glucose deprivation-evoked neuronal cell damage, and EB even increased the detrimental effects of these insults. Further experiments using the human neuroblastoma SH-SY5Y cells showed that CA but not ED or EB attenuated the cell damage induced by hydrogen peroxide and that the composition of culture medium is the critical factor in evaluating neuroprotective effects in this model. Our data indicate that the neuroprotective potential of CA, ED, and EB may be revealed in vitro only under specific conditions, with their rather narrow micromolar concentrations, relevant cellular model, type of toxic agent, and exposure time. Nevertheless, of the three compounds tested, CA displayed the most consistent neuroprotective effects.
Topics: Humans; Animals; Mice; Edaravone; Neuroprotective Agents; Hydrogen Peroxide; Neuroblastoma; Azoles; Glutamic Acid; Abietanes; Organoselenium Compounds; Isoindoles
PubMed: 38202702
DOI: 10.3390/molecules29010119 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2024To assess the effects of decompressive craniectomy combined with edaravone on the postoperative neurological functions and hemodynamics of patients with severe traumatic...
OBJECTIVES
To assess the effects of decompressive craniectomy combined with edaravone on the postoperative neurological functions and hemodynamics of patients with severe traumatic brain injury (STBI).
METHODS
The subjects included totally 186 STBI patients admitted during January 2018 and January 2021. The random number table method was adopted to set an operation group (n=82) and a combined medication group (n=104) for the subjects. The changes of the clinical indicators were observed.
RESULTS
Compared with the operation group, the combined medication group had higher Neurobehavioral Cognitive Status Examination score, Barthel index score, total response rate and heart rate (<0.05). Besides, by contrast to those of the operation group, the mean arterial pressure, myocardial zymogram indicators, postoperative neurological function indicators and total incidence rate of complications of the combined medication group were reduced (<0.05). In comparison with the operation group, the combined medication group exhibited raised ipsilateral contralateral blood velocities (<0.05). Furthermore, the combined medication group had a better postoperative 1-year prognosis than the operation group (<0.05).
CONCLUSION
Edaravone in combination with decompressive craniectomy benefits the postoperative improvement of neurological functions of STBI patients, effectively stabilizes the hemodynamics, induces few complications and improves the prognosis.
Topics: Humans; Edaravone; Decompressive Craniectomy; Brain Injuries, Traumatic; Hemodynamics; Heart Rate
PubMed: 38195127
DOI: 10.17712/nsj.2024.1.20230057 -
Biological & Pharmaceutical Bulletin 2024We recently reported that the gastrointestinal (GI) fluid volume is influenced by the solution osmolality, and proposed that this effect may play a role in beverage-drug...
We recently reported that the gastrointestinal (GI) fluid volume is influenced by the solution osmolality, and proposed that this effect may play a role in beverage-drug interactions. Here, we investigated whether osmolality-dependent fluid secretion can explain the difference in the magnitudes of fruit juice-drug interactions depending on the type of fruit juice (grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ)). The osmolality of GFJ, OJ, and AJ used in this study was found to be 552, 686, and 749 mOsm/kg, respectively. Measurements of intestinal fluid movement following beverage administration by the in situ closed-loop technique revealed the following rank order for fluid volume in rat ileum: AJ > OJ > GFJ > purified water, suggesting that water movement is dependent on the osmolality of these beverages. Such changes in GI fluid volume are expected to alter the luminal drug concentration, potentially contributing to the magnitude of beverage-drug interactions. Indeed, in vivo pharmacokinetic study in rats revealed that the plasma concentration of atenolol, a low-permeability drug, was the highest after oral administration in purified water, followed by GFJ and OJ, and was the lowest after administration in AJ. In contrast, antipyrine, a high-permeability drug, showed no significant difference in plasma concentration after administration in purified water and fruit juices, suggesting that the absorption of high-permeability drugs is less affected by solution osmolality. Our findings indicate that differences in the magnitude of beverage-drug interactions can be at least partly explained by differences in the osmolality of the beverages ingested.
Topics: Rats; Animals; Malus; Fruit and Vegetable Juices; Citrus paradisi; Citrus sinensis; Food-Drug Interactions; Beverages; Osmolar Concentration; Water; Fruit
PubMed: 38171780
DOI: 10.1248/bpb.b23-00490 -
Viruses Nov 2023Singapore grouper iridovirus (SGIV) is a virus with high fatality rate in the grouper culture industry. The outbreak of SGIV is often accompanied by a large number of...
Singapore grouper iridovirus (SGIV) is a virus with high fatality rate in the grouper culture industry. The outbreak of SGIV is often accompanied by a large number of grouper deaths, which has a great impact on the economy. Therefore, it is of great significance to find effective drugs against SGIV. It has been reported that edaravone is a broad-spectrum antiviral drug, most widely used clinically in recent years, but no report has been found exploring the effect of edaravone on SGIV infections. In this study, we evaluated the antiviral effect of edaravone against SGIV, and the anti-SGIV mechanism of edaravone was also explored. It was found that the safe concentration of edaravone on grouper spleen (GS) cells was 50 µg/mL, and it possessed antiviral activity against SGIV infection in a dose-dependent manner. Furthermore, edaravone could significantly disrupt SGIV particles and interference with SGIV binding to host cells, as well as SGIV replication in host cells. However, edaravone was not effective during the SGIV invasion into host cells. This study was the first time that it was determined that edaravone could exert antiviral effects in response to SGIV infection by directly interfering with the processes of SGIV infecting cells, aiming to provide a theoretical basis for the control of grouper virus disease.
Topics: Animals; Iridovirus; Bass; Edaravone; Ranavirus; Antiviral Agents; Fish Diseases; DNA Virus Infections; Fish Proteins
PubMed: 38005914
DOI: 10.3390/v15112237 -
Molecules (Basel, Switzerland) Nov 2023Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have...
Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.
Topics: Humans; Edaravone; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Adamantane; Riluzole; Amantadine
PubMed: 38005288
DOI: 10.3390/molecules28227567 -
Molecules (Basel, Switzerland) Nov 2023In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate...
In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate derivative is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (-) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative () which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against β-carbonic anhydrase. The amount of cellular protein released by is directly correlated to the concentration of compound , which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound . This finding supports compound 's antibacterial properties and explains how the formation of holes in the cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against β-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound () declared a greater activity than the other synthesized compounds.
Topics: Escherichia coli; Antipyrine; Carbonic Anhydrases; Anti-Infective Agents; Molecular Docking Simulation; Structure-Activity Relationship; Molecular Structure; Carbonic Anhydrase Inhibitors
PubMed: 38005213
DOI: 10.3390/molecules28227491 -
Clinical Therapeutics Dec 2023Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a...
PURPOSE
Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.
METHODS
Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.
FINDINGS
After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.
IMPLICATIONS
In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.
CLINICALTRIALS
gov.
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Glucuronides; Neuroprotective Agents; Sulfates
PubMed: 37953075
DOI: 10.1016/j.clinthera.2023.09.025