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Animals : An Open Access Journal From... Mar 2024Our objective was to assess the pharmacokinetic characteristics of metamizole when administered together with tramadol in a single intravenous dose to donkeys. Ten male...
Our objective was to assess the pharmacokinetic characteristics of metamizole when administered together with tramadol in a single intravenous dose to donkeys. Ten male animals received 10 mg∙kg of dipyrone associated with 2 mg∙kg of tramadol (TM) and 25 mg∙kg of dipyrone with 2 mg∙kg of tramadol (TM). Venous blood samples were taken from groups to determine the pharmacokinetics after drug administration, using initial brief intervals that were followed by extended periods until 48 h. Restlessness and ataxia were observed in two animals in the TM group. Analysis revealed prolonged detectability of tramadol, 4-methylamine antipyrine, 4-aminoantipyrine (up to 24 h), and O-desmethyltramadol (up to 12 h) after administration. Although metamizole and its metabolites showed no significant pharmacokinetic changes, tramadol and O-desmethyltramadol exhibited altered profiles, likely because of competition for the active sites of CYP450 enzymes. Importantly, the co-administration of metamizole increased the bioavailability of tramadol and O-desmethyltramadol in a dose-dependent manner, highlighting their potential interactions and emphasizing the need for further dose optimization in donkey analgesic therapies. In conclusion, metamizole co-administered with tramadol interferes with metabolism and this interference can change the frequency of drug administration and its analgesic efficacy.
PubMed: 38540027
DOI: 10.3390/ani14060929 -
Free Radical Biology & Medicine May 2024Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; Edaravone; Zebrafish; Neurodegenerative Diseases; Oxidation-Reduction
PubMed: 38531462
DOI: 10.1016/j.freeradbiomed.2024.03.016 -
ACS Omega Mar 2024Electrochemical experiments such as potentiodynamic polarization, electrochemical impedance spectroscopy, and gravimetric studies have been used to examine the corrosion...
Electrochemical experiments such as potentiodynamic polarization, electrochemical impedance spectroscopy, and gravimetric studies have been used to examine the corrosion inhibitory efficacy of 4-[(4-nitrobenzylidene)-amino]-antipyrine (4-NBAAP) on mild steel (MS) in 1 M HCl. 4-NBAAP inhibits the corrosion of MS through a mixed inhibition mechanism, according to the electrochemical investigation. The efficiency of 4-NBAAP increases with an increase in the inhibitor concentration and decreases with an increase in temperature. The adsorption of 4-NBAAP molecules on the MS surface follows the Langmuir adsorption isotherm. To find the relationship between the 4-NBAAP molecular structure and inhibitive effect, a few thermodynamic parameters were computed. The experimental results obtained from gravimetric and different electrochemical investigations prove the superiority of the inhibitor at higher concentrations in controlling the corrosion process of the steel in aggressive environments. Also, quantum chemical studies were performed to provide further insights into the inhibition mechanism.
PubMed: 38524480
DOI: 10.1021/acsomega.3c10048 -
International Journal of Molecular... Mar 2024The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free... (Review)
Review
The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.
Topics: Animals; Female; Pregnancy; Amyotrophic Lateral Sclerosis; Antioxidants; Antipyrine; Edaravone; Free Radical Scavengers; Neurodegenerative Diseases; Neuroprotective Agents; Placenta
PubMed: 38474192
DOI: 10.3390/ijms25052945 -
Chemistry & Biodiversity May 2024Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and...
Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.
Topics: Animals; Edaravone; Ischemic Stroke; Rats; Platelet Aggregation Inhibitors; Platelet Aggregation; Neuroprotective Agents; Molecular Docking Simulation; Male; Mice; Molecular Structure; Structure-Activity Relationship; Rats, Sprague-Dawley; Drug Discovery; Pyridazines; Oxidative Stress
PubMed: 38424689
DOI: 10.1002/cbdv.202400110 -
The Science of the Total Environment Apr 2024The complexity of the aquatic environment scenario, including the impact of urban wastewater, together with the huge number of potential hazardous compounds that may be...
High resolution mass spectrometry-based screening for the comprehensive investigation of organic micropollutants in surface water and wastewater from Pasto city, Colombian Andean highlands.
The complexity of the aquatic environment scenario, including the impact of urban wastewater, together with the huge number of potential hazardous compounds that may be present in waters, makes the comprehensive characterization of the samples an analytical challenge, particularly in relation to the presence of organic micropollutants (OMPs). Nowadays, the potential of high-resolution mass spectrometry (HRMS) for wide-scope screening in environmental samples is out of question. Considering the physicochemical characteristics of OMPs, the coupling of liquid (LC) and gas chromatography (GC) to HRMS is mandatory. In this work, we have explored the combined use of LC and GC coupled to Quadrupole-Time-of-Flight Mass Spectrometry (QTOF MS) for screening of surface water and wastewater samples from Pasto (Nariño), a town of the Colombian Andean highlands (average altitude 2527 m), located in an important agricultural area. The upper basin of the Pasto River is impacted by phytosanitary products used in different crops, whereas the domestic wastewater is directly discharged into the river without any treatment, enhancing the anthropogenic impact on the water quality. The OMP searching was made by target (standards available) and suspect (without standards) approaches, using home-made databases containing >2000 compounds. Up to 15 pesticides (7 insecticides, 6 fungicides and 2 herbicides) were identified in the sampling point of the Pasto River up to the town, while no pharmaceuticals were found at this site, illustrating the impact of agriculture practices. On the contrary, 14 pharmaceuticals (7 antibiotics and 3 analgesics, among others) were found in river samples collected in the middle and down to the town sites, revealing the impact of the urban population. Interestingly, some transformation products, including metabolites, such as carbofuran-3-hydroxy and 4-acetylamino antipyrine were identified in the screening. Based on these data, future monitoring will apply target quantitative LC-MS/MS methods for the most relevant compounds identified.
Topics: Wastewater; Chromatography, Liquid; Colombia; Tandem Mass Spectrometry; Environmental Monitoring; Water Pollutants, Chemical; Gas Chromatography-Mass Spectrometry
PubMed: 38417505
DOI: 10.1016/j.scitotenv.2024.171293 -
International Immunopharmacology Mar 2024Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells....
Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1β, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.
Topics: Animals; Mice; Male; Microglia; Edaravone; Astrocytes; Brain Ischemia; Neuroinflammatory Diseases; Mice, Inbred C57BL; Stroke; Infarction, Middle Cerebral Artery; Inflammation; Leukocytes
PubMed: 38382262
DOI: 10.1016/j.intimp.2024.111700 -
Skin Pharmacology and Physiology 2023Percutaneous drug delivery systems are attractive not only as a therapeutic strategy but also for cosmetic treatment. Iontophoresis is a well-recognized method for...
INTRODUCTION
Percutaneous drug delivery systems are attractive not only as a therapeutic strategy but also for cosmetic treatment. Iontophoresis is a well-recognized method for promoting transdermal absorption of ionized compounds. Franz cells are generally used to estimate drug permeation of skin by iontophoresis. However, methods using Franz cells are less versatile; for instance, the method is unsuited for use with a portable electric facial care device having a working probe of a certain size and weight. In this study, we constructed a semi-dry apparatus for use with an electric facial care device.
METHODS
The apparatus has a multilayer structure consisting of mouse skin and 3 filter papers, modeled after the Franz cell. The skin permeation of the drug edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) was then measured using this apparatus.
RESULTS
Edaravone permeation depended on working time, drug concentration, and ionization ratio of edaravone when iontophoresis was carried out with an electric facial care device. Furthermore, glycyrrhizic acid, α-tocopheryl phosphate, retinoic acid, and ascorbyl palmitate, which are recognized as functional cosmetic materials, also permeated the skin by applying iontophoresis with the device.
CONCLUSION
These results suggest that the developed measuring apparatus is applicable for use with a portable electric facial care device and that iontophoresis using a portable electric facial care device is potentially useful in the cosmetic field.
Topics: Mice; Animals; Pharmaceutical Preparations; Administration, Cutaneous; Iontophoresis; Edaravone; Skin
PubMed: 38368874
DOI: 10.1159/000536500 -
Chemistry & Biodiversity Apr 2024The paper is focused on biological activity and theoretical study of the structure and properties of a new azo derivative of β-diketones and its complexes with some...
The paper is focused on biological activity and theoretical study of the structure and properties of a new azo derivative of β-diketones and its complexes with some metals. The aim of our work was to study the structure and properties of the newly synthesized compound as well as to theoretically determine the possibility of complex formation with the Cu(II) or Co(II) ions. A compound with the same substituents R=R=CH was chosen for the study. A synthesized azo compound based on 4-amino antipyrine and its complexes with Cu(II), Co(II) in solution and solid phase is reported. The structures of these compounds have been testified by X-ray, IR and NMR spectroscopy. The combined experimental and theoretical approach was used. To study the structure and properties of the synthesized compound, as well as its possible complex formation with the Cu(II), quantum-chemical calculations were carried out the 6-31G basis set and the electron density functional theory (DFT) method. These 3-(1-phenyl-2,3-dimethyl-pyrazolone-5) azopentadione-2,4 (PDPA) with Cu(II) and Co(II) complexes had effective inhibition against butyrylcholinesterase and acetylcholinesterase. IC values were found as 19.03, 3.64 μM for AChE and 28.47, 8.01 μM for BChE, respectively. Cholinesterase inhibitors work to slow down the acetylcholine's deterioration.
Topics: Acetylcholinesterase; Butyrylcholinesterase; Coordination Complexes; Metals; Models, Theoretical; Molecular Docking Simulation; Copper; Cobalt
PubMed: 38367267
DOI: 10.1002/cbdv.202301861 -
Annals of Nuclear Medicine May 2024Brain ischemia-reperfusion injury is a complex process, and neuroinflammation is an important secondary contributing pathological event. Neutrophils play major roles in...
BACKGROUND
Brain ischemia-reperfusion injury is a complex process, and neuroinflammation is an important secondary contributing pathological event. Neutrophils play major roles in ischemic neuroinflammation. Once activated, neutrophils express formyl peptide receptors (FPRs), which are special receptors of a class of chemoattractants and may be potential targets to regulate the activity of neutrophils and control cerebral ischemic injury. This study was aimed to explore the ameliorating effect of Cyclosporin H (CsH), a potent FPR antagonist, on brain ischemic injury by inhibiting the activation and migration of neutrophils, and improving cerebral blood flow.
METHODS
We employed a middle cerebral artery occlusion (MCAO) Model on rats and performed behavioral, morphological, and microPET imaging assays to investigate the potential restoring efficacy of CsH on cerebral ischemic damages. Peptide N-cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF), an antagonist to the neutrophil FPR with a high binding affinity, was used for imaging neutrophil distribution.
RESULTS
We found that CsH had similar effect with edaravone on improving the neurobehavioral deficient symptoms after cerebral ischemia-reperfusion, and treatment with CsH also alleviated ischemic cerebral infarction. Compared with the MCAO Model group, [F]FDG uptake ratios of the CsH and edaravone treatment groups were significantly higher. The CsH-treated groups also showed significant increases in [F]FDG uptake at 144 h when compared with that of 24 h. This result indicates that like edaravone, treatment with both doses of CsH promoted the recovery of blood supply after cerebral ischemic event. Moreover, MCAO-induced cerebral ischemia significantly increased the radiouptake of [Ga]Ga-cFLFLF at 72 h after ischemia-reperfusion operation. Compared with MCAO Model group, radiouptake values of [Ga]-cFLFLF in both doses of CsH and edaravone groups were all decreased significantly. These results showed that both doses of CsH resulted in a similar therapeutic effect with edaravone on inhibiting neutrophil infiltration in cerebral infarction.
CONCLUSION
Potent FPR antagonist CsH is promisingly beneficial in attenuating neuroinflammation and improving neurobehavioral function against cerebral infarction. Therefore, FPR may become a novel target for regulating neuroinflammation and improving prognosis for ischemic cerebrovascular disorders.
Topics: Rats; Animals; Neutrophil Infiltration; Edaravone; Fluorodeoxyglucose F18; Neuroinflammatory Diseases; Gallium Radioisotopes; Brain Ischemia; Positron-Emission Tomography; Infarction, Middle Cerebral Artery; Reperfusion Injury; Cyclosporine
PubMed: 38360964
DOI: 10.1007/s12149-024-01900-0