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European Journal of Pharmaceutical... May 2024To date, characterization of the first-pass effect of orally administered drugs consisting of local intestinal absorption and metabolism, portal vein transport and...
Ex vivo gut-hepato-biliary organ perfusion model to characterize oral absorption, gut-wall metabolism, pre-systemic hepatic metabolism and biliary excretion; application to midazolam.
To date, characterization of the first-pass effect of orally administered drugs consisting of local intestinal absorption and metabolism, portal vein transport and hepatobiliary processes remains challenging. Aim of this study was to explore the applicability of a porcine ex-vivo perfusion model to study oral absorption, gut-hepatobiliary metabolism and biliary excretion of midazolam. Slaughterhouse procured porcine en bloc organs (n = 4), were perfused via the aorta and portal vein. After 120 min of perfusion, midazolam, atenolol, antipyrine and FD4 were dosed via the duodenum and samples were taken from the systemic- and portal vein perfusate, intestinal faecal effluent and bile to determine drug and metabolite concentrations. Stable arterial and portal vein flow was obtained and viability of the perfused organs was confirmed. After intraduodenal administration, midazolam was rapidly detected in the portal vein together with 1-OH midazolam (E of 0.16±0.1) resulting from gut wall metabolism through oxidation. In the intestinal faecal effluent, 1-OH midazolam and 1-OH midazolam glucuronide (E 0.051±0.03) was observed resulting from local gut glucuronidation. Biliary elimination of midazolam (0.04±0.01 %) and its glucuronide (0.01±0.01 %) only minimally contributed to the enterohepatic circulation. More extensive hepatic metabolism (F 0.35±0.07) over intestinal metabolism (F 0.78±0.11) was shown, resulting in oral bioavailability of 0.27±0.05. Ex vivo perfusion demonstrated to be a novel approach to characterize pre-systemic extraction of midazolam by measuring intestinal as well as hepatic extraction. The model can generate valuable insights into the absorption and metabolism of new drugs.
PubMed: 38574899
DOI: 10.1016/j.ejps.2024.106760 -
Medicina (Kaunas, Lithuania) Feb 2024Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation... (Review)
Review
Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.
Topics: Humans; Edaravone; Antioxidants; Oxidative Stress; Eye Diseases; Retinal Diseases; Ophthalmic Solutions
PubMed: 38541080
DOI: 10.3390/medicina60030354 -
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 -
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 -
BMC Public Health Feb 2024Edaravone dexborneol and dl-3-n-butylphthalide are two innovative brain cytoprotective drugs from China that have been approved and widely prescribed for acute ischemic...
BACKGROUND
Edaravone dexborneol and dl-3-n-butylphthalide are two innovative brain cytoprotective drugs from China that have been approved and widely prescribed for acute ischemic stroke, and the cost of the two drugs are partially paid by the Chinese medical insurance system. This study aimed to investigate and compare the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke from the Chinese healthcare system's perspective.
METHODS
A model combining a short-term decision tree model with 90 days and a long-term Markov model with a life-time horizon (40 years) was developed to simulate the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke over a lifetime horizon. Since the absence of a head-to-head clinical comparison of two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was conducted by adjusting the patient characteristics using individual patient data from pivotal phase III trial of edaravone dexborneol and published aggregated data of dl-3-n-butylphthalide. Health outcomes were measured in quality-adjusted life years (QALYs). Utilities and costs (Chinese Yuan, CNY) were derived from publications and open-access database. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of results.
RESULTS
Compared with patients in dl-3-n-butylphthalide arm, edaravone dexborneol arm was found to be cost-effective in 90 days and highly cost-effective as the study horizons extended. With a similar direct medical cost, patients in edaravone dexborneol arm slightly gained an additional 0.1615 QALYs in life-time. In the long term (40 years), patients in edaravone dexborneol arm and dl-3-n-butylphthalide arm yielded 8.0351 and 7.8736 QALYs with the overall direct medical cost of CNY 29,185.23 and CNY 29,940.28, respectively. The one-way sensitivity analysis suggested that the incremental cost-effectiveness ratio was most sensitive to the price of edaravone dexborneol and dl-3-n-butylphthalide.
CONCLUSION
Edaravone dexborneol is a cost-effective alternative compared with dl-3-n-butylphthalide for acute ischemic stroke patients in current medical setting of China.
Topics: Humans; Edaravone; Cost-Benefit Analysis; Ischemic Stroke; Delivery of Health Care; Stroke; Quality-Adjusted Life Years; Benzofurans
PubMed: 38347500
DOI: 10.1186/s12889-024-17959-3 -
International Journal of Molecular... Jan 2024Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances... (Review)
Review
Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.
Topics: Humans; Edaravone; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Antioxidants; Neoplasms; Free Radical Scavengers
PubMed: 38338912
DOI: 10.3390/ijms25031633