Effectiveness of edaravone in preventing contrast-induced nephropathy in high-risk patients undergoing coronary angiography: A randomized, double-blind trial.

Contrast-induced nephropathy (CIN) is a serious complication that occurs subsequent to the administration of contrast media for therapeutic angiographic interventions. As of present, no effective therapy exists to prevent its occurrence. This single-center double-blind randomized controlled trial aimed to evaluate the effect of edaravone, an antioxidant, in a group of high-risk patients undergoing coronary angiography. Ninety eligible patients with chronic kidney disease Stages 3-4 were randomly assigned to either the control group (n = 45) or the intervention group (n = 45). In the intervention group, one dosage of edaravone (60 mg) in 1 L of normal saline was infused via a peripheral vein 1 h prior to femoral artery-directed coronary angiography. Patients in the control group received an equal amount of infusion in their last hour before angiography. Both groups received intravenous hydration with 0.9% sodium 1 mL/kg/h starting 12 h before and continuing for 24 h after angiography. The primary outcome measure was the onset of CIN, defined as a 25% increase in serum creatinine levels 120 h after administration of contrast media. The occurrence of CIN was observed in 5.5% (n = 5) of the studied population: 2.2% of patients in the intervention group (n = 1) and 8.9% of controls (n = 4). However, this difference was not statistically significant. Administration of a single dosage of edaravone 1 h prior to infusion of contrast media led to a reduction in the incidence of CIN. Further investigations, employing larger sample sizes, are warranted to gain a comprehensive understanding of its efficacy.

Evaluation of acetanilide and antipyrine adsorption on lignin-derived activated carbons.

In this study, the removal of two emerging pollutants (EPs), antipyrine and acetanilide, through adsorption on activated carbons (ACs) prepared by chemical activation of Organosolv lignin with H3PO4 were evaluated. ACs with different pore size distribution were obtained at different impregnation ratios (H3PO4/lignin, 0.5-3.0 w/w) and activating temperatures (500-900 °C). The porosity and surface chemistry of the ACs were determined, and a bimodal size distribution of micropores and narrow mesopores was observed for the different ACs. These ACs were tested for antipyrine and acetanilide adsorption in aqueous solutions in a batch system at 20 °C and low concentration levels (0.5-10 ppm). In general, the ACs exhibited higher adsorption affinity to acetanilide than to antipyrine due to its smaller molecular size. Langmuir adsorption isotherm was able to describe the adsorption equilibrium data. A new Linear Driving Force (2-LDF) kinetic model, based on the bimodal size distribution of micropores and narrow mesopores observed for the ACs has been developed. The new model provided a more accurate description of the batch adsorption rates than that obtained from conventional kinetic models, and also enabled to relate the pore size distribution of the adsorbent with the adsorption kinetics. The validity of this model was checked in small-scale column fixed bed adsorption for the AC showing the highest affinity for both EP. The kinetic model and equilibrium adsorption isotherm obtained from the batch experiments were successfully used to provide an accurate description of the bed service time and the full breakthrough profile of acetanilide and antipyrine.

Monosaccharide Analysis After One-Pot Derivatization Followed by Reverse-Phase Liquid Chromatography Separation and UV/Vis Detection.

Derivatization of monosaccharides with 1-phenyl-3-methyl-5-pyrazolone (PMP) introduces two chromophores per sugar molecule. Their separation on a superficially porous C18 reverse-phase column, using common liquid chromatography equipment, results in short analysis times (under 20 min) and high sensitivity (limit of quantitation 1 nmol). This method allows for complex monosaccharide mixtures to be separated and quantified using a reasonably simple and safe derivatization procedure.

Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.

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.

Enhanced the treatment of ischemic stroke through intranasal temperature-sensitive hydrogels of edaravone and borneol inclusion complex.

Since ischemic stroke occurs by a combination of multiple mechanisms, therapies that modulate multiple mechanisms are required for its treatment. The combination of edaravone (EDA) and borneol can significantly ameliorate the symptoms of neurological deficits in cerebral ischemia-reperfusion model in rats. In this study, the solubility of borneol and edaravone was improved by hydroxypropyl-ß-cyclodextrin and PEG400. Furthermore, a nasal temperature-sensitive hydrogel containing both edaravone and borneol inclusion complex (EDA-BP TSGS) was developed to overcome the obstacles of ischemic stroke treatment including the obstruction of the blood-brain barrier (BBB) and the unavailability and untimely of intravenous injection. The effectiveness of the thermosensitive hydrogel was investigated in transient middle cerebral artery occlusion/reperfusion model rats (MCAO/R). The results showed that EDA-BP TSGS could significantly alleviate the symptoms of neurological deficits and decrease the cerebral infarct area and the degree of brain damage. In summary, nasal EDA-BP TSGS is a secure and effective brain-targeting formulation that may provide a viable option for the clinical prophylaxis and treatment of ischemic stroke.

Antimicrobial Potency and E. coli ß-Carbonic Anhydrase Inhibition Efficacy of Phenazone-Based Molecules.

In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative 3. The as-prepared carbodithioate derivative 3 is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (4-9) 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 (10). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative (11) which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (12). 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 E. coli ß-carbonic anhydrase. The amount of cellular protein released by E. coli is directly correlated to the concentration of compound 9, which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound 9. This finding supports compound 9's antibacterial properties and explains how the formation of holes in the E. coli cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against E. coli ß-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound (9) declared a greater activity than the other synthesized compounds.

Heterogeneous electro-Fenton system using Fe-MOF as catalyst and electrocatalyst for degradation of pharmaceuticals.

In recent years, heterogeneous electro-Fenton processes have gained considerable attention as an alternative to homogeneous processes. In this context, the aim of this study is the use of a commercial iron metal-organic framework (Fe-MOF), Basolite® F-300, as a base material for the design of a heterogeneous electro-Fenton treatment system for the removal of antipyrine. Initially, the catalyst was applied as powder in aqueous solution and three key parameters of the electro-Fenton process (pH, Fe-MOF concentration and current density) were evaluated and optimized by a Central Composite Design Face Centred (CCD-FC) using antipyrine removal and energy consumption as response functions. Near complete antipyrine removal (94%) was achieved under optimal conditions: pH 3, Fe-MOF 157.78 mg/L and current density 6.67 mA/cm2, obtaining an energy consumption of 0.29 W·h per mg of antipyrine removed. Later, two electrocatalysts (Fe-MOF functionalized cathodes), prepared by different Fe-MOF immobilisation approaches (composite of carbon black/polytetrafluoroethylene or by electrospinning on Ni foam), were synthesized. Their characterisation showed notable Fe-MOF incorporation into the material and favourable properties as electrocatalysts. Both Fe-MOF functionalized cathodes were evaluated in the removal of antipyrine at different pH (acidic and natural) and current density (27.78 and 55.56 mA/cm2), achieving in the best conditions removal levels around 80% in 1 h without any operational problems. In addition, several intermediates generated during the treatment were identified and their toxicity estimated. According to the obtained results, the degradation compounds have less toxicity than the parent compounds, confirming the effectiveness of the treatment.

Simultaneous LC-MS/MS quantification of SGLT2 inhibitors and antipyrine in medium and tissue from human ex vivo placenta perfusions.

A liquid chromatography - tandem mass spectrometry (LC-MS/MS) method has been developed to simultaneously measure four sodium glucose co-transporter 2 (SGLT2) inhibitors and the transfer marker antipyrine (ANTI) in perfusion medium and placental tissue collected from ex vivo human placental perfusions. The four SGLT2 inhibitors were empagliflozin (EMPA), dapagliflozin (DAPA), ertugliflozin (ERTU) and canagliflozin (CANA). Chromatographic separation was achieved on an Uptisphere® C18 reversed phase column (50 mm × 4.6 mm × 5 µm) within 2.85 min, using a gradient elution with 10 mM ammonium formate in water (mobile phase A) and acetonitrile (mobile phase B) both with 0.1% formic acid. Analysis of ammonium adduct ions was performed on an AB SCIEX 6500+ triple quadrupole mass spectrometer using positive electrospray ionisation and scheduled multiple reaction monitoring (sMRM). The transitions were m/z 468.00 â†’ 355.20 (EMPA), m/z 426.00 â†’ 167.20 (DAPA), m/z 437.10 â†’ 206.90 (ERTU), m/z 462.00 â†’ 249.00 (CANA) and m/z 189.20 â†’ 55.90 (ANTI). The method was validated according to the European Medicines Agency guidelines and was proven to be selective, linear within a concentration range of 1-1000 µg/L (DAPA, CANA, ANTI) and 1-500 µg/L (EMPA, ERTU), accurate, precise and free of carry-over, instabilities, recovery and matrix effect issues. This newly developed method is suitable to analyse perfusion medium and placenta tissue samples collected during ex vivo human placenta perfusions. It thereby enables quantification of transport across the placental barrier of the SGLT2 inhibitors EMPA, DAPA, ERTU and CANA as well as the transfer marker ANTI.

Clinical Efficacy and Short-Term Prognosis of Butylphthalide and Sodium Chloride Injection Compared to Edaravone in the Treatment of Patients with Acute Stroke.

Background: Acute stroke is characterized by rapid progression, high mortality, and disability rates, making it a significant focus in clinical research. Brain-protective agents, such as butylphthalide and edaravone, have emerged as important therapeutic options for acute stroke. Objective: This study aimed to explore how butylphthalide and edaravone promote healing in acute stroke, drawing on relevant data, literature, clinical experience, and personal concepts. Design: The study design involves a narrative review, which comprehensively explores the pathogenesis of stroke by referencing relevant data and literature. Clinical experience and personal insights were incorporated to provide a holistic understanding. The primary focus was analyzing the mechanisms through which butylphthalide and edaravone facilitate healing in stroke patients. Results: The review revealed that butylphthalide exhibited multiple beneficial effects, including the protection of mitochondria, reduction of the inflammatory response, enhancement of microcirculation, decrease in blood-brain barrier permeability, and improving nerve cell function. On the other hand, edaravone demonstrated its efficacy by reducing oxidative stress response, inhibiting inflammatory response, and regulating the metabolism of arachidonic acid and apoptosis. These findings highlight the distinct mechanisms through which butylphthalide and edaravone contribute to the healing process in patients with stroke. Conclusions: This study highlights the positive impact of butylphthalide and edaravone on the therapeutic effect and short-term prognosis in acute stroke patients. The findings provide valuable guidance for future research and enhance our understanding of these drugs' mechanisms, offering the potential for improved stroke management and patient outcomes.

Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆9 -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.

Cannabis use during pregnancy may cause fetal toxicity driven by in utero exposure to (-)-∆9 -tetrahydrocannabinol (THC) and its psychoactive metabolite, (±)-11-hydroxy-∆9 -THC (11-OH-THC). THC concentrations in the human term fetal plasma appear to be lower than the corresponding maternal concentrations. Therefore, we investigated whether THC and its metabolites are effluxed by placental transporters using the dual cotyledon, dual perfusion, term human placenta. The perfusates contained THC alone (5 µM) or in combination (100-250 nM) with its metabolites (100 nM or 250 nM 11-OH-THC, 100 nM COOH-THC), plus a marker of P-glycoprotein (P-gp) efflux (1 or 10 µM saquinavir), and a passive diffusion marker (106 µM antipyrine). All perfusions were conducted with (n = 7) or without (n = 16) a P-gp/BCRP (breast-cancer resistance protein) inhibitor, 4 µM valspodar. The maternal-fetal and fetal-maternal unbound cotyledon clearance indexes (m-f-CLu,c,i and f-m-CLu,c,i ) were normalized for transplacental antipyrine clearance. At 5 µM THC, the m-f-CLu,c,i , 5.1 ± 2.1, was significantly lower than the f-m-CLu,c,i , 13 ± 6.1 (P = 0.004). This difference remained in the presence of valspodar or when the lower THC concentrations were perfused. In contrast, neither metabolite, 11-OH-THC/COOH-THC, had significantly different m-f-CLu,c,i vs. f-m-CLu,c,i . Therefore, THC appears to be effluxed by placental transporter(s) not inhibitable by the P-gp/BCRP antagonist, valspodar, while 11-OH-THC and COOH-THC appear to passively diffuse across the placenta. These findings plus our previously quantified human fetal liver clearance, extrapolated to in vivo, yielded a THC fetal/maternal steady-state plasma concentration ratio of 0.28 ± 0.09, comparable to that observed in vivo, 0.26 ± 0.10.

Activity and stability of bifunctional perovskite/carbon-based electrodes for the removal of antipyrine by electro-Fenton process.

Bifunctional perovskite/carbon-black(CB)/polytetrafluoroethylene(PTFE) electrodes for electro-generation and catalytic decomposition of hydrogen peroxide to oxidizing hydroxyl radicals have been fabricated. These electrodes were tested for electroFenton (EF) removal of antipyrine (ANT) as a model antipyretic and analgesic drug. The influence of the binder loading (20 and 40 wt % PTFE) and type of solvent (1,3-dipropanediol and water) was studied for the preparation of CB/PTFE electrodes. The electrode prepared with 20 wt % PTFE and water exhibited a low impedance and remarkable H2O2 electro-generation (about 1 g/L after 240 min, a production rate of ca. 6.5 mg/h·cm2). The incorporation of perovskite on CB/PTFE electrodes was also studied following two different methods: i) direct deposition on the CB/PTFE electrode surface and ii) addition in the own CB/PTFE/water paste used for the fabrication. Physicochemical and electrochemical characterization techniques were used for the electrode's characterization. The dispersion of perovskite particles in the own electrode matrix (method ii) exhibited a higher EF performance than the immobilisation onto the electrode surface (method i). EF experiments at 40 mA/cm2 and pH 7 (non-acidified conditions) showed ANT and TOC removals of 30% and 17%, respectively. The increase of current intensity up to 120 mA/cm2 achieved the complete removal of ANT and 92% of TOC mineralisation in 240 min. The bifunctional electrode also proved high stability and durability after 15 h of operation.

Development of Edaravone Ionic Liquids and Their Application for the Treatment of Cerebral Ischemia/Reperfusion Injury.

Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.

Efficient elimination of phenazone by an electro-assisted Fe3+-EDDS/PS process at neutral pH: Kinetics, mechanistic insights and toxicity evaluation.

The feasibility of the degradation of phenazone (PNZ), a common anti-inflammatory drug used for reducing pain and fever, in water at neutral pH by an electrochemically assisted Fe3+-ethylenediamine disuccinate-activated persulfate process (EC/Fe3+-EDDS/PS) was investigated. The efficient removal of PNZ at neutral pH condition was mainly attributed to the continuous activation of PS via electrochemically driven regenerated Fe2+ from a Fe3+-EDDS complex at the cathode. The influence of several critical parameters, including current density, Fe3+ concentration, EDDS to Fe3+ molar ratio, and PS dosage, on PNZ degradation was evaluated and optimized. Both hydroxyl radicals (•OH) and sulfate radicals (SO4●-) were considered major reactive species responsible for PNZ degradation. To understand the mechanistic model of action at the molecular level, the thermodynamic and kinetic behaviors of the reactions between PNZ with •OH and SO4●- were theoretically calculated using a density functional theory (DFT) method. The results revealed that radical adduct formation (RAF) is the most favorable pathway for the •OH-driven oxidation of PNZ, while single electron transfer (SET) appears to be the dominant pathway for the reaction of SO4●- with PNZ. In total, thirteen oxidation intermediates were identified, and hydroxylation, pyrazole ring opening, dephenylization, and demethylation were speculated to be the major degradation pathways. Furthermore, predicted toxicity to aquatic organisms indicated that PNZ degradation resulted in products that were less harmful. However, the developmental toxicity of PNZ and its intermediate products should be further investigated in the environment. The findings of this work demonstrate the viability of effectively removing organic contaminants in water at near-neutral pH by using EDDS chelation combined with electrochemistry in a Fe3+/persulfate system.

Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents.

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.

Design, synthesis and biological evaluation of novel antipyrine based α-aminophosphonates as anti-Alzheimer and anti-inflammatory agent.

Herein, a series of novel antipyrine based α-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for in vitro 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 4j inhibited both AChE and BuChE (IC50 = 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 4j exhibits mixed-type inhibition against both AChE and BuChE, with Ki values of 3.003 µM and 5.750 µM, respectively. Further, protein denaturation and proteinase inhibitory assays were used to test in vitro anti-inflammatory potential. It was found that compound 4o exhibited highest activity against protein denaturation (IC50 = 42.64 ± 0.19 µM) and proteinase inhibition (IC50 = 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.

Azaindole grafted titanium dioxide for the photodegradation of pharmaceuticals under solar irradiation.

The application of metal-free organic molecules grafted titanium dioxide (TiO2) as photocatalysts for the degradation of pharmaceuticals under solar light has been scarcely studied. Herein, a novel photocatalyst was synthesized anchoring a bipolar electron-donor and -acceptor molecule based on azaindole derivative (AZA4) onto TiO2 aiming to improve the photoactivity under simulated solar irradiation. The TiO2-azaindole (TiO2-AZA4) was fully characterized, confirming that AZA4 was successfully grafted onto TiO2 and improving the light absorption. The grafted TiO2 was applied in the photodegradation of acetaminophen in water, showing a significantly better photocatalytic performance compared to that of pure TiO2 under both solar and visible irradiations. AZA4 grafting leads to the TiO2 band gap narrowing and favors the charge separation, thus improving the TiO2 photoactivity. The photocatalytic performance of TiO2-AZA4 was evaluated using different conditions such as photocatalyst dose or initial pH of the solution, and the radical species involved in the process were investigated. The high activity of TiO2-AZA4 was confirmed in the photodegradation of a mixture of pharmaceuticals, namely acetaminophen, ibuprofen, and antipyrine, further demonstrating its stability and catalytic performance in a novel continuous flow test under simulated solar irradiation, thus finding a new strategy to design solar-light driven photocatalysts for the degradation of pollutants in water.

The in vitro anti-inflammatory activity of N-antipyrine-3,4-dichloromaleimide derivatives is due to an immunomodulatory effect on cytokines environment.

BACKGROUND AND AIM: Inflammation is the immune response to a harmful stimulus, and its purpose is to destroy foreign agents so that the affected site can be repair. When uncontrolled or unresolved, inflammation can lead to significant tissue damage. Many classes of compounds are used today as anti-inflammatory drugs. However, there is an ongoing demand for new, more effective molecules with higher safety margins. In this regard, the anti-inflammatory effect of six synthetic compounds of N-antipyrine-3,4-dichloromaleimide was evaluated. METHODS: RAW 264.7 cells were used to evaluate the cytotoxicity and the anti-inflammatory activity, by measuring the effect of these molecules on nitric oxide, IL-1ß, IL-6, MCP-1 (CCL2), TNF-α, INF-γ, IL-4, and IL-13 levels, as well as under NF-κB activation. RESULTS: Some of the tested compounds showed significant cytotoxicity (CC50 < 100 µM). Subsequently, the potential of nitric oxide (NO) inhibition as screening for potential anti-inflammatory action was evaluated. Three of the compounds tested showed a promising profile (1, 3, and 5). When the effect of these compounds was evaluated on the production of IL-1ß, IL-6, MCP-1 (CCL2), TNF-α, and INF-γ, only N-antipyrine-3,4-dichloromaleimide (1) and N-antipyrine-3-chloro-4-(3,4-dichloroaniline) maleimide (3) showed significant inhibition profiles. These two compounds were also able to increase the production of cytokines known for having an anti-inflammatory profile (IL-4 and IL-13) and inhibit the phosphorylation of the p-p65 NF-κB subunit significantly. CONCLUSION: In conclusion, these two compounds present a significant and unusual anti-inflammatory mechanism (increasing the production of anti-inflammatory mediators). They are therefore considered promising prototypes for the development of new anti-inflammatory drugs with immunomodulatory characteristics.

The Influence of Drugs Solubilities and Chitosan-TPP Formulation Parameters on the Mean Hydrodynamic Diameters and Drugs Entrapment Efficiencies into Chitosan-TPP Nanoparticles.

Chitosan is a natural, biocompatible polymer. The aim of this work was to study the influence of drug solubility in 2% v/v acetic acid, formulation parameters, on mean hydrodynamic (MHD) diameters and drug entrapment efficiencies (% EE) into chitosan-TPP nanoparticles (NPs). Drugs of different aqueous solubilities with nearly similar molecular weights were chosen and admixed at several concentrations in 2% acetic acid at different chitosan concentrations and at fixed chitosan to TPP concentrations/volumes ratios. The NPs were freeze-dried, and the supernatants were utilized to determine % EE. Theophylline- and antipyrine-loaded NPs showed the best short-term physical stability in terms of MHD diameters. Antipyrine-loaded NPs possessed the larger MHD diameters, while vitamin C-loaded NPs showed the smallest ones. The relationships between the ratio of drug concentration relative to their solubilities in acetic acid were almost linear for antipyrine and vitamin C-loaded NPs when plotted against and the MHD diameters of NPs, and linear for antipyrine- and theophylline-loaded NPs when plotted against % EE with antipyrine NPs possessing the highest % EE. However, vitamin C- and propylthiouracil-loaded NPs exhibited curvilinear patterns with comparatively lower % EE. The concentration of chitosan, drug solubility in dispersion medium, and the ratio of the concentration of admixed drug relative to its solubility in dispersion medium were found critical in determining % EE and MHD diameters of NPs. It was evident that drugs with extremely low or high solubilities in dispersion medium resulted in low % EE when admixed at both low and high concentrations.

Effect of Excessive Serotonin on Pharmacokinetics of Cephalexin after Oral Administration: Studies with Serotonin-Excessive Model Rats.

PURPOSE: Serotonin (5-HT) is important for gastrointestinal functions, but its role in drug absorption remains to be clarified. Therefore, the pharmacokinetics and oral absorption of cephalexin (CEX) were examined under 5-HT-excessive condition to understand the role of 5-HT. METHODS: 5-HT-excessive rats were prepared by multiple intraperitoneal dosing of 5-HT and clorgyline, an inhibitor for 5-HT metabolism, and utilized to examine the pharmacokinetics, absorption behavior and the intestinal permeability for CEX. RESULTS: Higher levels of 5-HT in brain, plasma and small intestines were recognized in 5-HT-excessive rats, where the oral bioavailability of CEX was significantly enhanced. The intestinal mucosal transport via passive diffusion of CEX was significantly increased, while its transport via PEPT1 was markedly decreased specifically in the jejunal segment, which was supported by the decrease in PEPT1 expression on brush border membrane (BBM) of intestinal epithelial cells. Since no change in antipyrine permeability and significant increase in FITC dextran-4 permeability were observed in 5-HT-excessive rats, the enhanced permeability for CEX would be attributed to the opening of tight junction, which was supported by the significant decrease in transmucosal electrical resistance. In 5-HT-excessive rats, furthermore, total body clearance of CEX tended to be larger and the decrease in PEPT2 expression on BBM in kidneys was suggested to be one of the reasons for it. CONCLUSIONS: 5-HT-excessive condition enhanced the oral bioavailability of CEX in rats, which would be attributed to the enhanced permeability across the intestinal mucosa via passive diffusion through the paracellular route even though the transport via PEPT1 was decreased.