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Objective: To formulate a ZIF-8 nano mimetic enzyme conjugated with platinum metal (ZIF-8@Pt) that can scavenge reactive oxygen species (ROS) and to explore its potential applications in the treatment of rheumatoid arthritis (RA). Methods: The ZIF-8@Pt nanozyme was created by in situ reduction. Characterization of the nanozyme was then performed and its ability to mimic enzymes was investigated. Cell experiments were conducted using RAW264.7 cells, which were divided into three groups, including the untreated group (UT), the positive control group receiving lipopolysaccharide (LPS), which was designated as the LPS group, and the ZIF-8@Pt group receiving ZIF-8@Pt and LPS treatment. The cell experiments were conducted to evaluate the anti-inflammatory properties of ZIF-8@Pt through scavenging intracellular ROS. On the other hand, a collagen-induced arthritis (CIA) model was induced in rats. Similar to the group designations in the cell experiments, the rats were assigned to three groups, including a healthy control group (the UT group), a positive control group receiving a local injection of PBS solution in the knee joint, which was referred to as the control group, and a treatment group receiving a local injection of ZIF-8@Pt solution in the knee joint, which was referred to as the ZIF-8@Pt group. General evaluation, imaging observation, assessment of inflammatory factors, and pathological evaluation were performed to assess the therapeutic efficacy of ZIF-8@Pt against RA. Results: The in vitro experiment revealed significant difference in the levels of intracellular ROS and LPS-induced M1-type macrophage polarization between the LPS group and the ZIF-8@Pt group (P<0.05). The in vivo experiment showed that significant difference in the levels of inflammatory factors, including interleukin-1ß (IL-1ß), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and arginase-1 (Arg-1) in the knee joints of the CIA rats between the LPS group and the ZIF-8@Pt group (P<0.05). Comparing the findings for the ZIF-8@Pt group and the control group, pathology assessment revealed that ZIF-8@Pt reduced local hypoxia and suppressed osteoclastic activity, neovascularization, and M1-type macrophage polarization (P<0.05). Conclusion: The ZIF-8@Pt enzyme mimetic inhibits macrophage inflammatory polarization by ROS scavenging, thereby improving inflammation in RA. Furthermore, the ZIF-8@Pt nanozyme improves the hypoxic environment and inhibits angiogenesis and bone destruction, demonstrating promising therapeutic efficacy for RA.
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Artritis Reumatoide , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratas , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Ratones , Células RAW 264.7 , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Platino (Metal)/química , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismo , Depuradores de Radicales Libres/uso terapéutico , Interleucina-1beta/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
BACKGROUND: The use of both edaravone (EDA) and hyperbaric oxygen therapy (HBOT) is increasingly prevalent in the treatment of delayed encephalopathy after carbon monoxide poisoning (DEACMP). This meta-analysis aims to evaluate the efficacy of using EDA and HBOT in combination with HBOT alone in the treatment of DEACMP. METHODS: We searched and included all randomized controlled trials (RCTs) published before November 6, 2023, from 12 Chinese and English databases and clinical trial centers in China and the United States. The main outcome indicator was the total effective rate. The secondary outcome indicators included the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), Hasegawa Dementia Scale (HDS), Fugl-Meyer Assessment (FMA), Superoxide Dismutase (SOD), and Malondialdehyde (MDA). Statistical measures utilized include risk ratios (RR), weighted mean difference (WMD), and 95 % confidence intervals (95 % CI). RESULTS: Thirty studies involving a combined total of 2075 participants were ultimately incorporated. It was observed that the combination of EDA with HBOT for the treatment of DEACMP demonstrated an improvement in the total effective rate (RR: 1.25; 95 % CI: 1.20-1.31; P < 0.01), MMSE (WMD: 3.67; 95 % CI: 2.59-4.76; P < 0.01), MoCA (WMD: 4.38; 95 % CI: 4.00-4.76; P < 0.01), BI (WMD: 10.94; 95 % CI: 5.23-16.66; P < 0.01), HDS (WMD: 6.80; 95 % CI: 4.05-9.55; P < 0.01), FMA (WMD: 8.91; 95 % CI: 7.22-10.60; P < 0.01), SOD (WMD: 18.45; 95 % CI: 16.93-19.98; P < 0.01); and a reduction in NIHSS (WMD: -4.12; 95 % CI: -4.93 to -3.30; P < 0.01) and MDA (WMD: -3.05; 95 % CI: -3.43 to -2.68; P < 0.01). CONCLUSION: Low-quality evidence suggests that for DEACMP, compared to using HBOT alone, the combined use of EDA and HBOT may be associated with better cognition and activity of daily living. In the future, conducting more meticulously designed multicenter and large-sample RCTs to substantiate our conclusions is essential.
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Intoxicación por Monóxido de Carbono , Edaravona , Oxigenoterapia Hiperbárica , Oxigenoterapia Hiperbárica/métodos , Humanos , Edaravona/uso terapéutico , Intoxicación por Monóxido de Carbono/complicaciones , Intoxicación por Monóxido de Carbono/terapia , Terapia Combinada/métodos , Encefalopatías/etiología , Encefalopatías/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Depuradores de Radicales Libres/uso terapéuticoRESUMEN
Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.
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Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Edaravona , Estrés Oxidativo , Ácido Valproico , Animales , Ácido Valproico/farmacología , Ácido Valproico/administración & dosificación , Edaravona/farmacología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Femenino , Estrés Oxidativo/efectos de los fármacos , Masculino , Administración Oral , Embarazo , Ratas , Ratas Sprague-Dawley , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/uso terapéutico , Relación Dosis-Respuesta a Droga , Conducta Estereotipada/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Interacción Social/efectos de los fármacosRESUMEN
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.
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Medios de Contraste , Angiografía Coronaria , Edaravona , Humanos , Edaravona/uso terapéutico , Edaravona/administración & dosificación , Método Doble Ciego , Medios de Contraste/efectos adversos , Masculino , Femenino , Angiografía Coronaria/efectos adversos , Persona de Mediana Edad , Anciano , Depuradores de Radicales Libres/uso terapéutico , Depuradores de Radicales Libres/administración & dosificación , Creatinina/sangre , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Antipirina/análogos & derivados , Antipirina/uso terapéutico , Resultado del TratamientoRESUMEN
Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.
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Ferroptosis , Depuradores de Radicales Libres , Accidente Cerebrovascular Isquémico , Ferroptosis/efectos de los fármacos , Animales , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/síntesis química , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Humanos , Ratones , Relación Estructura-Actividad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/síntesis química , Descubrimiento de Drogas , Masculino , Estructura Molecular , Ratones Endogámicos C57BLRESUMEN
Spinal cord injury (SCI) causes irreversible cell loss and neurological dysfunctions. Presently, there is no an effective clinical treatment for SCI. It can be the only intervention measure by relieving the symptoms of patients such as pain and fever. Free radical-induced damage is one of the validated mechanisms in the complex secondary injury following primary SCI. Hydrogen sulfide (H2S) as an antioxidant can effectively scavenge free radicals, protect neurons, and improve SCI by inhibiting the p38MAPK/mTOR/NF-κB signaling pathway. In this report, we analyze the pathological mechanism of SCI, the role of free radical-mediated the p38MAPK/mTOR/NF-κB signaling pathway in SCI, and the role of H2S in scavenging free radicals and improving SCI.
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Depuradores de Radicales Libres , Sulfuro de Hidrógeno , FN-kappa B , Transducción de Señal , Traumatismos de la Médula Espinal , Serina-Treonina Quinasas TOR , Proteínas Quinasas p38 Activadas por Mitógenos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Sulfuro de Hidrógeno/uso terapéutico , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , FN-kappa B/metabolismo , Animales , Depuradores de Radicales Libres/uso terapéutico , Depuradores de Radicales Libres/farmacología , Transducción de Señal/efectos de los fármacos , Ratas , Ratones , Radicales Libres/metabolismo , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , HumanosRESUMEN
Acute lung injury (ALI) is a life threatening disease in critically ill patients, and characterized by excessive reactive oxygen species (ROS) and inflammatory factors levels in the lung. Multiple evidences suggest that nanozyme with diversified catalytic capabilities plays a vital role in this fatal lung injury. At present, we developed a novel class of polydopamine (PDA) coated cerium dioxide (CeO2) nanozyme (Ce@P) that acts as the potent ROS scavenger for scavenging intracellular ROS and suppressing inflammatory responses against ALI. Herein, we aimed to identify that Ce@P combining with NIR irradiation could further strengthen its ROS scavenging capacity. Specifically, NIR triggered Ce@P exhibited the most potent antioxidant and anti-inflammatory behaviors in lipopolysaccharide (LPS) induced macrophages through decreasing the intracellular ROS levels, down-regulating the levels of TNF-α, IL-1ß and IL-6, up-regulating the level of antioxidant cytokine (SOD-2), inducing M2 directional polarization (CD206 up-regulation), and increasing the expression level of HSP70. Besides, we performed intravenous (IV) injection of Ce@P in LPS induced ALI rat model, and found that it significantly accumulated in the lung tissue for 6 h after injection. It was also observed that Ce@P + NIR presented the superior behaviors of decreasing lung inflammation, alleviating diffuse alveolar damage, as well as promoting lung tissue repair. All in all, it has developed the strategy of using Ce@P combining with NIR irradiation for the synergistic enhanced treatment of ALI, which can serve as a promising therapeutic strategy for the clinical treatment of ROS derived diseases as well.
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Lesión Pulmonar Aguda , Cerio , Indoles , Polímeros , Especies Reactivas de Oxígeno , Cerio/química , Cerio/farmacología , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Polímeros/química , Polímeros/farmacología , Indoles/química , Indoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratas , Ratones , Masculino , Células RAW 264.7 , Pulmón/efectos de los fármacos , Pulmón/patología , Antioxidantes/farmacología , Antioxidantes/química , Ratas Sprague-Dawley , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Rayos Infrarrojos , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/uso terapéutico , Nanopartículas/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Citocinas/metabolismoRESUMEN
With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.
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Envejecimiento , Depuradores de Radicales Libres , Nanoestructuras , Estrés Oxidativo , Especies Reactivas de Oxígeno , Especies Reactivas de Oxígeno/metabolismo , Humanos , Nanoestructuras/química , Envejecimiento/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/químicaRESUMEN
BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone. METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach. RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty. CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.
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Esclerosis Amiotrófica Lateral , Edaravona , Edaravona/uso terapéutico , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Depuradores de Radicales Libres/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Resultado del TratamientoRESUMEN
Background: Inflammatory bowel disease (IBD) is closely related to higher intracellular oxidative stress. Therefore, developing a novel method to scavenge the harmful reactive oxygen species (ROS) and alleviate colon inflammation to treat IBD is a promising strategy. Methods: CeO2@PDA-PEG (CeO2@PP) were synthesized by modifying ceria (CeO2) nanorods with polydopamine (PDA) and polyethylene glycol (PEG). The ROS scavenging ability of CeO2@PP was detected by using flow cytometry and confocal laser scanning microscope (CLSM). The anti-inflammatory ability of CeO2@PP was determined in vitro by treating lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The biocompatibility of CeO2@PP was evaluated in vivo and in vitro. Moreover, the therapeutic effects of CeO2@PP in vivo were estimated in a dextran sulfate sodium salt (DSS)-induced colitis mouse model. Results: Physicochemical property results demonstrated that PDA and PEG modification endowed CeO2 nanorods with excellent dispersibility and colloidal stability. CeO2@PP maintained superior enzyme-like activity, including superoxide dismutase (SOD) and catalase (CAT), indicating antioxidant ability. Moreover, in vitro results showed that CeO2@PP with PDA promotes LPS-induced RAW 264.7 macrophages into M2-type polarization. In addition, in vitro and in vivo results showed that CeO2@PP have great biocompatibility and biosafety. Animal experiments have shown that CeO2@PP have excellent anti-inflammatory effects against DSS-induced colitis and effectively alleviated intestinal mucosal injury. Conclusion: The nanoplatform CeO2@PP possessed excellent antioxidant and anti-inflammatory properties for scavenging ROS and modulating macrophage polarization, which is beneficial for efficient colitis therapy.
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Colitis , Depuradores de Radicales Libres , Indoles , Nanotubos , Polímeros , Especies Reactivas de Oxígeno , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Polímeros/química , Polímeros/farmacología , Polímeros/uso terapéutico , Colitis/tratamiento farmacológico , Colitis/patología , Inflamación/tratamiento farmacológico , Inflamación/patología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Polaridad Celular , Cerio , Animales , Ratones , Células RAW 264.7 , Masculino , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
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.
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Isquemia Encefálica , Líquidos Iónicos , Accidente Cerebrovascular Isquémico , Daño por Reperfusión , Ratas , Animales , Edaravona , Antipirina/farmacología , Antipirina/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Distribución Tisular , Daño por Reperfusión/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológicoRESUMEN
INTRODUCTION/AIMS: In this study we examined the relationship between urate levels at baseline and functional change measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score after edaravone treatment. METHODS: Data from the edaravone trials MCI186-16, MCI186-17, and MCI186-19 were analyzed, including the following treatment sequence groups: edaravone-edaravone (EE, n = 113); edaravone-placebo (EP, n = 45); and placebo-edaravone (PE, n = 146). Subgroups were defined as low baseline urate (below the median value of 4.8 mg/dL) and high baseline urate (≥4.8 mg/dL). The differences in ALSFRS-R total score change and urate change were evaluated using the mixed model for repeated measurement for overall population, by urate-level subgroup, and by trial. RESULTS: Compared with the PE group, the EE group showed a slower decline in ALSFRS-R score, regardless of the urate baseline level, and a slower decline in urate level in the higher baseline urate subgroup. Smaller changes in ALSFRS-R score and urate were observed in patients diagnosed with "probable, laboratory-supported ALS." There was a positive correlation between changes from baseline to cycle 12 in urate levels and ALSFRS-R score. DISCUSSION: Edaravone treatment in ALS patients diagnosed with "definite ALS" or "probable ALS" showed slowing of disease progression, regardless of baseline urate level. In addition, because edaravone treatment was associated with a slower decline in urate level in the higher baseline urate subgroup and urate-level changes were associated with changes in ALSFRS-R score, urate level, and/or change may be one indicator in predicting disease progression after edaravone administration.
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Esclerosis Amiotrófica Lateral , Humanos , Progresión de la Enfermedad , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Ácido Úrico , Ensayos Clínicos como AsuntoRESUMEN
INTRODUCTION/AIMS: Edaravone in amyotrophic lateral sclerosis (ALS) was analyzed in two phase 3 studies (MCI186-16 and MCI186-19). Those trials enrolled patients with Japanese ALS severity grades 1 and 2 (less severe ALS), but many patients progressed to grades 3 and 4 during the double-blind treatment period. The placebo patients who initiated edaravone treatment in the open-label periods provided an opportunity to assess the effects of edaravone in more severe ALS. This study also assessed the association between ALS Functional Rating Scale-Revised (ALSFRS-R) slope and biomarker changes after open-label edaravone initiation. METHODS: Change in ALSFRS-R slope in placebo patients before and after initiating edaravone treatment was assessed using the random coefficient model. The association of ALSFRS-R change and blood marker changes was explored by the least absolute shrinkage and selection operator (LASSO) method of machine learning. RESULTS: Twenty-four percent of patients (35/146) in the placebo-edaravone group showed ≥25% slowing of decline in the ALSFRS-R slope. Within the 25% slower-decline group, 60% (21/35) had Japanese ALS severity grades 3 or 4 at the start of edaravone treatment. The LASSO model identified serum urate as associated with the percentage change in ALSFRS-R slope. The rate of decrease in urate was smaller in the 25% slower-decline group than in the non-25% slower-decline group during edaravone treatment. DISCUSSION: This post hoc analysis indicated that ALS patients, including those with advanced ALS severity grades, may receive benefit in the group of patients whose urate levels are stable during the course of the edaravone treatment.
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Esclerosis Amiotrófica Lateral , Edaravona , Ácido Úrico , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/fisiopatología , Progresión de la Enfermedad , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Ácido Úrico/sangre , Método Doble Ciego , Ensayos Clínicos Fase III como AsuntoRESUMEN
The Food and Drug Administration has approved an oral suspension form of edaravone (Radicava ORS) for the treatment of amyotrophic lateral sclerosis.Edaravone should be taken on an empty stomach in the morning either by mouth or through a feeding tube. Feeding tubes should be flushed before and after drug administration.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Humanos , SuspensionesRESUMEN
INTRODUCTION: Ischemic stroke is a major cause of death and disability. Despite major advances in reperfusion therapies, most patients don´t benefit from these treatments as the time window for such interventions is limited. Therefore, other treatment options are desirable. Edaravone has been demonstrated in previous studies to reduce neurologic deficits in stroke patients. OBJECTIVE: To test the hypothesis that edaravone reduces functional dependence in ischemic stroke patients. MATERIAL AND METHODS: Systematic review and meta-analysis of randomized controlled trials and observational studies comparing edaravone to placebo in adult patients with ischemic stroke. The efficacy outcomes of interest were good and excellent functional outcomes at 90 days, defined as modified Rankin Scale (mRS) scores of 0-2 and 0-1 respectively. The safety outcomes of interest were intracranial hemorrhage and mortality. RESULTS: 19 studies were included. Edaravone treatment was associated with improved chances of 90-day good (OR=1.31, 95% CI 1.06-1.67) and excellent (OR=1.26, 95% CI 1.04-1.54) functional outcomes. Mortality was also lower in edaravone treated patients (OR=0.50, 95% CI 0.45-0.56). There were no differences in terms of intracranial hemorrhage. Most studies were observational and performed in Asian populations, especially Japan. Heterogeneity was high for all outcomes but reduced when analysis was restricted to randomized trials. CONCLUSION: Edaravone is a promising treatment for ischemic stroke patients, with a more favorable time window. However, more randomized studies including patient populations outside Asia are required to confirm this hypothesis.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Adulto , Antipirina/uso terapéutico , Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Humanos , Hemorragias Intracraneales/inducido químicamente , Accidente Cerebrovascular/complicaciones , Resultado del TratamientoRESUMEN
Edaravone has been widely used in the treatment of acute ischemic stroke. However, there has been no oral preparation of edaravone in the clinic. In this study, we assessed the effect and possible mechanisms of oral edaravone on the middle cerebral artery occlusion (MCAO) model in rats. Highly bioavailable form of novel edaravone formulation developed using self-nanomicellizing solid dispersion strategy which showed up to 16.1-fold improved oral bioavailability was considered oral edaravone. The male rats (n = 84) were randomly divided into sham; model; oral edaravone in low dose (10 mg/kg), medium dose (20 mg/kg), and high dose (30 mg/kg); and edaravone by intraperitoneal administration group (IP group, 10 mg/kg). Rats were treated with different drugs 5 h after the operation, twice a day for 7 days. The behavioral data were dose-dependently improved by oral edaravone and sensorimotor functions of the high dose group were similar to those of the edaravone by IP route group. Furthermore, oral edaravone significantly reduced cerebral infarction area and downregulated the levels of caspase-3, GFAP, Iba1, 3-NT, and 4-HNE, whereas upregulated those of Vamp-2 and Map-2 in a dose-dependent manner. Especially effect of the high dose on these molecules was equal to that of edaravone by IP administration. Taken together, our data suggest that the improvement of sensorimotor deficits by oral edaravone in high doses after ischemia is similar to that in edaravone by IP administration. Neuroprotection of oral edaravone is at least partial by minimizing oxidative stress, the overactivation of glial cells, and the levels of the apoptosis-associated proteins, and alleviating synaptic damage in a dose-dependent manner.
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Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Animales , Antipirina/uso terapéutico , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Masculino , Neuroprotección , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , RatasRESUMEN
Recent discoveries have implicated the potential of Cannabidiol (CBD) in the prevention of Alzheimer's disease (AD). However, how CBD affects such neurodegenerative disorders remains unclear. Herein, Caenorhabditis elegans (C. elegans) was used as the model organism to elucidate the mechanism by which CBD ameliorates AD in vivo. CBD was found to alleviate the progression of Aß-induced AD but not tau protein-induced AD or α-syn-induced Parkinson's disease. CBD inhibited the aggregation of Aß in C. elegans. However, CBD failed to prevent the formation of ß-sheet aggregation in vitro. Moreover, CBD was found to scavenge reactive oxygen species (ROS) in vivo without inducing the overexpression of antioxidative genes. In addition, CBD treatment enhanced the worm resistance to oxidative stress, which was independent of the classical transcription factors DAF-16 and SKN-1. These results supported that the in vivo antioxidative activity of CBD was most likely due to its intrinsic antioxidative property. Furthermore, the phenolic hydroxyl groups of CBD were found to be critical for scavenging ROS in vitro and in vivo, alleviating the aggregation of Aß in vivo, and ameliorating Aß-associated neurotoxicity. These studies show that CBD protects against AD in C. elegans via the ROS scavenging activity of its phenolic hydroxyl groups, which provides insight for further structure-activity relationship studies of CBD as an AD therapeutic.
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Enfermedad de Alzheimer/tratamiento farmacológico , Cannabidiol/farmacología , Depuradores de Radicales Libres/farmacología , Animales , Caenorhabditis elegans/efectos de los fármacos , Cannabidiol/química , Cannabidiol/uso terapéutico , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
Hybrid compounds containing structural fragments of the Rho kinase inhibitor fasudil and the NRF2 inducers caffeic and ferulic acids were designed with the aid of docking and molecular mechanics studies. Following the synthesis of the compounds using a peptide-coupling methodology, they were characterized for their ROCK2 inhibition, radical scavenging, effects on cell viability (MTT assay), and NRF2 induction (luciferase assay). One of the compounds (1d) was selected in view of its good multitarget profile and good tolerability. It was able to induce the NRF2 signature, promoting the expression of the antioxidant response enzymes HO-1 and NQO1, via a KEAP1-dependent mechanism. Analysis of mRNA and protein levels of the NRF2 pathway showed that 1d induced the NRF2 signature in control and SOD1-ALS lymphoblasts but not in sALS, where it was already increased in the basal state. These results show the therapeutic potential of this compound, especially for ALS patients with a SOD1 mutation.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Ácidos Cumáricos/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/síntesis química , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/toxicidad , Anciano , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ácidos Cumáricos/síntesis química , Ácidos Cumáricos/toxicidad , Femenino , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/toxicidad , Células HEK293 , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/agonistas , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Pulmonary delivery of anti-inflammatory siRNA presents a promising approach for localized therapy of acute lung injury (ALI), while polycationic vectors can be easily trapped by the negatively charged airway mucin glycoproteins and arbitrarily internalized by epithelial cells with nontargetability for immunological clearance. Herein, we report a material, the dopamine (DA)-grafted hyaluronic acid (HA-DA), coating on an anti-TNF-α vector to address these limitations. HA-DA was simply synthesized and facilely coated on poly(ß-amino ester) (BP)-based siRNA vectors via electrostatic attraction. The resulting HA-DA/BP/siRNA displayed significantly enhanced mucus penetration, attributable to the charge screen effect of HA-DA and the bioadhesive nature of the grafting DA. After transmucosal delivery, the nanosystem could target diseased macrophages via CD44-mediated internalization and rapidly escape from endo/lysosomes through the proton sponge effect, resulting in effective TNF-α regulation. Meanwhile, DA modification endowed the coating material with robust antioxidative capability to scavenge a broad spectrum of reactive oxygen/nitrogen species (RONS), which protected the lung tissue from oxidative damage and synergized with anti-TNF-α to inhibit a cytokine storm. As a result, a remarkable amelioration of ALI was achieved in a lipopolysaccharide (LPS)-stimulated mice model. This study provides a multifunctional coating material to facilitate pulmonary drug delivery for the treatment of lung diseases.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Dopamina/uso terapéutico , Portadores de Fármacos/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Ácido Hialurónico/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , Animales , Dopamina/análogos & derivados , Dopamina/síntesis química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Liberación de Fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Humanos , Ácido Hialurónico/análogos & derivados , Ácido Hialurónico/síntesis química , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Moco/metabolismo , Células 3T3 NIH , Nanopartículas/química , Nanopartículas/uso terapéutico , Polímeros/síntesis química , Polímeros/química , Células RAW 264.7 , ARN Interferente Pequeño/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1-6 µM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases.