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1.
Mol Pharm ; 21(7): 3566-3576, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38899552

RESUMO

Oxidative stress is pivotal in retinal disease progression, causing dysfunction in various retinal components. An effective antioxidant, such as probucol (PB), is vital to counteract oxidative stress and emerges as a potential candidate for treating retinal degeneration. However, the challenges associated with delivering lipophilic drugs such as PB to the posterior segment of the eye, specifically targeting photoreceptor cells, necessitate innovative solutions. This study uses formulation-based spray dry encapsulation technology to develop polymer-based PB-lithocholic acid (LCA) nanoparticles and assesses their efficacy in the 661W photoreceptor-like cell line. Incorporating LCA enhances nanoparticles' biological efficacy without compromising PB stability. In vitro studies demonstrate that PB-LCA nanoparticles prevent reactive oxygen species (ROS)-induced oxidative stress by improving cellular viability through the nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. These findings propose PB-LCA nanoparticles as a promising therapeutic strategy for oxidative stress-induced retinopathies.


Assuntos
Antioxidantes , Ácido Litocólico , Nanopartículas , Estresse Oxidativo , Polímeros , Probucol , Espécies Reativas de Oxigênio , Probucol/farmacologia , Probucol/administração & dosagem , Probucol/química , Estresse Oxidativo/efeitos dos fármacos , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Ácido Litocólico/química , Ácido Litocólico/farmacologia , Animais , Polímeros/química , Linhagem Celular , Antioxidantes/farmacologia , Antioxidantes/química , Fator 2 Relacionado a NF-E2/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Heme Oxigenase-1/metabolismo , Humanos
2.
J Control Release ; 371: 555-569, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38844179

RESUMO

The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.


Assuntos
Felodipino , Simulação de Dinâmica Molecular , Solubilidade , Cães , Animais , Felodipino/administração & dosagem , Felodipino/farmacocinética , Felodipino/química , Probucol/administração & dosagem , Probucol/farmacocinética , Probucol/química , Carvedilol/administração & dosagem , Carvedilol/farmacocinética , Carvedilol/química , Lipídeos/química , Líquidos Corporais/química , Líquidos Corporais/metabolismo , Ácidos e Sais Biliares/química , Masculino , Secreções Intestinais/química
3.
Biol Pharm Bull ; 47(6): 1154-1162, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38880623

RESUMO

Probucol is a hyperlipidemic drug with antioxidant properties. It has been reported to prevent mitochondrial dysfunction, reduce oxidative stress, and suppress neurotoxicity in neurodegenerative disease models, including Parkinson's disease models. However, the molecular mechanisms underlying the neuroprotective effects of probucol have been not examined yet. Thus, in this study, we investigated whether probucol can alleviate the effects of a mitochondrial complex I inhibitor, rotenone, on a human neuroblastoma cell line (SH-SY5Y). We evaluated the cell viability and cytotoxicity and apoptosis rates of SH-SY5Y cells treated with rotenone and probucol or edaravone, a known free-radical scavenger. Subsequently, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels in the cells were evaluated to determine the effects of probucol on mitochondrial function. We found that rotenone caused cytotoxicity, cell apoptosis, and mitochondrial dysfunction, enhanced ROS generation, and impaired MMP. However, probucol could inhibit this rotenone-induced decrease in cell viability, MMP loss, intracellular ROS generation, and apoptosis. These results suggest that probucol exerts neuroprotective effects via MMP stabilization and the inhibition of ROS generation. Additionally, this effect of probucol was equal to or greater than and more persistent than that of edaravone. Thus, we believe probucol may be a promising drug for the treatment of neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases.


Assuntos
Apoptose , Sobrevivência Celular , Potencial da Membrana Mitocondrial , Fármacos Neuroprotetores , Probucol , Espécies Reativas de Oxigênio , Rotenona , Probucol/farmacologia , Rotenona/toxicidade , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia
4.
Ther Deliv ; 15(4): 237-252, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38469721

RESUMO

Aim: Excessive free radicals contribute to oxidative stress and mitochondrial dysfunction in sensorineural hearing loss (SNHL). The antioxidant probucol holds promise, but its limited bioavailability and inner ear barriers hinder effective SNHL treatment. Methodology: We addressed this by developing probucol-loaded nanoparticles with polymers and lithocholic acid and tested them on House Ear Institute-Organ of Corti cells. Results: Probucol-based nanoparticles effectively reduced oxidative stress-induced apoptosis, enhanced cellular viability, improved probucol uptake and promoted mitochondrial function. Additionally, they demonstrated the capacity to reduce reactive oxygen species through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Conclusion: This innovative nanoparticle system holds the potential to prevent oxidative stress-related hearing impairment, providing an effective solution for SNHL.


Hearing loss affects millions of people worldwide, and its prevalence is expected to double by 2050. Current treatments have limitations, pushing researchers to explore new options. Oxidative stress is a key player in hearing loss and is known to damage inner ear hair cells. While antioxidants, known for their protective effects, hold promise, delivering them effectively to the inner ear is challenging. Scientists have been testing nanoparticles loaded with the antioxidant probucol to fight hearing loss. In this study, these particles protected inner ear cells in cell studies, offering potential hope for preventing hearing problems. This research is a significant step toward finding better treatments for hearing loss.


Assuntos
Orelha Interna , Perda Auditiva Neurossensorial , Nanopartículas , Humanos , Probucol/farmacologia , Estresse Oxidativo , Antioxidantes/farmacologia , Perda Auditiva Neurossensorial/terapia
5.
Aging (Albany NY) ; 16(5): 4363-4377, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38441564

RESUMO

BACKGROUND: Neuronal injury in chronic cerebral hypoperfusion (CCH) is the main pathogenic factor of vascular dementia (VD). Clinically, there isn't a drug specifically for VD; instead, the majority of medications used to treat Alzheimer's disease (AD) are also used to treat VD. Based on the proven anti-inflammatory and antioxidant effects of Probucol, we hypothesized that it may have therapeutic effects on VD, but more research is required to determine its exact mechanism of action. METHODS: In vivo experiment: We used SD rats and most commonly used bilateral carotid artery occlusion (2-VO) in VD for modeling. After successful modeling, SD rats were given Probucol 3.5 mg/kg/day for 8 weeks to evaluate the therapeutic effect. In vitro experiment: BV-2 microglia of rats were cultured and divided into Control group and Probucol group. Each group was treated with hypoxia-hypoglycemia, hypoxia-hypoglycemia hydrogen peroxide and hypoxia-hypoglycemia hydrogen peroxide Syk inhibitor respectively. RESULTS: The results of immunofluorescence and Western blot showed that Probucol could significantly improve the cognitive impairment induced by CCH, and the neuronal damage was also attenuated. On the one hand, the underlying mechanism of Probucol was to reduce oxidative stress and cell apoptosis of hippocampal neurons by inhibiting the expression of phosphorylated spleen tyrosine kinase (P-Syk); On the other hand, it exerted a protective effect by reducing NLRP3-dependent cell pyroptosis and inhibiting neuroinflammation induced by microglia activation. CONCLUSION: Probucol could reduce oxidative stress and cell apoptosis by inhibiting the Syk/ROS signaling pathway, thereby improving CCH-induced cognitive impairment in vitro and in vivo.


Assuntos
Isquemia Encefálica , Demência Vascular , Hipoglicemia , Ratos , Animais , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Demência Vascular/metabolismo , Probucol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Piroptose , Peróxido de Hidrogênio/farmacologia , Isquemia Encefálica/metabolismo , Hipocampo/metabolismo , Hipóxia/metabolismo
6.
Chem Pharm Bull (Tokyo) ; 72(2): 190-199, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38369345

RESUMO

A co-amorphous model drug was prepared by the spray-drying (SD) of probucol (PC) and atorvastatin calcium trihydrate salt (ATO) as low water solubility and co-former components, respectively. The physicochemical properties of the prepared samples were characterized by powder X-ray diffraction (PXRD) analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and dissolution tests. Stability tests were also conducted under a stress environment of 40 °C and 75% relative humidity. The results of PXRD measurements and thermal analysis suggested that PC and ATO form a co-amorphous system by SD. Thermal analysis also indicated an endothermic peak that followed an exotherm in amorphous PC and a physical mixture (PM) of amorphous PC and ATO; however, no endothermic peak was detected in the co-amorphous system. The dissolution profiles for PC in the co-amorphous sample composed of PC and ATO were improved compared to those for raw PC crystals or the PM. Stability tests indicated that the co-amorphous material formed by PC and ATO can be stored for 35 d without crystallization, whereas amorphous PC became crystallized within a day. Therefore, co-amorphization of PC and ATO prepared by SD is considered to be a useful method to improve the solubility of PC in water.


Assuntos
Probucol , Água , Atorvastatina , Probucol/química , Estabilidade de Medicamentos , Cristalografia por Raios X , Difração de Raios X , Água/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Varredura Diferencial de Calorimetria
7.
Transl Neurodegener ; 13(1): 6, 2024 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-38247000

RESUMO

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Probucol/uso terapêutico , Barreira Hematoencefálica
8.
Acta Biomater ; 175: 262-278, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38141933

RESUMO

Hepatic fibrosis is a common pathological process in chronic liver diseases, characterized by excessive reactive oxygen species (ROS), activated hepatic stellate cells (HSCs), and massive synthesis of extracellular matrix (ECM), which are important factors in the development of liver cirrhosis, liver failure, and liver cancer. During the development of hepatic fibrosis, ECM collagen produced by activated HSCs significantly hinders medication delivery to targeted cells and reduces the efficiency of pharmacological therapy. In this study, we designed a multifunctional hyaluronic acid polymeric nanoparticle (HA@PRB/COL NPs) based on autophagy inhibitor probucol (PRB) and collagenase type I (COL) modification, which could enhance ECM degradation and accurately target HSCs through specificity binding CD44 receptor in hepatic fibrosis therapy. Upon encountering excessive collagen I-deposition formed barrier, HA@PRB/COL NPs performed the nanodrill-like function to effectively degrade pericellular collagen I, leading to greater ECM penetration and prominent HSCs internalization capacity of delivered PRB. In mouse hepatic fibrosis model, HA@PRB/COL NPs were efficiently delivered to HSCs through binding CD44 receptor to achieve efficient accumulation in fibrotic liver. Further, we showed that HA@PRB/COL NPs executed the optimal anti-fibrotic activity by inhibiting autophagy and activation of HSCs. In conclusion, our novel dual-functional co-delivery system with degrading fibrotic ECM collagen and targeting activated HSCs exhibits great potentials in the treatment of hepatic fibrosis in clinic. STATEMENT OF SIGNIFICANCE: The excess release of extracellular matrix (ECM) such as collagen in hepatic fibrosis hinders medication delivery and decreases the efficiency of pharmacological drugs. We aimed to develop a nano-delivery carrier system with protein hydrolyzed surfaces and further encapsulated an autophagy inhibitor (PRB) to enhance fibrosis-related ECM degradation-penetration and hepatic stellate cells (HSCs) targeting in hepatic fibrosis niche (HA@PRB/COL NPs). The COL of HA@PRB/COL NPs successfully worked as a scavenger to promote the digestion of the ECM collagen I barrier for deeper penetration into fibroid liver tissue. It also accurately targeted HSCs through specifically binding to the CD44 receptor and subsequently released PRB to inhibit autolysosome and ROS generation, thus preventing HSCs activation. Our HA@PRB/COL NPs system provided a promising therapeutic strategy for hepatic fibrosis in a clinic setting.


Assuntos
Células Estreladas do Fígado , Nanopartículas , Camundongos , Animais , Células Estreladas do Fígado/metabolismo , Probucol/farmacologia , Probucol/metabolismo , Probucol/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Cirrose Hepática/metabolismo , Fígado/patologia , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Colagenases/metabolismo , Modelos Animais de Doenças
9.
Int Ophthalmol ; 43(12): 4595-4604, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37688651

RESUMO

PURPOSE: This study investigated the protective effect of probucol on Müller cells exposed to high glucose conditions and examined potential mechanisms of action. METHODS: Primary human retinal Müller cells were incubated with high glucose (HG, 35 mM) in the present or absence of different concentrations of probucol for 24 h. Cell viability was determined using the CCK-8 method. Mitochondrial membrane potential (MMP) was measured using JC-1 staining and cell cycle by flow cytometry. The expression of nuclear factor E2-related factor 2 (Nrf2), glutamate-cysteine ligase catalytic subunit, and p62 was quantified using quantitative polymerase chain reaction and western blot. RESULTS: We found that HG inhibited cell proliferation, arrested cell cycle, and increased MMP in human Müller cells. Probucol activated the Nrf2/p62 pathway and upregulated the anti-apoptotic protein, Bcl2, and attenuated HG-mediated damage in Müller cells. CONCLUSIONS: Our results suggest that probucol may protect Müller cells from HG-induced damage through enhancing the Nrf2/p62 signaling pathway.


Assuntos
Células Ependimogliais , Probucol , Transdução de Sinais , Humanos , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Fator 2 Relacionado a NF-E2 , Probucol/farmacologia
10.
Toxicol Ind Health ; 39(11): 638-650, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37705340

RESUMO

Manganese (Mn) is an abundant element used for commercial purposes and is essential for the proper function of biological systems. Chronic exposure to high Mn concentrations causes Manganism, a Parkinson's-like neurological disorder. The pathophysiological mechanism of Manganism remains unknown; however, it involves mitochondrial dysfunction and oxidative stress. This study assessed the neuroprotective effect of probucol, a hypolipidemic agent with anti-inflammatory and antioxidant properties, on cell viability and oxidative stress in slices of the cerebral cortex and striatum from adult male Wistar rats. Brain structure slices were kept separately and incubated with manganese chloride (MnCl2) and probucol to evaluate the cell viability and oxidative parameters. Probucol prevented Mn toxicity in the cerebral cortex and striatum, as evidenced by the preservation of cell viability observed with probucol (10 and 30 µM) pre-treatment, as well as the prevention of mitochondrial complex I inhibition in the striatum (30 µM). These findings support the protective antioxidant action of probucol, attributed to its ability to prevent cell death and mitigate Mn-induced mitochondrial dysfunction.


Assuntos
Antioxidantes , Manganês , Ratos , Animais , Masculino , Manganês/toxicidade , Ratos Wistar , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Probucol/farmacologia , Probucol/metabolismo , Neuroproteção , Estresse Oxidativo , Encéfalo
11.
Nanomedicine (Lond) ; 18(12): 923-940, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37529927

RESUMO

Background: Sensorineural hearing loss has been associated with oxidative stress. However, an antioxidant that passes effectively through the ear remains elusive. Method: Probucol (PB)-based nanoparticles were formed using a spray-drying encapsulation technique, characterized and tested in vitro. Results: Uniform, spherical nanoparticles were produced. The addition of lithocholic acid to PB formulations did not affect drug content or production yield, but it did modify capsule size, surface tension, electrokinetic stability and drug release. Cell viability, bioenergetics and inflammatory profiles were improved when auditory cells were exposed to PB-based nanoparticles, which showed antioxidant properties (p < 0.05). Conclusion: PB-based nanoparticles can potentially protect the auditory cell line from oxidative stress and could be used in future in vivo studies as a potential new therapeutic agent for sensorineural hearing loss.


Oxidative stress is an imbalance of cellular processes in which the production of free radicals outweighs the cellular defense mechanism. The association of oxidative stress with the pathophysiology of sensorineural hearing loss (SHL) is well established. SHL development is associated with chronic damage in the structure of the inner ear or auditory nerve. Therefore, potent antioxidants such as probucol could be one way to prevent or treat SHL. However, due to its isolated position, SHL is challenging to treat, imposing a desperate need for refining existing therapeutic methods; one way to do this is by optimizing the formulation using nanoparticles. We aimed to design a novel, stable formulation of PB using polymers and excipients to develop nanoparticles and examine the efficiency of these formulations on the HEI-OC1 stress cell line. We found that the prepared nanoparticle is robust and stable and protects HEI-OC1 from cellular toxicity and oxidative stress. It could be a novel therapeutic agent to treat or prevent SHL.


Assuntos
Perda Auditiva Neurossensorial , Nanopartículas , Humanos , Probucol/farmacologia , Antioxidantes/farmacologia , Ácidos e Sais Biliares/farmacologia , Estresse Oxidativo , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/prevenção & controle , Audição , Preparações Farmacêuticas
12.
Drug Dev Res ; 84(7): 1496-1512, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37571798

RESUMO

A reliable and efficient in vitro model is needed to screen drugs for Alzheimer's disease (AD), as many drugs are currently in the developmental stage. To address this, we developed an in vitro model using amniotic membrane-derived mesenchymal stem cells (AM-MSCs) to screen novel drugs for AD. We differentiated AM-MSCs into neurons and degenerated them using beta amyloid1-42 (Aß). We then tested AD drugs, which are commercially available such as donepezil, rivastigmine, memantine, citicoline, and two novel drugs, that is, probucol, an anti-hyperlipidaemic drug, and NMJ-2, a cinnamic acid analogue for their potential to protect the cells against neurodegeneration. We used gene expression and immunofluorescence staining to assess the neuroprotective ability of these drugs. We also measured the ability of these drugs to reduce lactate dehydrogenase, reactive oxygen species, and nitric oxide levels, as well as their ability to stabilize the mitochondrial membrane potential and increase acetylcholine (ACh) levels. The AD drugs and novel drugs reduced cytotoxicity and oxidative stress, stabilized mitochondrial membrane potential, and restored ACh levels. Furthermore, they reduced BACE1 expression, with a concomitant increase in the expression of cholinergic markers. This AM-MSCs-based AD-like model has immense potential to be an accurate human model and an alternative to animal models for testing a large number of lead compounds in a short time. Our results also suggest that the novel drugs probucol and NMJ-2 may protect against Aß-induced neurodegeneration.


Assuntos
Doença de Alzheimer , Células-Tronco Mesenquimais , Animais , Humanos , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide , Probucol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ácido Aspártico Endopeptidases , Células-Tronco Mesenquimais/metabolismo
13.
Cochrane Database Syst Rev ; 8: CD013573, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37565307

RESUMO

BACKGROUND: Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease. It is caused by atherosclerosis; that is, the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem. OBJECTIVES: To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes. SEARCH METHODS: We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, two other databases, and three trials registers from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs), irrespective of publication status and language, comparing a pharmacological intervention to placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third author resolved disagreements when necessary. We assessed the evidence certainty for key outcomes using GRADE. MAIN RESULTS: We included 34 RCTs with 11,571 participants. Data for meta-analysis were available from only 22 studies with 6887 participants. The mean follow-up period was 2.5 years. None of the 34 included studies assessed neurological impairment and quality of life. Antiplatelet agent (acetylsalicylic acid) versus placebo Acetylsalicylic acid (1 study, 372 participants) may result in little to no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47 to 2.47), stroke-related mortality (RR 1.40, 95% CI 0.54 to 3.59), progression of carotid stenosis (RR 1.16, 95% CI 0.79 to 1.71), and adverse events (RR 0.81, 95% CI 0.41 to 1.59), compared to placebo (all low-certainty evidence). The effect of acetylsalicylic acid on major bleeding is very uncertain (RR 0.98, 95% CI 0.06 to 15.53; very low-certainty evidence). The study did not measure neurological impairment or quality of life. Antihypertensive agents (metoprolol and chlorthalidone) versus placebo The antihypertensive agent, metoprolol, may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95% CI 0.02 to1.16; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95% CI 0.17 to 1.94; 1 study, 793 participants) compared to placebo (both low-certainty evidence). However, chlorthalidone may slow the progression of carotid stenosis (RR 0.45, 95% CI 0.23 to 0.91; 1 study, 129 participants; low-certainty evidence) compared to placebo. Neither study measured neurological impairment, major bleeding, adverse events, or quality of life. Anticoagulant agent (warfarin) versus placebo The evidence is very uncertain about the effects of warfarin (1 study, 919 participants) on major bleeding (RR 1.19, 95% CI 0.97 to 1.46; very low-certainty evidence), but it may reduce adverse events (RR 0.89, 95% CI 0.81 to 0.99; low-certainty evidence) compared to placebo. The study did not measure neurological impairment, ipsilateral major or disabling stroke, stroke-related mortality, progression of carotid stenosis, or quality of life. Lipid-lowering agents (atorvastatin, fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin) versus placebo or no treatment Lipid-lowering agents may result in little to no difference in ipsilateral major or disabling stroke (atorvastatin, lovastatin, pravastatin, and rosuvastatin; RR 0.36, 95% CI 0.09 to 1.53; 5 studies, 2235 participants) stroke-related mortality (lovastatin and pravastatin; RR 0.25, 95% CI 0.03 to 2.29; 2 studies, 1366 participants), and adverse events (fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin; RR 0.76, 95% CI 0.53 to1.10; 7 studies, 3726 participants) compared to placebo or no treatment (all low-certainty evidence). The studies did not measure neurological impairment, major bleeding, progression of carotid stenosis, or quality of life. AUTHORS' CONCLUSIONS: Although there is no high-certainty evidence to support pharmacological intervention, this does not mean that pharmacological treatments are ineffective in preventing ischaemic cerebral events, morbidity, and mortality. High-quality RCTs are needed to better inform the best medical treatment that may reduce the burden of carotid stenosis. In the interim, clinicians will have to use other sources of information.


Assuntos
Aterosclerose , Estenose das Carótidas , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Varfarina , Estenose das Carótidas/complicações , Estenose das Carótidas/tratamento farmacológico , Metoprolol , Atorvastatina , Clortalidona , Fluvastatina , Pravastatina , Probucol , Rosuvastatina Cálcica , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/etiologia , Hemorragia , Aspirina/efeitos adversos , AVC Isquêmico/complicações , Aterosclerose/complicações
14.
ACS Chem Neurosci ; 14(16): 2857-2867, 2023 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-37499207

RESUMO

Oxidative glutamate toxicity is regarded as one of the injurious mechanisms associated with ischemic stroke, which represents a major health problem and requires improved pharmacological treatments. We designed and synthesized two new probucol analogues [2,6-di-tert-butyl-4-selenocyanatophenol (C1) and 4,4'-diselanediylbis (2,6-di-tert-butylphenol) (C2)] and investigated their effects against glutamate-induced neuronal oxidative toxicity in vitro in cultured HT22 cells, compared with their parental compound (probucol). In addition, C2, which exhibited the lowest toxicity, was investigated in an in vivo rodent model of ischemic stroke. Glutamate caused concentration- and time-dependent cytotoxicity in HT22 neuronal cells, which was preceded by increased levels of oxidants and depletion of the antioxidant glutathione. The analogues (C1 and C2), but not probucol, significantly decreased the levels of oxidants (including mitochondrial superoxide anion and lipid reactive oxygen species (ROS)) and protected against glutamate-induced cytotoxicity. In the in vivo model of ischemic stroke, which was based on central injections of the vasoconstrictor agent endothelin-1 (800 pmol/site), C2 (20 or 50 mg/kg/day, intraperitoneally, for 4 consecutive days after stroke) displayed significant beneficial effects against ischemic injury in vivo, improving rats' motor-related behavioral skills and decreasing stroke-related striatal gliosis. This is the first study to design, synthesize, and present a probucol analogue (C2) with in vivo beneficial effects against ischemic stroke. This novel compound, which was able to mitigate glutamate-induced oxidative toxicity in vitro, represents a promising neuroprotective drug.


Assuntos
AVC Isquêmico , Fármacos Neuroprotetores , Ratos , Animais , Probucol/farmacologia , Neuroproteção , Ácido Glutâmico/toxicidade , Roedores , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Oxidantes/farmacologia
15.
Stomatologiia (Mosk) ; 102(3): 16-22, 2023.
Artigo em Russo | MEDLINE | ID: mdl-37341076

RESUMO

THE AIM OF THE STUDY: Was to evaluate the effectiveness and duration without a relapse period in patients with HPV-associated pathology of the oral mucosa and in combination with lesions of the anogenital region during combined therapy, including destruction and Panavir. MATERIALS AND METHODS: The study included 60 women diagnosed with «Viral warts. Genital condyloma of the oral cavity. 15 patients were also diagnosed with «Anogenital warts¼. The patients were divided into three groups of 20 women (15 with HPV-associated pathology of the oral cavity; 5 with combined HPV-associated pathology of the oral cavity and anogenital area). In the first group, the drug Panavir was administered intravenously. Between the third and fourth injections radiosurgical destruction of condylomas was carried out followed by Panavir gel applications until complete epithelialization of the destruction zone and further use of Panavir-inlight spray in the oral cavity and Panavir-intim spray in the anogenital area for 4 weeks. In the second group, the destruction of genital warts was carried out only with local treatment identical to that in the first group. In the third group after destruction applications of an oil solution of vitamin A were added to the oral mucosa 3-4 times a day until complete epithelization of the lesion, an alcohol solution of fucorcin and panthenol cream were applied externally in the anogenital area. RESULTS: According to clinical and laboratory monitoring after 3, 6 and 12 months, HPV elimination in the first group was achieved in 70, 85 and 90% of cases; in the second group in 50, 75 and 80%; in the third group in 30, 40 and 40%, respectively; within 12 months, relapses in the first group were registered in 10% of cases; in the second and third groups in 20% and 45% of cases, respectively. CONCLUSION: Combined therapy including destruction and complex use of different dosage forms of the drug Panavir showed higher clinical efficacy and allowed to achieve a reduction in the rate of condyloma relapses.


Assuntos
Infecções por Papillomavirus , Radiocirurgia , Verrugas , Humanos , Feminino , Mucosa Bucal , Infecções por Papillomavirus/tratamento farmacológico , Probucol
16.
Br J Pharmacol ; 180(20): 2605-2622, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37263748

RESUMO

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol-lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI. EXPERIMENTAL APPROACH: Male mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule-associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol-mediated effects was examined in primary cultures of cortical neurons. KEY RESULTS: Probucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post-injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA-12. CONCLUSIONS AND IMPLICATIONS: Probucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post-injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.


Assuntos
Lesões Encefálicas Traumáticas , Receptor trkB , Camundongos , Animais , Masculino , Receptor trkB/metabolismo , Probucol/farmacologia , Probucol/uso terapêutico , Tropomiosina , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Regeneração Nervosa
17.
NPJ Syst Biol Appl ; 9(1): 18, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-37221264

RESUMO

Type 2 Diabetes (T2D) is often managed with metformin as the drug of choice. While it is effective overall, many patients progress to exhibit complications. Strategic drug combinations to tackle this problem would be useful. We constructed a genome-wide protein-protein interaction network capturing a global perspective of perturbations in diabetes by integrating T2D subjects' transcriptomic data. We computed a 'frequently perturbed subnetwork' in T2D that captures common perturbations across tissue types and mapped the possible effects of Metformin onto it. We then identified a set of remaining T2D perturbations and potential drug targets among them, related to oxidative stress and hypercholesterolemia. We then identified Probucol as the potential co-drug for adjunct therapy with Metformin and evaluated the efficacy of the combination in a rat model of diabetes. We find Metformin-Probucol at 5:0.5 mg/kg effective in restoring near-normal serum glucose, lipid, and cholesterol levels.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Animais , Ratos , Probucol , Perfilação da Expressão Gênica , Estresse Oxidativo
18.
BMJ Open ; 13(5): e068915, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37253501

RESUMO

OBJECTIVE: This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database. DESIGN: An approach of Chinese national database analysis was employed to screen clinical trials involving non-statin antihyperlipidaemic drugs from 1989 to 2019. SETTING: The database was provided by the China National Medical Products Administration Information Centre. PARTICIPANTS: In total, 117 clinical studies with 8800 patients were selected from 2650 clinical trials of the Anti-hyperlipidemic Drug Database. INTERVENTIONS: The non-statin antihyperlipidaemic drugs were divided into three groups: (1) fibrates (fenofibrate, gemfibrozil, bezafibrate, etofylline clofibrate); (2) nicotinic acid and derivatives (niacin, acipimox) and (3) others (probucol, cholestyramine). RESULTS: The results of this study show that first, gastrointestinal symptoms were the most common reactions (6.975%), which account for approximately 50% of the reported cases with ADRs. Second, cholestyramine (16.418%) and gemfibrozil (13.158%) were the most common gastrointestinal side effect-causing non-statin antihyperlipidaemic drugs, which account for one-third of the population. Third, niacin (7.879%) and gemfibrozil (5.000%) were the most likely cause of liver disease symptoms. Finally, niacin (10.909%) and acipimox (18.847%) were the major non-statin antihyperlipidaemic drugs with skin symptoms. CONCLUSION: This study revealed that gastrointestinal symptoms were the most common ADRs of fibrates, probucol and cholestyramine in the Chinese population. For nicotinic acid and derivatives, the ADRs of skin symptoms were the most common in China.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Niacina , Humanos , Niacina/efeitos adversos , Genfibrozila/uso terapêutico , Probucol/uso terapêutico , Resina de Colestiramina/uso terapêutico , Hipolipemiantes/efeitos adversos , Ácidos Fíbricos/efeitos adversos
19.
Int J Pharm ; 640: 122959, 2023 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-37086931

RESUMO

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low Tg (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs.


Assuntos
Nanopartículas , Probucol , Composição de Medicamentos/métodos , Solubilidade , Polímeros/química , Povidona/química , Tensoativos/química , Água/química
20.
PLoS Biol ; 21(3): e3001977, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36862640

RESUMO

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.


Assuntos
Gotículas Lipídicas , Probucol , Animais , Probucol/farmacologia , Inteligência Artificial , Mitofagia , Peixe-Zebra
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