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Drugs Oct 1991A free radical is any species capable of independent existence that contains one or more unpaired electrons. Free radical reactions have been implicated in the pathology... (Review)
Review
A free radical is any species capable of independent existence that contains one or more unpaired electrons. Free radical reactions have been implicated in the pathology of more than 50 human diseases. Radicals and other reactive oxygen species are formed constantly in the human body, both by deliberate synthesis (e.g. by activated phagocytes) and by chemical side-reactions. They are removed by enzymic and nonenzymic antioxidant defence systems. Oxidative stress, occurring when antioxidant defences are inadequate, can damage lipids, proteins, carbohydrates and DNA. A few clinical conditions are caused by oxidative stress, but more often the stress results from the disease. Sometimes it then makes a significant contribution to the disease pathology, and sometimes it does not. Several antioxidants are available for therapeutic use. They include molecules naturally present in the body [superoxide dismutase (SOD), alpha-tocopherol, glutathione and its precursors, ascorbic acid, adenosine, lactoferrin and carotenoids] as well as synthetic antioxidants [such as thiols, ebselen (PZ51), xanthine oxidase inhibitors, inhibitors of phagocyte function, iron ion chelators and probucol]. The therapeutic efficacy of SOD, alpha-tocopherol and ascorbic acid in the treatment of human disease is generally unimpressive to date although dietary deficiencies of the last two molecules should certainly be avoided. Xanthine oxidase inhibitors may be of limited relevance as antioxidants for human use. Exciting preliminary results with probucol (antiatherosclerosis), ebselen (anti-inflammatory), and iron ion chelators (in thalassaemia, leukaemia, malaria, stroke, traumatic brain injury and haemorrhagic shock) need to be confirmed by controlled clinical trials. Clinical testing of N-acetylcysteine in HIV-1-positive subjects may also be merited. A few drugs already in clinical use may have some antioxidant properties, but this ability is not widespread and drug-derived radicals may occasionally cause significant damage.
Topics: Animals; Antioxidants; Free Radicals; Humans
PubMed: 1723362
DOI: 10.2165/00003495-199142040-00003 -
BMJ Open May 2023This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database.
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.
Topics: Humans; Niacin; Gemfibrozil; Probucol; Cholestyramine Resin; Hypolipidemic Agents; Fibric Acids; Drug-Related Side Effects and Adverse Reactions
PubMed: 37253501
DOI: 10.1136/bmjopen-2022-068915 -
Journal of Atherosclerosis and... Feb 2021Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD).
METHODS
PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients.
RESULTS
The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport.
CONCLUSION
Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).
Topics: Aged; Anticholesteremic Agents; Antioxidants; Biological Transport; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cholesterol, HDL; Cholesterol, LDL; Drug Monitoring; Female; Humans; Hyperlipidemias; Male; Probucol; Secondary Prevention; Stroke; Treatment Outcome
PubMed: 32336695
DOI: 10.5551/jat.55327 -
Neurobiology of Aging Sep 2014The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility... (Review)
Review
The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1-42 concentrations without significant modifications of lipid hydroperoxide levels.
Topics: Alleles; Alzheimer Disease; Amyloid beta-Peptides; Anticholesteremic Agents; Apolipoprotein E4; Apolipoproteins E; Brain; Female; Genetic Association Studies; Homeostasis; Humans; Lipid Metabolism; Male; Peptide Fragments; Phosphorylation; Probucol; tau Proteins
PubMed: 24973118
DOI: 10.1016/j.neurobiolaging.2014.03.037 -
PLoS Biology Mar 2023Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic...
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.
Topics: Animals; Probucol; Lipid Droplets; Artificial Intelligence; Mitophagy; Zebrafish
PubMed: 36862640
DOI: 10.1371/journal.pbio.3001977 -
British Journal of Pharmacology Jan 2020Abdominal aortic aneurysm (AAA) is a degenerative disease with irreversible and progressive dilation of the artery. But there are few options for efficacious treatment...
BACKGROUND AND PURPOSE
Abdominal aortic aneurysm (AAA) is a degenerative disease with irreversible and progressive dilation of the artery. But there are few options for efficacious treatment except for traditional surgery. Probucol has been widely applied to treat hyperlipidaemia and atherosclerosis in clinic, but whether it can protect against AAA remains unknown. In this study, the protective effects of probucol against AAA and its related mechanisms were explored.
EXPERIMENTAL APPROACH
The model of AAA was induced in mice by periaortic application of elastase (40 min) to the abdominal aorta. Probucol at different doses was administered by daily gavage, starting on the same day as AAA was induced, for 14 days. In vitro, cultures of rat vascular smooth muscle cells (VSMCs) were stimulated with TNF-α. Haem oxygenase (HO)-1 siRNA and HO-1 plasmid were used to regulate the expression or activity of HO-1 in the VSMCs and to clarify the effects of HO-1.
KEY RESULTS
Probucol dose-dependently prevented the development of AAA, reflected by decreased incidence of AAA, diameter of aortic dilation, elastin degradation, and infiltration of inflammatory cells. Probucol also protected VSMCs from oxidative injury and enhanced elastin biosynthesis. This anti-inflammatory effects of probucol on VSMCs were significantly decreased when HO-1 was inhibited by siRNA.
CONCLUSION AND IMPLICATIONS
Probucol protected against AAA through inhibiting the degradation of elastin induced by inflammation and oxidation and by facilitating the biosynthesis of elastin. HO-1 played a crucial role in the anti-inflammatory effects of probucol in VSMCs.
Topics: Animals; Anticholesteremic Agents; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Cells, Cultured; Heme Oxygenase-1; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Pancreatic Elastase; Probucol; Rats; Rats, Sprague-Dawley
PubMed: 31478560
DOI: 10.1111/bph.14857 -
PloS One 2017Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage....
Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol-a commercially available drug for treating hypercholesterolemia-has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O2 for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2'-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.
Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Female; Hyperoxia; Lung Injury; Mice; Mice, Inbred C57BL; NADP; NF-kappa B; Oxidative Stress; Probucol; Signal Transduction
PubMed: 28384256
DOI: 10.1371/journal.pone.0175129 -
BMJ Open Feb 2022Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aβ) in the peripheral circulation is...
INTRODUCTION
Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer's disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer's study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD.
METHODS AND ANALYSIS
The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target sample is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer's Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention.
ETHICS AND DISSEMINATION
The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063; Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events.
TRIAL REGISTRATION NUMBER
Australian New Zealand Clinical Trials Registry (ACTRN12621000726853).
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Australia; Clinical Trials, Phase II as Topic; Cognition; Double-Blind Method; Humans; Mice; Probucol; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 35190446
DOI: 10.1136/bmjopen-2021-058826 -
Cordyceps sinensis prevents contrast-induced nephropathy in diabetic rats: its underlying mechanism.International Journal of Clinical and... 2018Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). This study investigated the renal protective effect of cordyceps sinensis (CS)...
Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). This study investigated the renal protective effect of cordyceps sinensis (CS) in a diabetic rat model of CIN and the mechanism of its effect. Sixty SD rats were randomly divided into 4 groups, the control group, model group, probucol group, and CS group. We used a diabetic rat model of Iodixanol-induced CIN. Serum creatinine (Scr), blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL) levels were measured to evaluate renal function. Total antioxidative ability (T-AOC), superoxide dismutase (SOD), and malonaldehyde (MDA) levels were assessed to discuss the effect of probucol and CS on oxidative stress. The pathologic changes in the kidney were observed by hematoxylin and eosin (HE) staining and periodic acid-Schiff (PAS) staining. Apoptosis was assessed by transmission electron microscopy and TUNEL staining. Caspase-3, Bax, Bcl2 and phospho-p38 mitogen-activated protein kinase (MAPK) protein expressions were assessed by Western blotting. The model group of rats showed significantly elevated levels of BUN, Scr, urinary KIM-1, NGAL, and parameters of oxidative stress (P<0.05). Both the probucol and CS groups demonstrated significantly lower Scr, BUN, and urinary KIM-1, NGAL levels compared to the model group (P<0.05), with no significant difference between these two groups. The probucol group and the CS group had significantly lower MDA and higher T-AOC, SOD than the model group after modeling (P<0.05). Caspase-3, Bax activation were effectively repressed while Bcl-2 expression was increased by probucol and CS pretreatment. Mechanistically, probucol and CS decreased the expression of JNK protein and increased the expression of ERK protein. CS can effectively reduce kidney damage caused by contrast medium. The underlying mechanism may be that CS accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress and influencing MAPK signal pathways.
PubMed: 31949644
DOI: No ID Found -
Diabetes & Vascular Disease Research Jan 2019An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2... (Comparative Study)
Comparative Study
An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2 diabetes. Our previous studies demonstrated that selected anti-inflammatory/anti-oxidative agents can preserve the integrity of blood-brain barrier and prevent neuroinflammation in mouse models of dysfunctional blood-brain barrier. Therefore, we have tested whether the previously proven blood-brain barrier protective agent, probucol, can prevent blood-brain barrier breakdown and cognitive decline in a dietary-induced murine model of diabetic insulin resistance. After 6-month chronic ingestion of a diet high in fat and fructose, the mice became insulin resistant. The high-fat and high-fructose-fed mice showed significant cognitive decline assessed by Morris water maze, concomitant with significant elevations in cortical and hippocampal glial acidic fibrillary protein and Fluoro Jade-C staining, indicating heightened neuroinflammation and neurodegeneration, respectively. The integrity of blood-brain barrier in high-fat and high-fructose-fed mice was substantially compromised, and this showed a significant association with heightened neurodegeneration. Co-provision of probucol with high-fat and high-fructose diet completely prevented the cognitive decline and blood-brain barrier dysfunction. Similarly, metformin was able to restore the cognitive function in high-fat and high-fructose-fed mice, while its blood-brain barrier protective effects were modest. These data suggest that probucol may prevent cognitive decline induced by insulin resistance by preserving the integrity of blood-brain barrier, whereas metformin's neuroprotective effects may be mediated through a separate pathway.
Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Blood-Brain Barrier; Cerebral Cortex; Cognition; Cognition Disorders; Cytokines; Diabetes Mellitus, Experimental; Diet, High-Fat; Fructose; Glial Fibrillary Acidic Protein; Hippocampus; Hypoglycemic Agents; Inflammation Mediators; Insulin Resistance; Male; Maze Learning; Metformin; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Probucol
PubMed: 30156119
DOI: 10.1177/1479164118795274