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PloS One 2015Restenosis after percutaneous coronary intervention (PCI) is a remained clinical problem which limits long-term success of PCI. Although there was recognition that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Restenosis after percutaneous coronary intervention (PCI) is a remained clinical problem which limits long-term success of PCI. Although there was recognition that probucol in treating restenosis after percutaneous transluminal coronary angioplasty, the efficacy of probucol on restenosis after stent-implantation is controversial. So this meta-analysis was conducted to investigate the association between probucol and late restenosis.
METHODS
Articles were assessed by four trained investigators, with divergences resolved by consensus. PubMed, EMBASE, ScienceDirect and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocated to treatment and a comparison of probucol-treated patients and control patients (not treated with lipid-lowering drug) undergoing PCI.
RESULTS
Fifteen studies with 859 subjects were analyzed. Major outcome, binary angiographic restenosis defined as >50% stenosis upon follow-up angiography, was significantly decreased with probucol treatment (RR = 0.59 [0.43, 0.80] among vessels, P = 0.0007; and RR = 0.52 [0.40, 0.68] among patients, P<0.00001). Probucol also increased the minimal luminal diameter (SMD = 0.45 [0.30, 0.61], P<0.00001) and decreased late loss upon follow-up after 6 months (SMD = -0.41 [-0.60, -0.22], P<0.0001). Moreover, there was a significantly lower incidence of major adverse cardiac events (MACE) in the probucol group than control group (RR = 0.69 [0.51, 0.93], P = 0.01).
CONCLUSION
Probucol is more than a lipid-lowering drug. It is also effective in reducing the risk of restenosis and incidence of MACE after PCI.
Topics: Anticholesteremic Agents; Cardiovascular Agents; Combined Modality Therapy; Coronary Disease; Humans; Percutaneous Coronary Intervention; Probucol; Treatment Outcome
PubMed: 25898372
DOI: 10.1371/journal.pone.0124021 -
Chonnam Medical Journal Sep 2017Delayed arterial healing at culprit sites after drug-eluting stent (DES) placement for acute myocardial infarction (AMI) is associated with increased risk of late stent... (Review)
Review
Delayed arterial healing at culprit sites after drug-eluting stent (DES) placement for acute myocardial infarction (AMI) is associated with increased risk of late stent thrombosis. The Korea Acute Myocardial Infarction Registry was established in commemoration of the 50 anniversary of Korea Circulation Society. Between November 2005 and December 2016, more than 62,000 patients were registered from 50 primary percutaneous coronary intervention (PCI) centers in Korea. DES in AMI may be safe and effective, however, there is concern about increased stent thrombosis after DES implantation in AMI patients, requiring longer-term dual anti-platelet therapy to reduce the risk of late stent thrombosis. Device innovation is needed to overcome issues such as stent thrombosis and restenosis by using new coating materials with biocompatible polymers, different coating methods using non-polymer techniques, bioabsorbable stents and pro-healing stents. In this review article, we describe the current usage of DES in AMI in Korea and introduce novel DES uses in development for patients with AMI. We have developed many types of DES in our research laboratory. Abciximab-coated stents inhibited platelet thrombi and restenosis. Furthermore, anti-oxidants (carvedilol, probucol and alpha-lipoic acid) were used for stent coating. Currently we are developing novel DESs using polymer-free and natural binding techniques, peptide coating stents, gene-and-drug delivery, bioabsorbable stents using 3D printing, endothelial progenitor cell capturing stents to promote reendothelialization and reduce stent thrombosis. New DESs in development may be safe and effective in preventing late stent thrombosis and restenosis in patients with AMI.
PubMed: 29026706
DOI: 10.4068/cmj.2017.53.3.187 -
International Journal of Molecular... May 2023CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research... (Review)
Review
CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being translated into practical and effective applications in the clinic.
Topics: Animals; Humans; Autoimmune Diseases; Autoimmunity; Autophagy; Lectins, C-Type; Monosaccharide Transport Proteins; Risk Factors
PubMed: 37175930
DOI: 10.3390/ijms24098224 -
Cardiovascular Diabetology Sep 2016Improved outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention remain an unmet clinical need. We assessed the long-term efficacy and... (Comparative Study)
Comparative Study Randomized Controlled Trial
Five-year clinical outcomes in patients with diabetes mellitus treated with polymer-free sirolimus- and probucol-eluting stents versus second-generation zotarolimus-eluting stents: a subgroup analysis of a randomized controlled trial.
BACKGROUND
Improved outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention remain an unmet clinical need. We assessed the long-term efficacy and safety of novel polymer-free sirolimus- and probucol-eluting stent in diabetic patients enrolled in intracoronary stenting and angiographic results: test efficacy of sirolimus- and probucol-eluting versus zotarolimus-eluting stents 5 trial.
METHODS
In a pre-specified subgroup analysis, outcomes of diabetic patients treated with a sirolimus- and probucol-eluting stent or a second-generation zotarolimus-eluting stent were compared. The primary endpoint was a device-oriented composite outcome comprising cardiac death, target vessel-related myocardial infarction (MI), or target lesion revascularization (TLR) at 5-year follow-up. Event-free survival was assessed using the Kaplan-Meier method. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated from univariate Cox proportional hazards models.
RESULTS
A total of 870 patients with diabetes mellitus were treated with either a sirolimus- and probucol-eluting stent (n = 575) or a second-generation zotarolimus-eluting stent (n = 295). At 5 years, the rate of device-oriented composite endpoint was comparable between the sirolimus- and probucol-eluting stent and the second-generation zotarolimus-eluting stent (32.9 versus 33.4 %, HR 0.88, 95 % CI 0.76-1.26). No significant differences were observed between the sirolimus- and probucol-eluting stent and the second-generation zotarolimus-eluting stent groups in the incidence of cardiac death (15.6 versus 16.7 % HR 0.92, 95 % CI 0.63-1.32), target-vessel MI (4.6 versus 6.6 %, HR 0.73, 95 % CI 0.40-1.34), and TLR (18.6 versus 18.8 %, HR 1.00, 95 % CI, 0.72-1.41). The rate of definite or probable stent thrombosis was low and similar in both groups (2.5 versus 2.6 %, HR 1.02, 95 % CI, 0.41-2.52).
CONCLUSIONS
In patients with diabetes the long-term efficacy and safety of a polymer-free sirolimus- and probucol-eluting stent were comparable to a second-generation durable polymer zotarolimus-eluting stent. Trial registration ClinicalTrials.gov NCT00598533. Registered 10 January 2008.
Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Diabetic Angiopathies; Disease-Free Survival; Drug-Eluting Stents; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Probucol; Proportional Hazards Models; Prosthesis Design; Retreatment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome
PubMed: 27586678
DOI: 10.1186/s12933-016-0429-y -
International Immunopharmacology Mar 2023Osteoporosis is a systemic and endocrine bone disorder distinguished by declined bone mineral density, compromised bone strength, and destruction of trabecular...
Osteoporosis is a systemic and endocrine bone disorder distinguished by declined bone mineral density, compromised bone strength, and destruction of trabecular structure. The abnormally excessive osteoclastogenesis and bone erosion play imperative roles in the progression of osteoporosis. However, treatment of osteoporosis is far from satisfactory due to poor adherence to existing medications and adverse reactions, there is an urgent to develop novel therapies for osteoporosis. Probucol, a synthetic compound with two characteristic phenolic rings, owns anti-inflammatory and antioxidant properties. Accumulating evidence have indicated that intracellular reactive oxygen species (ROS) is closely related to osteoclastogenesis. Hence, we investigated the potential effects of probucol on osteoclastogenesis in vivo and in vitro. In this study, TRAP staining and bone slice resorption assay showed that probucol suppressed RANKL-induced osteoclast formation and function. The mRNA and protein levels of osteoclastogenesis marker genes were reduced by probucol in a concentration-dependent manner. Besides, probucol suppressed osteoclast differentiation by inhibiting ROS production, MAPKs and NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of probucol on osteoclast formation and function. Consistent with the above findings, in vivo experiments demonstrated that probucol visibly alleviated bone loss caused by estrogen deficiency. In brief, these results showed the potential of anti-oxidant compound probucol in the treatment of osteoporosis, highlighting Nrf2 as a promising target in osteoclast-related disease.
Topics: Female; Humans; Antioxidants; Bone Resorption; Cell Differentiation; NF-E2-Related Factor 2; NF-kappa B; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; Probucol; RANK Ligand; Reactive Oxygen Species
PubMed: 36758295
DOI: 10.1016/j.intimp.2023.109820 -
Cardiovascular Therapeutics Aug 2013Polymer-free sirolimus- and probucol-eluting stents (Real Dual drug-eluting stents [DES]) is as effective as first-generation DES in treating coronary artery stenosis.... (Comparative Study)
Comparative Study Randomized Controlled Trial
Real polymer-free sirolimus- and probucol-eluting versus biodegradable polymer sirolimus-eluting stents for obstructive coronary artery disease: DKPLUS-Wave 1, a multicenter, randomized, prospective trial.
BACKGROUND
Polymer-free sirolimus- and probucol-eluting stents (Real Dual drug-eluting stents [DES]) is as effective as first-generation DES in treating coronary artery stenosis. It is unknown whether sirolimus-eluting stents containing biodegradable polymer (Excel) would be superior to real Dual DES. This study aimed to investigate the difference in target vessel revascularization (TVR) at 12 months in patients with coronary artery disease treated by the implantation of Dual DES or Excel stents.
METHODS
Three hundred and forty-six patients with de novo coronary artery disease were recruited from six centers in China and randomly assigned to either the Dual DES or the Excel group. The primary endpoint was the occurrence of TVR at 12 months. The secondary endpoint was angiographic in-stent restenosis and late lumen loss at 13 months. Stent thrombosis (ST) served as the safety endpoint. Dual anti-platelet therapy (DAPT) was prescribed for 6 months.
RESULTS
Clinical follow-up for 12 months and repeat angiography at 13 months were available in 100% and >90% of patients, respectively. The ISR and in-stent late loss were significantly different between the Excel (3.1%, 0.09 ± 0.11 mm) and the Dual DES (19.5%, 0.36 ± 0.32 mm, P < 0.001, P < 0.001, respectively) groups. The TVR (3.5%) in the Excel group was significantly less than in the Dual DES group (13.9%, P = 0.001). The ST rate beyond 12 months in the Dual DES group was 0%, and this was 1.2% in the Excel group (P = 0.499).
CONCLUSIONS
The Excel stent was statistically superior to the Dual DES in terms of restenosis, late loss, and TVR for long lesions.
Topics: Absorbable Implants; Aged; Cardiovascular Agents; Chi-Square Distribution; China; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Disease-Free Survival; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Polymers; Probucol; Prospective Studies; Prosthesis Design; Sirolimus; Time Factors; Treatment Outcome
PubMed: 22954234
DOI: 10.1111/j.1755-5922.2012.00319.x -
Annals of Palliative Medicine Mar 2021Symmetrical dimethylarginine (ADMA) endogenously inhibits nitric oxide synthase (NOS) and strongly indicates oxidant stress, whose formation primarily derived from type...
BACKGROUND
Symmetrical dimethylarginine (ADMA) endogenously inhibits nitric oxide synthase (NOS) and strongly indicates oxidant stress, whose formation primarily derived from type 1 protein arginine N-methyltransferase (PRMT1) and whose metabolism was governed by type 1 dimethylarginine dimethylaminohydrolase (DDAH1). This study aimed to evaluate participation of the PRMT1-ADMA-DDAH1 metabolism axis in the kidneys of type 2 diabetes model rats and human subjects, and the effect of probucol on this axis and renal function.
METHODS
A total of 30 rats were randomly assigned to a normal group (NC, n=10), diabetic group (DM, n=10), and a diabetics under probucol treatment group (PM, n=10). Throughout 8 weeks of probucol treatment, plasma NOS, the malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and catalase (CAT) activity were evaluated by chemical colorimetric approach. ADMA concentration was evaluated with an enzyme-linked immunosorbent assay (ELISA) and analysis of expression of PRMT1 and DDAH1 in kidneys with reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and western blotting were performed.
RESULTS
The expression of DDAH1 in the kidney, and the plasma NOS, NO, SOD, and CAT activities in diabetic group were lower, while MDA and the expression of PRMT1 and ADMA were higher in contrast to the control group. In diabetics rats receiving probucol, the expressions of DDAH1 and ADMA were downregulated, whereas that of PRMT1 was upregulated. Probucol inhibited the indexes of oxidative stress and improved the kidney function in both diabetic rats and humans.
CONCLUSIONS
We found that the expression of the PRMT1-ADMA-DDAH1 axis was altered in the kidneys of diabetic rats. Moreover, results indicated that probucol therapy regulates expression at both ends of this axis, which may preserve renal function by reducing oxidant stress. Therefore, probucol may partially restore expression of the PRMT1-ADMA-DDAH1 axis in diabetic kidneys, immigrate oxidant stress, and enhance renal function.
Topics: Amidohydrolases; Animals; Arginine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Humans; Nitric Oxide; Probucol; Protein-Arginine N-Methyltransferases; Rats; Repressor Proteins
PubMed: 33849119
DOI: 10.21037/apm-21-417 -
Molecular Vision 2009Vitamin E is an important natural antioxidant, and its most common and biologically active form is alpha-tocopherol. In addition to this, specific regulatory effects of... (Review)
Review
Vitamin E is an important natural antioxidant, and its most common and biologically active form is alpha-tocopherol. In addition to this, specific regulatory effects of vitamin E have been revealing. The body exerts a certain effort to regulate its tissue levels with specific tocopherol transport proteins and membrane receptors. Antiproliferative and protein kinase C-suppressing effects of alpha-tocopherol have been previously demonstrated, which have not been mimicked by beta-tocopherol or probucol. Protein kinase C promises to be an important area of interest in the means of glaucoma and cataractogenesis. It has been shown in different models that retinal vascular dysfunction due to hyperglycemia could be prevented by alpha-tocopherol via the diachylglycerol-protein kinase C pathway. Glutamate transporter activity has been shown to be modulated by protein kinase C. This pathway is also important in intraocular pressure-lowering effects of prostaglandin and its analogs in glaucoma therapy. Filtran surgery became another possible area of usage of alpha-tocopherol since its antiproliferative effect has been demonstrated in human Tenon's capsule fibroblasts. Prevention of posterior capsule opacification is another area for future studies. It is evident that when correct and safe modulation is the objective, alpha-tocopherol merits a concern beyond its mere antioxidant properties.
Topics: Animals; Antioxidants; Humans; Protein Kinase C; Signal Transduction; alpha-Tocopherol
PubMed: 19390643
DOI: No ID Found -
Asian Journal of Andrology 2020Autophagy and apoptosis have been regarded as important processes in the development of diabetic erectile dysfunction (DMED). Probucol is considered to have...
Autophagy and apoptosis have been regarded as important processes in the development of diabetic erectile dysfunction (DMED). Probucol is considered to have anti-apoptotic effects, but its relationship with autophagy has not been reported. The aim of this study was to investigate the effects and mechanisms of probucol on erectile function. Thirty Sprague-Dawley (SD) male rats (12 weeks old) were fasted for 12 h. Twenty SD rats were injected with a single intraperitoneal injection of 60 mg kg streptozotocin (STZ). Ten rats were given vehicle only and used as a sham group. After 72 h, 20 STZ-treated rats with random blood glucose concentrations consistently greater than 16.7 mmol l were used as successfully established diabetic rats. The diabetic rats were divided randomly into two groups and treated with a daily gavage of probucol at a dose of 0 or 500 mg kg for 12 weeks. After treatment, the intracavernous pressure (ICP) was used to measure erectile function upon electrical stimulation of the cavernous nerve. After euthanasia, penile tissue was examined using immunohistochemistry and Western blot to assess the protein levels of B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), microtubule-associated protein light chain 3-II (LC3-II), mammalian target of rapamycin (mTOR), and sequestosome 1 (P62). Caspase-3 activity was measured to determine apoptosis using a caspase-3 assay kit. After 12 weeks of treatment, the erectile function of the probucol group was significantly better than that of the DM group (P < 0.05). Bax and LC3-II protein expression and caspase-3 activity were significantly lower in the probucol group than those in the DM group (all P < 0.05), while Bcl-2, mTOR, and P62 protein expression levels were significantly higher than those in the DM group (all P < 0.05). We demonstrated that probucol inhibited apoptosis and autophagy in STZ-induced diabetic rats.
Topics: Animals; Antioxidants; Apoptosis; Autophagy; Caspase 3; Diabetes Mellitus, Experimental; Erectile Dysfunction; Male; Microtubule-Associated Proteins; Penile Erection; Penis; Probucol; Proto-Oncogene Proteins c-bcl-2; Rats; Sequestosome-1 Protein; TOR Serine-Threonine Kinases; bcl-2-Associated X Protein
PubMed: 31464204
DOI: 10.4103/aja.aja_89_19 -
European Journal of Pharmaceutics and... Jul 2022Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro...
Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
Topics: Administration, Oral; Atazanavir Sulfate; Hydrogen-Ion Concentration; Intestinal Absorption; Pharmaceutical Preparations; Probucol; Solubility
PubMed: 35605926
DOI: 10.1016/j.ejpb.2022.05.010