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1.
Int Heart J ; 59(6): 1416-1424, 2018 Nov 28.
Article in English | MEDLINE | ID: mdl-30305582

ABSTRACT

The phenotype shifting of vascular smooth muscle cells (VSMCs) was indicated to play a role during the initial stage of atherosclerotic plaque formation by facilitating extracellular matrix deposition. This study was aimed at investigating the involvement of the apoptosis signal-regulating kinase 1 (ASK1) /mitogen-activated protein kinase (MAPK) kinases (MKKs) /p38 MAPK pathway in the advanced glycation end product (AGE) -induced fibrotic response of VSMCs. The effect of the novel ASK1 inhibitor AGI-1067 was also studied.Cultured human coronary smooth muscle cells (HCSMCs) were exposed to AGEs. AGI-1067 and siRNAs silencing mkk3, mkk6, and p38 mapk were used to treat the cells. The activation of MKK3, MKK6, and p38 MAPK was assessed by immunoblotting. Fibrotic response was assessed by the fluorescence immunohistochemistry staining of collagen I and collagen VIII. Activation of immunoprecipitation determined the association of ASK1 and its inhibitor thioredoxin. A kinase assay was used to determine ASK1 activity.AGE incubation significantly activated ASK1, MKK3, and MKK6, which led to activation of p38 MAPK, resulting in upregulated fibrotic response in HCSMCs. However, siRNAs knocking down mkk3, mkk6, and p38 mapk impaired this fibrotic response. AGI-1067 administration not only dramatically inhibited the activation of ASK1/MKKs/p38 MAPK but also suppressed the expression of the downstream proteins, including transforming growth factor-ß1, connective tissue growth factor, collagen I, and collagen VIII in HCSMCs exposed to AGEs.The ASK1/MKKs/p38 MAPK pathway was activated by AGEs, leading to the fibrotic response in VSMCs. AGI-1067 reversed this process by maintaining the inactive state of ASK1.


Subject(s)
Coronary Vessels/drug effects , Glycation End Products, Advanced/metabolism , MAP Kinase Kinase 3/metabolism , MAP Kinase Kinase 6/metabolism , MAP Kinase Kinase Kinase 5/antagonists & inhibitors , Probucol/analogs & derivatives , p38 Mitogen-Activated Protein Kinases/metabolism , Blotting, Western , Cardiovascular Agents/pharmacology , Cells, Cultured , Coronary Vessels/metabolism , Coronary Vessels/pathology , Fibrosis , Humans , Immunoprecipitation , MAP Kinase Kinase Kinase 5/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Probucol/pharmacology , Signal Transduction
2.
Mol Neurobiol ; 54(2): 1513-1530, 2017 03.
Article in English | MEDLINE | ID: mdl-26852411

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder characterized by non-motor and motor disabilities. This study investigated whether succinobucol (SUC) could mitigate nigrostriatal injury caused by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. Moreover, the effects of SUC against MPTP-induced behavioral impairments and neurochemical changes were also evaluated. The quantification of tyrosine hydroxylase-positive (TH+) cells was also performed in primary mesencephalic cultures to evaluate the effects of SUC against 1-methyl-4-phenylpyridinium (MPP+) toxicity in vitro. C57BL/6 mice were treated with SUC (10 mg/kg/day, intragastric (i.g.)) for 30 days, and thereafter, animals received MPTP infusion (1 mg/nostril) and SUC treatment continued for additional 15 days. MPTP-infused animals displayed significant non-motor symptoms including olfactory and short-term memory deficits evaluated in the olfactory discrimination, social recognition, and water maze tasks. These behavioral impairments were accompanied by inhibition of mitochondrial NADH dehydrogenase activity (complex I), as well as significant decrease of TH and dopamine transporter (DAT) immunoreactivity in the substantia nigra pars compacta and striatum. Although SUC treatment did not rescue NADH dehydrogenase activity inhibition, it was able to blunt MPTP-induced behavioral impairments and prevented the decrease in TH and DAT immunoreactivities in substantia nigra (SN) and striatum. SUC also suppressed striatal astroglial activation and increased interleukin-6 levels in MPTP-intoxicated mice. Furthermore, SUC significantly prevented the loss of TH+ neurons induced by MPP+ in primary mesencephalic cultures. These results provide new evidence that SUC treatment counteracts early non-motor symptoms and neurodegeneration/neuroinflammation in the nigrostriatal pathway induced by intranasal MPTP administration in mice by modulating events downstream to the mitochondrial NADH dehydrogenase inhibition.


Subject(s)
Anticholesteremic Agents/therapeutic use , Corpus Striatum/drug effects , Parkinsonian Disorders/drug therapy , Probucol/analogs & derivatives , Substantia Nigra/drug effects , Animals , Anticholesteremic Agents/pharmacology , Corpus Striatum/metabolism , Corpus Striatum/pathology , Female , Male , Memory Disorders/drug therapy , Memory Disorders/metabolism , Memory Disorders/pathology , Mice , Mice, Inbred C57BL , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Pregnancy , Probucol/pharmacology , Probucol/therapeutic use , Random Allocation , Rats , Rats, Sprague-Dawley , Smell/drug effects , Smell/physiology , Substantia Nigra/metabolism , Substantia Nigra/pathology
3.
Platelets ; 28(3): 295-300, 2017 May.
Article in English | MEDLINE | ID: mdl-27681689

ABSTRACT

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10-5-10-4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.


Subject(s)
Antioxidants/pharmacology , Blood Platelets/drug effects , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Probucol/analogs & derivatives , Adenosine Diphosphate/pharmacology , Animals , Blood Platelets/cytology , Blood Pressure/drug effects , Blood Pressure/physiology , Collagen/antagonists & inhibitors , Collagen/pharmacology , Heart Rate/drug effects , Heart Rate/physiology , Iliac Artery/drug effects , Iliac Artery/physiology , Male , Myography , Platelet Function Tests , Platelet-Rich Plasma/cytology , Probucol/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Tissue Culture Techniques , Xanthine/antagonists & inhibitors , Xanthine/pharmacology , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/pharmacology
4.
Behav Brain Res ; 305: 30-6, 2016 May 15.
Article in English | MEDLINE | ID: mdl-26921691

ABSTRACT

Bradykinesia and hypokinesia represent well-known motor symptoms of Parkinson's disease (PD). While bradykinesia (slow execution of movements) is present in less affected PD patients and aggravates as the disease severity increases, hypokinesia (reduction of movement) seems to emerge prominently only in the more affected patients. Here we developed a model based on the central infusion of low dose (40µg) 6-hydroxydopamine (6-OHDA) in mice in an attempt to discriminate bradykinesia (accessed through forelimb inability) from hypokinesia (accessed through locomotor and exploratory activities). The potential beneficial effects of succinobucol against 6-OHDA-induced forelimb inability were also evaluated. One week after the beginning of treatment with succinobucol (i.p. injections, 10mg/kg/day), mice received a single i.c.v. infusion of 6-OHDA (40µg/site). One week after 6-OHDA infusion, general locomotor/exploratory activities (open field test), muscle strength (grid test), forelimb skill (single pellet task), as well as striatal biochemical parameters related to oxidative stress and cellular homeostasis (glutathione peroxidase, glutathione reductase and NADH dehydrogenases activities, lipid peroxidation and TH levels), were evaluated. 6-OHDA infusions did not change locomotor/exploratory activities and muscle strength, as well as the evaluated striatal biochemical parameters. However, 6-OHDA infusions caused significant reductions (50%) in the single pellet reaching task performance, which detects forelimb skill inability and can be used to experimentally identify bradykinesia. Succinobucol partially protected against 6-OHDA-induced forelimb inability. The decreased forelimb ability with no changes in locomotor/exploratory behavior indicates that our 6-OHDA-based protocol represents a useful tool to mechanistically study the dissociation of bradykinesia and hypokinesia in PD.


Subject(s)
Adrenergic Agents/administration & dosage , Forelimb/physiopathology , Hypokinesia/chemically induced , Hypokinesia/physiopathology , Oxidopamine/administration & dosage , Animals , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Feeding Behavior/drug effects , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Histocompatibility Antigens Class I/metabolism , Hypokinesia/diagnosis , Injections, Intraventricular , Lipid Peroxidation/drug effects , Male , Mice , Muscle Strength/drug effects , Peptide Fragments/metabolism , Probucol/administration & dosage , Probucol/analogs & derivatives , Psychomotor Performance/drug effects , Thiobarbituric Acid Reactive Substances/metabolism
5.
Theranostics ; 6(3): 435-45, 2016.
Article in English | MEDLINE | ID: mdl-26909117

ABSTRACT

Cancer metastasis is the leading reason for the high mortality of breast cancer. Herein, we report on a pH-responsive host-guest nanosystem of succinobucol (PHN) with pH-stimuli controlled drug release behavior to improve the therapeutic efficacy on lung metastasis of breast cancer. PHN was composed of the host polymer of ß-cyclodextrin linked with multiple arms of N,N-diisopropylethylenediamine (ßCD-DPA), the guest polymer of adamantyl end-capped methoxy poly(ethylene glycol) (mPEG-Ad), and the active agent of succinobucol. PHN comprises nanometer-sized homogenous spherical particles, and exhibits specific and rapid drug release in response to the intracellular acidic pH-stimuli. Then, the anti-metastatic efficacy of PHN is measured in metastatic 4T1 breast cancer cells, which effectively confirms the superior inhibitory effects on cell migration and invasion activities, VCAM-1 expression and cell-cell binding of RAW 264.7 to 4T1 cells. Moreover, PHN can be specifically delivered to the sites of metastatic nodules in lungs, and result in an obviously improved therapeutic efficacy on lung metastasis of breast cancer. Thereby, the pH-responsive host-guest nanosystem can be a promising drug delivery platform for effective treatment of cancer metastasis.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/complications , Drug Delivery Systems , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Probucol/analogs & derivatives , Animals , Antineoplastic Agents/administration & dosage , Cell Movement/drug effects , Disease Models, Animal , Female , Hydrogen-Ion Concentration , Mice, Inbred BALB C , Nanostructures/administration & dosage , Nanostructures/chemistry , Neoplasm Invasiveness , Polyethylene Glycols/metabolism , Probucol/administration & dosage , Probucol/pharmacokinetics , Treatment Outcome , beta-Cyclodextrins/metabolism
6.
Adv Healthc Mater ; 5(4): 439-48, 2016 Feb 18.
Article in English | MEDLINE | ID: mdl-26711864

ABSTRACT

Cancer metastasis is the main cause for the high mortality in breast cancer patients. Herein, we first report succinobucol-loaded pH-responsive wormlike micelles (PWMs) with sequential targeting capability to inhibit lung metastasis of breast cancer. PWMs can in a first step be delivered specifically to the sites of metastases in the lungs and then enable the intracellular pH-stimulus responsive drug release in cancer cells to improve the anti-metastatic effect. PWMs are identified as nanofibrillar assemblies with a diameter of 19.9 ± 1.9 nm and a length within the 50-200 nm range, and exhibited pH-sensitive drug release behavior in response to acidic intracellular environments. Moreover, PWMs can obviously inhibit the migration and invasion abilities of metastatic 4T1 breast cancer cells, and reduce the expression of the metastasis-associated vascular cell adhesion molecule-1 (VCAM-1) at 400 ng mL(-1) of succinobucol. In particular, PWMs can induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, thereby leading to an 86.6% inhibition on lung metastasis of breast cancer. Therefore, the use of sequentially targeting PWMs can become an encouraging strategy for specific targeting and effective treatment of cancer metastasis.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Lung Neoplasms/prevention & control , Micelles , Neoplasm Metastasis/prevention & control , Probucol/analogs & derivatives , Animals , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Female , Hydrogen-Ion Concentration , Mice , Mice, Inbred BALB C , Mice, Nude , Nanoparticles/chemistry , Polyethylene Glycols/chemistry , Probucol/pharmacology , RAW 264.7 Cells , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolism
7.
Mol Neurobiol ; 53(2): 1280-1295, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25619973

ABSTRACT

Succinobucol (succinyl ester of probucol) is a lipid-lowering compound with anti-inflammatory and antioxidant properties. Recent experimental evidence has highlighted the potential neuroprotective effects of succinobucol. In the present study, cultured neuroblastoma (SH-SY5Y) cells were used to investigate mechanisms mediating the potential protective effect of succinobucol against mitochondrial metabolic impairment and oxidative stress induced by 3-nitropropionic acid (3-NP), a succinate dehydrogenase inhibitor that has been used in experimental models of the Huntington disease (HD). 3-NP decreased cellular viability after 24 h of incubation. This decline in cellular viability was preceded by (i) reduced mitochondrial complex II activity, (ii) increased reactive species generation, (iii) decreased mitochondrial membrane potential (ΔΨm), and (iv) diminished glutathione (GSH) levels. Succinobucol pretreatment (6 days) significantly prevented 3-NP-induced loss of cellular viability, generation of reactive oxygen species, and decrease of ΔΨm. However, succinobucol pretreatment did not protect against 3-NP-induced inhibition of mitochondrial complex II activity, pointing to the mitigation of secondary events resultant from mitochondrial complex II inhibition. Succinobucol pretreatment (6 days) significantly increased (50 %) the levels of GSH in SH-SY5Y cells, and this event was paralleled by significant increases in glutamate cysteine ligase messenger RNA (mRNA) expression and activity (GCL; the first enzyme in the GSH biosynthesis). The present findings are the first to show that succinobucol increases GSH levels via upregulation of GCL activity (possibly through the activation of the nuclear (erythroid-derived 2)-related factor (Nrf2)/antioxidant response element (ARE) pathway), displaying protective effects against mitochondrial dysfunction-derived oxidative stress.


Subject(s)
Glutamate-Cysteine Ligase/metabolism , Glutathione/metabolism , Hypolipidemic Agents/pharmacology , Mitochondria/metabolism , Oxidative Stress/drug effects , Probucol/analogs & derivatives , Up-Regulation/drug effects , Buthionine Sulfoximine/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Glutamate-Cysteine Ligase/genetics , Glutathione Peroxidase/metabolism , Humans , Hydroquinones/pharmacology , Mitochondria/drug effects , Nitro Compounds , Probucol/pharmacology , Propionates , Protective Agents/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Time Factors
8.
J Control Release ; 205: 162-71, 2015 May 10.
Article in English | MEDLINE | ID: mdl-25598420

ABSTRACT

The prevention and treatment of lung metastasis of breast cancer remain a major challenge. The vascular cell adhesion molecule-1 (VCAM-1) could provide a potential therapeutic target in lung metastasis. Herein, succinobucol (SCB), a water-insoluble potent and selective VCAM-1 inhibitor, was assembled with triblock polymer poloxamer P188 into nanoparticles due to the intermolecular hydrophobic interactions. The experimental results showed that the SCB loaded nanoparticles (SN) could greatly improve the oral delivery and suppress the lung metastasis of breast cancer. The cell migration and invasion abilities of metastatic 4T1 breast cancer cells were obviously inhibited by SN. Moreover, the VCAM-1 expression on 4T1 cells was significantly reduced by SN, and the cell-cell binding ratio of RAW 264.7 cells to 4T1 cells greatly decreased from 47.4% to 3.2%. Furthermore, the oral bioavailability of SCB was greatly improved about 13-fold by SN, and the biodistribution in major organs was evidently enhanced. In particular, in the metastatic breast cancer model, the lung metastasis was notably reduced by SN treatment, and the VCAM-1 expression in lung tissues was significantly inhibited. Thereby, SN could evoke a new effective therapeutic efficacy of SCB on lung metastasis of breast cancer by inhibition of VCAM-1 expression.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Drug Carriers , Lung Neoplasms/prevention & control , Nanoparticles , Poloxamer/chemistry , Probucol/analogs & derivatives , Vascular Cell Adhesion Molecule-1/metabolism , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Biological Availability , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Movement/drug effects , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Female , Hydrophobic and Hydrophilic Interactions , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Nanomedicine , Neoplasm Invasiveness , Particle Size , Probucol/chemistry , Probucol/pharmacokinetics , Probucol/pharmacology , RAW 264.7 Cells , Rats, Sprague-Dawley , Signal Transduction/drug effects , Technology, Pharmaceutical/methods , Tissue Distribution
9.
Am J Physiol Gastrointest Liver Physiol ; 306(5): G439-44, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24407589

ABSTRACT

Feeding intolerance resulting from delayed gastric emptying is common in premature neonates. Metoclopramide (MCP), the most frequently used prokinetic drug in neonates, enhances gastric muscle contractility through inhibition of dopamine receptors. Although its therapeutic benefit is established in adults, limited data are available to support its clinical use in infants. Hypothesizing that developmentally dependent differences are present, we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn, juvenile, and adult rats. The muscle strips were either contracted with electrical field stimulation (EFS) to induce cholinergic nerve-mediated acetylcholine release or carbachol, a cholinergic agonist acting directly on the muscarinic receptor. Although in adult rats MCP increased EFS-induced contraction by 294 ± 122% of control (P < 0.01), no significant effect was observed in newborn fundic muscle. MCP had no effect on the magnitude of the carbachol-induced and/or bethanechol-induced gastric muscle contraction at any age. In response to dopamine, an 80.7 ± 5.3% relaxation of adult fundic muscle was observed, compared with only a 8.4 ± 8.7% response in newborn tissue (P < 0.01). Dopamine D2 receptor expression was scant in neonates and significantly increased in adult gastric tissue (P < 0.01). In conclusion, the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression. To the extent that these novel data can be extrapolated to neonates, the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation.


Subject(s)
Dopamine Antagonists/pharmacology , Metoclopramide/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Animals , Animals, Newborn , Electrophysiological Phenomena/drug effects , Gastrointestinal Transit , Probucol/analogs & derivatives , Random Allocation , Rats , Rats, Sprague-Dawley , Stomach
10.
J Med Chem ; 56(8): 3330-8, 2013 Apr 25.
Article in English | MEDLINE | ID: mdl-23581491

ABSTRACT

Oxidative stress, inflammation, and hyperlipidemia are common factors involved in the pathophysiology of atherosclerosis and type 2 diabetes. We have previously developed multifunctional antidyslipidemic derivatives with antioxidant and antiatherogenic properties. We now report the design, synthesis, and evaluation of two such novel derivatives that incorporate a structural moiety of the antidiabetic agent succinobucol. The new compounds exhibited a much improved in vitro antioxidant and squalene synthase inhibitory activity (at lower micromolar concentrations) as well as a significant antihyperlipidemic effect, reducing plasma total cholesterol, triglycerides, and MDA by 65-90%. Compound 2 also indicated a good anti-inflammatory activity, decreasing edema by 44%, while it was further evaluated for its antidiabetic activity using a type 2 diabetes experimental mouse model. After 7 weeks of administration, it produced a significant antihyperglycemic and antihyperlipidemic activity. In conclusion, rational drug design led to a compound combining improved antioxidant, antidyslipidemic, and antidiabetic action that may serve as a potential therapeutic strategy in metabolic syndrome disorders.


Subject(s)
Antioxidants/pharmacology , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Animals , Antioxidants/chemical synthesis , Atherosclerosis/drug therapy , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Hyperlipidemias/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Lipoproteins, LDL/metabolism , Male , Mice , Oxidative Stress/drug effects , Probucol/analogs & derivatives , Probucol/pharmacology , Rats
11.
Mitochondrion ; 13(2): 125-33, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23333792

ABSTRACT

This study evaluated and compared the potential protective effects of probucol and succinobucol, two lipid-lowering compounds with anti-inflammatory and antioxidant properties, on oxidative stress and mitochondrial dysfunction induced by 3-nitropropionic acid (3-NP, a succinate dehydrogenase (SDH) inhibitor largely used as model of Huntington's disease) in rat brain mitochondria-enriched synaptosomes. 3-NP caused significant inhibition of mitochondrial complex II activity, induced mitochondrial dysfunction and oxidative stress. Probucol and succinobucol prevented oxidative stress, but only succinobucol was able to prevent the mitochondrial dysfunction induced by 3-NP. Succinobucol, which did not recover complex II inhibition, was able to protect against 3-NP-induced decreased of MTT reduction, indicating that SDH is not the only enzyme responsible for MTT reduction. The present findings suggest that succinobucol might be a novel strategy to slow or halt oxidative events in neurodegenerative conditions.


Subject(s)
Antioxidants/metabolism , Brain/drug effects , Mitochondria/drug effects , Nitro Compounds/toxicity , Oxidative Stress , Probucol/analogs & derivatives , Probucol/metabolism , Propionates/toxicity , Animals , Electron Transport Complex II/metabolism , Male , Rats , Rats, Wistar
12.
Catheter Cardiovasc Interv ; 81(4): 698-708, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22581717

ABSTRACT

OBJECTIVE: The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model. BACKGROUND: Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties. METHODS: Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES), or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS). RESULTS: The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days); 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES, and 0.36 ± 0.17 mm for SucRES (P < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (P < 0.05), whereas RES reduced inflammation compared with BMS (P < 0.05). CONCLUSION: In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting.


Subject(s)
Cardiovascular Agents/toxicity , Coronary Vessels/drug effects , Drug-Eluting Stents , Inflammation/chemically induced , Percutaneous Coronary Intervention/instrumentation , Probucol/analogs & derivatives , Animals , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/pharmacokinetics , Cattle , Cell Survival/drug effects , Cells, Cultured , Coronary Vessels/metabolism , Coronary Vessels/pathology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Endothelial Cells/drug effects , Endothelial Cells/pathology , Fibrin/metabolism , Inflammation/pathology , Male , Metals , Models, Animal , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Neointima , Percutaneous Coronary Intervention/adverse effects , Probucol/administration & dosage , Probucol/pharmacokinetics , Probucol/toxicity , Prosthesis Design , Sirolimus/administration & dosage , Swine
13.
Stat Med ; 32(5): 719-38, 2013 Feb 28.
Article in English | MEDLINE | ID: mdl-22855368

ABSTRACT

When comparing two treatment groups in a time-to-event analysis, it is common to use a composite event consisting of two or more distinct outcomes. The goal of this paper is to develop a statistical methodology to derive efficiency guidelines for deciding whether to expand a study primary endpoint from E1 (for example, non-fatal myocardial infarction and cardiovascular death) to the composite of E1 and E2 (for example, non-fatal myocardial infarction, cardiovascular death or revascularisation). We investigate this problem by considering the asymptotic relative efficiency of a log-rank test for comparing treatment groups with respect to a primary relevant endpoint E1 versus the composite primary endpoint, say E, of E1 and E2, where E2 is some additional endpoint.


Subject(s)
Biostatistics/methods , Endpoint Determination/statistics & numerical data , Randomized Controlled Trials as Topic/statistics & numerical data , AIDS Vaccines/administration & dosage , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/mortality , Anti-HIV Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , Humans , Probucol/analogs & derivatives , Probucol/therapeutic use
14.
Am J Ther ; 20(6): 638-53, 2013.
Article in English | MEDLINE | ID: mdl-20838206

ABSTRACT

Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 "less well-validated" option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and colesevelam, which is approved by the United States Food and Drug Administration for both type-2 diabetes and hyperlipidemia. It will further review the clinical data on the novel emerging agents of sodium-glucose cotransporter-2 inhibitors, tagatose, and succinobucol, all currently in phase III clinical trials. This review article can serve as an aid for clinicians to identify clinical indications in which these new agents can be applied in the treatment algorithm.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Design , Hypoglycemic Agents/therapeutic use , Algorithms , Allylamine/analogs & derivatives , Allylamine/pharmacology , Allylamine/therapeutic use , Animals , Colesevelam Hydrochloride , Diabetes Mellitus, Type 2/physiopathology , Hexoses/pharmacology , Hexoses/therapeutic use , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacology , Incretins/pharmacology , Incretins/therapeutic use , Islet Amyloid Polypeptide/pharmacology , Islet Amyloid Polypeptide/therapeutic use , Probucol/analogs & derivatives , Probucol/pharmacology , Probucol/therapeutic use , Sodium-Glucose Transporter 2 , Sodium-Glucose Transporter 2 Inhibitors
15.
J Pharm Sci ; 101(5): 1794-802, 2012 May.
Article in English | MEDLINE | ID: mdl-22323097

ABSTRACT

Four different polymorphs, A, C, D, and E, of succinobucol were isolated and characterized by means of solid-state nuclear magnetic resonance spectroscopy, single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, and attenuated total reflection-infrared spectroscopy. From a number of experiments, the same polymorphs (C, D, and E) and an equilibrium phase mixture B consisting of polymorphs C and D were repeatedly gained using different solvents or their mixtures. Although polymorph A was obtained directly from recrystallization only on few occasions, polymorphs C, D, and E proved to be metastable kinetic polymorphs, which slowly transform to a thermodynamically more stable form A during long-term storage. The single-crystal structures of polymorph C and D were determined by X-ray single-crystal diffraction.


Subject(s)
Probucol/analogs & derivatives , Calorimetry, Differential Scanning , Crystallization , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Molecular , Powder Diffraction , Probucol/analysis , Probucol/chemistry , Spectrophotometry, Infrared , Thermogravimetry
16.
Free Radic Biol Med ; 52(5): 871-9, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22203369

ABSTRACT

Probucol inhibits the proliferation of vascular smooth muscle cells in vitro and in vivo, and the drug reduces intimal hyperplasia and atherosclerosis in animals via induction of heme oxygenase-1 (HO-1). Because the succinyl ester of probucol, succinobucol, recently failed as an antiatherogenic drug in humans, we investigated its effects on smooth muscle cell proliferation. Succinobucol and probucol induced HO-1 and decreased cell proliferation in rat aortic smooth muscle cells. However, whereas inhibition of HO-1 reversed the antiproliferative effects of probucol, this was not observed with succinobucol. Instead, succinobucol but not probucol induced caspase activity and apoptosis, and it increased mitochondrial oxidation of hydroethidine to ethidium, suggestive of the participation of H(2)O(2) and cytochrome c. Also, succinobucol but not probucol converted cytochrome c into a peroxidase in the presence of H(2)O(2), and succinobucol-induced apoptosis was decreased in cells that lacked cytochrome c or a functional mitochondrial complex II. In addition, succinobucol increased apoptosis of vascular smooth muscle cells in vivo after balloon angioplasty-mediated vascular injury. Our results suggest that succinobucol induces apoptosis via a pathway involving mitochondrial complex II, H(2)O(2), and cytochrome c. These unexpected results are discussed in light of the failure of succinobucol as an antiatherogenic drug in humans.


Subject(s)
Apoptosis/drug effects , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/physiology , Probucol/analogs & derivatives , Animals , Aorta/cytology , Caspase 3/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Cytochromes c/metabolism , DNA Fragmentation , Electron Transport Complex II/metabolism , Enzyme Induction/drug effects , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Hydrogen Peroxide/metabolism , Male , Metalloporphyrins/pharmacology , Mitochondria/drug effects , Mitochondria/enzymology , Muscle, Smooth, Vascular/enzymology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/enzymology , Probucol/pharmacology , Protoporphyrins/pharmacology , Rabbits , Rats
17.
Molecules ; 16(11): 9404-20, 2011 Nov 10.
Article in English | MEDLINE | ID: mdl-22075571

ABSTRACT

Synthesis, detailed structural characterization (X-ray, NMR, MS, IR, elemental analysis), and studies of toxicity, antioxidant activity and bioavailability of unique potent anti-atherosclerotic succinobucol-steroid conjugates are reported. The conjugates consist of, on one side, the therapeutically important drug succinobucol ([4-{2,6-di-tert-butyl-4-[(1-{[3-tert-butyl-4-hydroxy-5-(propan-2-yl)phenyl]sulfanyl}ethyl)sulfanyl]phenoxy}-4-oxo-butanoic acid]) possessing an antioxidant and anti-inflammatory activity, and on the other side, plant stanol/sterols (stigmastanol, ß-sitosterol and stigmasterol) possessing an ability to lower the blood cholesterol level. A cholesterol-succinobucol prodrug was also prepared in order to enhance the absorption of succinobucol through the intestinal membrane into the organism and to target the drug into the place of lipid metabolism-The enterohepatic circulation system. Their low toxicity towards mice fibroblasts at maximal concentrations, their antioxidant activity, comparable or even higher than that of ascorbic acid as determined by direct quenching of the DPPH radical, and their potential for significantly altering total and LDL cholesterol levels, suggest that these conjugates merit further studies in the treatment of cardiovascular or other related diseases. A brief discussion of succinobucol's ability to quench the radicals, supported with a computational model of the electrostatic potential mapped on the electron density surface of the drug, is also presented.


Subject(s)
Probucol/analogs & derivatives , Steroids/chemistry , Steroids/pharmacokinetics , 3T3 Cells , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/toxicity , Antioxidants/chemistry , Antioxidants/pharmacokinetics , Antioxidants/toxicity , Biological Availability , Biphenyl Compounds/chemistry , Clinical Trials as Topic , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Free Radicals/chemistry , Humans , Mice , Mice, Inbred BALB C , Molecular Structure , Picrates/chemistry , Probucol/chemistry , Probucol/pharmacokinetics , Probucol/toxicity , Static Electricity , Steroids/toxicity
18.
Nihon Rinsho ; 69(1): 105-9, 2011 Jan.
Article in Japanese | MEDLINE | ID: mdl-21226269

ABSTRACT

How to manage residual atherosclerosis risk after the statin therapy is a major concern in cardiovascular medicine. In addition to life-style modifications, new drugs against atherosclerotic and inflammatory vascular diseases are expected. In current clinical trials, phospholipase A2 inhibitors(darapladib, varespladib), RVX-208, D-4F, CETP inhibitors (anacetrapib, dalcetrapib), succinobucol are investigated. Some has been failed, but others are still promising. On molecular target basis of PAF-AH, CETP, PON, ABC transporters of A1 and G1, SR-BI, HO-1, potential benefits and side effects are discussed.


Subject(s)
Atherosclerosis/drug therapy , Drug Design , Molecular Targeted Therapy , Acetates/therapeutic use , Amides , Apolipoprotein A-I/therapeutic use , Atherosclerosis/etiology , Benzaldehydes/therapeutic use , Blood Proteins/therapeutic use , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Clinical Trials as Topic , Esters , Humans , Indoles/therapeutic use , Keto Acids , Oxazolidinones/therapeutic use , Oximes/therapeutic use , Probucol/analogs & derivatives , Probucol/therapeutic use , Quinazolines/therapeutic use , Quinazolinones , Sulfhydryl Compounds/therapeutic use
19.
Mol Cell Endocrinol ; 323(2): 246-55, 2010 Jul 29.
Article in English | MEDLINE | ID: mdl-20211684

ABSTRACT

The antioxidant and anti-inflammatory compound AGI-1067 (succinobucol) has potential as an oral anti-diabetic agent. AGI-1067 reduces H(b)A1c, improves fasting plasma glucose, and reduces new-onset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10 microM AGI-1067 increased glucose-stimulated insulin secretion (11 mM) without affecting secretion in basal (3 mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7 mM and 11 mM glucose, but had no effect in 28 mM or basal glucose. AGI-1067-pretreated islets also showed enhanced calcium responses to methyl pyruvate and alpha-ketoisocaproate at low doses, but not high doses. The AGI-1067-mediated effects on glucose-stimulated calcium were maintained during continuous diazoxide exposure, suggesting effects on the K(ATP)-channel-independent pathway. AGI-1067 also reduced cytokine-induced islet cell death and expression of iNOS, a key component in cytokine signaling. This is the first report of direct stimulatory and protective effects of a first-in-class potential anti-diabetic agent on pancreatic islets.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Probucol/analogs & derivatives , Animals , Antihypertensive Agents/pharmacology , Calcium/metabolism , Cell Death/drug effects , Cytokines/metabolism , Diazoxide/pharmacology , Gene Expression/drug effects , Glucose/metabolism , Humans , Hypoglycemic Agents/pharmacology , Insulin Secretion , Islets of Langerhans/physiology , Keto Acids/pharmacology , Male , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Potassium Channels/metabolism , Probucol/pharmacology , Tolbutamide/pharmacology
20.
Indian J Med Sci ; 64(6): 285-91, 2010 Jun.
Article in English | MEDLINE | ID: mdl-22885321

ABSTRACT

Cardiovascular diseases remain a major cause of morbidity and mortality worldwide, regardless of the recent advances in medical and surgical treatment, for as life expectancy in the developed countries increases, cardiovascular conditions affecting the elderly also rises. Atherosclerosis and cardiovascular diseases take a huge toll on the society, making them the leading cause of death in developed countries. Phenomenal advances in the pathophysiology of cardiovascular disease and the molecular signaling pathways has revealed the role of endothelial dysfunction involved therein and thus has raised the possibility of novel therapeutic targets. Such potential cellular targets include the vascular smooth muscle cells, monocyte/macrophage cell lines, platelets, and endothelial cells. Certain studies affirm that antiplatelet agents, antioxidant therapies, amino acid supplementation, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers may prevent or slow the progression of the disease process. The race is on for new medicines that can treat and prevent heart attacks and strokes, arising out of atherosclerosis, which kills nearly 1 million people a year in the U.S.A alone.


Subject(s)
Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Anticholesteremic Agents/therapeutic use , Benzaldehydes/therapeutic use , Clinical Trials as Topic , Endothelin Receptor Antagonists , Fibrinolytic Agents/therapeutic use , Humans , Immunologic Factors/therapeutic use , Isoxazoles/therapeutic use , Lipoxygenase Inhibitors/therapeutic use , Metalloendopeptidases/therapeutic use , Oxazolidinones/therapeutic use , Oximes/therapeutic use , Phospholipase A2 Inhibitors/therapeutic use , Probucol/analogs & derivatives , Probucol/therapeutic use , Pyrimidines/therapeutic use , Quinolines/therapeutic use , Thiophenes/therapeutic use
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