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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.
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PMID:Pioglitazone: an antidiabetic drug with the potency to reduce cardiovascular mortality. 1650 18

The placebo-controlled Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) is the only study of secondary prevention in patients with type 2 diabetes to have shown a benefit. While treatment with pioglitazone did not significantly reduce the primary composite endpoint, it did significantly lower the incidence of many of its components, including all-cause mortality, nonfatal myocardial infarction (including silent infarctions), stroke, acute coronary syndrome and limb amputation. Pioglitazone also reduced the relative risk of the combined endpoint of death, myocardial infarction and stroke by 16% compared to placebo. In the subgroup of patients with myocardial infarction, the risk of myocardial infarction and acute coronary syndromes was reduced with the active treatment, which also substantially reduced (-47%) the risk of stroke in patients with prior stroke. Pioglitazone has furthermore demonstrated numerous antiatherogenic effects in clinical and preclinical investigations.
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PMID:Organ protection in the secondary prevention of type 2 diabetes. 1724 77

The recent analysis of the French MONICA registries report a reduction in the incidence of fatal MI related to improvement of care whereas the overall incidence of coronary events remain stable, suggesting the need for a better primary prevention. The extensive review of the death certificates and the analysis of the death classification from the same registries indicate an under estimation of MI-related death in the national death registry. It is also confirmed that instead of 50%, approximately 80% of coronary death are explained by the four major risk factors including smoking, hypercholesterolemia, hypertension and diabetes. The international REACH registry has enrolled more than 67 000 individuals including patients with symptomatic atherothrombotic disease and patients with multiple risk factors. The analysis of baseline characteristics and of the one year FU shows a high residual risk and a lack of efficacy of secondary prevention. The existence of a symptomatic disease and the number of symptomatic localization of atherothrombosis are critical factors to predict recurrence of major vascular events Secondary analysis of the INTERHEART study provide the essence of what should any physician know about the relationship between coronary heart disease and smoking, either active or passive. Prevention with respect to this risk factor remains very insufficient. Varenicline, a new nicotinic receptor partial agonist, should help patients involved in smoking cessation program. The established detrimental effects of perioperative smoking represent a unique opportunity to promote smoking cessation in individuals scheduled for surgery. The major cardiovascular impact of second hand smoking has been recently demonstrated by the short-term effects of banning smoking in public places on the incidence of acute coronary events. The SPARCL study has demonstrated the benefit of high dose of atorvastatine to prevent recurrent acute ischemic cerebrovascular event in patients with a prior history of stroke or TIA. In the open ASTEROID study, high doses of rosuvastatine confirm the possibility of reducing the volume of coronary atheroma analyzed by IVUS. The expected benefit of glitazones to reduce the incidence of death, MI and stroke in diabetes patients with a prior history of vascular event has been confirmed in the PROactive study. Pioglitazone provided a clear reduction of recurrent vascular events in diabetes patient with a prior MI at a cost of a significant increase of the risk of heart failure. In the DREAM study, neither ramipril nor rosiglitazone have reduced the incidence of cardiovascular events significantly. The moderate benefit of the fenofibrate to prevent cardiovascular events in the FIELD study, which was carried out in diabetics mostly in primary prevention, needs to be considered after adjustment on statin use in a higher proportion of patients of the placebo group. Postprandial hyperglycaemia, analyzed by the peak of glycaemia after a load in glucose, has been confirmed as a more powerful independent predictive factor of the risk of cardiovascular event than fasting glycaemia. The systematic screening postprandial hyperglycaemia represents an interesting strategy for primary prevention which warrants further investigation. If obesity is a risk factor whose impact on morbi-mortality is well established, a French study shows that body mass index has an unfavourable influence on the cognitive functions in middle-aged men and women.
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PMID:[The best of epidemiology and cardiovascular prevention in 2006]. 1740 66

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.
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PMID:Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats. 1803 80

The effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on hypertensive cardiovascular injury is unknown. We examined the effect of pioglitazone on hypertensive cardiovascular injury and the significance of combination of pioglitazone with angiotensin type 1 receptor blocker. Stroke-prone spontaneously hypertensive rats (SHRSP) were orally given pioglitazone, candesartan, or combined pioglitazone and candesartan for 4 weeks to compare their effects on cardiovascular injury. Pioglitazone, without lowering blood pressure, significantly suppressed cardiac inflammation and fibrosis and reduced vascular endothelial dysfunction, and these beneficial effects were associated with the reduction of superoxide by inhibition of cardiovascular NADPH oxidase. Thus, pioglitazone protects against hypertensive cardiovascular injury, by inhibiting reactive oxygen species (ROS). Combination of pioglitazone and candesartan suppressed cardiac hypertrophy, inflammation, and interstitial fibrosis of SHRSP to a greater extent than either monotherapy, and reduced vascular endothelial dysfunction of SHRSP more than either monotherapy. Furthermore, more beneficial effects of their combination on cardiovascular injury were associated with more reduction of NADPH oxidase-mediated cardiovascular ROS. To elucidate the underlying molecular mechanism, we examined cardiovascular NADPH oxidase subunits. Pioglitazone monotherapy significantly attenuated cardiovascular p22(phox) and Rac1 in SHRSP, whereas pioglitazone combined with candesartan more attenuated p22(phox) and significantly reduced Nox1. Thus, additive suppression of cardiovascular NADPH oxidase by the combination was attributed to its additive attenuation of p22(phox) and Nox1 protein levels. In conclusion, we showed that pioglitazone protected against hypertensive cardiovascular damage, and the combination of pioglitazone and candesartan exerted more beneficial effects on hypertensive cardiovascular injury by more suppressing ROS.
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PMID:Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan. 1857 65

Interleukin-6 (IL-6) exerts neuroprotective effects after cerebral ischaemia but can also exacerbate inflammation and induce neuronal death. The current study investigates the role of cerebral peroxisome proliferator-activated receptor(s) gamma (PPARgamma) in the regulation of IL-6 expression in the peri-infarct cortical tissue in rats exposed to focal cerebral ischaemia. Pioglitazone, a high-affinity PPARgamma ligand, was infused intracerebroventricularly (i.c.v.) via osmotic minipumps over a 5-day period before, during and 24 h or 48 h after middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. The expression of PPARgamma and IL-6 in cortical tissue adjacent to the ischaemic core was studied 24 h and 48 h after MCAO. Pioglitazone augmented the ischaemia-induced upregulation of PPARgamma at both time points. Cerebral ischaemia substantially increased IL-6 expression in the peri-infarct cortical tissue. Twenty-four hours after MCAO, the majority of microglial cells/macrophages showed an intense IL-6 immunoreactivity. IL-6 was also localized in neurons, but the distribution of neurons positively stained for IL-6 at the border of the infarct was very heterogeneous. Pioglitazone effectively decreased the number of IL-6-immunoreactive cells and IL-6 protein levels at 24 h but not at 48 h after MCAO. Pioglitazone treatment reduced the infarct size and improved neurological functions. The present study demonstrates that cerebral PPARgamma suppresses the expression of IL-6 in ischaemic brain tissue during the initial phase of ischaemic stroke, in which the overproduction of IL-6 may aggravate neuronal damage, but not at later time points, when IL-6 promotes neuroprotection and inhibits neuronal death.
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PMID:Peroxisome proliferator-activated receptorsgamma (PPARgamma) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia. 1897 94

Thiazolidinediones (TZDs) are widely used in the type 2 diabetes mellitus (DMT2) treatment but have also been tested in cardiovascular prevention. DMT2 is associated with a marked increment in cardiovascular risk, and its prevention represents a main target in cardiometabolic protection. Both Troglitazone (Troglitazone in Prevention of Diabetes study) and Rosiglitazone (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication study) significantly reduced new-onset diabetes. A similar topic will be investigated with pioglitazone (Actos Now for Prevention of Diabetes). In the Prospective Pioglitazone Clinical Trial in Macrovascular events the primary end point (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndromes, endovascular or surgical intervention in the coronary/leg arteries and amputation above ankles) was unaffected, whereas the secondary one (all-cause mortality, nonfatal myocardial infarction and stroke) was reduced by pioglitazone (-16%, p=0.027) compared to placebo in 5,238 patients with DMT2 and macrovascular disease. In contrast, a meta-analysis (Nissen and Wolski, N Engl J Med. 2007;356:2457-2471) reported that rosiglitazone treatment is associated with a significant increase in myocardial infarction risk (p=0.03) and a borderline significant increase in the risk of death from cardiovascular causes (p=0.06). Nevertheless, the possibility that rosiglitazone might affect cardiovascular events should be evaluated by the ongoing trial Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD). Interim findings early from RECORD did not show significant differences between the rosiglitazone and the control group regarding myocardial infarction and death from cardiovascular and any cause. Additional large-scale trials are awaited to clarify the of role TZDs in cardiovascular outcomes.
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PMID:Cardiovascular risk and cardiometabolic protection: role of glitazones. 1903 66

A recent meta-analysis suggested that the use of rosiglitazone increases the risk of myocardial infarction (MI) in patients with type 2 diabetes mellitus. It is unclear whether this is a class effect of thiazolidinediones (TZD). We did a meta-analysis to evaluate cardiovascular outcomes with the use of pioglitazone. Randomized, controlled trials in which pioglitazone was compared with placebo or other hypoglycemic agents were considered for analysis. Studies were included if the data for MI were available. Studies were identified with use of relevant search words in Medline, Pubmed, EMBASE, CINAHL, and Cochrane databases. Data abstraction was done by 2 individual authors using a standardized protocol. The relative risk across all study groups was computed by the Mantel-Haenszel method, and interstudy heterogeneity was assessed by the chi method. All results were computed according to 95% confidence intervals. Five trials (N = 9965) met the inclusion criteria for analysis. The relative risk for MI was 0.86 (0.69-1.07; P = 0.17). The relative risks for stroke and revascularization were 0.79 (0.61-1.02; P = 0.07) and 0.40 (0.13-1.23; P = 0.11), respectively. Pioglitazone does not increase the risk for MI and may decrease the risk for stroke and revascularization.
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PMID:Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized, controlled trials. 1912 32

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (thiazolidinediones) have anti-inflammatory effects and improve endothelium function. Here, we analyzed the effects of pioglitazone on short- and longer-term outcome after mild transient brain ischemia. 129/SV mice were subjected to 30 min filamentous middle cerebral artery occlusion (MCAo), followed by reperfusion. Post event, animals were treated with daily intraperitoneal (i.p.) pioglitazone (20 mg/kg body weight) or vehicle. Pioglitazone given acutely after transient brain ischemia/reperfusion reduced lesion size and the number of Iba1-expressing microglia in the ischemic striatum at three days. In vitro, pioglitazone attenuated migration and proliferation of primary mouse microglia. However, analysis at 6 weeks after MCAo/reperfusion no longer yielded an effect of pioglitazone on either lesion size or Iba1+ cell counts. Regarding functional longer-term outcome, we also did not detect a beneficial effect of pioglitazone on motor function measured either on the pole test or the wire hanging test or on learning and memory in the Morris water maze. Our study thus underscores the importance of extending experimental stroke studies to an analysis of longer-term outcome.
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PMID:Acute neuroprotection by pioglitazone after mild brain ischemia without effect on long-term outcome. 1914 54

Despite of the huge socio-economic burden, stroke still represents an unmet therapeutic need. Researchers failed to reproduce preclinical efficacy in subsequent clinical development. To bridge this translation failure, the Stroke Therapy Academic Industry Round Table (STAIR) has suggested a rigorous, robust, and detailed preclinical evaluation in at least 2 species and multiple cerebral ischemia models to avoid the clinical failure. Considering these recommendations, in the present study, we have investigated the effects of pioglitazone in global model cerebral ischemic-reperfusion (IR) injury in gerbils. Global cerebral IR injury, produced by bilateral carotid artery occlusion for 5 min, was characterized by neurological deficits, hyperlocomotion, and neurodegeneration in the hippocampal CA1 region. Global ischemia was also associated with oxidative stress and DNA fragmentation as evident from increased malondialdehyde (MDA) levels and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells. Global cerebral IR injury associated neurological damage was significantly attenuated by pioglitazone pretreatment as evident from reduction in neurological symptoms, hyperlocomotion, and CA1 hippocampal neuronal damage in IR-challenged gerbils. Pioglitazone pretreatment also attenuated the oxidative stress and DNA fragmentation after cerebral IR injury. Pioglitazone post-treatment has also significantly reduced the CA1 hippocampal neuronal damage and DNA fragmentation after cerebral IR injury in IR-challenged gerbils. This study demonstrates the neuroprotective activity of pioglitazone in global cerebral IR injury and its neuroprotective effects may be attributed to reduction in oxidative stress and DNA fragmentation.
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PMID:Protective effects of pioglitazone against global cerebral ischemic-reperfusion injury in gerbils. 1930 20


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