scholarly journals Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-13 ◽  
Author(s):  
Jennifer G. Robinson
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Adverse Effects ◽  
Microvascular Complications ◽  
Harmful Effect ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonists ◽  
Cardiovascular Benefit

Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR- agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

scholarly journals Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Manoj Govindarajulu ◽  
Priyanka D. Pinky ◽  
Jenna Bloemer ◽  
Nila Ghanei ◽  
Vishnu Suppiramaniam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Effects ◽  
Therapeutic Potential ◽  
Protein Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Continuous Increase ◽  
Therapeutic Benefits ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

scholarly journals The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

2009 ◽  
Vol 30 (7) ◽  
pp. 935-946 ◽  
Author(s):  
Wolfgang Linz ◽  
Paulus Wohlfart ◽  
Manuel Baader ◽  
Kristin Breitschopf ◽  
Eugen Falk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

2019 ◽  
Vol 133 (3) ◽  
pp. 531-544 ◽  
Author(s):  
Tzu-Hao Li ◽  
Ying-Ying Yang ◽  
Chia-Chang Huang ◽  
Chih-Wei Liu ◽  
Hung-Cheng Tsai ◽  
...  
Keyword(s):  
Liver Injury ◽  
Energy Homeostasis ◽  
Intestinal Barrier ◽  
Peroxisome Proliferator ◽  
Intestinal Epithelial ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Steatohepatitis ◽  
Ppar Agonists ◽  
Apoptosis And Inflammation ◽  
Adipose Dysfunction

Abstract Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

scholarly journals Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Chie Iitake ◽  
Daisaku Masuda ◽  
Masahiro Koseki ◽  
Shizuya Yamashita
Keyword(s):  
Acute Pancreatitis ◽  
Serum Triglyceride ◽  
High Serum ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Serum Triglycerides ◽  
Oral Tablet ◽  
Peroxisome Proliferator Activated Receptor ◽  
Severe Hypertriglyceridemia ◽  
Potential Efficacy

Abstract Background Currently available treatments have only been partly successful in patients with severe hypertriglyceridemia, including those with high serum triglycerides above 1,000 mg/dL (11.3 mmol/L), who often suffer from acute pancreatitis. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) which has been developed as an affordable oral tablet in Japan. We herein report the first three patients with severe hypertriglyceridemia who were successfully treated with pemafibrate. Methods Three patients with fasting serum triglyceride (TG) levels above 1,000 mg/dL (11.3 mmol/L) were treated with pemafibrate (0.2–0.4 mg/day, 0.1–0.2 mg BID). Results Serum TGs decreased from 2,000–3,000 mg/dL (22.6–33.9 mmol/L) to < 250 mg/dL (2.8 mmol/L) without adverse effects in all three patients. Serum TGs in Patient 1 and 2 decreased from 1,326 mg/dL (15.0 mmol/L) to 164 mg/dL (1.9 mmol/L) and from 2,040 mg/dL (23.1 mmol/L) to 234 mg/dL (2.6 mmol/L), respectively. Patient 3 with type 2 diabetes and 12.1% (109 mmol/mol) hemoglobin A1c had a TG level of 2,300 mg/dL (26.0 mmol/L). Even after glycemic control improved, TG remained high. After pemafibrate administration, TG decreased to 200 mg/dL (2.3 mmol/L). All patients showed no serious adverse events. Conclusions Pemafibrate demonstrated potential efficacy and safety for severe hypertriglyceridemia which may contribute to the prevention of acute pancreatitis, in a manner that can be easily prescribed and used as an oral tablet.

MO19390 (SAiL): Incidence of thromboembolic events and congestive heart failure with first-line bevacizumab (Bv)-based therapy in advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19003-e19003
Author(s):  
N. Pavlakis ◽  
V. Hirsh ◽  
M. Reck ◽  
Y. Wu ◽  
E. Dansin
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Special Interest ◽  
Locally Advanced ◽  
Thromboembolic Events ◽  
First Line ◽  
Standard Chemotherapy ◽  
Eligibility Criteria ◽  
Serious Adverse Events ◽  
Ecog Ps

e19003 Background: MO19390 (SAiL) is a single-arm, multicenter, international trial evaluating the safety and efficacy of first-line Bv with standard chemotherapy in over 2,000 patients (pts). Methods: Key eligibility criteria were untreated locally advanced, metastatic or recurrent non-squamous NSCLC, ECOG PS 0–2, tumor not abutting major blood vessels, no uncontrolled HTN (systolic >150mmHg and/or diastolic >100mmHg) or active cardiovascular disease at baseline. Pts received Bv (7.5 or 15mg/kg) with standard chemotherapy for up to six cycles. Non-progressors proceeded to receive Bv until disease progression. The primary endpoint was safety, including the incidence of serious adverse events (SAEs) related to Bv, and the incidence of AEs of special interest. Results: Safety analyses (data cut-off July 2008) were based on 2,008 pts. Pts (%) were: male 60.1; stage IIIB/IV 19.5/80.5 (no data for 3 pts); adenocarcinoma/large cell/other 85.8/7.1/7.1; ECOG PS 0/1/2 38.1/56.1/5.8. 4.2% of pts were receiving anticoagulants at baseline. A total of 1,008 pts (50.2%) experienced at least one adverse event of special interest (all grades). Of these, 172 pts (8.6%) experienced an arterial or venous thromboembolism, which included pulmonary embolism (49 pts; 2.4%), deep vein thrombosis (40 pts; 2.0%), thrombophlebitis (26 pts; 1.3%), myocardial infarction (12 pts; 0.6%), cerebral hemorrhage (2 pts; 0.1%), cerebral ischemia (4 pts; 0.2%) and cerebrovascular accident (6 pts; 0.3%). 59 pts (2.9%) experienced congestive heart failure (CHF). Conclusions: The incidence of thromboembolic events and CHF was low in Bv-treated pts enrolled in the SAiL trial. These results, taken together with the overall safety analysis from the SAiL trial, confirm that Bv-based therapy has a well-established and manageable safety profile. Updated results will be presented. [Table: see text]

scholarly journals PPAR Agonist-Mediated Protection against HIV Tat-Induced Cerebrovascular Toxicity is Enhanced in MMP-9-Deficient Mice

2014 ◽  
Vol 34 (4) ◽  
pp. 646-653 ◽  
Author(s):  
Wen Huang ◽  
Lei Chen ◽  
Bei Zhang ◽  
Minseon Park ◽  
Michal Toborek
Keyword(s):  
Neuronal Loss ◽  
Specific Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brain Infection ◽  
Ppar Γ ◽  
Ppar Agonists ◽  
Bbb Permeability ◽  
Deficient Mice ◽  
Hiv 1

The strategies to protect against the disrupted blood–brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPAR α agonist) or rosiglitazone (PPAR γ agonist). In contrast, exposure to GW9662 (PPAR γ antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1.

Targeting the Tumor Stroma with Peroxisome Proliferator Activated Receptor (PPAR) Agonists

2009 ◽  
Vol 9 (7) ◽  
pp. 816-821 ◽  
Author(s):  
Annika Bundscherer ◽  
Albrecht Reichle ◽  
Christian Hafner ◽  
Stefanie Meyer ◽  
Thomas Vogt
Keyword(s):  
Tumor Stroma ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonists
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