Disease relevance of Ragaglitazar

• PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly [1].
• Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia [2].
• Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia [2].
• In summary, our findings showed that in the urothelium of ragaglitazar-treated animals, hypertrophy (increased size and protein content per cell) was an early change, that affected the whole bladder urothelial cell population [3].
• These data indicates that dual PPARalpha and gamma activator ragaglitazar can be beneficial for the treatment of hypertension and vascular disease commonly associated with type 2 diabetes [4].

High impact information on Ragaglitazar

• The impact of PPAR gamma activation on feeding and feed efficiency appears to be partially independent because the PPAR alpha component of ragaglitazar completely counteracts the orexigenic actions of PPAR gamma activation without marked impact on feed efficiency [5].
• Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding [5].
• A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed [6].
• We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats [1].
• Ragaglitazar [(-) DRF 2725; NNC 61-0029] is a coligand of PPARalpha and PPARgamma [7].

Biological context of Ragaglitazar

• These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes [2].
• However, the protein changes were stronger (Egr-1 induction) or of a longer duration (S6 phosphorylation) in ragaglitazar-treated animals [8].
• Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93% [9].
• The aim of this study is to investigate the effect of ragaglitazar on blood pressure and endothelial function in insulin resistant animal model and non-insulin resistant hypertensive models [4].
• Ragaglitazar also showed significant improvement in acetylcholine-induced relaxation in isolated aorta of Zucker fa/fa, SHR, 2K1C and also potentiated the insulin-induced vasorelaxation in Zucker fa/fa rats [4].

Anatomical context of Ragaglitazar

• We examined early (precancerous) changes in the bladder urothelium of rats orally dosed with ragaglitazar, using a newly developed flow cytometric method [3].

Associations of Ragaglitazar with other chemical compounds

• Development and validation of a high-resolution capillary electrophoresis method for multi-analysis of ragaglitazar and arginine in active pharmaceutical ingredients and low-dose tablets [10].
• Rats were dosed orally for 16 days with bladder carcinogenic (ragaglitazar) as well as non-bladder carcinogenic (fenofibrate and rosiglitazone) PPAR agonists and protein changes were assayed in the urinary bladder urothelium by Western blotting [8].
• Ragaglitazar showed significant reduction (P<0.001) of systolic blood pressure (SBP) in insulin resistant fa/fa rats, with concomitant reduction in plasma triglycerides (TG) and insulin levels while pioglitazone (10 mg kg(-1)) showed significant (P<0.05) but comparatively less reduction [4].
• A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar) [11].

Gene context of Ragaglitazar

• Ragaglitazar: a novel PPAR alpha PPAR gamma agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models [7].
• Ragaglitazar induced expression of the transcription factor Egr-1, phosphorylation of the c-Jun transcription factor and phosphorylation of the ribosomal S6 protein were observed [8].

Analytical, diagnostic and therapeutic context of Ragaglitazar

• Development and validation of a high-precision capillary electrophoresis method for main component assay of ragaglitazar [12].
• Quantitative determination of ragaglitazar in rat plasma by HPLC: validation and application in pharmacokinetic study [13].
• A specific, accurate, precise and reproducible high-performance liquid chromatography (HPLC) method was developed for the estimation of ragaglitazar [(-) DRF 2725, NNC 61-0029], a novel anti-diabetic agent, in rat plasma [13].
• Following 3 weeks of oral ragaglitazar dosing, increases in physical size occurred in a generalized fashion in rat bladder urothelial cells, determined by flow cytometry [3].

References