New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

César, Fernanda Andrade de; Rudnicki, Martina; Heras, Beatriz de las; Lima, Manfredo; Pitta, Ivan R.; Abdalla, Dulcinéia Saes Parra

doi:10.1016/j.vph.2015.03.009

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…Recently, it was reported that the treatment of LDLr −/− mice with Lyso-7 reduces the development of atherosclerotic lesions, reduces blood glucose levels, improves the lipid profile and downregulates CD40 and CD40L expression with no effect on body weight of the animals [48]. These results indicate that Lyso-7 attenuated atherosclerosis progression by modulating inflammation and lipid metabolism with limited side effects in mice [48].…”

Section: Without Perfusion Perfusedmentioning

confidence: 92%

“…As the endothelium in some tissues is one of the probable cell target of Lyso-7 new PPAR agonist, the association of this molecule with the MCT oily core of NC could introduce beneficial effects to improve drug targeting to endothelium, enhancing the insulin-sensitizing effects and the management of atherosclerosis related to this class of drugs [45][46][47]. Recently, it was reported that the treatment of LDLr −/− mice with Lyso-7 reduces the development of atherosclerotic lesions, reduces blood glucose levels, improves the lipid profile and downregulates CD40 and CD40L expression with no effect on body weight of the animals [48]. These results indicate that Lyso-7 attenuated atherosclerosis progression by modulating inflammation and lipid metabolism with limited side effects in mice [48].…”

Section: Without Perfusion Perfusedmentioning

confidence: 99%

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Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation

Garcia

Oliveira

Pitta

et al. 2015

Journal of Controlled Release

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We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.

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Section: Without Perfusion Perfusedmentioning

confidence: 92%

Section: Without Perfusion Perfusedmentioning

confidence: 99%

Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation

Garcia

Oliveira

Pitta

et al. 2015

Journal of Controlled Release

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“…Based on the crucial role of thiazolidinediones in the treatment of diabetes, and given the risk associated with the use of the available drugs of this class (AlSalman et al, 2000;Maeda, 2001;Scheen, 2001;Scheen, 2003;Marcy et al, 2004;Alemán-González-Duhart et al, 2016), the development of new safer thiazolidinediones is of current interest (Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016;Naim et al, 2017;Thangavel et al, 2017). Since glitazones do not cause liver damage in laboratory animals, comparing these to new thiazolidinediones in order to research the mechanism of toxicity can be misleading (Patel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Most of these candidates possess substitutions in the carbon 5 of the thiazolidinedione ring only. However, substitutions in the nitrogen at position 3 have shown good pharmacological activities in models of diabetes (Mourao et al, 2005) and atherosclerosis (Cesar et al, 2015). Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice.…”

Section: Introductionmentioning

confidence: 99%

“…Mourão et al (2005) published a study on the synthesis of 5-benzylidene and 5-acridinylidene derivatives, both of which were N-3 substituted; these compounds showed hypoglycemic activity in mice. Many other authors have used similar approaches with promising outcomes (da Costa Leite et al, 2007;Barros et al, 2010;Araújo et al, 2011;Amato et al, DMD # 79012 5 2012;Santin et al, 2013a;Santin et al, 2013b;Cesar et al, 2015;Rudnicki et al, 2016;Silva et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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Number of references: 55Number of words in the Abstract: 241 Number of words in the Introduction: 750Number of words in the Discussion: 828Nonstandard abbreviations: ADME, absorption, distribution, metabolism, and excretion; CL h , hepatic clearance; CL int , intrinsic clearance; ESI, electrospray ionization; GQ-11, 5-(indol-3-ylmethylene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione; HLM, human liver microsome; LC-HRMS, liquid chromatography coupled to high resolution mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple reaction monitoring; PPARγ, peroxisome proliferatoractivated receptor gamma; RLM, rat liver microsome; t 1/2 , half-life; TZD, thiazolidinedione;This article has not been copyedited and formatted. The final version may differ from this version. AbstractThiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

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Role of an indole-thiazolidiene PPAR pan ligand on actions elicited by G-protein coupled receptor activated neutrophils

Santin

Machado

Drewes

et al. 2018

Biomedicine & Pharmacotherapy

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New indole-thiazolidine attenuates atherosclerosis in LDLr−/− mice

Cited by 10 publications

References 31 publications

Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation

Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

Role of an indole-thiazolidiene PPAR pan ligand on actions elicited by G-protein coupled receptor activated neutrophils

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