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Development and validation of bioanalytical method and preclinical pharmacokinetics of the compound [5 - (5-bromo-1H-indol-3-metieleno) -3 - (4-chloro-benzyl)-thiazolidine-2 ,4-dione)] (LYSO-07)

Grant number: 12/21216-9
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): February 01, 2013
Effective date (End): February 28, 2014
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Rosangela Gonçalves Peccinini
Grantee:Elias Carvalho Padilha
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Thiazolidinediones (TZDs), also known as glitazones, are drugs used in the treatment of diabetes mellitus type 2 (DM2) and act primarily by reducing peripheral insulin resistance. TZDs act by activating the nuclear receptor PPAR-g (peroxisome proliferator-activated receptors) which regulates the expression of genes related to glucose and lipid metabolism, responsible for glucose uptake mediated by insulin in peripheral tissues and the differentiation of preadipocytes in adipocytes, among other effects.Besides TZDs reducing blood glucose, such as classic hypoglycemics, they also have anti-inflammatory effect, lower blood pressure, lower cholesterol and triglycerides as well as mitigate the cardiovascular risks arising from DM2.The first generation of this class, represented by troglitazone, has high liver toxicity, and was withdrawn from the U.S. market in March 2000, shortly after its launch in 1997. Still, on September 29, 2010, the Anvisa pharmacovigilance department informed through Resolution No. 1466 of 28/09/2010, the cancellation of the register of the drug Avandia ® - trade name upon which rosiglitazone was marketed. Pioglitazone, still under the supervision of regulatory organs, remains on the market, where the risk / benefit measure is still being weighted for their use in therapy.Given the broad therapeutic potential of this class of drugs, many researchers have synthesized new TZD candidates in order to obtain greater specificity on the many therapeutic effects that they can assume, or to decrease the toxicity, improving the risk / benefit ratio to the patient . In this context, the Laboratory of Drug Synthesis and Planning from the Federal University of Pernambuco selected several promising compounds in relation to anti-atherosclerosis activity. Among the compounds with best performances stood out Lyso-7, a derivative of thiazolidine-2 ,4-dione (5 - (5-bromo-1H-indol-3-metieleno) -3 - (4-chloro-benzyl) - thiazolidine-2, 4 - dione). The experimental results of the biological activity of the molecule showed its ability to inhibit leukocyte recruitment and increase vascular permeability, making the new TZD a candidate for anti-inflammatory drug. The activity of the compound is still being studied in order to elucidate the anti-inflammatory effects of the new compound and its promising application in therapeutics.According Waterbeend (2001), most of the failure of new drugs and medicines in the market is due to unfavorable pharmacokinetics and toxicity. Thus, besides the investigation of pharmacological activity, it is imperative to evaluate, in an early stage, the pharmacokinetic profile of Lyso-07 to avoid factors that may make future investments not viable for this drug candidate. Still, this pre-clinical stage is of great importance to any substance to reach subsequent clinical studies.This study aims to develop and validate an analytical method for the determination of Lyso-07 in plasma and assessment of pharmacokinetic profile of this drug in Wistar rats. (AU)

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PADILHA, Elias Carvalho. Desenvolvimento e validação de método bioanalítico aplicado em estudo de farmacocinética pré-clínica e ensaio preliminar de segurança de novo derivado de tiazolidinodiona com atividade antiinflamatória - LYSO-07. 2014. Master's Dissertation - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.

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