A new diethylcarbamazine formulation (NANO-DEC) as a therapeutic tool for hepatic fibrosis.

The aim of the present study was to assess if the uninterrupted and prolonged administration of nanoparticles containing diethylcarbamazine (NANO-DEC) would cause liver, kidney and heart toxicity and then analyze for the first time its action in model of liver fibrosis. Thus, NANO-DEC was administered in C57BL/6 mice daily for 48 days, and at the end the blood was collected for biochemical analyzes. In the long-term administration assay, the evaluation of serological parameters (CK-MB, creatinine, ALT, AST and urea) allowed the conclusion that NANO-DEC prolonged administration did not cause hepatic, renal and cardiac damage. For fibrosis assays, C57BL/6 mice were divided into six groups: 1) control (Cont); 2) carbon tetrachloride (CCl4); 3) CCl4 + DEC 25 mg/kg; 4) CCl4 + DEC 50 mg/kg; 5) CCl4 + NANO-DEC 5 mg/kg and 6) CCl4 + NANO-DEC 12.5 mg/kg. Carbon tetrachloride induced hepatic fibrosis observed through increased inflammatory (TNF-α, IL-1ß, COX-2, NO and iNOS) and fibrotic markers (TGF-ß and TIMP-1), changes in the hepatic morphology, high presence of collagen fibers and elevated serum levels of AST, ALT and ALP. Treatment with NANO-DEC exhibited a superior anti-inflammatory and anti-fibrotic effects compared to the DEC traditional formulation, restoring liver morphology, reducing the content of collagen fibers and serological parameters, besides decreasing the expression of inflammatory and fibrotic markers. The present formulation of nanoencapsulated DEC is a well tolerated anti-inflammatory and anti-fibrotic drug and therefore could be a potential therapeutic tool for the treatment of chronic liver disorders.

New thiazolidinedione LPSF/GQ-2 inhibits NFκB and MAPK activation in LPS-induced acute lung inflammation.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are responsible for high mortality rates in critical patients. Despite >50 years of intensive research, there is no pharmacologically effective treatment to treat ALI. PPARs agonists, chemically named thiazolidinediones (TZDs) have emerged as potential drugs for the treatment of ALI and ARDS due to their anti-inflammatory efficacy. The present study aims to evaluate the potential anti-inflammatory effects of new TZDs derivatives, LPSF/GQ-2 and LPSF/RA-4, on ALI induced by LPS. BALB/c mice were divided into five groups: 1) Control; 2) LPS intranasal 25 µg; 3) LPSF/GQ-2 30 mg/kg + LPS; 4) LPSF/RA-4 20 mg/kg + LPS; and 5) DEXA 1 mg/Kg + LPS. BALF analyses revealed that LPSF/GQ-2 and LPSF/RA-4 reduced NO levels in BALF and inflammatory cell infiltration induced by LPS. MPO levels were also reduced by the LPSF/GQ-2 and LPSF/RA-4 pre-treatments. In contrast, histopathological analyses showed better tissue protection with LPSF/GQ-2 than DEXA and LPSF/RA-4 groups. Similarly, LPSF/GQ-2 reduced inflammatory markers (IL-1, iNOS, TNFα, IL-1ß, IL-6) better than LPSF/RA-4. The LPSF/GQ-2 anti-inflammatory action could be attributed to the inhibition of NFκB, ERK, p38, and PARP pathways. In contrast, LPSF/RA-4 had no effect on the expression of p38, JNK, NFκB. The present study indicates that LPSF/GQ-2 presents a potential therapeutic role as an anti-inflammatory drug for ALI.

Characterization and evaluation of nanoencapsulated diethylcarbamazine in model of acute hepatic inflammation.

Previous studies from our laboratory have demonstrated that Diethylcarbamazine (DEC) is a potent anti-inflammatory drug. The aim of the present study was to characterize the nanoencapsulation of DEC and to evaluate its effectiveness in a model of inflammation for the first time. C57BL/6 mice were divided into six groups: 1) Control; 2) Carbon tetrachloride (CCl4); 3) DEC 25mg/kg+CCl4; 4) DEC 50mg/kg+CCl4; 5) DEC-NANO 05mg/kg+CCl4 and 6) DEC-NANO 12.5mg/kg+CCl4. Liver fragments were stained with hematoxylin-eosin, and processed for Western blot, ELISA and immunohistochemistry. Serum was also collected for biochemical measurements. Carbon tetrachloride induced hepatic injury, observed through increased inflammatory markers (TNF-α, IL-1ß, PGE2, COX-2 and iNOS), changes in liver morphology, and increased serum levels of total cholesterol, triglycerides, TGO and TGP, LDL, as well as reduced HDL levels. Nanoparticles containing DEC were characterized by diameter, polydispersity index and zeta potential. Treatment with 12.5 nanoencapsulated DEC exhibited a superior anti-inflammatory action to the DEC traditional dose (50mg/kg) used in murine assays, restoring liver morphology, improving serological parameters and reducing the expression of inflammatory markers. The present formulation of nanoencapsulated DEC is therefore a potential therapeutic tool for the treatment of inflammatory hepatic disorders, permitting the use of smaller doses and reducing treatment time, while maintaining high efficacy.