Avaliação farmacológica de uma nanodispersão contendo GYY4137 (doador de liberação lenta de H₂S) na psoríase experimental.

Abstract

Psoriasis is a chronic inflammatory disease, immune-mediated, with a high world incidence, whose skin lesions and intense itching, reduce markedly the life quality of patients. Previously, the group has shown that systemic treatment with the slow release donor of hydrogen sulfide (H 2 S), GYY4137, significantly inhibited skin inflammation and itching in a experimental model of psoriasis induced by imiquimod (IMQ). In order to further this knowledge, the aims of this study were: i) to develop and characterize topical formulations (four microemulsion and one nanodispersion), as a vehicle for GYY4137; ii) to evaluate the therapeutic effect of the selected formulation on the itching behaviour, inflammation and Psoriasis Area Severity Index (PASI) in mice BALB/c iii) to evaluate differences in H 2 S generation in animal skin with psoriasis and iv) ascertain comparatively the pharmacological effect and toxicological potential of the selected formulation containing 4% GYY4137 in relation to the same formulation containing dexamethasone. Amongst the developed formulation, the nanodispersion proved to be less irritating in murine skin, since neither inflammation nor skin rash was observed in animals, unlike the other four preparations. The daily topical application of IMQ cream (5%; 65 mg; Germed, Brazil) in the mice shaved dorsal skin and ear surface, for five consecutive days, promoted itching as well as signs and symptoms consistent with the signs and symptoms of psoriasis (PASI) compared to the control group, which received the vehicle (Vaseline). Control or animals with psoriasis were treated daily once or twice with a nanodispersion (65 mg) containing GYY4137, dexamethasone or vehicle. PASI and pruritus were measured daily while the concentration of inflammatory cytokines (IL-6 and IL-1β), peripheral leukocytes, spleen, splenomegaly, myeloperoxidase activity (MPO) and other inflammatory markers were measured on the last (6 th) day. The therapy with one or two daily doses of nanodispersion containing 4% GYY4137 showed that two daily doses showed to be (P <0.05) more effective in reducing the inflammatory parameters and PASI, but only reduced, in a not significant manner, the itching behaviour. Animal with psoriasis also showed a reduction in H 2 S skin generation, wich was partially reversed by GYY4137 (4%, 2x/day) treatment. Regarding the formulation containing dexamethasone, it should be noted that the pharmacological effects were statistically similar to those obtained with 4% GYY4137, except that the effects produced by the latter was safer since neither systemic effects nor toxicological potential were observed. In conclusion, the treatment with the nanodispersion containing 4% GYY4137 exhibited safer therapeutic potential for reducing signs and symptoms associated with psoriasis.

Nanodispersões de fase líquido-cristalina como carreadoras de siRNA no tratamento tópico da psoríase: Avaliação em modelos in vitro e in vivo

“…A dispersão dos géis de fase cúbica e de fase hexagonal em água forma pequenas partículas denominadas "cubossomos" e "hexossomos", respectivamente e, comumente, é realizada por técnicas de fragmentação como a homogeneização em alta pressão ou sonicação (SIEKMANN et al, 2002;LOPES et al, 2006a;GUO et al, 2010a;MA;GUI, 2014 impostas pela pele, além de promover a penetração cutânea de macromoléculas e outros tipos de moléculas, conforme demostrado por trabalhos do grupo de pesquisa (LOPES et al, 2006a(LOPES et al, , 2006bSPERETTA;PRAÇA et al, 2012;PETRILLI et al, 2013PETRILLI et al, , 2016 VICENTINI et al, 2013b;ROSSETTI et al, 2016). Além disso, estudos prévios do grupo, demonstraram a habilidade de uma nanodispersão líquido-cristalina de fase hexagonal, composta por MO, pelo promotor de absorção cutânea ácido oleico e o polímero catiônico PEI, em promover a liberação cutânea de siRNA e reduzir os níveis da proteína modelo gliceraldeído 3-fosfato desidrogenase (GAPDH) (VICENTINI et al, 2013b).Simultaneamente a outros estudos reportados na literatura que também utilizaram sistemas à base de monoleína e adjuvantes catiônicos para a liberação funcional de siRNA (LEAL et al, 2010;ZHEN et al, 2012;BORGHETI-CARDOSO et al, 2014, 2015PETRILLI et al, 2016), ressaltam-se a relevância e aplicabilidade de sistemas líquido-cristalinos para veiculação de siRNA na terapia gênica. …”