RESUMO
Topical aciclovir cream (ACV, Zovirax Cream) containing 40% propylene glycol (PG), the optimum found for skin penetration, is clinically effective in the treatment of recurrent herpes labialis. One hundred and thirty-nine ACV generic creams were analysed and 80% of these contained less than 20% PG. From this, we hypothesised that these generics might be bioinequivalent to the innovator cream. A pilot in vitro skin permeation study compared the innovator cream with two generics containing about 15% PG. Next, 10 generics containing 0-15% PG were tested in an independent laboratory. Finally, a PG dose-ranging study was conducted in Zovirax cream base. In all studies, human skin was used and ACV analysed by LC-MS-MS. In the pilot study, the innovator cream delivered 7.5-fold more ACV than the two generics. Superiority was confirmed in the second study against all 10 ACV generic creams. By grouping the creams according to PG content, a relationship to ACV skin permeation was suggested. The PG dose effect was confirmed in the third study. These studies suggest that not all marketed ACV creams are bioequivalent to the clinically proven innovator. Given the magnitude of the differences seen, there is concern over therapeutic inequivalence of generic ACV creams to the innovator cream.
Assuntos
Aciclovir/farmacocinética , Medicamentos Genéricos/farmacocinética , Pele/metabolismo , Aciclovir/química , Cromatografia Líquida , Cultura em Câmaras de Difusão , Medicamentos Genéricos/química , Excipientes/química , Humanos , Técnicas In Vitro , Espectrometria de Massas , Pomadas , Projetos Piloto , Polietilenoglicóis/química , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Equivalência TerapêuticaRESUMO
The importance of radical-induced damage to DNA is apparent from the ever-increasing number of publications in this area. This review focuses on the damage caused to DNA by reactive oxygen-centred radicals, however formed. These may be hydroxyl radicals, which arise either from the radiolysis of water by ionizing radiation (gamma-rays or X-rays), or from a purely chemical source. Alternatively, metal-bound oxyl radicals (M-O.) are also active intermediates in DNA-cleaving reactions and may be formed from synthetic compounds or from natural products such as bleomycin (BLM). Chemical mechanisms leading to the observed degradation products are covered in detail. The biological effects of some of the DNA base lesions formed are touched upon, concentrating on the molecular mechanisms behind the initial events that lead to mutagenesis.