RESUMO
BACKGROUND: Celecoxib (CXB) has been explored as an anti-inflammatory or chemopreventive drug for topical treatment of skin diseases and cancer. OBJECTIVE: The main aim of this work was to investigate the potential of dimethylsufoxide (DMSO) and Azone (AZ) as penetration enhancers (P.Es) for topical delivery of CXB. METHOD: The in vitro studies, drug release, skin permeability and potential cytotoxicity/genotoxicity were carried out with formulations containing or not DMSO or AZ (5% and 10%). Skin irritation in rabbits and topical anti-inflammatory activity in mice were assayed in vivo. RESULTS: Skin permeation was minimal while higher retention in stratum corneum (SC) and epidermis plus dermis was found (28.0 and 3-fold respectively) from 10.0% AZ compared to the control indicating a localized CXB effect. CXB associated to 5% or 10% DMSO has shown high drug permeation through skin with low retention. Associations of CXB with both enhancers were not cytotoxic or genotoxic, suggesting safety for cutaneous application. In vivo skin irritation assays of all formulations indicated mild irritation effects and, thus, possible use for longer periods. In vivo anti-inflammatory tests showed that ear edema could be inhibited by CXB associated with 5.0% DMSO (53.0%) or 10.0% AZ (40.0%). These inhibition values were almost 2-fold higher when compared to a commercial formula. CONCLUSION: Although DMSO- associated CXB is an efficient edema inhibitor its high skin permeation suggests risks of systemic effects, whereas association to 10% AZ may improve topical delivery of the drug with good anti-inflammatory activity and no cytotoxic/genotoxic or significant skin irritation effects.
Assuntos
Azepinas/administração & dosagem , Celecoxib/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Dimetil Sulfóxido/administração & dosagem , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Azepinas/química , Azepinas/uso terapêutico , Celecoxib/química , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dimetil Sulfóxido/química , Dimetil Sulfóxido/uso terapêutico , Edema/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Masculino , Camundongos , Testes de Mutagenicidade , Coelhos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Irritação da Pele , SuínosRESUMO
Direct electric current has several therapeutic uses such as antibacterial and antiprotozoal action, tissues scarring and regeneration, as well as tumor treatment. This method has shown promising results in vivo and in vitro, with significant efficacy and almost no side effects. Considering lack of studies regarding direct electric current mutagenic and/or genotoxic effects, the present work evaluated both aspects by using five different bacterial experimental assays: survival of repair-deficient mutants, Salmonella-histidine reversion mutagenesis (Ames test), forward mutations to rifampicin resistance, phage reactivation, and lysogenic induction. In these experimental conditions, cells were submitted to an approach that allows evaluation of anodic, cathodic, and electro-ionic effects generated by 2 mA of direct electric current, with doses ranging from 0.36 to 3.60 Coulombs. Our results showed these doses did not induce mutagenic or genotoxic effects.
Assuntos
Eletricidade/efeitos adversos , Escherichia coli/genética , Testes de Mutagenicidade , Salmonella typhimurium/genética , Bacteriófagos/fisiologia , Farmacorresistência Bacteriana/genética , Escherichia coli/fisiologia , Escherichia coli/virologia , Viabilidade Microbiana/genética , Salmonella typhimurium/fisiologia , Salmonella typhimurium/virologiaRESUMO
Cisplatin is currently used in tumor chemotherapy to induce the death of malignant cells through blockage of DNA replication. It is a commonly used chemotherapeutic agent binding mono- or bifunctionally to guanines in DNA. Escherichia coli K12 mutant strains deficient in nucleotide excision repair (NER) were submitted to increasing concentrations of cisplatin, and the results revealed that uvrA and uvrB mutants are sensitive to this agent, while uvrC and cho mutants remain as the wild type strain. The time required for both gene expression turn-off and return to normal weight DNA in wild-type E. coli was not accomplished even after 4 h post-treatment with cisplatin, while the same process takes place within 1.5 h after ultraviolet radiation (UV). Besides, a heavily damaging action of cisplatin can be seen not only by persistent nicks on genomic DNA, but also by NER gene expression exceeding manifold that seen after equivalent lethal doses of UV. Moreover, cisplatin caused an increase in uvrB gene expression from its putative upstream promoter P3 in an SOS-independent manner.
Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Quebras de DNA de Cadeia Simples , Escherichia coli/genética , Resposta SOS em Genética/genética , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Mutação , Regiões Promotoras Genéticas , Transcrição Gênica , Raios Ultravioleta , Regulação para CimaRESUMO
Hydrogen peroxide is an important reactive oxygen species (ROS) that arises either during the aerobic respiration process or as a by-product of water radiolysis after exposure to ionizing radiation. The reaction of hydrogen peroxide with transition metals imposes on cells an oxidative stress condition that can result in damage to cell components such as proteins, lipids and principally to DNA, leading to mutagenesis and cell death. Escherichia coli cells are able to deal with these adverse events via DNA repair mechanisms, which enable them to recover their genome integrity. These include base excision repair (BER), nucleotide excision repair (NER) and recombinational repair. Other important defense mechanisms present in Escherichia coli are OxyR and SosRS anti-oxidant inducible pathways, which are elicited by cells to avoid the introduction of oxidative lesions by hydrogen peroxide. This review summarizes the phenomena of lethal synergism between UV irradiation (254 nm) and H2O2, the cross-adaptive response between different classes of genotoxic agents and hydrogen peroxide, and the role of copper ions in the lethal response to H2O2 under low-iron conditions.
Assuntos
Dano ao DNA , Escherichia coli , Peróxido de Hidrogênio , Cobre , Reações Cruzadas , Genoma , FerroRESUMO
Chemotherapeutic agents such as mitomycin C or nitrogen mustards induce DNA inter-strand cross-links (ICL) and are highly toxic, thus constituting an useful tool to treat some human degenerative diseases, such as cancer. Additionally, psoralens plus UV-A (PUVA), which also induce ICL, find use in treatment of patients afflicted with psoriasis and vitiligo. The repair of DNA ICL generated by different molecules involves a number of multi-step DNA repair pathways. In bacteria, as in eukaryotic cells, if DNA ICL are not tolerated or repaired via nucleotide excision repair (NER), homologous recombination or translesion synthesis pathways, these DNA lesions may lead to mutations and cell death. Herein, we bring new insights to the role of Escherichia coli nucleotide excision repair genes uvrA, uvrB and uvrC in the repair of DNA damage induced by some chemotherapeutic agents and psoralen derivatives plus UV-A. These new observations point to a novel role for the UvrB protein, independent of its previously described role in the Uvr(A)BC complex, which could be specific for repair of monoadducts, intra-strand biadducts and/or ICL.