title: Simvastatin ointment, a new treatment for skin inflammatory conditions.
abstract: BACKGROUND
  Statins represent a class of drugs that effectively lowers cholesterol, however they also possess pleiotropic effects, like promotion of angiogenesis, prevention of bone loss, immunomodulatory and anti-inflammatory effects.
  
  
  OBJECTIVE
  Thus, the aim of this study was to investigate the activity of simvastatin topically applied in mice in acute and chronic skin inflammation models.
  
  
  METHODS
  Skin inflammation was induced in mice ears by topical application of 12-O-tetradecanoylphorbol acetate (TPA). In the acute model, ear oedema was measured by the increase of ear thickness 6h after TPA (2.5μg/ear). The chronic inflammatory process was induced by multiple applications of TPA (2.0μg/ear) for nine alternate days, and the oedema was measured daily as the increase in ear thickness.
  
  
  RESULTS
  Topical treatment was applied immediately after TPA in acute model or started at 5th day of chronic experiment. For acute model treatment was simvastatin (0.24, 0.71 and 2.40μM), dexamethasone (0.13μM), both in acetone or vehicle alone (acetone). In chronic model simvastatin (1% and 3%) and dexamethasone (0.5%) were incorporated in ointment preparations, and a group received ointment alone (vehicle). Samples of ear tissue (6mm) were taken from acute and chronic models, weighted and prepared for histological analysis and myeloperoxidase (MPO) enzymatic activity evaluation. Application of simvastatin in acetone reduced the ear oedema after a single TPA application in a dose dependent manner [ID(50) of 0.47 (0.22-1.13) μM], and the MPO enzymatic activity up to 61±10%. Also, both simvastatin ointment preparations 1% and 3% reduced acute TPA-induced ear oedema in 55±7% and 65±8%, respectively. In the chronic model, simvastatin ointment 1% was able to reduce ear oedema (25±3%) and ear weight (10±1%), though 3% formulation augmented both parameters. Histological analysis revealed a reduction of swelling and leukocyte migration in the acute model for both the formulations of simvastatin (1% and 3%), while in chronic model simvastatin 1% decreased ear swelling and epidermal thickness, but simvastatin 3% increased both parameters.
  
  
  CONCLUSIONS
  The results confirm the anti-inflammatory activity of simvastatin when applied topically in both acute and chronic models of skin inflammation. Besides, the formulation of simvastatin ointment 1% shows to be a very effective formulation for a chronic usage.
authors.affiliation: Department of Pharmacology, Universidade Federal do Paraná, PR, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Adami
authors.forename: Arthur da Silveira
authors.initials: Ada S
authors.lastname: Prudente
authors.forename: Daniel Augusto Gasparin Bueno
authors.initials: DA
authors.lastname: Mendes
authors.forename: Cintia Delai da Silva
authors.initials: CD
authors.lastname: Horinouchi
authors.forename: Daniela Almeida
authors.initials: DA
authors.lastname: Cabrini
authors.forename: Michel Fleith
authors.initials: MF
authors.lastname: Otuki
mesh_terms: D000208:Acute Disease; D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D002908:Chronic Disease; D017453:Dermatitis, Irritant / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D009824:Ointments; D009195:Peroxidase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009824:Ointments; D018809:Proliferating Cell Nuclear Antigen; D019821:Simvastatin; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate