title: Diphenylhydantoin sodium promotes early and marked angiogenesis and results in increased collagen deposition and tensile strength in healing wounds.
abstract: BACKGROUND
  Sodium diphenylhydantoin (DpH) (phenytoin) was first introduced as an antiepileptic in 1938. One of its side effects, gingival hyperplasia, prompted investigation into the possible application of this drug as a promoter of wound healing. Since the late 1950s phenytoin has been used in a variety of clinical situations. However, its exact mechanism of action is still debated. The aim of this study was to determine the effect of DpH on wound healing in an incisional rat model.
  
  
  METHODS
  A four dorsal wound model was used, and each cephalad wound had a polyvinyl alcohol sponge placed in a subcutaneous pocket just above its cephalad end. Caudal and cephalad wounds were treated with 10 mg DpH in 200 microliters carrier, and the other two wounds received an equal volume of the saline vehicle as controls on the day of wounding and on the third and sixth postoperative days. The animals were killed on the tenth postwounding day. Tensile strength of fresh and fixed scars was determined using constant speed tensiometry, and wound hydroxyproline was determined spectophotometrically.
  
  
  RESULTS
  There was a highly significant increase in both fresh and fixed wound tensile strength of all DpH-treated wounds compared with controls (p < 0.001). This was reflected by a significant increase in polyvinyl alcohol sponge hydroxyproline in DpH-treated wounds compared with saline-treated wounds (p = 0.002). Histologic examination of these wounds was performed at 3 and 6 days after wounding. There was moderate fibroblast infiltration with a marked inflammatory infiltrate and neovascularization in the DpH-treated wounds compared with controls at 3 days. By day 6, the inflammatory infiltrate had almost totally receded in the treated wounds, but fibroblast infiltration and angiogenesis were still persistently marked. In comparison, the saline-treated wounds still had moderate inflammatory and fibroblast infiltrate and mild angiogenesis.
  
  
  CONCLUSIONS
  DpH alters the natural course of wound healing and may be of benefit in clinical situations where defective wound collagen deposition may lead to poor wound healing and consequent morbidity and mortality.
authors.affiliation: RCSI Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: M L
authors.initials: ML
authors.lastname: DaCosta
authors.forename: M C
authors.initials: MC
authors.lastname: Regan
authors.forename: M
authors.initials: M
authors.lastname: al Sader
authors.forename: M
authors.initials: M
authors.lastname: Leader
authors.forename: D
authors.initials: D
authors.lastname: Bouchier-Hayes
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010672:Phenytoin / Q000627:therapeutic use*; D011161:Porifera; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D010672:Phenytoin; D003094:Collagen; D006909:Hydroxyproline