title: Doxorubicin chemomyectomy in orbicularis oculi: increasing drug infiltration at the injection site.
abstract: OBJECTIVE
  Doxorubicin is an effective agent for chemomyectomy of the orbicularis oculi muscle when injected directly into the eyelid. However, the amount of muscle loss often differs throughout the medial to lateral extent of the eyelid. In order to increase uniform muscle loss in rabbit eyelids, doxorubicin was injected together with agents known to increase the spread of drugs at their injection site in an attempt to increase infiltration of the doxorubicin in the plane of the orbicularis oculi muscle.
  
  
  METHODS
  Three agents were injected, singly or in combination, 20 min prior to doxorubicin administration. Drugs included: collagenase, hyaluronidase, bupivacaine, and hyaluronidase and bupivacaine together. Doxorubicin was injected at a dose of either 0.5 mg, 1 mg or 2 mg. Muscle loss from the co-treatments was compared with that seen with doxorubicin alone as assessed by light microscopic morphometric analysis of the treated eyelids one month after treatment.
  
  
  RESULTS
  Injection of doxorubicin alone resulted in a dose-related muscle loss. Injections of either collagenase or hyaluronidase prior to doxorubicin treatment did not alter muscle loss compared with doxorubicin alone. The combination of hyaluronidase and bupivacaine slightly increased muscle loss over doxorubicin alone at the lower doses of doxorubicin. Muscle loss was increased further after doubling the dose of hyaluronidase. Collagenase pretreatment exacerbated eyelid skin injury. Hyaluronidase did not influence the skin toxicity of doxorubicin at doses of 1 or 2 mg, but did result in a delayed onset and a shorter duration of skin injury at the 0.5 mg dose of doxorubicin.
  
  
  CONCLUSIONS
  Only hyaluronidase combined with bupivacaine increased doxorubicin induced myotoxicity in the orbicularis oculi muscle, presumably by increasing doxorubicin infiltration at the intramuscular injection site throughout the length of the muscle fibers. Thus, the combined injection of hyaluronidase and bupivacaine prior to doxorubicin treatment improves doxorubicin chemomyectomy by increasing drug infiltration throughout the full extent of the orbicularis oculi muscle. Future studies will be directed at achieving better penetration of the drug into individual muscle cells.
authors.affiliation: Department of Ophthalmology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: McLoon
authors.forename: J D
authors.initials: JD
authors.lastname: Wirtschafter
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002045:Bupivacaine / Q000494:pharmacology; D017364:Collagenases / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004338:Drug Combinations; D005143:Eyelids / Q000187:drug effects* / Q000294:innervation / Q000473:pathology; D005152:Facial Muscles / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D009121:Muscle Denervation / Q000379:methods; D009801:Oculomotor Muscles / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D011817:Rabbits
chemical_list: D000779:Anesthetics, Local; D000903:Antibiotics, Antineoplastic; D004338:Drug Combinations; D004317:Doxorubicin; D006821:Hyaluronoglucosaminidase; D017364:Collagenases; D002045:Bupivacaine