title: Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms.
abstract: OBJECTIVE
  To classify the headache syndromes under treatment with calcineurin inhibitors and to investigate whether the latter influence the nitric oxide production of human brain microvascular cells (HBMEC).
  
  
  BACKGROUND
  Single cases of cyclosporine-induced headaches have been reported. Since calcineurin inhibitors are known to influence the renal metabolism of NO, a key molecule in tension-type headache and migraine, we were interested whether calcineurin inhibitors might change NO metabolism in HBMEC as well.
  
  
  METHODS
  Headache symptoms of 74 patients receiving cyclosporine and/or tacrolimus for organ transplantation were retrospectively assessed. Furthermore, the effect of cyclosporine and tacrolimus on nitric oxide production in human brain microvascular endothelial cells was investigated after incubation.
  
  
  RESULTS
  Only 18 of the 74 patients reported no headache 1-36 months after liver, lung, or bone-marrow transplantation, 28 reported a new headache, and 17 an increase in the frequency or intensity of a pre-existing headache. The headache was generally classified as migraine without aura (IHS 1.1) or migraine-like headache (IHS 1.6). Furthermore, we found significantly increased NO production after co-incubation of calcineurin inhibitors with human brain microvascular endothelial cells.
  
  
  CONCLUSIONS
  The pathophysiological mechanism of these headaches may be connected with an endothelial dysfunction in terms of increased production of NO.
authors.affiliation: Klinikum Grosshadern, Department of Neurology, Munich, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Ferrari
authors.forename: Monika
authors.initials: M
authors.lastname: Empl
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
authors.forename: Petra
authors.initials: P
authors.lastname: Sostak
authors.forename: Stefanie
authors.initials: S
authors.lastname: Förderreuther
authors.forename: Andreas
authors.initials: A
authors.lastname: Straube
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000098:blood supply; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006261:Headache / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*; D019737:Transplants
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D016559:Tacrolimus