title: Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol.
abstract: The attenuated androgen Danazol can partially reverse the biochemical defect and prevent angioedema in patients with inherited C1-inhibitor (C1-INH) deficiency (hereditary angioedema, HAE). Though its clinical effectiveness is independent from significant increase of C1-INH plasma levels, its mechanism of action remains unknown. Since angioedema is a local phenomenon, it could be controlled by restoring tissue levels of C1-INH. We measured the expression of C1-INH mRNA in peripheral blood mononuclear cells (PBMCs) of 13 patients with HAE type 1 (seven untreated and asymptomatic, and six on Danazol at the minimal effective dose) and of eight normal controls. mRNA levels were quantitated by computerized optical densitometry of reverse transcriptase-PCR products, normalized for the amount of glyceraldehyde-3-phosphate-dehydrogenase and expressed as percent of normal pooled RNAs. Each determination represented the mean of three separate experiments. Measurement of C1-INH mRNA in two patients before and after 1 month of Danazol 400 mg per day demonstrated a post-treatment increase of 15 and 21%, respectively. When HAE patients and controls were analyzed as groups, C1-INH mRNA levels of patients untreated and asymptomatic (median 73%, range 65-78) were significantly lower (P=0.001) compared to controls (median 101%, range 87-121) and to patients on Danazol (median 91%, range 82-96); the difference among the last two groups was not statistically significant. Our data demonstrate that minimal effective doses of Danazol increase the expression of C1-INH mRNA in PBMC of HAE patients even in the absence of a significant increase of C1-INH plasma levels.
authors.affiliation: Department of Internal Medicine, IRCCS Maggiore Hospital, University of Milan, Via Pace 9, Milan 20122, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pappalardo
authors.forename: Lorenza C
authors.initials: LC
authors.lastname: Zingale
authors.forename: Marco
authors.initials: M
authors.lastname: Cicardi
mesh_terms: D000328:Adult; D000799:Angioedema / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D050718:Complement C1 Inhibitor Protein; D003181:Complement C4 / Q000032:analysis; D003613:Danazol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D003613:Danazol