title: Vitamin D and experimental invasive aspergillosis.
abstract: Immune cells express the vitamin D receptor and vitamin D metabolizing enzymes. Favorable vitamin D effects have been indicated in tuberculosis. Vitamin D deficiency increases T helper (Th) 2 responses to Aspergillus, and it suppresses Th2 responses in cystic fibrosis-allergic bronchopulmonary aspergillosis. Can vitamin D modulate the proinflammatory effects of amphotericin B (AmB) therapy in aspergillosis? Groups of mice were infected intravenously (IV) with 3-8 × 10(6) Aspergillus fumigatus conidia. In six experiments, doses of 0.08, 2, or 4 μg/kg calcitriol (active form of vitamin D) were given intraperitoneally +/- AmB-deoxycholate (AmBd) at 0.4, 0.8, 1.2, 1.8, 3.3, or 4.5 mg/kg or 0.8 or 1.2 mg/kg IV. Calcitriol doses were selected to range from doses used in humans to those just below doses shown to decalcify murine bones. In most experiments, doses of calcitriol and AmBd (or control diluents) were given five times, on alternate days, to minimize drug-drug interactions. Calcitriol treatment began on the day of challenge, and survival assessed for 10 days. In no experiments did calcitriol alone significantly worsen or enhance survival or affect residual infection in survivors. Calcitriol also did not affect the efficacy of AmBd. In a representative experiment, AmBd at 0.8 or 1.2 mg/kg IV alone +/- calcitriol at 2 μg/kg enhanced survival (P ≤ 0.01). However, the AmBd regimens with calcitriol were not different than those without, and calcitriol alone was identical to controls. In disseminated invasive aspergillosis, calcitriol did not affect outcome nor influence antifungal efficacy.
authors.affiliation: Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA, USA College of Letters and Sciences, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sirivoranankul
authors.affiliation: Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA, USA.
authors.forename: Marife
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Chen
authors.affiliation: Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA, USA Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA clemons@cimr.com.
authors.forename: Karl V
authors.initials: KV
authors.lastname: Clemons
authors.affiliation: Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, CA, USA Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D051379:Mice; D016019:Survival Analysis
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D002117:Calcitriol
keywords: Aspergillus fumigatus; amphotericin B; murine model; systemic aspergillosis; vitamin D