title: Inhaled recombinant interferon gamma in patients with lung cancer: pharmacokinetics and effects on chemiluminescence responses of alveolar macrophages and peripheral blood neutrophils and monocytes.
abstract: OBJECTIVE
  A Phase I trial was conducted to investigate clinical toxicity, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AM) and peripheral blood neutrophils and monocytes after inhalation of recombinant interferon (r IFN)-gamma.
  
  
  METHODS
  Eight patients with lung cancer inhaled r IFN-gamma as single doses of 0.1, 0.2, 0.6, 1.8, or 5.4 mg. Bronchoalveolar lavage was performed three times, 21 h before as well as 3 and 27 h after inhalation.
  
  
  RESULTS
  Interferon-gamma was detectable in bronchoalveolar lavage fluid (BALF) samples taken 3 h after inhalation in doses of > or = 0.6 mg. Before inhalation, AM in four out of seven patients studied showed vigorous lucigenin-enhanced CL responses to N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan particles. Furthermore, the responses were markedly increased 3 h after inhalation. In three out of seven patients, AM in the pretreatment BALF samples showed low or no CL responses, and the responses did not increase after inhalation of IFN-gamma, suggesting that the patients were anergic. Postinhalation CL responses did not correlate with the dose of IFN-gamma inhaled. Circulating IFN-gamma was detected in one patient receiving the highest dose. No changes referable to IFN-gamma inhalation were found in the CL responses of blood neutrophils and monocytes. During the 24 h follow-up, two patients developed transient fever-reactions.
  
  
  CONCLUSIONS
  The findings suggest that inhalation may provide a way to increase alveolar concentrations of IFN-gamma and to augment respiratory burst capacity of AM without any major side effects. This approach may have clinical implications for the treatment of tumors and infections of the respiratory tract.
authors.affiliation: Department of Pulmonary Medicine, Helsinki University Central Hospital, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Halme
authors.forename: P
authors.initials: P
authors.lastname: Maasilta
authors.forename: H
authors.initials: H
authors.lastname: Repo
authors.forename: M
authors.initials: M
authors.lastname: Ristola
authors.forename: E
authors.initials: E
authors.lastname: Taskinen
authors.forename: K
authors.initials: K
authors.lastname: Mattson
authors.forename: K
authors.initials: K
authors.lastname: Cantell
mesh_terms: D000328:Adult; D000336:Aerosols; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000188:drug therapy*; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016897:Respiratory Burst / Q000187:drug effects; D013997:Time Factors
chemical_list: D000336:Aerosols; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D007371:Interferon-gamma