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responses while having little effect on B-lymphocytes. Systemic treatment with CsA
is often associated with nephrotoxicity, hepatotoxicity, dyspnea, fatigue, and other
serious side effects, for which local drug delivery to the lungs may be more attrac-
tive, at least for lung transplantation. Pulmonary delivery of CsA was first reported
in an investigation by Burckart [183] in which the aerosolized CsA was adminis-
tered to normal anesthetized intubated dogs at the dose level of 200 mg daily for
eight doses via the endotracheal tube, and the blood and tissue concentrations were
measured. The studies showed that whole-blood CsA level and proximal and distal
airway CsA concentrations increased, with a negligible rise in kidney and heart tis-
sue, and the aerosolized administration of CsA did not appear to cause any damage
as measured by blood gases in the animals or by histological examination. With the
use of this radiolabeled nebulizer solution, pulmonary deposition studies were car-
ried out in five patients with chronic refractory rejection. Regional deposition of the
99m
Tc-tagged CsA was measured using a gamma camera, and the dose-delivered to
lung was ranged from 20 to 53 mg. A significant relationship was observed between
regional drug deposition and regional perfusion to the allograft. The plasma levels
peaked at 5 min, with bioavailability of 77.5
7.2% and 66.3
4.5%, respectively
[184]. The bioavailability of aerosolized CsA was 80.1
4.1% in adults. The inves-
tigators concluded that CsA was absorbed by the lungs into the systemic circulation
in rats in high concentrations, independent of age and type of delivery system.
9.6.1.2 Interferons
IFNs originally were recognized by their ability to induce resistance to viral infec-
tion and exert antitumor effects through a variety of mechanisms involving both
direct and indirect action on tumor cells. The human IFN-
class is a heterogeneous
group of polypeptides, which confer resistance to viruses on target cells, inhibit cell
proliferation, and regulate expression of MHC class I antigens. IFN-
α
β
is related to
IFN-
have been
found to share the same receptor and have very similar biological activities. IFN-
α
with about 30% amino acid sequence homology. IFN-
α
and IFN-
β
α
and IFN-
is known as a type II
IFN. The specific anatomy of the lung has supported the rationale of local therapy
with IFNs in an attempt to achieve high local drug concentrations with better activa-
tion of local effector cells, such as macrophages, and a decrease of systemic tox-
icity. Earlier animal studies and clinical experience with inhaled IFN was obtained
in two series of patients with bronchioalveolar carcinoma [151] showed that pulmo-
nary route was promisable route for the delivery of IFNs. In an another study [185],
healthy volunteers received doses ranging from 250 to 100
β
have been collectively called type I, whereas IFN-
γ
μ
g recombinant IFN-
γ
daily for 3 days. Each individual was evaluated by BAL before the first inhalation,
1 h after the first inhalation, and 24 h after the third inhalation. In a control group,
IFN-
g.
The study demonstrated that systemic (subcutaneous) administration was followed
by detectable levels of IFN in serum, but not in the ELF; the activation of blood
monocytes, but not of alveolar macrophages; and multiple systemic adverse effects.
With inhalational therapy, IFN-
γ
was administered subcutaneously at a maximally tolerated dose of 250
μ
γ
cannot be measured in serum but is detectable in
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