Most drugs targeted to the respiratory tract are used for their
local action. For example, ephidrine for nasal decongestion, beta-2
agonists for bronchodilatation, and inhaled steroids to suppress the
inflammation seen in asthmatic airways. Since the drug is delivered
directly to its required site, only a small quantity is needed for
an adequate therapeutic response, and consequently there is a low
incidence of systemic side effects compared with oral or intravenous
administration. More recently, it has become apparent that the
lining of the respiratory tract, from nasal mucosa to airways and
alveoli, may be used for the absorption of a drug for its systemic
effect. This route of administration may be particularly attractive
if it avoids the metabolic destruction encountered when some drugs
are administered by alternative routes (for instance, peptides and
proteins are rapidly destroyed by peptidases when Oven by the oral
route). If there is a lack ofclinical response to an aerosolized
drug, it is important to question whether the drug has failed or
whether delivery to the site of action is inadequate. To deliver
therapeutic agents by inhalation to the lower respiratory tract,
inhaled drug particles must have appropriate aerodynamic
characteristics. In addition, the anatomy and pathophysiology of the
patient's respiratory tract, mode of inhalation through the
inhaler, and the characteristics of the inhalational device itself,
may significantly affect drug deposition.

C.  O'Callaghan

Targeting Drug Delivery to the Lungs by Inhalation

To compare the effectiveness of cromolyn sodium (CS)
(10 mg) and nedocromil sodium (NS) (4 mg) administered
by a metered dose inhaler (MDI) with a spacer
device in preventing exercise-induced asthma (EIA), eight
asthmatic children with EIA were studied in a
randomized double-blind, cross-over, placebo-controlled
study, CS and NS provided significant, comparable protection
from EIA and both were better than placebo. We
conclude that CS and NS administered by a pressurized
aerosol with a spacer device provide equal protection
against EIA in children.

F. M. de Benedictis

G.  Tuteri

A.  Niccoli

D.  Mezzetti

L.  Rossi

L.  Bruni

The Effect of Cromolyn Sodium and Nedocromil Sodium Administered by A pressurized Aerosol with A spacer
Device on Exercise-Induced Asthma in Children

Eighteen asthmatic children were challenged with ultrasonically
nebulized cold distilled water (UNCDW). Blood gas composition was
monitored transcutaneously (tcpO2 and tcpCO2)
during and after the challenge. Assuming as basal the response to
this UNCDW test, nine children (Group A) were then chosen at random
to inhale cromoglycate by aerosol delivery for 8 days. Nine children
(Group B), acting as a control, inhaled saline for 8 days. At the
end of this therapy, each child repeated the UNCDW test. Statistical
analysis with t-test for paired data was used to compare the results
of each child to both tests. Mean basal tcpO2 and
tcpCO2 were all within the expected normal range. In all
children, both mean tcpO2 and tcpCO2 were
reduced during and after UNCDW inhalation. Mean tcpCO2
values during the challenge were significantly (<mml:math alttext="$p &#60; 0.001$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) lower than the corresponding steady state 2 rain after the UNCDW
challenge, with a mean drop of &#8722;7% (2.1 S.D.). Mean
tcpO2 values remained significantly decreased
(<mml:math alttext="$p &#60; 0.001$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) from the fifth mitt of the UNCDW challenge to the end of the
observation period, with a mean drop of &#8722;20% (15.5
S.D.). After treatment with cromoglycate (Group A), the mean
tcpCO2 values during UNCDW did not change significantly
from those ofsteady state conditions: &#8722;0.8% (0.5 S.D.);
whereas mean tcpO2 values decreased by &#8722;4%
(4.9 S.D.). The control children treated with saline (Group B)
showed mean tcpCO2 and tcpO2 values which were
significantly different (<mml:math alttext="$p &#60; 0.001$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>p</mml:mi><mml:mo>&#60;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) from those of the steady
state conditions: mean drop of tcpCO2, &#8722;6%
(4.2 S.D.); mean drop of tcpO2, &#8722;20% (4.7
S.D.). In conclusion, it emerges that: UNCDW induces nonspecific
broncho-constriction in asthmatic children with a typical drop of
tcpCO2 and tcpO2; the treatment with
cromoglycate normalizes the time course of tcpCO2
(hyper-reactivity) and reduces dramatically the drop of
tcpO2 time course (hyper-responsivity) during and after
the UNCDW test.

L.  Mappa

S.  Bavaro

G.  Moramarco

D.  Torio

D.  Falciatore

G.  Ciccarone

L.  Cicciomessere

N.  Rigillo

Effect of Cromoglycate on Gas Changes, During Bronchial Challenge by UNCDW in Children with Asthma

To test the hypothesis that mononuclear cell products could increase
the expression of HLA-DR and ICAM-1 molecules in bronchial
epithelial cells (BECs), subconfluent cultures of human BECs,
obtained from surgically resected bronchi, were incubated with
PHA-activated blood mononuclear cell conditioned media (BCM-CM) or
recombinant IFN-γ. The presence of HLA-DR and ICAM-1 molecules
on BECs was then evaluated by specific antibody staining and
flow-cytometry analysis. The addition to BEC cultures of different
concentrations of PHA-stimulated BMC-CM, or of IFN-γ induced a
dosedependent increase of HIA-DR and ICAM-1 expression, while no
effect was observed with unstimulated BMC-CM. The ability of
nedocromil sodium and, as control, of dexamethasone, to prevent the
upregulation of HLA-DR and ICAM-1 expression on BECs was then
tested. Increasing concentrations (10−7 to 10−4 M) of nedocromil
significandy inhibited HLA-DR and ICAM-1 expression by BECs in a
dose-dependent fashion. A similarly dose-dependent inhibitory effect
was also observed with dexamethasone, which, however, was less
active than nedocromil on HL-ADR expression and more active on
ICAM-1 expression. Finally, nedocromil and dexamethasone showed a
significant synergistic effect on the expression of both cell
surface molecules at the lowest concentrations tested.

O. Sacco

S. Lantero

L. Scarso

V. Frangova

V. Ottolini

G. A. Rossi

The Increased Expression of HLA-DR and ICAM-1 Molecules by Human Bronchial Epithelial
Cells, Induced by Activated Mononuclear Cells, is Downregulated by Nedocromil Sodium

Johar C. de Jongste

Introduction: Anti-inflammatory Treatment of Childhood Asthma: Cromoglycate and
Nedocromil as Non-steroidal Alternatives?

The effect of nedocromil sodium on the plasma membrane fluidity of
polymorphonuclear leukocytes (PMNs) was investigated by measuring
steady-state fluorescence anisotropy of
1-[4-trimethylammonium-phenyl]-6-phenyl- 1,3,5-hexatriene (TMA-DPH)
incorporated in the membrane. Our results show that nedocromil
sodium 300 μM significantly decreased membrane fluidity of PMNs.
The decrease in membrane fluidity of PMNs induced by fMLP was
abolished in the presence of nedocromil sodium. These data suggest
that nedocromil sodium interferes with the plasma membranes of PMNs
and modulates their activities.

A. Kantar

N. Oggiano

P. L. Giorgi

G. V. Coppa

R. Gabbianelli

S. Bruni

F. M. Cutrona

R. Fiorini

Effect of Nedocromil Sodium on Polymorphonuclear Leukocyte Plasma Membrane

A. Corrias

Preface

Although basic mechanisms of bronchial hyper-responsiveness (BHR)
are still incompletely understood, inflammation of airways is likely
to play a fundamental role in modulating BHR in patients with
asthma. The involvement of several inflammatory cells (eosinophils,
mast cells, lymphocytes, neutrophils, macrophages and platelets) and
of bioactive mediators secreted by these cells in the pathogenesis
of asthma is well documented. Sodium cromoglycate and nedocromil
sodium are two pharmacological agents which have anti-allergic and
anti-inflammatory properties. Their clinical effectiveness in mild
to moderate asthma, and the capacity to reduce BHR under different
natural and experimental conditions, make them valuable drugs for
maintenance therapy in patients with asthma.

E. A. Valletta

A. L. Boner

Cromoglycate and Nedocromil: Influence on Airway Reactivity

The most appropiate management for bronchial asthma is the control
of airway inflammation. Corticosteroids are the most effective
anti-inflammatory drugs available, but they have a number of side
effects; most of these are dose-dependent. In children, asthma
control should be accomplished with low steroid doses possibly given
by inhalation. In a double-bind placebo-controlled crossover study a
group of children with mild to moderate asthma received NED 16
mg/day or BDP 400 &#956;g/day. Values for FEV1, PEF, symptoms use
ofbronchodilators overlapped, whereas bronchial hyper-responsiveness
assessed by histamine bronchoprovocation challenge was better with
BDP than NED. In another case, one boy with high bronchial
hyper-reactivity assessed by provocation test with hypertonic
solution, experienced a significant improvement only after 2 weeks
of therapy with Deflazacort (2 mg/Kg/day) followed by 4 months on
combined treatment with NED (16 mg/day) and BDP (300 &#956;/day). Authors
conclude that NED could have a steroidsparing effect over long-term use.

A. F. Capristo

M. Miraglia del Giudice Jr

C.  Alfaro

N.  Maiello

Corticosteroid-Sparing Effect of Chromoglycate Sodium and Nedocromil

The purpose of this study was to evaluate whether
nedocromil sodium benefits urban asthmatic children
showing seasonal bronchial hyper-reactivity to ultrasonic
nebulization of distilled water (UNDW). A prospective,
randomized, placebo-controlled, parallel-group,
double-blind study was carried out at the outpatient
pulmonology service at a tertiary-care teaching hospital.
Twelve children living in Milan, who were 7&#8211;17 years of
age, who were SPT and RAST-negative to perennial allergens,
who were suffering from episodic asthma, and
showing seasonal bronchial hyper-reactivity to UNDW
during winter, participated in this study. All the children
received either placebo or nedocromil sodium, 4 mg
every 6 h for 6 weeks. Spirometry and UNDW challenge
were done at the following times: day&#8722;7; day 0; day 1; day
7; day 14; day 28; day 42. No differences were found in
the basal spirometric parameters, which were normal in
both nedocromil and placebo groups. Bronchial reactivity
to UNDW was found to be significantly decreased in
the group treated with nedocromtl starting from day 7. It
is therefore concluded that nedocromil sodium can reverse
bronchial hyper-reactivity caused by seasonal factors
such as cold, viral infections and atmospheric pollutants
in children suffering from asthma.

A.  Fiocchi

P.  Signoroni

P.  Bruni

M.  Galeone

E.  DeCet

S.  Bogacki

Effect of Nedocromil Sodium on Aspecific Bronchial Hyper-Reactivity in Asthmatic Children

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