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Inhaled therapy for pulmonary hypertension is an interesting
concept as it offers selectivity of hemodynamic effects
for the lung vasculature, thus avoiding systemic side
effects. Selective pulmonary vasodilatation has been described
for inhaled nitric oxide (NO) but use of this agent has
several drawbacks. Most importantly, there are no data
demonstrating improved survival with long-term inhaled
NO treatment, and there is evidence that this agent possesses
less vasodilator potency than do the prostanoids in primary
pulmonary hypertension (PPH) patients.1,2 The intravenous
prostacyclin epoprostenol (Flolan) has been shown to improve
survival, exercise capacity, and hemodynamics in patients
with severe PPH.3-5 Epoprostenol has been approved for
treatment of PPH in the United States and several European
countries.
Iloprost, a Stable Prostacyclin
Analog
Iloprost is a prostacyclin analog that has the same biologic
profile as the natural substance with respect to prostaglandin
receptor binding and cellular effects.6 This explains
why during continuous intravenous use its effects as well
as its side effects are the same as those of epoprostenol.7
In contrast, the chemical stability is considerably different.
Epoprostenol has to be freshly dissolved, continuously
cooled, and protected from light to provide full activity,
while iloprost is stable at room temperature and normal
light. Epoprostenol has a half-life in vivo of 3 to 5
minutes, while iloprost has a serum half-life of 20 to
25 minutes.8
For these reasons iloprost has practical advantages for
daily use compared with epoprostenol, and it has been
approved for treatment of pulmonary arterial hypertension
(PAH) in New Zealand. While epoprostenol is available
in the United States and Europe, iloprost is not approved
for use in the United States.
The dosages used with continuous epoprostenol range between
10 and 50 ng/kg/min, while the dosages for continuous
intravenous iloprost range between 1 and 5 and rarely
up to 10 ng/kg/min. The reasons for this huge difference
have not been not fully elucidated but probably result
from a higher potency of iloprost (about 5:1) and the
different delivery method, as well as from more aggressive
dosing with intra-venous epoprostenol in the United States
compared with Europe.
Prostanoid Inhalation
Patients receiving prostanoids are prone to side effects
such as headache, jaw pain, leg pain, and diarrhea, and
there may be complications with the delivery system. These
findings are well documented for continuous intravenous
epoprostenol therapy 3,9,10 and have also been reported
with the subcuta-neous delivery of the prostacyclin preparation
treprostinil.11 Oral application of prostanoids (beraprost)
may decrease delivery-associated risks, but this therapy
has not yet proved effective in severe disease, although
in moderately ill PPH patients there was a significant
benefit in a controlled study.12
 In
order to selectively treat the pulmonary vessels in the
ventilated areas of the lung, inhaled prostacyclin and
ilo-prost were ultimately considered as treatment options.
Due to the fact that the intraacinar pulmonary arteries
are tightly surrounded by alveolar surfaces (Figure 1),
it is possible to vasodilate these vessels via the alveolar
deposition of a prostanoid. For acute vasodilator test-ing
with inhaled prostacyclin or iloprost, a special inhalation
device with a drug-saving reservoir for delivery of aerosols
is utilized.
For long-term therapy, repetitive inhalations with iloprost,
six to nine times per day are required (Figure 2). Each
inhalation takes approximately 10 to 15 minutes. With
newer devices, it is possible to reduce the inhalation
time to about 4 minutes 13 and to avoid noisy delivery
by using ultrasound energy for nebulization.
In patients with severe PAH, we have demonstrated that
inhalation of aerosolized iloprost results in a substantial
decrease in pulmonary artery pressure and pulmonary vascular
resistance. This decrease is concomitant with an increase
in cardiac output, in the absence of a significant decrease
in mean arterial pressure (Figure 3) or worsening ventilation-per-fusion
mismatch.14,15
In a statistical comparison of the effects of intravenous
epoprostenol and inhaled iloprost, the mean acute effect
on pulmonary vascular resistance was equal. However, during
treatment with inhaled iloprost, pulmonary artery pressure
decreased significantly and systemic artery pressure remained
stable, whereas during treatment with intravenous epoprostenol,
systemic pressure decreased significantly and pulmonary
artery pressure was minimally changed.14 These observations
were consistent with preceding findings in mechanically
ventilated patients with acute respiratory failure.16-22
In uncontrolled studies, inhaled iloprost was effective
in decompensated right heart failure 23 and led to favorable
long-term hemodynamic improvement.24
AIR Study
A large randomized double-blind placebo-controlled multicen-ter
study in Europe with inhaled iloprost has been performed
(Aerosolized Iloprost Randomized, AIR).25 A total of 203
patients with PPH or other forms of PAH were enrolled.
These included New York Heart Association (NYHA) Functional
Class III or IV patients with PAH due to appetite suppressants
or collagen vascular diseases and those with associated
or non-operable thromboembolic pulmonary hypertension.
In the ilo-prost and placebo groups, about 50% had PPH
and 50% had PAH of other causes. About 60% were in NYHA
Functional Class III and 40% in Functional Class IV.
The primary end point of the study, defined as an improve-ment
in NYHA Functional Class combined with at least 10% improvement
in the 6-minute walk test and no prior deteriora-tion
or death (combined clinical end point), was reached  by
3.4 times more patients in the iloprost group compared
with the placebo group (16.8% vs 4.9%; P = .007). Treatment
effects did not differ between subgroups. This effect
was achieved with a mean inhaled iloprost dosage of 0.37
ng/kg/min (Figure 4).
In the 6-minute walk test the treatment effect was 36.4
meters in favor of iloprost (P < .004, Figure 5). There
was a treatment effect with iloprost on NYHA Functional
Class (P < .05), quality of life assessments by means
of the EuroQoL visual analogue scale (P < .05), and on
the Mahler Dyspnea Transition Index (P < .05). Hemodynamics
significantly deteriorated in the placebo group, whereas
in the ilo-prost group, although preinhalation values
were unchanged compared with baseline, postinhalation
values were significantly improved. Importantly, the number
of patients remaining on study medication was significantly
higher in the iloprost than in the placebo group (Figure
6).
Over 3 months of therapy, there was no indication of
tachyphylaxis. In the iloprost group, 1 patient (1.0%)
died during the double-blind study period vs 4 patients
(4.0%) in the placebo group. Overall, iloprost therapy
was well tolerated. Cough, headache, and flushing occurred
more commonly in the iloprost group. These adverse events
were mild and mostly transient. Syncope occurring in the
iloprost group was more often rated as serious, compared
with the placebo group, but was commonly not associated
with clinical deterioration. It can be concluded from
this study that inhalation of iloprost is an effective
and safe therapy for patients with severe (NYHA Functional
Class III and IV) PPH and for patients with the other
causes of PAH that were studied.
Future Perspectives
In addition to treatment of PPH, the pulmonary selectivity
of inhaled iloprost provides the chance to safely apply
prostanoids in patients who are prone to systemic hypotension,
such as patients with portopulmonary hypertension, and
in emergency situations. The intrapulmonary selectivity
allows prostanoid application in patients who are prone
to intrapulmonary right-to-left shunt, such as patients
with pulmonary fibrosis.15 The inhaled application may
be combined with other effective treatments for PAH, although
this has not yet been studied in a controlled fashion.
A more specific positive interaction is the use of inhaled
iloprost in combination with phosphodiesterase (PDE) inhibitors.
The specific pulmonary vasodilating effects of iloprost
that may be mediated by an intracellular increase of cAMP
can be increased by blocking the breakdown of this second
messenger by means of PDE inhibition.26-31 We noticed
excellent clinical results with the combination of inhaled
iloprost and sildenafil, a specific PDE 5 inhibitor 32
and have been successfully using this combination for
more than a year in a considerable number of patients.
At present sildenafil is not approved for use as therapy
for PAH, but clin-ical studies are under way. Inhalation
intervals could be lengthened and pulmonary selectivity
could still potentially be achieved with the concominant
use of PDE inhibitors. This approach could also lead to
simpler delivery methods, such as via metered dose inhaler,
for treatment of PAH.
Conclusions
Inhaled iloprost has been shown to be effective for the
treat-ment of PAH and may provide an alternative to the
use of intravenous epoprostenol. When the clinical effects
of inhaled iloprost and intravenous epoprostenol are compared,
iloprost inhalation has clear advantages but also certain
drawbacks. Most importantly, inhalation provides potent
pulmonary vasodilatation with minimal systemic side effects
and no risk of catheter-related complications. Additionally,
iloprost could be considered as therapy in patients with
pre-existent ventila-tion- perfusion mismatch and in those
who are prone to devel-op such a mismatch during systemic
prostanoid application. The most important disadvantage
is the fact that the hemody-namic effects of inhaled iloprost
last only 30 to 90 minutes, and that six to nine inhalations
are needed to achieve good clinical results. In addition,
sustained hemodynamic improve-ment and long-term survival
with long-term use of inhaled ilo-prost have yet to be
demonstrated in more than a small num-ber of patients.
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