Eur Respir J 2001; 17: 14±19
`Printed in UK ± all rights reserved
`
`Copyright #ERS Journals Ltd 2001
`European Respiratory Journal
`ISSN 0903-1936
`
`Ultrasonic versus jet nebulization of iloprost
`in severe pulmonary hypertension
`
`T. Gessler*, T. Schmehl*, M.M. Hoeper#, F. Rose*, H.A. Ghofrani*, H. Olschewski*,
`F. Grimminger*, W. Seeger*
`
`*Dept of Internal Medicine, Justus-
`Liebig-University of Giessen, Giessen,
`#Dept
`of Respiratory
`Germany,
`Medicine, Hannover Medical School,
`Hannover, Germany.
`
`Correspondence: W. Seeger
`Dept of Internal Medicine II
`Justus-Liebig-University
`Klinikstr. 36
`Giessen
`D-35392
`Germany
`Fax: 49 6419942359
`
`Keywords: Iloprost
`nebulization
`pulmonary hypertension
`
`Received: July 24 2000
`Accepted after revision October 4 2000
`
`Ultrasonic versus jet nebulization of iloprost in severe pulmonary hypertension.
`T. Gessler, T. Schmehl, M.M. Hoeper, F. Rose, H.A. Ghofrani, H. Olschewski,
`F. Grimminger, W. Seeger. #ERS Journals Ltd 2001.
`ABSTRACT: Inhalation of iloprost, a stable prostacyclin analogue, is a promising
`perspective in the treatment of pulmonary hypertension. In initial clinical studies, a
`conventional jet nebulizer system was successfully used to decrease pulmonary vascular
`resistance and pressure, requiring however, up to twelve inhalations of 12±15 min per
`day. The aim of this study was to investigate if the application of an equal dose of
`iloprost at a drastically reduced duration of inhalation with the use of a more ef®cient
`ultrasonic nebulizer, leads to comparable haemodynamic effects, without escalation of
`side effects.
`The physical features of the jet nebulizer system (Ilo-NebTM) and the ultrasonic
`nebulizer (Multisonic CompactTM) were characterized by laser diffractometry and a
`Tc99m-tracer technique. Mass median aerodynamic diameters were 3.2 mm for the jet
`and 3.9 mm for the ultrasonic nebulizer. Total output (mean‹sd) was 60‹7 mL.min-1
`(jet) and 163‹15 mL.min-1(ultrasonic), and ef®ciency of the devices was 39‹3% (jet) and
`86‹5% (ultrasonic). Based on these data, a total inhalative dose of 2.8 mg iloprost was
`delivered by jet nebulization within 12 min and by ultrasonic nebulization within 4 min,
`in 18 patients with severe primary and secondary pulmonary hypertension (New York
`Heart Association class III and IV), in a randomized crossover design. Haemodynamics
`were assessed by right heart catheterization.
`Inhalation with the ultrasonic device and jet nebulizer, reduced mean‹sem pulmonary
`artery pressure from 54.3‹2.1 to 47.1‹2.0 and from 53.5‹2.2 to 47.0‹2.2 mmHg,
`respectively, and mean‹sem pulmonary vascular resistance from 1073‹109 to 804‹87
`and from 1069‹125 to 810‹83 dyn.s.cm-5, respectively. Both modes of aerosolization
`were well tolerated.
`In conclusion, due to the markedly higher ef®ciency and output of the ultrasonic
`device, wastage of drug is largely avoided and the duration of inhalation can be
`shortened to one-third, with comparable haemodynamic effects and without enforcing
`side effects.
`Eur Respir J 2001; 17: 14±19.
`
`Severe pulmonary hypertension is a life threatening
`disease, characterized by an increase in arterial pres-
`sure and vascular resistance in the pulmonary circula-
`tion [1]. Dyspnoea and reduced exercise capacity are
`the prominent clinical symptoms; death is most closely
`associated with an increase in right atrial pressure and
`a decrease in cardiac output due to right-sided heart
`failure [2]. Several
`investigations with intravenous
`administration of prostacyclin have demonstrated the
`vasodilatory capacity of this prostanoid in primary
`pulmonary hypertension (PPH) [3±5] as well as in
`forms of secondary pulmonary hypertension (SPH) [6,
`7]. Moreover, in a controlled study continuous prosta-
`cyclin infusion was shown to improve exercise capacity
`and survival in patients suffering from severe PPH [8].
`Disadvantages of this intravenous approach are the
`lack of pulmonary selectivity, giving way to systemic
`side effects, as well as infectious complications related
`to the long-term use of an intravenous catheter.
`In a recent approach to overcome these short-
`comings, aerosolization of
`the stable prostacyclin
`
`analogue iloprost was employed for pulmonary vaso-
`dilation in both PPH and severe SPH [9±13]. Prefer-
`ential vasorelaxation in the pulmonary circulation was
`demonstrated with this approach, the maximum pul-
`monary vasodilatory potency corresponding to that of
`intravenous prostacyclin. At present, limited data on
`long-term clinical use of iloprost inhalation are avai-
`lable, indicating an improvement in exercise capacity
`and pulmonary haemodynamics after 12 months of
`iloprost aerosol therapy in 24 patients with PPH [14].
`Phase II
`(randomized, parallel-group comparative
`clinical) as well as phase III (double-blind, randomized,
`placebo-controlled clinical)
`studies addressing the
`impact of iloprost nebulization on exercise capacity
`and mortality in PPH and severe secondary pulmonary
`hypertension are currently under way.
`In all previous studies investigating short-term or
`long-term iloprost nebulization [9±14], a continuous
`output jet nebulizer with a reservoir and ®lter system
`was used. However, the limited output of this device
`requires long inhalation periods of 12±15 min for
`
`Liquidia's Exhibit 1062
`Page 1
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`

`

`ULTRASONIC VERSUS JET NEBULIZATION OF ILOPROST
`
`15
`
`delivery of an adequate iloprost dose for pulmonary
`vasodilation. Moreover, the therapeutic use of iloprost
`aerosolization in pulmonary hypertension demands
`multiple daily inhalation manoeuvres, since the pulmo-
`nary vasodilatory effect of each single inhalation levels
`off within y1 h, thus resulting in a total duration of
`inhalation of up to 3 h per day. In addition, limited
`ef®ciency of the jet nebulizer system causes a notable
`waste of the drug. Therefore, a reduction of inhalation
`time with the use of a more ef®cient nebulizer system
`will markedly improve iloprost aerosol therapy. A
`recently developed ultrasonic nebulizer device might
`offer the possibility to overcome these limitations.
`However, no data on aerosol delivery of prostanoids
`with this different technical approach are presently
`available. The present study characterized the physical
`features of the ultrasonic nebulizer. Based on these
`data, a comparison of the haemodynamic effects of an
`equivalent dose of iloprost delivered in a crossover
`design by the jet nebulizer within 12 min and the
`ultrasonic device within 4 min during right heart
`catheter tests, was performed. Patients with severe
`primary and secondary pulmonary hypertension were
`used. It was investigated whether the iloprost applica-
`tion at a notably shorter duration of inhalation would
`result in comparable pulmonary vasodilatory effects
`without enforcing side effects.
`
`Methods
`
`Physical characterization of the devices
`
`the devices were
`The following parameters of
`analysed: particle size distribution, total output of the
`nebulizer, effective output at
`the mouthpiece and
`aerosol loss in the different components of the device.
`Mass median aerodynamic diameter (MMAD) and
`geometric standard deviation (Gsd) of the aerosol were
`determined using a laser diffractometer (HelosTM;
`Sympatec, Clausthal, Germany) at room temperature
`and with a distance of 1 cm between mouthpiece and
`laser beam. The jet nebulizer system investigated in this
`study (Ilo-NebTM; Nebu-Tec company, Elsenfeld, Ger-
`many) consisted of a Bennett-RaindropTM jet nebulizer,
`a reservoir, ®lters, valves and tubes and was driven by a
`Pari BoyTM compressor (Pari, Starnberg, Germany) at
`80 kPa (®g. 1). For the ultrasonic nebulizer system
`(Multisonic CompactTM; Schill company, Probstzella,
`Germany) with an operating ultrasound frequency of
`1.7 MHz (®g. 2), an air¯ow of 40 L.min-1 was applied
`for particle size measurements. The ®lled-in volume was
`4 mL iloprost diluted in physiological saline for both
`devices.
`The total output of the nebulizers and the output at
`the mouthpiece were quanti®ed by a Tc99m-tracer-
`technique with an additional ®lter at the mouthpiece of
`the system for aerosol trapping. To mimic aerosol
`inhalation in patients, a volunteer performed the inha-
`lation manoeuvres through the ®lter at the mouthpiece
`(tidal volume y1.5 L, breathing frequency y11.min-1,
`inspiration:expiration ratio y1:1.8). After each inhala-
`tion period (12 min for the jet nebulizer, 4 min for the
`ultrasonic nebulizer), the systems were disassembled
`
`EF
`
`RF
`
`EV
`
`a)
`
`MP
`
`IV
`
`R
`
`JN
`
`C
`
`2%
`
`1%
`
`2%
`
`10%
`
`4%
`
`42%
`
`39%
`
`b)
`
`Fig. 1. ± Schematic depiction of a) the jet nebulizer device, with
`b) deposition fractions of a Tc99m-labelled test aerosol in the dif-
`ferent parts of the device being given as per cent of total output.
`In these experiments, the output at mouthpiece was captured in
`an additional ®lter mounted at this site. EF: expiration ®lter;
`EV: expiration valve; MP: mouthpiece; IV:
`inspiration valve;
`RF: reservoir ®lter; R: reservoir; JN: Bennett-RaindropTM jet
`nebulizer; C: PariboyTM Compressor.
`
`and the activity deposited in the various parts of the
`nebulizer was determined using a gamma-counter. The
`ef®ciency, de®ned as the ratio of the output at the
`mouthpiece to total output of
`the nebulizer, was
`calculated from the activities in the components.
`
`Patients
`
`A total of 18 patients with severe pulmonary hyper-
`tension was included in the investigation, all of whom
`were classi®ed as New York Heart Association class III
`or IV. Seven patients suffered from primary pulmonary
`hypertension and 11 patients showed pulmonary hyper-
`tension related to thromboembolism (six patients), con-
`nective tissue disease (three patients), lung ®brosis (one
`patient) and portal hypertension (one patient) (diag-
`nosis according to World Health Organization confe-
`rence [1]). Diagnostic procedures included transthoracic
`or transoesophageal echocardiography, chest radiog-
`raphy, high resolution and spiral computer tomography
`of the lung, ventilation-perfusion scans, lung function
`testing including carbon monoxide-diffusion capacity,
`pulmonary angiograms and pulmonary artery catheter.
`Baseline values for mean‹sem pulmonary artery pres-
`sure at rest, and pulmonary vascular resistance were
`54.1‹2.2 mmHg and 1076‹121 dyn.s.cm-5, respectively.
`All patients gave written informed consent to the test
`trial, which was approved by the local institutional
`ethics committees of the participating centres.
`
`Liquidia's Exhibit 1062
`Page 2
`
`

`

`16
`
`a)
`
`MP
`
`EF
`
`EV
`
`b)
`
`86%
`
`6%
`
`8%
`
`IF
`
`IV
`
`B
`
`O
`
`AC
`
`DC
`
`HA
`
`0%
`
`MU
`
`the ultrasonic nebulizer
`Fig. 2. ± Schematic depiction of a)
`device, with b) deposition fractions of a Tc99m-labelled test aero-
`sol in the different parts of the device being given as per cent of
`total output. In these experiments, the output at mouthpiece was
`captured in an additional ®lter mounted at this site. EF: expira-
`tion ®lter; EV: expiration valve; MP: mouthpiece; AC: aerosol
`chamber; DC: drug chamber; HA: hand apparatus; IV: inspira-
`tion valve; IF:
`inspiration ®lter; B: baf¯e; O: oscillator; MU:
`main unit.
`
`Catheter and inhalation protocol
`
`Before starting the device comparison with inhaled
`iloprost, a ®breoptic thermodilution pulmonary artery
`catheter was employed for measurement of pulmonary
`artery pressure (PAP), pulmonary artery wedge pres-
`sure (PAWP), central venous pressure (CVP) and
`cardiac output (CO). A femoral artery catheter was
`used to assess systemic arterial pressure (SAP). Based
`on these data, cardiac index (CI), pulmonary vascular
`resistance (PVR) and systemic vascular resistance
`(SVR) were calculated.
`in a
`Each patient
`inhaled with both devices
`randomized order. The ®rst inhalation was performed
`
`T. GESSLER ET AL.
`
`after achieving a stable baseline of haemodynamic
`variables; the second inhalation started 2 h after the
`end of the ®rst inhalation. PAP, PAWP, CVP, CO and
`SAP were recorded before (baseline) and 0, 5, 15, 30
`and 60 min after the end of each inhalation.
`For inhalation manoeuvres with the jet nebulizer,
`iloprost was diluted in saline to a ®nal concentration of
`10 mg.mL-1, and 4 mL of the solution were placed in the
`nebulizer. The nebulizer was then driven with room air
`at a pressure of 80 kPa for an inhalation period of
`12 min. For inhalation manoeuvres with the ultrasonic
`nebulizer system, iloprost was diluted in saline to a ®nal
`concentration of 5 mg.mL-1 and 4 mL of the solution
`were introduced into the nebulizer. Patients then
`inhaled the nebulized drug for a period of 4 min.
`This procedure was based on the physical characteriza-
`tions of the nebulizers, targeting to achieve an equi-
`valent dose (2.8 mg) of the vasodilatory prostanoid at
`the mouthpiece with both systems.
`
`Statistics
`
`All values are presented as means‹sem unless
`otherwise noted. Statistical comparisons of haemody-
`namic parameters at 0, 5, 15, 30 min after inhalation
`versus baseline (pre inhalation) were performed for each
`device using paired t-tests. The exact Wilcoxon matched
`pair signed-rank test was used if data did not show
`normal distribution in Kolmogorov-Smirnov tests. For
`multiple testing, the Holm correction was applied [15].
`To compare the in¯uence of the different devices on
`haemodynamic parameters, the differences of post
`versus pre inhalation values for both devices were
`calculated. These differences were analysed with the
`same statistical procedures as described above.
`
`Results
`
`The physical parameters of both nebulizers are
`shown in table 1. In ®gure 1 and 2,
`the aerosol
`deposition in the different parts of the devices is
`depicted: 61% of the generated aerosol was lost within
`the jet nebulizer device, compared to only 14% in the
`ultrasonic device. Based on these data, the "standard"
`iloprost aerosol application, as investigated in previous
`clinical studies with employment of the currently tested
`jet nebulizer device, was calculated to result in a total
`iloprost dose at the mouthpiece of 2.8 mg (12 min
`inhalation period, iloprost concentration 10 mg.mL-1).
`To achieve an equivalent dose when using the
`ultrasonic nebulizer device, the iloprost concentration
`was reduced to 5 mg.mL-1 and the inhalation time to
`4 min to match the higher output at the mouthpiece of
`the ultrasonic nebulizer.
`The kinetics of haemodynamic parameters pre-, and
`up to one hour postiloprost inhalation, for both devices
`are shown in ®gures 3 and 4. The iloprost inhalations
`with both devices were well tolerated. Side effects, such
`as cough or ¯ush occurred in only few patients to very
`moderate degrees and never led to discontinuation of
`inhalation. The iloprost delivery via both devices
`resulted in a signi®cant reduction of PAP, PVR and
`the PVR/SVR ratio, as well as in an increase of CI
`(®gs 3 and 4; table 2). In addition, some minor and
`
`Liquidia's Exhibit 1062
`Page 3
`
`

`

`ULTRASONIC VERSUS JET NEBULIZATION OF ILOPROST
`
`17
`
`Table 1. ± Comparison of physical parameters of
`nebulizer devices
`
`the
`
`MMAD mm
`Gsd
`Total output of nebulizer
`mL.min-1
`Output at mouthpiece
`mL.min-1
`Ef®ciency %
`
`Jet
`nebulizer
`system
`
`3.2‹0.1
`1.8‹0.0
`60‹7
`
`23‹3
`
`39‹3
`
`Ultrasonic
`nebulizer
`system
`
`3.9‹0.2
`1.6‹0.1
`163‹15
`
`140‹13
`
`86‹5
`
`Data are presented as mean‹sd; n=6. MMAD: mass median
`aerodynamic diameter; Gsd: geometric standard deviation.
`
`rapidly transient decrease in systemic arterial pressure
`was noted. All changes in haemodynamic variables
`largely levelled off within y1 h. There was no stati-
`stically signi®cant difference between responses to the
`jet and ultrasonic nebulization techniques, except for
`the CI, which increased more rapidly and more
`prominently when applying the iloprost dose in the
`ultrasonic nebulization manoeuvre, as compared to the
`standard jet nebulization protocol (increase in CI 0.44
`L.min-1.m-2 versus 0.19 L.min-1.m-2 assessed 5 min after
`termination of inhalation manoeuvre; p<0.05).
`
`Discussion
`
`The physical characterization of both the jet and
`ultrasonic nebulizers, demonstrated that particle sizes
`of both systems are within a range suitable for alveolar
`deposition [16±18]. Particle sizes of
`the presently
`investigated ultrasonic nebulizer (Multisonic Com-
`pactTM) are dependent on the gas ¯ow through the
`system; the applied ¯ow of 40 L.min-1 matches realistic
`mean inspiratory ¯ow conditions,
`resulting in a
`MMAD of 3.9 mm.
`the ultrasonic nebulizer
`The
`total output of
`(163 mL.min-1) is 2.7 times higher than that of the jet
`nebulizer. The difference between the two systems is
`even more pronounced with regard to the output at
`mouthpiece: this parameter, describing the amount of
`aerosol delivered de facto to the inhaling patient, is
`more than six times higher in the ultrasonic nebulizer
`system as compared to the jet nebulizer. This is mainly
`
`due to a notable aerosol loss at the inspiration valve of
`the jet nebulizer device (®g. 1), with preferential depo-
`sition of large particles. The design of the ultrasonic
`nebulizer does not require any valve in the inspiratory
`aerosol ¯ow, leading to a high ef®ciency of the device:
`86% of the total aerosol output is available at the
`mouthpiece for inhalation. Moreover, the ultrasonic
`device offers, due to its compact construction, the
`advantage of an easy handling and maintenance, as
`compared to the jet nebulizer.
`the
`Both systems avoid drug contamination of
`environment by the use of ®lters, thereby minimizing
`the risk of drug exposure to the medical staff. This is of
`particular importance when aerosolizing highly ef®ca-
`cious drugs, such as vasoactive agents or antibiotics, as
`demonstrated for pentamidine in recent studies [19, 20].
`Based on the data of the physical characterization,
`the inhalation time for delivery of an equivalent iloprost
`dose at the mouthpiece (2.8 mg) was reduced from
`12 min with the jet nebulizer system to 2 min with the
`ultrasonic nebulizer, when retaining the same concen-
`tration of the iloprost solution (10 mg.mL-1). In preli-
`minary catheter investigations, however, some increase
`in systemic side effects was observed when administer-
`ing the total iloprost dose of 2.8 mg via the inhalation
`route for such a short time period. Therefore, we
`reduced the iloprost concentration from 10 mg.mL-1 to 5
`mg.mL-1 when employing the ultrasonic nebulizer, and
`consequently doubled the inhalation time to 4 min with
`this device. This inhalation protocol was generally well
`tolerated. Furthermore, by diluting the prostanoid
`solution, drug waste in the dead space of the nebulizer
`was reduced.
`When directly comparing the haemodynamic effects
`of equivalent iloprost doses delivered either by jet or
`ultrasonic nebulization in a crossover design, a marked
`pulmonary vasodilation with a decrease in pulmonary
`artery pressure and pulmonary vascular resistance, and
`increase in CI was noted in response to both modes of
`aerosol administration. Strength and time course of
`the iloprost effect were comparable for both devices.
`Thus, the total amount of inhaled iloprost and not the
`duration of the inhalation manoeuvre (4 versus 12
`min) is obviously the main determinant for both the
`strength and the duration of the pulmonary vasodila-
`tion effect. This is also true for the systemic effects, as
`both modes of aerosol administration caused prefer-
`ential pulmonary vasodilation (re¯ected by a decrease
`
`Table 2. ± Haemodynamic parameters pre- and postinhalation (greatest effects)
`
`mPAP mmHg
`PVR dyn.s.cm-5
`CI L.min-1.m-2
`PVR/SVR
`mSAP mmHg
`SVR dyn.s.cm-5
`
`Jet nebulizer system
`
`Ultrasonic nebulizer system
`
`Pre
`
`53.5‹2.2
`1069‹125
`2.24‹0.17
`0.56‹0.04
`91.8‹3.8
`1877‹135
`
`Post
`
`47.0‹2.2
`810‹83
`2.48‹0.15*
`0.49‹0.04
`86.3‹2.7
`1612‹100
`
`Pre
`
`54.3‹2.1
`1073‹109
`2.22‹0.17
`0.56‹0.03
`90.6‹2.5
`1874‹124
`
`Post
`
`47.1‹2.0
`804‹87
`2.66‹0.19*
`0.50‹0.03
`82.5‹2.4
`1462‹113
`
`mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; CI: cardiac index; SVR: systemic vascular
`resistance; PVR/SVR: ratio of PVR tp SVR; mSAP: mean systemic artery pressure; Pre: pre-inhalation value; Post: extreme
`value up to 60 min postinhalation (all extreme values are minimums except those marked with * which are maximum). Values
`are given as mean‹sem for n=18 patients.
`
`Liquidia's Exhibit 1062
`Page 4
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`

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`I
`
`I
`
`I
`
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`
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`+++
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`+
`
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`
`T. GESSLER ET AL.
`
`a)
`
`0.6
`
`0.55
`
`0.5
`
`0.45
`
`0.4
`
`100
`
`90
`
`PVR/SVR
`
`b)
`
`mSAP mmHg
`
`I
`
`I
`
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`
`I
`
`**
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`+++
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`18
`
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`60
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`
`50
`
`45
`
`40
`
`mPAP mmHg
`
`b)
`
`1200
`
`1000
`
`I
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`
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`
`80
`
`70
`
`c)
`
`2100
`
`1800
`
`1500
`
`1200
`
`900
`
`SVR dyn·s·cm-5
`
`I
`
`***
`
`***
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`
`***
`
`***
`***
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`
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`
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`
`-10
`
`0
`
`10
`
`30
`20
`Time min
`
`40
`
`50
`
`60
`
`-10
`
`0
`
`10
`
`30
`20
`Time min
`
`40
`
`50
`
`60
`
`800
`
`600
`
`PVR dyn·s·cm-5
`
`c)
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`CI L·min-1·m-2
`
`Fig. 3. ± Responses of mean pulmonary artery pressure (mPAP),
`pulmonary vascular resistance (PVR) and cardiac index (CI) to
`iloprost inhalation (2.8 mg) via jet nebulizer (12 min; %) and
`ultrasonic nebulizer (4 min; &). To normalize for the different
`length of the inhalation period, time was set at zero at the end
`of the aerosolization manoeuvre for both techniques. Statistical
`differences between pre- and postaerosolization data are indica-
`ted for both approaches (*: p<0.05; **: p<0.01; ***: p<0.001 for
`ultrasonic nebulization; +: p<0.05; ++: p<0.01; +++: p<0.001 for
`jet nebulization).
`
`Fig. 4. ± Responses of the ratio of pulmonary vascular resis-
`tance to systemic vascular resistance (PVR/SVR), mean systemic
`artery pressure (mSAP) and systemic vascular resistance (SVR)
`to iloprost inhalation (2.8 mg) via jet nebulizer (12 min; %) and
`ultrasonic nebulizer (4 min &). To normalize for the different
`length of the inhalation period, time was set at zero at the end
`of the aerosolization manoeuvre for both techniques. Statistical
`differences between pre- and postaerosolization data are indica-
`ted for both approaches (*: p<0.05; **: p<0.01; ***: p<0.001 for
`ultrasonic nebulization; +: p<0.05; ++: p<0.01; +++: p<0.001 for
`jet nebulization).
`
`in the PVR/SVR ratio), with a very minor drop in
`systemic arterial pressure. Although not signi®cantly
`different by statistical analysis (excepting CI increase),
`there was a tendency for a more prominent pulmonary
`and systemic vasodilatation potency (with correspond-
`ing cardiac output response) in the early postaero-
`solization period upon employment of the ultrasonic
`
`nebulization manoeuvre. These observations might
`support the hypothesis of a spill-over to the systemic
`circulation and hence systemic vasodilatation acting as
`a driving force of increased cardiac output.
`The pulmonary vasodilator effect levelled off within
`y1 h, independent of the device used. Therefore, the
`inhalation frequency remains unchanged with up to 12
`
`Liquidia's Exhibit 1062
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`

`

`inhalations per day; the notably shorter duration of
`inhalation with the new device, however, may improve
`compliance and quality of life of the patients. Never-
`theless, the long-term impact of iloprost aerosol therapy
`in pulmonary hypertension patients has still to be
`con®rmed by the ongoing double-blind randomized
`studies.
`The maximum decrease in pulmonary artery pressure
`and resistance in response to 2.8 mg iloprost delivered
`by jet or ultrasonic nebulization in the present study
`ranged somewhat lower than the maximum pulmonary
`vasodilator effect previously described for this app-
`roach in severe pulmonary hypertension [9±13]. How-
`ever, these previous studies included mostly patients
`suffering from PPH or pulmonary hypertension asso-
`ciated to connective tissue disease. In contrast, the
`present investigation included more SPH than PPH
`patients, including six patients with severe pulmonary
`hypertension related to thromboembolism (classed as
`SPH patients). This fact may well explain the somewhat
`lower pulmonary vasodilator response in the present
`study as compared to the previous investigations with
`iloprost aerosol delivery.
`In conclusion, ultrasonic nebulization is suitable for
`inhalation of
`iloprost in severe pulmonary hyper-
`tension, inducing preferential pulmonary vasodilation.
`Markedly higher ef®ciency and output of the currently
`investigated ultrasonic device,
`in comparison to a
`standard jet aerosolization technique, avoids wastage
`of drug and allows shortening of the inhalation time to
`y30%, with comparable haemodynamic effects. The
`delivery of a standard iloprost dose of 2.8 mg in the
`notably reduced inhalation time did not induce side
`effects and was well tolerated by all patients. Long-term
`use of the ultrasonic nebulization device, performed
`in selected patients beyond the scope of the present
`study, as yet has shown no technical drawbacks. Thus
`employment of ultrasonic aerosol generation offers
`more effective alveolar deposition of vasoactive drugs
`in severe pulmonary hypertension, as compared to
`conventional jet nebulization.
`
`Acknowledgements. The authors thank M.
`Hollenhorst for statistical assistance and R.L.
`Snipes for carefully reviewing the manuscript.
`Parts of T. Gessler's thesis are incorporated into
`this report.
`
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