Thomas Schmehl

Inhaled iloprost To treat severe pulmonary hypertension : An uncontrolled trial

Progressive right-heart failure is the ultimate cause of death for most patients with primary pulmonary hypertension. The prognosis is particularly poor for patients with New York Heart Association functional class IV disease and severely increased central venous pressure (1). Prostacyclin was the first drug shown to be life-saving in a controlled study of primary pulmonary hypertension (2). However, the lack of pulmonary selectivity of the vasodilatory effect and consequent systemic side effects limit the usefulness of prostacyclin (3). Patients with severe arterial hypotension and preexistent shunt areas in the lung often cannot tolerate intravenous prostacyclin (4-6). Inhaled nitric oxide has pulmonary selectivity, but its vasodilatory potency in the pulmonary vasculature is lower than that of prostacyclin (7, 8). Because nitric oxide has a short half-life, interruption of nitric oxide inhalation may provoke an immediate rebound hypertensive crisis (9, 10). In patients with severe primary or secondary pulmonary hypertension, we recently demonstrated that inhalation of aerosolized iloprost, the stable analogue of prostacyclin, substantially decreases pulmonary artery pressure and resistance and increases cardiac output without a significant decrease in systemic artery pressure and ventilation-perfusion mismatch (11, 12). This observation was consistent with previous findings in mechanically ventilated patients with acute respiratory failure, in whom aerosolized vasodilatory prostanoids effected selective pulmonary vasodilatation and preferential distribution of the nebulized vasodilator to the best-ventilated lung areas, with improvement of ventilation-perfusion matching (5, 12-18). We also reported on a patient with circulatory shock and right ventricular decompensation due to severe primary pulmonary hypertension (4) and a patient with decompensating right-heart failure due to collagen vascular disease-induced lung fibrosis (5). Both conditions were refractory to maximum conventional therapy; inhaled iloprost, however, seemed to improve hemodynamics and long-term survival. We extended these findings in an open, uncontrolled trial of 19 patients with primary or secondary pulmonary hypertension, all of whom presented with life-threatening pulmonary hypertension and progressive right-heart failure. Methods Patients Between May 1995 and May 1998, we enrolled 19 patients with severe pulmonary hypertension from six university hospitals in Germany. Eighty-seven patients were eligible for therapy with inhaled iloprost, but we enrolled only patients who met criteria for clinical instability. Clinical instability was defined as the occurrence of at least one of the following: 1) rapid deterioration of exercise tolerance, as indicated by a decrease of more than 30% in the distance walked in 6 minutes in the past 1 to 2 months; 2) central venous pressure of 17 mm Hg or higher during physical rest with adequate diuretic therapy; 3) cardiogenic edema that was refractory to intravenous diuretic therapy; 4) cardiogenic ascites or pleural effusion that was refractory to diuretic therapy; 5) hepatic failure, indicated by an increase in bilirubin level above 86 mol/L [5 mg/dL] or aminotransferase levels more than three times the upper limit of normal; 6) renal failure, as indicated by a creatinine concentration greater than 159 mol/L [1.8 mg/dL] or oligoanuria; or 7) cardiogenic somnolence. Severe pulmonary hypertension was diagnosed in all patients before study entry. Diagnostic procedures included transthoracic and, in most cases, transesophageal echocardiography; chest radiography; high-resolution computed tomography of the lung; spirometry; measurement of carbon monoxide diffusion capacity; electrocardiography; and laboratory measurements, including thyroid hormones, antinuclear antibodies, and extractable nuclear antigens. Ventilation and perfusion scanning of the lung and spiral computed tomography or pulmonary angiography were done if pulmonary embolism was suspected. We excluded patients with fresh lung embolism or chronic lung embolism of central or segmental vessels and patients with active interstitial lung disease requiring high-dose steroids or immunosuppressant therapy. Patients with disorders of the left ventricle, mitral or aortic valve disease, severe liver disease, or hemorrhagic diathesis were not eligible. All patients gave written informed consent. The study was approved by the local ethics committees of all participating centers. Intervention Iloprost (Ilomedin, Schering AG, Berlin, Germany) was diluted in 0.9% saline (10 g/mL), jet-nebulized with room air at a pressure of 80 kPa (fluid flux, 0.07 mL/min; mass median aerodynamic diameter of particles, 3.2 m; geometric SD, 1.8 as determined by impactor technique) and delivered to a spacer connected to the afferent limb of a Y-valve mouthpiece for 12 to 15 minutes (total nebulized dose, 8.4 to 10.5 g). Patients inhaled 6 to 12 times daily after the baseline examination was performed. The frequency of inhalations was adjusted as necessary according to decreasing physical capacity or anginal symptoms between doses. The single dose was reduced if adverse effects (such as nausea) occurred during inhalation of the full dose. Patients were taught how to prepare the inhalation device and administer the drug by hospital staff. Study Protocol Before therapy with inhaled iloprost was started, a fiberoptic thermodilution pulmonary artery catheter was used to measure central venous pressure, pulmonary artery pressure, pulmonary artery wedge pressure, cardiac output, and central venous oxygen saturation (Svo2); a femoral artery catheter was used to measure systemic arterial pressure and systemic arterial oxygen saturation (Sao 2). The test trial included inhaled nitric oxide, 20 to 40 parts per million, and aerosolized iloprost as described above. Catheter studies were repeated after 3 months of therapy with inhaled iloprost. One patient (patient 17) entered the study 48 hours after start of therapy with intravenous prostacyclin for decompensating right-heart failure. On initiation of therapy with inhaled iloprost, the dose of intravenous prostacyclin was reduced in a stepwise manner from 20 ng/kg of body weight per minute to 0 within 1 week. In this patient, no baseline test with inhaled iloprost and nitric oxide was performed. The time from the diagnosis of clinical instability to the start of therapy was no more than 2 weeks. After hospital discharge, the investigators who performed the baseline measurements saw the patients every 4 weeks. At these visits, lung function tests and blood gas analysis were performed and patients were asked about adverse effects. Between study visits, patients were managed by their own physicians but could call the investigator if any problems occurred. The primary outcome of the study was the change in physical capacity in 3 months, assessed by the distance walked in 6 minutes. In addition, we monitored hemodynamic changes during short-term and long-term therapy with inhaled iloprost and followed patients until death, transplantation, or any other cause of cessation of therapy. Statistical Analysis Data are presented as the mean (SD) unless otherwise noted. The exact Wilcoxon matched-pair signed-rank test was used to assess the acute effects of inhaled iloprost (comparison of mean values before and after inhaled iloprost application) and the changes during 3 months of therapy (comparison of mean values at baseline and at 3 months) in the 12 patients for whom complete hemodynamic measurements at baseline and 3 months were available. Changes were assessed by using the Hodges-Lehmann point estimate, and the corresponding exact 95% CIs were calculated. For the 6-minute walk test, we assigned a value of 0 m to patients who had died in the 3 months from the start of iloprost therapy instead of doing a last-observation-carried-forward analysis. To calculate the Hodges-Lehmann point estimate and the 95% CIs, only the valid pairs were used: that is, patients who could not walk at baseline or at 3 months were excluded from analysis. A P value less than 0.05 was considered statistically significant. Role of the Funding Source The preparation and evaluation of data in this multicenter study was supported by PPH e.V., a German nonprofit patient self-care organization, and by the Deutsche Forschungsgemeinschaft. The conduct and reporting of the trial were not influenced by these organizations. Results Patient Characteristics All patients had clinical instability (Table 1). Seventeen patients had rapid deterioration; 12 had refractory edema, ascites, or pleural effusion; and 4 had commencing organ failure. Underlying disease was primary pulmonary hypertension in 12 patients, pulmonary hypertension associated with the CREST syndrome (calcinosis cutis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) without pulmonary fibrosis (isolated pulmonary hypertension) in 3 patients, chronic peripheral lung embolism in 2 patients, and lung fibrosis in 2 patients. No patient had taken anorexigens, and none had liver cirrhosis or HIV infection. Table 1. Patient Characteristics at Baseline and 3 Months Concomitant therapy included diuretics and anticoagulant agents in every patient. Seven patients were receiving long-term therapy with calcium antagonists before catheterization and continued to take these agents during therapy with inhaled iloprost. No patient began taking a calcium antagonist along with inhaled iloprost. Only one patient (patient 17) previously received intravenous prostanoids; this patient had received intravenous prostacyclin 48 hours before therapy with inhaled iloprost was started. The mean age of the patients was 39 14 years (Table 1). Patients with the CREST syndrome were, on average, older than those with primary pulmonary hypertension (58 12 years compared with 34 11 years). The physical capacity of the

Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension

For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean±sem age 62±11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863±38 dyn·s·cm−5) and a 6-min walking distance of 310±11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months’ treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759±62 dyn·s·cm−5. The 6-min walking distance increased significantly to 361±15 m after 3 months’ treatment, and to 366±18 m after 12 months’ treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long-term outcome of therapy.

Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features

Nanoparticles may be effective drug delivery systems for use in various pulmonary therapeutic schemes. This study investigated the effect of nebulization technology and nanoparticle characteristics on the features of aerosol generation. Suspensions of biodegradable nanoparticles consisting of commercially available poly(lactide-co-glycolide) and novel comb polymers were nebulized with a jet, ultrasonic, and piezo-electric crystal nebulizer. The effects of the nanoparticle suspensions on the aerosol droplet size, as well as the nanoparticle size before and after nebulization, were characterized via laser diffraction. While the individual nanoparticle suspensions showed no clinically relevant influence on aerosol droplet size, as compared to control experiments, an enhanced nanoparticle aggregation within the droplets was observed. This aggregation was further characterized by fluorescence and scanning electron microscopy. Dependency of aggregation on nebulizer technology and nanoparticle characteristics was noted. Nanoparticles exhibiting the highest surface hydrophobicity were particularly susceptible to aggregation when nebulized with a jet nebulizer. Aggregation was reduced with nanoparticles exhibiting a more hydrophilic surface or when using ultrasonic nebulizers. We conclude that the biodegradable nanoparticles contained in the suspensions did not affect the aerosol droplet size in a clinically relevant manner; however, both the nanoparticle characteristics and the technique of aerosol generation influence nanoparticle aggregation occurring during aerosolization.

Ultrasonic versus jet nebulization of iloprost in severe pulmonary hypertension

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 efficient ultrasonic nebulizer, leads to comparable haemodynamic effects, without escalation of side effects. The physical features of the jet nebulizer system (Ilo-Neb) and the ultrasonic nebulizer (Multisonic Compact) were characterized by laser diffractometry and a Tc99m-tracer technique. Mass median aerodynamic diameters were 3.2 microm for the jet and 3.9 microm for the ultrasonic nebulizer. Total output (mean+/-SD) was 60+/-7 microL.min(-1) (jet) and 163+/-15 microL.min(-1)(ultrasonic), and efficiency of the devices was 39+/-3% (jet) and 86+/-5% (ultrasonic). Based on these data, a total inhalative dose of 2.8 microg 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 1,073+/-109 to 804+/-87 and from 1,069+/-125 to 810+/-83 dyn.s.cm(-5), respectively. Both modes of aerosolization were well tolerated. In conclusion, due to the markedly higher efficiency 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.

Characterization of novel spray-dried polymeric particles for controlled pulmonary drug delivery.

Numerous studies have addressed the controlled pulmonary drug delivery properties of colloidal particles. However, only scant information on the potential of spray-drying for submicron particle preparation is available. By exploiting the advantages of spray-drying, the characteristics of submicron particles can be optimized to meet the requirements necessary for lung application. Submicron particles were prepared from organic poly(d,l-lactide-co-glycolide) (PLGA) solutions, and composite particles were spray-dried from aqueous PLGA nanosuspensions. The feed concentration, as well as the spray-mesh diameter influenced the resulting particle sizes. Nanoparticles were virtually unaffected after spray-drying. The aerodynamic characteristics of both particle species revealed aerosol particle sizes suitable for deposition in the deep lungs (≤4μm). While the entrapped drug was released within ~90min from the composite particles, extensive drug retardation (~480min) was observed for PLGA particles spray-dried from organic solution. These results suggest that nanospray-drying is a convenient method to prepare submicron, controlled drug delivery vehicles useful for pulmonary application potentially allowing access to alveolar tissue.

Pulmonary drug delivery with aerosolizable nanoparticles in an ex vivo lung model

The use of colloidal carrier systems for pulmonary drug delivery is an emerging field of interest in nanomedicine. The objective of this study was to compare the pulmonary absorption and distribution characteristics of the hydrophilic model drug 5(6)-carboxyfluorescein (CF) after aerosolization as solution or entrapped into nanoparticles in an isolated rabbit lung model (IPL). CF-nanoparticles were prepared from a new class of biocompatible, fast degrading, branched polyesters by a modified solvent displacement method. Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, aerosol characteristics as well as pulmonary dye absorption and distribution profiles after nebulization in an IPL were investigated. CF-nanoparticles were spherical in shape with a mean particle size of 195.3+/-7.1nm, a polydispersity index of 0.225+/-0.017 and a zeta-potential of -28.3+/-0.3mV. Encapsulation efficiencies of CF were as high as about 60% (drug loading of 3% (w/w)); 90% of the entrapped CF were released during the first 50min in vitro. Nanoparticle characteristics were not significantly affected by the aerosolization process utilizing a vibrating mesh nebulizer. After deposition of equal amounts of CF in the IPL, less CF was detected in the perfusate for CF-nanoparticles (plateau concentration 9.2+/-2.4ng/ml) when compared to CF aerosolized from solution (17.7+/-0.8ng/ml). In conclusion, the data suggest that inhalative delivery of biodegradable nanoparticles may be a viable approach for pulmonary drug delivery. Moreover, a targeting effect to the lung tissue is claimed.

Surfactant-Free, Biodegradable Nanoparticles for Aerosol Therapy Based on the Branched Polyesters, DEAPA-PVAL-g-PLGA

AbstractPurpose. This study describes the development of surfactant-free, biodegradable nanoparticle systems with varying physicochemical properties and their suitability for pulmonary application via nebulization. Methods. Nanoparticle suspensions were formulated from the branched polyester, diethylaminopropyl amine-poly(vinyl alcohol)-grafted-poly(lactide-co-glycolide) (DEAPA-PVAL-g-PLGA) alone, as well as with increasing amounts of carboxymethyl cellulose (CMC). Particle size, ζ potential, turbidity, and morphology (atomic force microscopy) were characterized. Three formulations were chosen for further study: Cationic nanoparticles without CMC, cationic nanoparticles with CMC, and anionic nanoparticles with an excess of CMC. Nanoparticle degradation was characterized, as well as stability during nebulization. Nanoparticle-cell interactions were investigated and quantified using confocal laser scanning microscopy and fluorescence spectrometry. Results. Nanoparticles ranged in size from 70-250 nm and displayed ζ potentials of +58.9 to −46.6 mV. Anionic nanoparticles showed the highest stability during nebulization. The degradation rate of each nanoparticle formulation decreased with increasing amounts of CMC. Cell association was highest among cationic nanoparticles (57% and 30%, respectively), although these were not internalized. Despite a lower rate of cell association (3%), anionic nanoparticles were internalized by A549 cells. Conclusions. Surfactant-free nanoparticles from DEAPA-PVAL-g-PLGA are versatile drug delivery systems; however, only the anionic formulations investigated were proven suitable for aerosol therapy.

Inhaled prostanoids in the therapy of pulmonary hypertension.

Prostacyclin and prostacyclin analogues are potent vasodilators and possess antithrombotic, anti-inflammatory and antiproliferative properties. These properties qualify them as efficient drugs for the treatment of pulmonary hypertension, a life-threatening illness characterized by an increase in artery pressure and vascular resistance in the pulmonary circulation. Diseased pulmonary vessels show specific remodeling with intimal fibrosis, medial hypertrophy, and adventitial thickening, as well as functional changes characterized by vasoconstriction and in situ thrombosis. The intravenous administration of prostacyclin is a well-established therapy option in severe pulmonary hypertension. However, lack of pulmonary and intrapulmonary selectivity can lead to life-threatening pulmonary and systemic side effects. Therefore, the application of prostanoids by inhalation had been proposed. Several studies with inhaled iloprost, a stable prostacyclin analogue, demonstrated preferential and potent vasorelaxation in the pulmonary circulation. In a randomized, double-blind, placebo controlled, multicenter study in 203 patients with pulmonary hypertension inhaled iloprost showed significant improvement of exercise capacity and pulmonary hemodynamics with excellent tolerability and safety. Consequently, inhaled iloprost has been approved in many countries for treatment of severe pulmonary hypertension. A major drawback of inhaled iloprost, however, is the short half-life and hemodynamic effect (30 to 60 min) demanding multiple daily inhalation manoeuvres (up to nine times). Strategies for further improvement of inhaled prostanoid therapy include use of prostacyclin analogues with longer half-life (e.g., treprostinil), combinations with oral drugs (e.g., phosphodiesterase inhibitors or endothelin receptor antagonists) and development of aerosolized controlled release formulations such as liposomes and nanoparticles. The therapy with prostacyclin and its analogues is a main pillar in the treatment of pulmonary hypertension, giving new hope to many patients suffering from this terrible disease. With inhaled iloprost, a new drug has enlarged the scope of aerosol therapies for treatment of pulmonary and systemic diseases.

Effects of cell-penetrating peptides and pegylation on transfection efficiency of polyethylenimine in mouse lungs

Cell‐penetrating peptides (CPPs) could potentially be used as vectors for intracellular delivery of proteins, peptides and nucleic acids. The present study examined different CPPs, such as TAT‐derived and arginine rich sequences, as well as model amphiphilic peptide, with respect to transfection efficiency of pegylated polyethylenimine (PEI) in A549, Calu‐3 cells and in mice after intra‐tracheal administration.

Biophysical investigation of pulmonary surfactant surface properties upon contact with polymeric nanoparticles in vitro

UNLABELLED Nanoparticulate drug carriers have been proposed for the targeted and controlled release of pharmaceuticals to the lung. However, inhaled particles may adversely affect the biophysical properties of pulmonary surfactant. This study examines the influence of polymeric nanoparticles with distinct physicochemical properties on the adsorption and dynamic surface tension lowering properties of pulmonary surfactant. Nanoparticles had a mean size of 100 nm with narrow size distributions. Although poly(styrene) and poly(D,L-lactide-co-glycolide) nanoparticles revealed a dose-dependent influence on biophysics of pulmonary surfactant, positively-charged nanoparticles made from poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) showed no effect. This behavior is attributed to the differences in ζ-potential and surface hydrophobicity, which in turn involves an altered adsorption pattern of the positively charged surfactant proteins to the nanoparticles. This study suggests that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be a viable drug-delivery vehicle for the inhalative treatment of respiratory diseases. FROM THE CLINICAL EDITOR Inhaled nanoparticulate drug carriers may adversely affect the biophysical properties of pulmonary surfactant. In this study the influence of polymeric nanoparticles was characterized from this standpoint, with the conclusion that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be viable drug-delivery vehicles for inhalational treatment.