[Show abstract][Hide abstract] ABSTRACT: Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.
Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).
Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.
The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.
[Show abstract][Hide abstract] ABSTRACT: 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.
European Respiratory Journal 12/2007; 30(5):922-7. DOI:10.1183/09031936.00039007 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which no effective treatment exists. In the present study, 12 IPF patients underwent analysis of gas exchange properties using the multiple inert gas elimination technique on day 1 before and after the administration of 125 mg bosentan, a dual endothelin antagonist. Following this, patients received chronic administration for 12 weeks (62.5 mg b.i.d. in week 1, 125 mg b.i.d. thereafter). The primary objective was to determine the effect of bosentan on gas exchange (day 1) and on oxygen saturation and minute ventilation (week 2). With one exception, where redistribution of total pulmonary blood flow from normal ventilation/perfusion (V'/Q') areas (93% before, 72% after bosentan) to low V'/Q' areas (0% before, 22.2% after) was encountered, no patient showed any change in gas exchange (mean+/-SD shunt flow (% of cardiac output) 8.5+/-3.4% before, 6.1+/-2.3% after bosentan; day 1) or oxygen saturation and minute ventilation (week 2). Similarly, none of the secondary parameters was significantly changed either at week 2 or at the end of the study period (week 12). Five patients developed respiratory infections and two died because of pneumonia; this was judged as being unrelated to bosentan intake. In conclusion, bosentan administration does not seem to induce clinically relevant gas exchange abnormalities in idiopathic pulmonary fibrosis patients.
European Respiratory Journal 05/2007; 29(4):713-9. DOI:10.1183/09031936.00149205 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension.
Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation.
Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR).
The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 mug displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 mug treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 mug treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects.
Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.
Journal of the American College of Cardiology 11/2006; 48(8):1672-81. DOI:10.1016/j.jacc.2006.06.062 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Portopulmonary hypertension (POPH) is regarded as a subtype of pulmonary arterial hypertension (PAH); however, established PAH therapies have not been evaluated for this condition. The current authors treated 14 patients (four male, 10 female; mean (range) age 55 (39-75) yrs) with moderate (n = 1) or severe (n = 13) POPH caused by alcoholic liver disease (n = 7), chronic viral hepatitis (n = 3), autoimmune hepatitis (n = 3), and hepatic manifestation of hereditary haemorrhagic teleangiectasia (n = 1) with oral sildenafil. Eight patients were newly started on pulmonary vasoactive treatment, while six patients were already on treatment with inhaled prostanoids (iloprost, n = 5; treprostinil, n = 1). During treatment with sildenafil, mean +/- sd 6-min walk distance increased from 312 +/- 111 m to 397 +/- 99 m after 3 months, and 407 +/- 97 m after 12 months. Mean +/- sd pro-brain natriuretic peptide levels decreased from 582 +/- 315 ng x mL(-1) to 230 +/- 278 ng x mL(-1), and to 189 +/- 274 ng x mL(-1) after 3 and 12 months, respectively. Two patients died after 1 and 2 months from liver failure and cardiac failure, respectively. There was a similar response to sildenafil treatment after 3 and 12 months in patients on monotherapy and those on combination therapy. In conclusion, sildenafil might be effective in monotherapy and in combination therapy with inhaled prostanoids in portopulmonary hypertension, leading to significant improvement by 3 months and sustained response over 12 months.
European Respiratory Journal 10/2006; 28(3):563-7. DOI:10.1183/09031936.06.00030206 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelin receptor antagonism has been introduced as an effective oral therapy of patients with idiopathic pulmonary arterial hypertension. In view of the pathophysiologic and histologic similarities between idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), there is a rationale for treating these patients with the oral dual (ET(A)/ET(B)) endothelin receptor antagonist bosentan.
Thirty-three patients with PAH-CHD (43 +/- 14 years, 23 with Eisenmenger syndrome) were treated with bosentan for a mean of 2.1 +/- 0.5 years. Efficacy was assessed by a panel of tests, including New York Heart Association functional class, 6-minute walking distance, and echocardiographic and hemodynamic parameters.
Mean 6-minute walking distance increased from 362 +/- 105 to 434 +/- 68 m (P = .001). New York Heart Association class also improved significantly (3.1 to 2.4, P = .0001). This was associated with slight trends in improvements of transcutaneous oxygen saturation (86% +/- 7% to 88% +/- 7%, P = .13) and maximum oxygen uptake (13.2 +/- 4.0 to 14.9 +/- 2.5, P = .18). Right ventricular systolic pressure measured by echocardiographic decreased from 111 +/- 32 to 106 +/- 22 mm Hg (P = .001). Bosentan treatment was well tolerated by all patients.
Long-term bosentan treatment in adult patients with PAH-CHD was well tolerated and improved functional status as well as exercise capacity. These findings have to be corroborated by controlled studies that are presently ongoing.
American heart journal 11/2005; 150(4):716. DOI:10.1016/j.ahj.2005.07.005 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New drugs for pulmonary arterial hypertension have shown efficacy in randomized controlled trials. Endothelin receptor antagonists (ERA) and prostanoids are most important for clinical practice. Bosentan represents the first approved orally active therapy for PAH. Besides its hepatotoxicity it is mostly well tolerated. The first approved prostanoid, epoprostenol, is currently first choice only for decompensated right heart failure in PAH. It has to be delivered continuously intravenously and is prone to complications, side effects and very high costs. Alternatively, subcutaneous treprostinil can be applied. It is less risky and expensive but may cause local pain at the infusion site. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively, iloprost is being used as continuous intravenous infusion. The phosphodiesterase-5 inhibitor sildenafil was effective in two randomized controlled trials but has not been approved for PAH therapy.
Der Internist 04/2005; 46(3):341-9. · 0.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neue Medikamente zur Therapie der pulmonal arteriellen Hypertonie (PAH) haben ihre Wirksamkeit in randomisierten kontrollierten Studien belegt. Die grte praktische Bedeutung haben hier Endothelinrezeptorantagonisten und Prostanoide. Bosentan ist die erste zugelassene oral verfgbare Therapie der PAH. Das Medikament ist abgesehen von einer seltenen Hepatotoxizitt meist gut vertrglich. Das zuerst zugelassene Prostanoid, Epoprostenol, ist nur noch fr die dekompensierte Rechtsherzinsuffizienz das Mittel der ersten Wahl, da es nur kontinuierlich intravens appliziert werden kann und durch Komplikationen, Nebenwirkungen und sehr hohe Kosten belastet ist. Als Alternative steht die subkutane Dauerinfusion des weniger risikoreichen und preiswerteren Treprostinil zur Verfgung. Dieses Prostanoid hat eine lngere Halbwertszeit, verursacht aber vielfach Schmerzen an der Injektionsstelle. Inhalatives Iloprost verbindet die Vorzge des Prostanoids mit einer (intra)pulmonal selektiven Wirkung. Iloprost wird alternativ auch als Dauerinfusion angewendet. Der Phosphodiesterase-5-Inhibitor Sildenafil zeigte eine signifikante Wirksamkeit in 2 randomisierten kontrollierten Studien, steht aber noch vor der Zulassung zur Therapie der PAH.New drugs for pulmonary arterial hypertension have shown efficacy in randomized controlled trials. Endothelin receptor antagonists (ERA) and prostanoids are most important for clinical practice. Bosentan represents the first approved orally active therapy for PAH. Besides its hepatotoxicity it is mostly well tolerated. The first approved prostanoid, epoprostenol, is currently first choice only for decompensated right heart failure in PAH. It has to be delivered continuously intravenously and is prone to complications, side effects and very high costs. Alternatively, subcutaneous treprostinil can be applied. It is less risky and expensive but may cause local pain at the infusion site. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively, iloprost is being used as continuous intravenous infusion. The phosphodiesterase-5 inhibitor sildenafil was effective in two randomized controlled trials but has not been approved for PAH therapy.
Der Internist 02/2005; 46(3):341-349. DOI:10.1007/s00108-004-1350-0 · 0.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic and antiproliferative properties. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension. Indeed, several prostanoids have been shown to be efficacious to treat pulmonary hypertension, while the main mechanism underlying the beneficial effects remains unknown. There are indications of beneficial combination effects of prostaglandins and phosphodiesterase inhibitors and endothelin receptor antagonists. This speaks in favor of combination therapies for pulmonary hypertension in the future. The mode of application of prostanoids used in randomized controlled studies has been quite variable: continuous i.v. infusion of prostacyclin, continuous s.c. infusion of treprostinil, p.o. application of beraprost, and inhaled application of iloprost. In addition, the applied doses were quite different, ranging from 0.25 ng/kg/min for inhaled iloprost to 30-50 ng/kg/min for i.v. prostacyclin. While the principal pharmacological properties of all prostanoids are very similar due to a main action on IP receptors, there are considerable differences in pharmacokinetics and metabolism, with half-lives of 2 min for prostacyclin and about 34 min for treprostinil for i.v. infused drugs and half-lives of about 85 min for s.c. infused treprostinil. In addition, the adverse effects largely depend on the doses used and the mode of application, although there is great variability between subjects. It remains to be determined which patients will profit most from which substance (or combination) and mode of application.
[Show abstract][Hide abstract] ABSTRACT: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost.
Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy.
Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged.
Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.
Journal of the American College of Cardiology 08/2003; 42(1):158-64. DOI:10.1016/S0735-1097(03)00555-2 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 +/- 228 dyn. s. cm-5. m2, cardiac index 2.0 l. min-1. m-2, 6-minute walking distance 312 +/- 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 +/- 177 L. min-1. m2, p = 0.004, cardiac index 2.4 +/- 0.2 L. min-1. m-2, p = 0.009, 6-minute walking distance 366 +/- 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.
American Journal of Respiratory and Critical Care Medicine 05/2003; 167(8):1139-41. DOI:10.1164/rccm.200210-1157BC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Die Therapie der schweren pulmonalen Hypertonie hat sich durch neue wirksame Medikamente, die in meist internationalen placebokontrollierten
Studien getestet wurden, enorm verbessert.Dennoch bleibt die Therapie dieser Erkrankung schwierig, bedingt durch die vielfältige
Pathogenese, die geringe Prävalenz in der Bevölkerung und die geringe Langzeiterfahrung mit den wirksamen medikamentösen Therapien
sowie deren Komplexität.Eine Heilung der Erkrankung ist weiterhin nicht möglich. Die aktuellen Therapien zielen auf eine langfristige
Verbesserung der Belastbarkeit und Zunahme der Lebenserwartung. Nur in seltenen Fällen gelingt es, den pulmonalen Druck in
die Nähe des Normbereichs zu senken. Es ist daher naheliegend, kombinierte Therapieverfahren anzuwenden, um die Ergebnisse
zu verbessern. Zu diesem Thema liegen aber erst begrenzte Erfahrungen vor. Die meisten Patienten mit pulmonaler Hypertonie
leiden an Erkrankungsformen, die in den zulassungsrelevanten erfolgreichen Studien ausgeschlossen wurden (beispielsweise Lungenerkrankungen).
Ob die Studienergebnisse auf solche Patienten übertragbar sind, ist eine offene Frage.
Der Internist 11/2002; 43(12):1498-1509. DOI:10.1007/s00108-002-0761-z · 0.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a model of acute pulmonary hypertension in intact rabbits, we investigated the vasodilatory potency of intravascularly administered urodilatin, a renal natriuretic peptide type A known to stimulate particulate guanylate cyclase. Urodilatin infusion was performed in the absence and presence of the phosphodiesterase (PDE) type 5 inhibitor dipyridamole. Stable pulmonary hypertension was evoked by continuous infusion of the thromboxane mimetic U46619, resulting in approximate doubling of the pulmonary artery pressure (PAP). When infused as sole agents, both urodilatin and dipyridamole dose-dependently attenuated the pulmonary hypertension, with doses for a 20% decrease in PAP being 30 ng/kg min for urodilatin and 10 microg/kg min for dipyridamole. A corresponding decrease in systemic arterial pressure (SAP) was noted to occur in response to both agents. Sequential intravenous administration of a subthreshold dose of dipyridamole (1 microg/kg min), which per se did not affect pulmonary and systemic hemodynamics, and a standard dose of urodilatin (30 ng/kg min) resulted in a significant amplification of both the PAP and the SAP decrease in response to the natriuretic peptide. At the same time, manifold enhanced plasmatic cyclic guanosine monophosphate (cGMP) levels were detected. Aerosolized dipyridamole also dose-dependently attenuated pulmonary hypertension, with only 1 microg/kg min being sufficient for a 20% decrease in PAP, with no SAP decline. Preceding administration of subthreshold aerosolized dipyridamole (50 ng/kg min) did, however, cause only a minor amplification of the pulmonary vasodilatory response to a subsequently infused standard dose of urodilatin. In conclusion, this is the first study to show that urodilatin does possess vasodilatory potency in the pulmonary circulation, and enhanced plasma levels of cGMP and synergy with the PDE5 inhibitor dipyridamole both strongly suggest that this effect proceeds via guanylate cyclase activation. The effect of infused urodilatin is, however, not selective for the pulmonary vasculature, as the systemic vascular resistance declines in a corresponding fashion.
American Journal of Respiratory Cell and Molecular Biology 09/2001; 25(2):219-25. DOI:10.1165/ajrcmb.25.2.4256 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.
American Journal of Respiratory and Critical Care Medicine 11/1999; 160(5 Pt 1):1500-6. DOI:10.1164/ajrccm.160.5.9901102 · 13.00 Impact Factor