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Robert Voswinckel,
Frank Reichenberger, Beate Enke,
Andre Kreckel,
Stefanie Krick,
Henning Gall,
Ralph Theo Schermuly,
Friedrich Grimminger,
Lewis J Rubin,
Horst Olschewski,
Werner Seeger,
Hossein A Ghofrani
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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.
Pulmonary Pharmacology & Therapeutics 10/2008; 21(5):824-32. · 2.80 Impact Factor
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Robert Voswinckel, Beate Enke,
Frank Reichenberger,
Markus Kohstall,
Andree Kreckel,
Stefanie Krick,
Henning Gall,
Tobias Gessler,
Thomas Schmehl,
Hossein A Ghofrani,
Ralph Theo Schermuly,
Friedrich Grimminger,
Lewis J Rubin,
Werner Seeger,
Horst Olschewski
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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. · 14.16 Impact Factor
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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. · 4.65 Impact Factor
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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.
Pharmacology [?] Therapeutics 06/2004; 102(2):139-53. · 8.56 Impact Factor
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Hossein A Ghofrani,
Frank Rose,
Ralph T Schermuly,
Horst Olschewski,
Ralph Wiedemann,
André Kreckel,
Norbert Weissmann,
Stefanie Ghofrani, Beate Enke,
Werner Seeger,
Friedrich Grimminger
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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. · 14.16 Impact Factor
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Hossein A Ghofrani,
Ralph T Schermuly,
Frank Rose,
Ralph Wiedemann,
Markus G Kohstall,
André Kreckel,
Horst Olschewski,
Norbert Weissmann, Beate Enke,
Stefanie Ghofrani,
Werner Seeger,
Friedrich Grimminger
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[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. · 11.08 Impact Factor
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[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.
Pharmacology & Therapeutics.
