Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.

Experience with inhaled iloprost and bosentan in portopulmonary hypertension.

Novel treatments, such as prostanoids or endothelin receptor antagonists, have been introduced for various forms of pulmonary arterial hypertension, but the long-term effects of these treatments on portopulmonary hypertension (PPHT) are unknown. In a retrospective analysis, the present authors assessed the safety and efficacy of inhaled iloprost, a prostacyclin analogue, and bosentan, an endothelin receptor antagonist, in patients with PPHT. In total, 31 consecutive patients with Child class A or B cirrhosis and severe PPHT were treated for up to 3 yrs with either inhaled iloprost (n = 13) or bosentan (n = 18), and the effects on exercise capacity, haemodynamics and survival were evaluated. In the iloprost group, the survival rates at 1, 2 and 3 yrs were 77, 62 and 46%, respectively. In the bosentan group, the respective survival rates were 94, 89 and 89%. Event-free survival rates, i.e. survival without transplantation, right heart failure or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension, was also significantly better in the bosentan group. Bosentan had significantly better effects than inhaled iloprost on exercise capacity, as determined by the 6-min walk test, as well as on haemodynamics. Both treatments proved to be safe, especially in regards of liver function. In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and bosentan appeared to be safe. Patients treated with bosentan had higher survival rates, but prospective controlled studies are required to confirm these findings.

Goal-oriented treatment and combination therapy for pulmonary arterial hypertension.

Combination therapy may improve outcome in patients with severe pulmonary arterial hypertension (PAH). PAH patients were treated according to a goal-oriented therapeutic strategy. Patients who did not reach the treatment goals with monotherapy received combination treatment according to a predefined strategy, including bosentan, sildenafil and inhaled iloprost. Intravenous iloprost and lung transplantation were reserved for treatment failures. End points were overall survival, transplantation-free survival, and survival free from transplantation and intravenous prostanoid treatment. Between January 2002 and December 2004, 123 consecutive patients with PAH were treated according to the novel approach. Survival at 1, 2 and 3 yrs was 93.0, 83.1 and 79.9%, respectively, which was significantly better than the survival of a historical control group, as well as the expected survival. Compared to the historical control group, the use of combination treatment also significantly improved the combined end point of death, lung transplantation and need for intravenous iloprost treatment. In conclusion, a therapeutic approach utilising combinations of bosentan, sildenafil and inhaled iloprost in conjunction with a goal-oriented treatment strategy provides acceptable long-term results in patients with severe pulmonary arterial hypertension, and reduces the need for intravenous prostaglandin treatment and lung transplantation.

Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids.

Primary pulmonary hypertension (PPH) is a life-threatening disease. Nonparenteral prostanoids, i.e. aerosolised iloprost or oral beraprost sodium show beneficial therapeutic effects but are not sufficiently active in all patients with this devastating disease. The purpose of the present study was to determine whether the endothelin-receptor antagonist bosentan is safe and effective in patients with PPH already receiving nonparenteral prostanoids. The effect of bosentan as add-on medication was studied in 20 patients with PPH, who received either inhaled iloprost (n=9) or oral beraprost (n=11) for a median period of 16+/-13 months, by means of the 6-min walk test and cardiopulmonary exercise testing. After 3 months of administration of bosentan in addition to prostanoids, the walking distance in the 6-min walk test increased by 58+/-43 m. Cardiopulmonary exercise testing revealed an increase in maximal oxygen consumption from 11.0+/-2.3 to 13.8+/-3.6 mL x kg(-1) x min(-1) accompanied by significant improvements in anaerobic threshold, oxygen pulse and minute ventilation/carbon dioxide production slope. Peak systolic blood pressure increased from 120+/-17 to 139+/-21 mmHg. Combination treatment was well tolerated by all patients. It is concluded that the addition of the endothelin-receptor antagonist bosentan to inhaled iloprost or oral beraprost therapy appears to be safe for patients with primary pulmonary hypertension, resulting in a marked increase in exercise capacity. Therefore, rigorous studies should address whether combination treatment is more effective than either therapeutic intervention alone.

Effects of inhaled salbutamol in primary pulmonary hypertension.

Although lung function is grossly normal in patients with primary pulmonary hypertension (PPH), mild-to-moderate peripheral airflow obstruction can be found in the majority of patients with this disease. Therefore, beta2-agonists may affect pulmonary function, blood gases and haemodynamics in patients with PPH. Pulmonary function testing, blood gas measurements and right heart catheterisation was performed in 22 patients with PPH and the acute effects of inhaled salbutamol (0.2 mg) were measured. Salbutamol caused an increase in the forced expiratory volume in one second (FEV1) from 2446+/-704 to 2550+/-776 mL. The mean expiratory flow at 50% of the vital capacity (MEF50) rose from 58+/-17 to 66+/-21% pred. The pulmonary artery pressures remained unchanged after inhalation of salbutamol, but the cardiac output increased significantly from 3.9+/-1.4 to 4.2+/-1.4 L x min(-1) accompanied by significant increases in stroke volume and mixed venous oxygen saturation as well as a significant decrease in pulmonary vascular resistance. The arterial oxygen tension rose from 9+/-2.4 kPa (68+/-18 mmHg) at baseline to 9.7+/-2.8 kPa (73+/-21 mmHg) after inhalation of salbutamol, the alveolo-arterial oxygen gradient values improved from 6+/-2.5 kPa (45+/-19 mmHg) to 5.1+/-2.9 kPa (38+/-22 mmHg), respectively. Inhaled salbutamol has beneficial acute effects on pulmonary function, blood gases and haemodynamics in patients with primary pulmonary hypertension.

Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension.

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6-min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6+/-0.2 L x min(-1) x m(-2) and a mixed-venous oxygen saturation of 52+/-6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6-min walk test increased from 205+/-94 to 329+/-59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.

[Long-term treatment of primary pulmonary hypertension with inhaled iloprost]. / Langfristige Behandlung der primären pulmonalen Hypertonie mit inhalativem Iloprost.

BACKGROUND: Continuous intravenous infusion of prostacyclin is an effective treatment for primary pulmonary hypertension. This approach, however, requires the insertion of a permanent central venous catheter with the potential risk of serious complications. Recently, administration of aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of treatment with aerosolized iloprost over a one-year period on exercise capacity and hemodynamic variables in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a cumulative daily dose of 100 to 150 micrograms for at least one year. The mean (+/- SD) walking distance in the 6-min-walk test increased from 278 +/- 96 meters at base line to 363 +/- 135 meters after 12 months (P < 0.0001). During the same period, the mean pulmonary artery pressure declined from 59 +/- 10 mmHg to 52 +/- 15 mmHg (P = 0.006), the cardiac output increased from 3.8 +/- 1.4 l/min to 4.4 +/- 1.3 l/min (P = 0.02), and the pulmonary vascular resistance declined from 1.205 +/- 467 dynes.s.cm-5 to 925 +/- 469 dynes.s.cm-5 (P = 0.0003). Treatment was generally well tolerated and except for mild coughing, minor headache and jaw pain in some patients, no side effects occurred. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue.

BACKGROUND: Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.