Pulmonary arterial hypertension treatment

Pulmonary arterial hypertension (PAH) For the treatment of PAH in patients with New York Heart Association (NYHA) Class II to IV symptoms to diminish symptoms associated with exercise. 

Opitz CF et al Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension Does selectivity matter Eur Heart J 2008 29 1936. [PMID 18562303]... 

Steiropoulos P, Trakada G, Bouros D Current pharmacological treatment of pulmonary arterial hypertension. Curr Clin Pharmacol 2008 3 11. [PMID 18690874]... 

Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension... 

Ahmadi-Simab K, Lamprecht P, Hellmisch B, Gross WL. Treatment of pulmonary arterial hypertension (PAH) with oral endothelin-receptor antagonist bosentan in systemic sclerosis BREATHE-1 trial and clinical experience. Z Rheumatol 2004 63(6) 495-7. [Article in German]... 

Humbert M, Sitbon O, Simonneau, G. Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2004 351 1425-1436. 

Galie N, Olschewski H, Oudiz R, et al. Ambrisentan for the treatment of pulmonary arterial hypertension results of the ambrisentan in pulmonary arterial hypertension. Randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008 117(23) 3010-19. 

Barst RJ, Langleben D, Badesch D, et al STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006 47(10) 2049-56. 

An added benefit is that inhalational therapy reduces potential undesirable negative side effects of treatment when compared to systemic delivery options. Singleagent tolerability via inhalation has been demonstrated in asthmatic and idiopathic pulmonary arterial hypertension (IPAH) patients. The current and future program is designed to test and confirm general efficacy as single therapeutic inhaled agent. 

Bosentan is an endothelin receptor antagonist. It antagonized endothelin (ET) receptor by binding to ET and ETg receptors in the endothelium and vascular smooth muscle. Bosentan is indicated in treatment of pulmonary arterial hypertension in patients with WHO class III and IV symptoms, to improve exercise ability, and decrease the rate of clinical worsening. 

Golpon HA, Welte T, Hoeper MM. Pulmonary arterial hypertension pathobioiogy, diagnosis, and treatment. Minerva Med 2005 96 303-314. 

Ambrisentan is a powerful receptor antagonist that is clinically used for the treatment of pulmonary arterial hypertension. Very recently, Shi s group has applied his methodology to the epoxidation of 3,3-diphenylacrylate 69, which was transformed in four steps into (-l-)-ambrisentan in 53% overall yield and can be carried out in large scale (120g) (Scheme 12.15) [106]. 

Secondary causes of pulmonary arterial hypertension (PAH), including appetite suppressant drugs associated with PAH, have been reviewed [97 j. Newer trends in the treatment of PAH, especially the status of prostacyclin analogues and endothelin-1 receptor antagonists, have been addressed. 

Used in the treatment of erectile dysfunction and pulmonary arterial hypertension... 

Melian, EB and Goa, KL (2002) Beraprost a review of its pharmacology and therapeutic efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension. Drugs, 62, 107-133. 

Bosentan The pharmacokinetic interaction of sildenafil and the dual endotheUn receptor antagonist bosentan, both of which are marketed for the treatment of pulmonary arterial hypertension, has been studied in 55 healthy men [31 ]. Bosentan reduced the Cnmx and AUCx of sildenafil, and sildenafil increased the corresponding values of bosentan. The clinical implications for combined therapy are not known. 

Observational studies STRIDE-2X is the 1-year open extension study of the 18 week STRIDE-2 (Sitaxsentan To Relieve ImpaireD Exercise) investigation that followed patients taking sitaxsentan or bosentan for pulmonary artery hypertension [87 ]. As well as efficacy measures, the researchers included time to withdrawal because of adverse events and time to rises in hepatic aminotransferases in the outcome measures. For the analysis population, the risk of raised aminotransferases to more than 3 times the upper limit of normal at 1 year was 6% with sitaxsentan 100 mg/day and 14% with bosentan. The cumulative risk of withdrawal at 1 year with raised aminotransferases was 3% with sitaxsentan 100 mg/day and 9% with bosentan. Other adverse events were peripheral edema, nasopharyngitis, dyspnea, and cough, consistent with previous trials in pulmonary artery hypertension. The overall withdrawal rates at 1 year were 15% with sitaxsentan 100 mg/ day and 30% with bosentan. Sitaxsentan therefore seems to have similar efficacy to bosentan and from this evidence may have the advantage of causing fewer hepatic adverse events in longer-term treatment (but see below). 

Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin W, Roecker EB, Harrison BC, Despain D, Dufton C. Longterm ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009 54(21) 1971-81. 

Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi A, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study) a double-blind. 

Benza RL, Bars RJ, Galie N, Frost A, Girgis RE, Highland KB, Strange C, Black CM, Badesch DB, Rubin L, Fleming TR, Naeije R. Sitaxsentan for the treatment of pulmonary arterial hypertension a 1-year, prospective, open-label observation of outcome and survival. Chest 2008 134(4) 775-82. 

The endothelins interact with two endothelin receptors, ETa and ETb. Endothelins are highly potent vasoconstrictors and endothelin antagonists have the potential to be used clinically to treat pulmonary arterial hypertension (PAH), congestive heart failure, stroke, kidney failure, asthma, pain, and cancer. The small molecule bosentan (Tracleer) interacts with both ETa and ETb receptors and was the first endothelin antagonist to be used clinically for the treatment of PAH. Additional compounds are in clinical development or have reached the market. ... 

---