Therapy for pulmonary hypertension

An ingenious therapy for pulmonary hypertension involves mixing low concentrations of gaseous NO with the air these patients breathe. The concentration is kept low enough that the oxidation of NO to toxic NO2 is negligible, and the vasodilatory effect is limited to the site of need—the pulmonary vascular bed. The procedure has been widely tested and is now approved by the FDA for treating hypoxic respiratory failure associated with persistent pulmonary hypertension of the newborn (19). 

Journois, D., Pouard, P., Mauriat, P., Malhere, T., Vouhe, P., and Safran, D. (1994). Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects. J. Tborac. Cardiovasc. Surg. 107, 1129-1135. 

Nagaya, N., Kangawa, K., Kanda, M, Uematsu, M., Horio, T., Fukuyama, N., Hino, J., Harada-Shiba, M., Okumura, H., Tabata, Y., Mochizuki, N., Chiba, Y, Nishioka, K., Miyatake, K., Asahara, T., Hara, H., and Mori, H. 2003. Hybrid cell - gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation, 108,889-895. 

Galie N et al Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl 3 Med 2005 353 2148. [PMID 16291984]... 

In a double-blind, placebo-controlled study, the Bosentan Randomized trial of Endothelin Antagonist Therapy for Pulmonary Arterial I lypertension (BREATHE-2), 33 patients took epoprostenol (2 ng/kg/ min initially, increasing to a mean dosage of 14 ng/kg/min at week 16) and were then randomized for 16 weeks in a 2 1 ratio to bosentan (62.5 mg bd for 4 weeks then 125 mg bd) or placebo (11). There was a non-significant trend towards hemodynamic and clinical improvement with to the combination. There were several early and late major complications (four withdrawals with bosentan + epoprostenol two deaths due to cardiopulmonary failure, one clinical worsening, and one increase in hepatic transaminases and one withdrawal due to increased hepatic transaminases with placebo + epoprostenol. Power was the major limitation of this study, in which only 33 patients were enrolled, and the results should be interpreted with caution. Additional information is needed to evaluate the benefit to harm balance of combined bosentan + epoprostenol therapy in pulmonary arterial hypertension. 

Rubin LJ, Badesch DB, Barst RJ, Gahe N, Black CM, Keogh A, Puhdo T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 346(12) 896-903. 

Galie N, Brundage BH, Ghofrani HA, et al. Pulmonary Arterial Hypertension and Response to Tandalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009 119(22) 2894-903. 

The purpose of this chapter is to briefly review selected aspects of the experimental basis for NO therapy of pulmonary hypertension and respiratory failure in PPHN and its potential role in treating severe RDS associated with prematurity. We further summarize current clinical data regarding the efficacy and safety of this treatment in term and preterm human neonates. 

Corris PA, Langleben D. The Achilles heel of endothelin receptor therapy for pulmonary arterial hypertension. Eur Respir J 2010 35(2) 460-1. 

V. Using the Airway for Gene Therapy of Pulmonary Hypertension... 

After many health problems and deaths, the FDA removed Pondimin and Redux from market. Since then, there have been 200 reported cases of primary pulmonary hypertension relating to fen-phen and dexfen-phen. Of those cases, 40 have resulted in death. The FDA has received more than 100 reports of heart valve damage directly related to fen-phen or fenfluramine therapy there are no reports from individuals taking phentermine alone for weight loss. 

It is indicated in pulmonary hypertension, prophylaxis of angina pectoris, post myocardial infarction therapy, CHF and acute LVF. It is not recommended for acute attacks of angina. 

Pulmonary hypertension is a devastating, potentially fatal disorder. Recent years have witnessed a great expansion in our understanding of the molecular pathophysiology of this condition. Options for therapy have just become available in recent years, focused either on the prostacyclin pathway or the nitric oxide pathway for pulmonary arteriolar relaxation. Continuous infusion of prostacyclin has been successful, demonstrating the relevance of the former pathway. The efficacy of both inhaled nitric oxide and systemic sildenafil support the latter. In the future, gene transfer could be used for sustained delivery of either of these agents, by means of... 

Pulmonary gene therapy is attractive for the treatmment of chronic bronchitis, cystic fibrosis, a-1 antitrypsin deficiency, familial emphysema, asthma, pulmonary infections, surfactant deficiency, pulmonary hypertension, lung cancer, and malignant mesothelioma. The pulmonary endothelium may act as a bioreactor for the production and secretion of therapeutic proteins, such as clotting factors and erythropoietin into the blood circulation. There is a potential benefit for acquired lung diseases, as well as cancers, to be controlled and possibly treated by expression of cytokines, surfactant, antioxidant enzymes, or mucoproteins within lung cells. 

On retrospective assessment of a large number of cirrhotic patients, some of whom we treated for more than 10 years, it is our impression that long-term administration of spironolactone -I- molsidomine + P-blocker is of therapeutic value for portal hypertension and, at least as far as this problem is concerned, also for primary and progressive pulmonary hypertension. Such combination therapy is also pharmacologically plausible, (s. p 743)... 

Fruehauf S, Steiger S, Topaly J, Ho AD. Pulmonary artery hypertension during interferon-alpha therapy for chronic myelogenous leukemia. Ann Hematol 2001 80(5) 308-10. 

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