Pulmonary hypertension therapy

Another target of pulmonary hypertension therapies is endothelin (Figure 8.5), which is elevated in this disease, correlates to disease severity, and is localized immunohistochemically to the plexogenic lesions. There are two endothelin receptors ETa and ETb. ETa is found primarily on vascular SM cells, mediates the vasoconstrictive and mitogenic response, and is a direct target of both ETa-specific and nonspecific endothelin... 

The long-term (i.e., more than 3 months after the first event) goals of therapy are to prevent complications such as the postthrom-botic syndrome, pulmonary hypertension, and recurrent VTE. 

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. 

Reynolds, A.M., Xia, W., Holmes, M.D., Hodge, S.J., Danilov, S., Curiel, D.T., Morrell, N.W., and Reynolds, P.N. (2007) Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L1182-L1192. 

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. 

Liu L, Liu H, Visner G, Fletcher BS. 2006. Sleeping beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats. FASEB J. 20 2594-2596. 

Schenk P, Petkov V, Madl C, Kramer L, Kneussl M, Ziesche R, Lang I. Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension. Chest 2001 119(1) 296-300. 

McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998 338(5) 273-7. 

Gugnani MK, Pierson C, Vanderheide R, Girgis RE. Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma a case of pulmonary capillary hemangiomatosis. Arthritis Rheum 2000 43(3) 699-703. 

Ogawa A, Matsubara H, Fujio H, Miyaji K, Nakamura K, Morita H, Saito H, Kusano KF, Emori T, Date H, Ohe T. Risk of alveolar hemorrhage in patients with primary pulmonary hypertension—anticoagulation and epoprostenol therapy. Circ J 2005 69(2) 216-20. 

Inhalation of aerosolized iloprost is being tested in patients with severe primary or secondary pulmonary hypertension refractory to conventional therapy. The aim is to produce predominantly pulmonary vasodilatation without significant systemic effects. In an uncontrolled series of 19 patients, the most common adverse effects of inhaled iloprost were coughing, nausea, edema, and thoracic pain (4). In most patients, these effects were transient and rarely required a change in therapy. 

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. 

Anticoagulant therapy may be life-saving in thromboembolic pulmonary hypertension. 

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)... 

Manchester D, Margolis HS, Sheldon RE. Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. Am J Obstet Gynecol 1976 126(4) 467-9. 

Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, Roy BJ, Keszler M, KinseUa JP. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000 342(7) 469-74. 

Younis TH, Alam A, Paplham P, Spangenthal E, McCarthy P. Reversible pulmonary hypertension and thalidomide therapy for multiple myeloma. Br J Haematol 2003 121(l) 191-2. 

---