Management of pulmonary arterial hypertension with a focus on combination therapies.
Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.
Benza
Raymond L
RL
Department of Medicine/Division of Cardiovascular Disease, University of Alabama-Birmingham, Birmingham, Alabama 35294-0006, USA. rbenza@uab.edu
Park
Myung H
MH
Keogh
Anne
A
Girgis
Reda E
RE
D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000627:therapeutic use; D011464:Epoprostenol / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D010879:Piperazines / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects; D011687:Purines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D016019:Survival Analysis
D000959:Antihypertensive Agents; D019332:Endothelin-1; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D011464:Epoprostenol; D000077300:Bosentan