Combination Therapy: The Future of Medical Management for PAH

Rationale for Combining Therapies

The current treatment strategy for PAH targets the mediators of the 3 main biologic pathways that are critical to its pathogenesis and progression (Figure 3). Endothelin receptor antagonists inhibit the activated endothelin pathway by blocking the biologic activity of the mediator endothelin-1, phosphodiesterase-5 (PDE-5) inhibitors increase endogenous availability of cyclic guanosine monophosphate (cGMP), which signals the vasorelaxing effects of the deficient mediator nitric oxide, and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin.[4] Combining these molecular targets makes intuitive sense, because all of these pathways are intimately involved in disease progression. A similar strategy of combining molecular targets has been very successful in the management of patients with chronic heart failure from left ventricular systolic dysfunction, where combination therapy is the standard of care.

Figure 3.  (click image to zoom)

Molecular targets for therapy in pulmonary arterial hypertension.
From: Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. The New England Journal of Medicine (c) 2004.      

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