PDE-5 Inhibitors in Scleroderma Raynaud Phenomenon and Digital Ulcers: Current Status of Clinical Trials PDF Print E-mail
Tuesday, 14 February 2012 13:59
Ann J. Impens, Kristine Phillips, and Elena Schiopu
Received 2 June 2011; Accepted 2 August 2011

Phosphodiesterases (PDEs) are isoenzymes that control the level of intracellular cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) by hydrolyzing them. The human genome encodes 21 PDE genes which are classified in 11 families. PDE isoenzyme 5 (PDE-5) selectively breaks down the cGMP, a critical smooth muscle tone regulator. Nitric oxide (NO), produced by nitric oxide synthase, signals the conversion of GMP into cGMP which accumulates inside the cell. Inhibition of the PDE-5 enzyme increases the available intracellular cGMP which leads to vasodilatation. Aside from corpus cavernosum, PDE-5 is found on a variety of tissues, including platelets, lungs, muscle, brain, retina, thymus, heart, liver, esophagus, stomach, pancreas, small intestine [1], arterial and venous vasculature, and endothelial cells.

Sildenafil, vardenafil, and tadalafil are the three commercially available PDE-5 inhibitors (PDE-5Is). All three PDE-5Is are available in oral formulation, are rapidly absorbed from the gastrointestinal tract, and aremetabolized by hepatic enzymes via cytochrome P450 [4]. Sildenafil and vardenafil have similar molecular structures, while the tadalafil molecule is different, the difference being reflected in the pharmacokinetic properties (Figure 1). Tadalafil is not affected by food ingestion and has a terminal half-life of 17.5 hours as opposed to sildenafil and vardenafil which are affected by fatty food intake and both have a half-life of approximately 4 hours.

The primary Food and Drug Administration- (FDA-) approved indication for the PDE-5Is is erectile dysfunction. In recent years, sildenafil (2005) and tadalafil (2009) have also been approved for use in pulmonary arterial hypertension. Vardenafil was recently shown to improve hemodynamic parameters in patients with pulmonary arterial hypertension in a randomized trial of 66 patients. Raynaud’s Phenomenon (RP) is an exaggerated vasoconstrictive response to cold and stress and is the presenting symptom in the majority of patients with systemic sclerosis (SSc). An important clinical manifestation of the scleroderma-related vasculopathy is the ischemic digital ulcer (DU) which is associated with significant morbidity. Use of PDE-5Is in SSc-related RP and DU makes pathophysiologic sense and has been explored in randomized fashion.

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