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.

Continue reading the full review paper, by downloading it from the link provided below.

 
More articles :

» Systemic Sclerosis Sine Scleroderma

HADI POORMOGHIM, MARY LUCAS, NOREEN FERTIG, and THOMAS A. MEDSGER, JR.ARTHRITIS & RHEUMATISM Vol. 43, No. 2, February 2000, pp 444–451 © 2000, American College of RheumatologyObjectiveTo describe the demographic, clinical, and laboratory...

» Unite Against Scleroderma

On May 1st 2011, the would be holding its first annual "Unite Against Scleroderma" Walk around the Queen's Park Savannah, Port Of Spain. It is our aim to help raise awareness of this rare autoimmune disease and the funding needed to aid those who...

» Interleukin-6: A New Therapeutic Target in Scleroderma

Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells,...

» Neutrophil Elastase Regulator Needed in Systemic Sclerosis

, which promotes and fibrosis, is suspected of playing a role in (SSc). Theresa C. Barnes, MD, from University of Liverpool, Aintree University Hospital, United Kingdom, and colleagues  of Rheumatology that the problem may not be too...

» Testing New Drugs for Early Diffuse Systemic Sclerosis

For patients with the connective tissue disease known as Systemic Sclerosis or – there are few reliable drug treatments. There has been emerging interest in the potential of a class of drugs called (TKI) to ameliorate a major feature of the...

» Blocking TGFβ via Inhibition of the αvβ6 Integrin: A Possible Therapy for Systemic Sclerosis Interstitial Lung Disease

Tamiko R. Katsumoto, Shelia M. Violette, and Dean SheppardReceived 27 May 2011; Accepted 15 August 2011Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of...