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 :

» Basal Activation of Type I Interferons (Alpha2 and Beta) and 2'5'OAS Genes

Danilo Bretas de Oliveira, Gabriel Magno de Freitas Almeida, Antonio Carlos Martins Guedes, Flavia Patrıcia Sena Teixeira Santos, Claudio Antonio Bonjardim, Paulo Cesar Peregrino Ferreira, and Erna Geessien KroonReceived 15 June 2011; Revised 10...

» Amira Pharmaceuticals Announces Efficacy of LPA1 Antagonist in a Preclinical Model of Scleroderma

Amira Pharmaceuticals, Inc. announced today that their collaborators, Andrew Tager, M.D. and Flavia V. Castelino, M.D. of Massachusetts General Hospital, Harvard Medical School, will present a preclinical proof-of-concept study which demonstrates...

» Joint Involvement And Aggressive Systemic Sclerosis

Clinical joint involvement is strikingly common in patients with systemic sclerosis () and is associated with a more active and severe disease phenotype, according to an analysis of the world’s largest systemic sclerosis (SSc) registry. proved to...

» Too Many Sugary Drinks, Definitely A Bad Thing

Bad news cola lovers: Soda isn't the healthiest thirst-quencher in the cooler. In fact, health risks surrounding sugary drinks are increasingly well-documented. Rates of heart disease, obesity, and type 2 diabetes are higher among people who sip...

» HSCT Benefits In Early Diffuse Cutaneous Systemic Sclerosis

Initial results from an international, investigator-initiated, open label phase 3 trial, presented at EULAR 2012, indicate that haematopoietic stem cell transplantation (HSCT) results in better long-term survival than conventional treatment for...

» What Is Scleroderma?

DefinitionDerived from the Greek words “sklerosis,” meaning hardness, and “derma,” meaning skin, Scleroderma literally means hard skin. Although it is often referred to as if it were a single disease, Scleroderma is really a symptom of a...