20091119-7

Sildenafil

Children’s Hospital of Philadelphia, November 18, 2009  –  Heart function significantly improved in children and young adults with single-ventricle congenital heart disease who have had the Fontan operation following treatment with sildenafil, a drug used to treat erectile dysfunction and pulmonary hypertension, say researchers from The Children’s Hospital of Philadelphia. 

Single-ventricle defects are a collection of cardiac malformations that impair the heart’s ability to pump blood. Examples include tricuspid atresia, pulmonary atresia/intact ventricular septum and hypoplastic left heart syndrome. 

The Fontan operation is a procedure that redirects systemic venous blood directly to the pulmonary arteries, bypassing the heart. It is the third surgery in a staged palliation for single-ventricle heart defects.

Researchers hypothesized that sildenafil may help cardiac performance by directly improving the squeeze of the heart muscle and by allowing for better filling of the heart.

In this study, researchers randomized 28 children and young adults who had undergone the Fontan operation to receive placebo or sildenafil three times a day for 6 weeks. After a 6-week break, subjects were switched to the opposite treatment course. The researchers found significant improvement in heart performance during treatment with sildenafil.

“The enhanced heart performance may improve exercise performance and quality of life in these children and young adults,” said David J. Goldberg, M.D., pediatric cardiologist at The Children’s Hospital of Philadelphia, who presented the abstract on Nov. 17 at the American Heart Association Scientific Sessions in Orlando, Fla.

Grants from The Mark H. and Blanche M. Harrington Foundation and from Big Hearts to Little Hearts provided funding for this study.


Story Source:

Adapted from materials provided by Children’s Hospital of Philadelphia.

More About Sildenafil……………

History 

Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer’s Sandwich, Kent, research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morriston Hospital in  Swansea.  Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.  Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the US Food and Drug Administration on March 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year.  It soon became a great success: annual sales of Viagra in the period 1999-2001 exceeded $1 billion.

Mechanism of action 

The mechanism of action of Sildenafil citrate involves the release of nitric oxide (NO) in the corpus cavernosum of the penis. NO binds to the receptors of the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries, resulting in increased inflow of blood and an erection.  Robert F. Furchgott won the Nobel Prize in Physiology or Medicine in 1998 for his discovery and analysis of endothelium-derived relaxing factor, a key part of the NO mechanism of action.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections.  Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis) and vardenafil (Levitra).

Sildenafil is metabolised by liver enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third. 

Pulmonary hypertension 

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.

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