The therapy may be prescribed off-label to treat other scleroderma symptoms related to restricted blood flow, including Raynaud’s phenomenon and digital ulcers. Generally, the treatment is prescribed after standard vasodilator therapies, such as calcium channel blockers, have failed.
How sildenafil works
In systemic scleroderma, damage caused by the immune system mistakenly attacking healthy tissues can trigger vasoconstriction, or the narrowing of blood vessels. This results in reduced blood flow through the affected areas.
In PAH, the blood vessels supplying the lungs constrict, resulting in high blood pressure. This strains the heart while it pumps blood through the lungs and reduces the oxygen available to the rest of the body.
Raynaud’s phenomenon results from reduced blood flow to the fingers or toes, which can cause them to become painfully cold while damaging tissue. This, in turn, can lead to digital ulcers, or sores on the extremities, that often become infected.
Sildenafil is a phosphodiesterase type 5 (PDE-5) inhibitor, which acts to dilate or widen the blood vessels. The enzyme PDE-5 is present in the walls of the blood vessels and normally acts to break down the small molecule cGMP. By inhibiting PDE-5, sildenafil increases cGMP levels in blood vessels.
cGMP signals to relax and widen the muscles of blood vessel walls. Increased levels of cGMP caused by sildenafil open up blood vessels and improve blood flow.
In PAH, this should reduce the burden on the heart, lower blood pressure, and improve oxygen transport throughout the body. The symptoms of Raynaud’s should also be reduced with improved circulation to the extremities. Sildenafil may also speed up the healing of digital ulcers.
Sildenafil in clinical trials
Sildenafil has been investigated in several clinical trials for PAH. These trials contributed to U.S. Food and Drug Administration approval for PAH in June 2005, followed by European Commission approval in October 2005.
Results from a clinical trial that enrolled 278 people with PAH, published in The New England Journal of Medicine, demonstrated that sildenafil can significantly reduce blood pressure in the lungs and improve the symptoms of PAH.
Sildenafil has also been tested in clinical trials for Raynaud’s phenomenon in people with scleroderma. A randomized, double-blind, controlled study of 57 patients in Europe investigated the safety and efficacy of a once-daily oral formulation of sildenafil over four weeks. The results, published in the journal Arthritis & Rheumatism, suggested that sildenafil significantly reduced the frequency of attacks compared to placebo but did not have a significant effect on the severity of symptoms.
A previous trial, published in the journal Circulation, examined sildenafil’s effect on 16 patients with Raynaud’s that was resistant to vasodilator therapies. Sildenafil significantly reduced the frequency, duration, and severity of the attacks compared to placebo. Furthermore, in the six sildenafil-treated patients with digital ulcers, visible healing occurred, compared to none in the placebo group.
A Phase 3 clinical trial (NCT01295736) called SEDUCE examined the effect of sildenafil on digital ulcers in 83 patients with systemic scleroderma in France. The results, published in the Annals of the Rheumatic Diseases, suggested that sildenafil may help reduce the number of digital ulcers present compared to a placebo.
However, the study’s primary objective, the rate of digital ulcer healing, was not met. One reason for this was that the healing rate in the placebo group was abnormally high, possibly because the study did not account for patients taking calcium channel blockers. More patients in the placebo group had been taking calcium channel blockers than in the sildenafil group. Despite this, the sildenafil group still saw an increase in the healing rate compared to placebo, although the difference was not considered significant.
Sildenafil may be prescribed off-label to treat digital ulcers.
Common side effects of sildenafil include indigestion, headaches, vision problems, and flushing. Others include muscle pain, diarrhea, sneezing, nosebleeds, difficulty breathing, and difficulty sleeping.
Sildenafil is also the main component of the erectile dysfunction medication Viagra.
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