Adcirca (tadalafil) is a medicine approved by the U.S. Food and Drug Administration to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries surrounding the lungs, and Raynaud’s phenomenon, a contraction or spasm of the small blood vessels in the hands and feet. Both conditions are commonly associated with systemic scleroderma. Adcirca is produced by United Therapeutics in the U.S. and Eli Lilly in Europe.
Scleroderma is an autoimmune disease in which the immune system mistakenly targets healthy connective tissue. In response, the body produces excessive collagen, which leads to the thickening and hardening of connective tissues. In systemic scleroderma, this tissue thickening can occur in the arteries of the lung and heart, causing them to narrow, which then leads to high blood pressure. This thickening of blood vessels can also occur in the small vessels in the hands and feet, which can lead to restriction of blood flow to the extremities, resulting in Raynaud’s phenomenon.
Cyclic GMP (cGMP) is a signaling molecule that promotes the relaxation of smooth muscles, such as those surrounding the arteries and veins, through a pathway called the cGMP pathway. When cGMP is present in sufficient amounts, smooth muscles relax. But cGMP is quickly degraded by an enzyme called phosphodiesterase 5 (PDE-5).
Adcirca a so-called PDE-5 inhibitor, prevents the action of this enzyme. Its chemical structure is very similar to that of cGMP so that it can bind to PDE-5, but it cannot be broken down by the enzyme. Any PDE-5 enzyme bound to Adcirca is not available to break down cGMP.
This block on the enzyme’s action prolongs the chemical life of cGMP, relaxing the smooth muscles in the blood vessels, which, in turn, lowers blood pressure.
Adcirca in clinical trials
A Phase 4 open-label clinical trial (NCT01042158) conducted at Johns Hopkins University studied the effects of combining tadalafil with Letairis (ambrisentan,) which is also an agent that widens the blood vessels, over a 36-week period to treat PAH in systemic scleroderma patients.
Researchers assessed patients’ heart size by magnetic resonance imaging (MRI) and blood vessel resistance near the heart by cardiac catheterization. They also measured the distance patients could walk using the six-minute walk test, which is a simple measure of aerobic exercise capacity as well as of any lung or heart distress as a result of exercise. They observed a significant improvement in the distance walked, and a decrease in heart volume and resistance following treatment, indicating that strain on the heart had lessened. The results of the study were published in the journal Pulmonary Circulation and the American Journal of Respiratory and Critical Care Medicine.
A Phase 3 clinical trial (NCT01117298) assessed the effects of tadalafil compared with a placebo in 30 systemic scleroderma patients with Raynaud’s. Patients received the treatment every other day for six months. The results showed that patients treated with tadalafil showed trends of improved lung function and an increase in the six-minute walking distance compared with those treated with placebo, as well as a decrease in Raynaud’s episodes. These results were presented at the 2014 American College of Rheumatology Meeting.
Another Phase 3 clinical trial (NCT00626665) tested the effectiveness of adding tadalafil to calcium channel blockers and other agents that widen the blood vessels to treat scleroderma patients with secondary Raynaud’s phenomenon who were having repeated attacks. Of the 25 enrolled patients, 24 completed the study, receiving a placebo or a tadalafil tablet of 20 mg every other day for six weeks — after which patients switched treatment following a washout period. The results, published in the journal Rheumatology, showed that patients had improved heart function, measured by echocardiogram and flow-mediated dilation of the brachial artery, in which the diameter of the brachial artery is measured by ultrasound while the patient wears a blood pressure cuff. Moreover, fingertip lesions caused by Raynaud’s healed and did not reoccur during treatment. No treatment-related adverse reactions were reported.
Common side effects of Adcirca include arm, back, or jaw pain, blurred vision, chest pain or discomfort, dizziness, headache, and confusion.
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