Thursday, May 19, 2011

Tacrolimus as a new approach to pulmonary artery hypertension?

I am just sitting here in Dulles airport on the way back from this year's ATS meeting and wanted to share with you a scientific story that has got me quite excited.

Actually I have just been sitting here for rather a long time but that is another story - I am just mentioning this as an excuse for typos etc that may creep in after 24 hours with no sleep.

Just a quick introduction - pulmonary artery hypertension (PAH) is a subset of pulmonary hypertension. PAH is characterized by increased remodelling of the pulmonary artery which takes blood from the right heart to the lung for reoxygenation. The remodeling process results in increased pulmonary artery pressure, right heart enlargement and eventually failure. The disease is rare but often fatal although life expectancy has increased due to a number of advances (prostacyclins, PDE5 inhibitors and endothelin receptor antagonsists).

The reported incidence of PAH is low; 1-5 new cases each year per million people. No one knows exactly what causes PAH - in fact it is an umbrella term for various disease subtypes. It occurs in some HIV patients; metaphetamine users; people with scleroderma; those infected with schistosomiasis (a water bourne parasite). In some patients it is heritable- familial PAH accounts for between 6%-10% and is associated with a defect in a protein called BMPII.

Now onto the exciting part - Stanford researchers have taken a large panel of approved medicines from a broad range of conditions and ran them through an assay of BMPII activity. One molecule lit the assay up - tacrolimus - also known as Prograf or FK506.

Tacrolimus is used in most transplant recipients as an immunosupressant; it prevents the activation of calcineurin and consequent expression of cytokines and their high‐affinity receptors.

In addition to re-expressing BMPII activty, the Stanford group demonstrated that tacrolimus can upregulate the BMPII pathway in cells taken from PAH patients and also correct haematological defect in BMPII KO mice or in a new PAH model induced by SUGEN and hypoxia.

Together these pieces of evidence offer convinging evidence that tacrolimus may just offer hope to some PAH patients - the next step is to test this concept. Tacrolimus has been approved and can therefore be used in patients.

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