Advances in PAH, lower-dose cyclosporine coming

June 4, 2007

New immunosuppressive regimens that combine Certican and low-dose Neoral to preverse renal function following heart transplants and Viagra to lower pulmonary arterial heypertension are coming soon to hospitals.

Coming soon to a hospital near you: new immunosuppressive regimens that combine everolimus (Certican, Novartis) and cyclosporine (modified) to preserve renal function following heart transplants and sildenafil (Viagra, Pfizer) to lower pulmonary arterial hypertension (PAH).













Daily sildenafil can dramatically increase exercise tolerance, Ghofrani said. But it is usually dosed at 50 mg three times daily for PAH. Three daily doses make treatment expensive as well as inconvenient, which has prompted researchers to test tadalafil (Cialis, Lilly/Icos) in PAH. Tadalafil is a good alternative because its longer duration of action may allow daily or less-frequent dosing.

Both PDE-5 inhibitors act on the nitrous oxide pathway to relax and enlarge arteries. In the penis, increased blood flow improves erections. In the lungs, increased blood flow lowers PAH and increases oxygen absorption. Ghofrani reported that early trials show oxygenation and exercise tolerance are improved even more if sildenafil is combined with inhaled iloprost (Ventavis, Actelion), a more familiar PAH treatment. "There is good rationale for combination therapy, but there are no large randomized, controlled trials yet," he said.

Another fairly new treatment is bosentan (Tracleer, Actelion), an oral dual endothelial receptor antagonist. The drug dramatically increases exercise tolerance with few serious adverse events, said Michael Landzberg, M.D., from the Boston Adult Congenital Heart & Pulmonary Hypertension Group at Children's Hospital.

Immunosuppressive therapy following organ transplants may also be about to change. Two studies presented at ISHLT support the use of everolimus with low-dose cyclosporine (modified) to preserve renal function. The combination is already used in Europe.

"Approval in Europe required postmarketing studies, especially renal function studies," explained Hans Lehmkuhl, M.D., senior physician in cardiovascular and thoracic surgery at Deutsches Herzzentrum, Berlin, Germany. "At six months, more than 90% of patients were still in the study, and we saw more discontinuation in the comparator group than in the everolimus group."

What the study did not see halfway through the one-year trial was clear superiority of everolimus/low-dose cyclosporine over mycophenolate mofetil (MMF) plus conventional cyclosporine dosing. The open-label study followed 176 adult heart transplant patients.