Using drug therapies to inhibit an enzyme called tryptophan hydroxylase 1 (TPH1) can significantly reduce pulmonary arterial pressure as well as pulmonary blood vessel wall thickness and blockade, according to a new study published in the Journal of Pharmacology and Experimental Therapeutics.
The study, “Tryptophan hydroxylase 1 (TPH1) Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension,” provides proof-of-concept evidence that TPH1 inhibition could be used to treat vascular remodeling in PH.
The results of the study also showed that when administered together with Letairis (ambrisentan), a drug that is approved for the treatment of PH, TPH1 inhibitors showed an additive effect in reducing lung blood vessel remodeling and pressure.
In order to test the long-term effect of pharmacologically inhibiting TPH1, a team of researchers led by Dr. Vishwas Paralkar, chief scientific officer at Karos Pharmaceuticals in New Haven, Connecticut, treated two rat models of PH with the TPH1 inhibitors KAR5585 and KAR5416.
They saw the two novel orally active compounds decreased the levels of serotonin in the blood, gut, and lungs of the animals in a dose dependent manner. They also significantly reduced pulmonary arterial pressure and pulmonary vessel wall thickness and occlusion.
In one of the rat models, the reduction of serotonin levels in the lungs significantly correlated with reductions in histamine levels and mast cell number, which play a role in inflammation.
“These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH,” the study’s authors wrote.
Interestingly, neither Letairis nor Adcirca (tadalafil) — drugs that dilate blood vessels and are approved for the treatment of PH — did not reduce the number of mast cells and were not as effective as the TPH1 inhibitors in treating vascular remodeling.
The authors concluded that TPH1 inhibition could be a novel, stand-alone therapy, offering a different mechanism of action than the current treatment options available for PH patients.
One of the TPH1 inhibitors, KAR5585, has already been tested in a Phase 1 clinical trial (NCT02746237) and could be a novel option for the treatment of PH in the future.
PH is a progressive disease characterized by a chronic elevation in pulmonary arterial pressure and extensive remodeling of the blood vessels of the lungs. Inflammation around the blood vessels with an accumulation of macrophages, lymphocytes, dendritic cells and mast cells is also a hallmark of the disease. Although the exact cause of the disease is not fully understood, previous research suggests that serotonin may play a role.
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