Pulmonary hypertension - sitaxsentan sodium
Pulmonary hypertension is characterised by raised blood pressure in the vessels supplying the lungs. If blood pressure in the pulmonary arteries is too high, the endothelial cells lining the capillaries in the lung become damaged and are unable to interact properly with smooth muscle cells. These muscles then overcontract, narrowing the blood vessels, restricting blood flow and, ultimately, enlarging the right ventricle. The result is chest pain, fainting and, in extreme cases, heart failure. Normal hypertension treatments are not effective, but the peptide endothelin appears to have some effect.
The vascular system is lined with endothelial cells that, as well as acting as a physical barrier to prevent blood cells and plasma constituents penetrating surrounding tissue, produce active substances that are involved in the contraction of vascular smooth muscle. Ultimately, these have the effect of raising the blood pressure. Endothelin is the most potent of these, and plays a pivotal role in the pathogenesis of hypertension; hence it is a potential target for antihypertensive medicines.
A potential drug is sitaxsentan sodium, formerly referred to as TBC-11251.1 Endothelin A has vasoconstrictive effects, while endothelin B has vasodilatory and clearance functions; sitaxsentan sodium has been shown to block the effects of the former, while maintaining the beneficial functions of the latter.2
A total of 178 patients with pulmonary arterial hypertension related to connective tissue disease or congenital heart disease were randomised to receive placebo or 100mg or 300mg of the active once a day for 12 weeks.3 Both doses increased the distance the patients could walk in six minutes compared with placebo, and those given the higher dose experienced a significantly improved change in percent of peak VO2. However, most of the other primary endpoints were not met.
Trials continue, and sitaxsentan sodium has the potential to be a useful therapy for this difficult to treat condition.