Angiotensin II Suppression in Humans by the Orally Active Renin Inhibitor SPP100; Comparison with Enalapril
Renin is the main determinant of Ang II levels. It therefore always appeared desirable to reduce Ang II levels by direct inhibition of renin. So far, all specific renin inhibitors lacked potency or were clinically ineffective after oral administration. We tested the new orally active non-peptidic renin inhibitor SPP100 in 18 healthy male volunteers on a constant sodium diet (100mmol/day) using a double-blind, threeway crossover protocol. In 3 periods of 8 days, separated by wash-outs of 1 week, each volunteer received 2 dosage levels of SPP100 once a day (40,80,160 or 640mg) and placebo or 20mg enalapril. SPP100 was well tolerated. Not surprisingly, blood pressure and heart rate remained unchanged in these normal volunteers. SPP100 plasma levels showed that steady state was reached after 8 days of dosing. The table below summarizes median plasma levels at peak (P, 0.5-6h) and trough (T, 24h after dosing) on Day 8: In conclusion, the renin inhibitor SPP100 dose-dependently decreases Ang II levels in humans following oral administration. The effect is long-lasting and at 160mg at least equivalent to that of 20mg enalapril. SPP100 has the clear potential to become the first renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in the therapy of hypertension, cardiovascular and renal disease.