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Juerg Nussberger, Gregoire Wuerzner, Chris Jensen, Hans R. Brunner, O-36: The orally active renin inhibitor SPP100 blocks the renin-angiotensin system in humans equally well as enalapril, American Journal of Hypertension, Volume 14, Issue S1, April 2001, Page 17A, https://doi.org/10.1016/S0895-7061(01)01353-X
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Abstract
The activity of the renin-angiotensin system (RAS) is mainly determined by the concentration of active renin. Direct inhibition of renin is therefore a primary goal for blocking the RAS. 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 volunteers on a constant sodium diet (100 mmol/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 blocks the RAS and decreases angiotensin levels in human subjects 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.
. | Placebo . | SPP 100 . | . | . | Enalapril . | |
---|---|---|---|---|---|---|
. | . | 40mg . | 80mg . | 160mg . | 640mg . | 20mg . |
Renin pg/ml P | 12 | 34 | 95 | 130 | 670 | 330 |
T | 11 | 19 | 39 | 64 | 373 | 58 |
PRA ng/ml/h P | 1.0 | 0.28 | 0.21 | 0.16 | 0.08 | 27 |
T | 1.4 | 0.89 | 0.60 | 0.41 | 0.39 | 3.5 |
Ang I fmol/ml P | 3.2 | 1.6 | 1.4 | 0.33 | 0.70 | 350 |
T | 7.0 | 7.1 | 6.1 | 4.8 | 3.1 | 34 |
Ang II fmol/ml P | 3.0 | 1.5 | 1.5 | 0.61 | 0.27 | 0.88 |
T | 4.5 | 3.7 | 3.5 | 3.2 | 2.5 | 4.2 |
. | Placebo . | SPP 100 . | . | . | Enalapril . | |
---|---|---|---|---|---|---|
. | . | 40mg . | 80mg . | 160mg . | 640mg . | 20mg . |
Renin pg/ml P | 12 | 34 | 95 | 130 | 670 | 330 |
T | 11 | 19 | 39 | 64 | 373 | 58 |
PRA ng/ml/h P | 1.0 | 0.28 | 0.21 | 0.16 | 0.08 | 27 |
T | 1.4 | 0.89 | 0.60 | 0.41 | 0.39 | 3.5 |
Ang I fmol/ml P | 3.2 | 1.6 | 1.4 | 0.33 | 0.70 | 350 |
T | 7.0 | 7.1 | 6.1 | 4.8 | 3.1 | 34 |
Ang II fmol/ml P | 3.0 | 1.5 | 1.5 | 0.61 | 0.27 | 0.88 |
T | 4.5 | 3.7 | 3.5 | 3.2 | 2.5 | 4.2 |
. | Placebo . | SPP 100 . | . | . | Enalapril . | |
---|---|---|---|---|---|---|
. | . | 40mg . | 80mg . | 160mg . | 640mg . | 20mg . |
Renin pg/ml P | 12 | 34 | 95 | 130 | 670 | 330 |
T | 11 | 19 | 39 | 64 | 373 | 58 |
PRA ng/ml/h P | 1.0 | 0.28 | 0.21 | 0.16 | 0.08 | 27 |
T | 1.4 | 0.89 | 0.60 | 0.41 | 0.39 | 3.5 |
Ang I fmol/ml P | 3.2 | 1.6 | 1.4 | 0.33 | 0.70 | 350 |
T | 7.0 | 7.1 | 6.1 | 4.8 | 3.1 | 34 |
Ang II fmol/ml P | 3.0 | 1.5 | 1.5 | 0.61 | 0.27 | 0.88 |
T | 4.5 | 3.7 | 3.5 | 3.2 | 2.5 | 4.2 |
. | Placebo . | SPP 100 . | . | . | Enalapril . | |
---|---|---|---|---|---|---|
. | . | 40mg . | 80mg . | 160mg . | 640mg . | 20mg . |
Renin pg/ml P | 12 | 34 | 95 | 130 | 670 | 330 |
T | 11 | 19 | 39 | 64 | 373 | 58 |
PRA ng/ml/h P | 1.0 | 0.28 | 0.21 | 0.16 | 0.08 | 27 |
T | 1.4 | 0.89 | 0.60 | 0.41 | 0.39 | 3.5 |
Ang I fmol/ml P | 3.2 | 1.6 | 1.4 | 0.33 | 0.70 | 350 |
T | 7.0 | 7.1 | 6.1 | 4.8 | 3.1 | 34 |
Ang II fmol/ml P | 3.0 | 1.5 | 1.5 | 0.61 | 0.27 | 0.88 |
T | 4.5 | 3.7 | 3.5 | 3.2 | 2.5 | 4.2 |
- angiotensin-converting enzyme inhibitors
- angiotensins
- enalapril
- hypertension
- kidney diseases
- renin-angiotensin system
- steady state
- heart rate
- renin
- angiotensin ii
- angiotensin i
- blood pressure
- diet
- administration, oral
- cardiovascular system
- plasma
- sodium
- antagonists
- trough concentration
- renin inhibitor