Aims: Interaction of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction with organic nitrates could lead to severe hypotension. NMI 861 is a combination of 7.7 mg yohimbine tartrate and 6 g l-arginine glutamate. A similar oral combination, which contains the same amount of yohimbine and L-arginine, has been shown to improve erectile function in previous studies.
Methods: In two placebo-controlled, randomized, double-blind, two-way crossover design studies we aimed to assess first the pharmacokinetics and pharmacodynamics of a single oral dose of NMI 861 administered in 16 healthy male subjects, and then the pharmacodynamics of orally administered NMI 861 in combination with intravenous nitroglycerine (GTN) in 12 healthy male subjects. Systolic (SBP) and diastolic (DBP) blood pressures, pulse rate and adverse events were measured in each study.
Results: NMI 861 was well tolerated by all subjects with no significant adverse reactions reported. For L-arginine, mean C(max) +/- SEM (range) was 42 +/- 2.2 (28-63) microg ml(-1) and t(max) (range) was 0.88 (0.50-1.5) h. AUC and t(1/2) were not calculated for L-arginine because of the presence of endogenous concentrations and the contribution from food sources. For yohimbine, mean C(max) was 42 +/- 11 (2.8-128) ng ml(-1); t(max) was 0.57 (0.25-1.0) h; mean AUC(0,8 h) was 65 +/- 24 (5.4-332), ng ml(-1) h and t(1/2) was 1.0 +/- 0.34 (0.40-6.0) h. There was a small but significant difference in the mean change from baseline for SBP from 0 to 6 h after NMI 861 treatment compared with placebo (0.8 +/- 1.4 vs-4.1 +/- 2.1 mmHg, respectively; 95% CI 0.0, 9.8 mmHg (P = 0.047)). There was no significant difference in SBP between treatments for the studied periods 6-12 h and 12-24 h. There was no significant difference in DBP or pulse between NMI 861 and placebo treatments for the three studied time periods. In the study designed to investigate the interaction of organic nitrate with NMI 861, subjects were infused intravenously with increasing doses of GTN (15 min each dose) at 2.5, 5, 10, 20 and 40 microg min(-1) starting 40 min after a single oral dose of either NMI 861 or placebo. There was no significant difference in the hypotensive response induced by GTN between the NMI 861 and placebo treatments. The mean maximum changes from baseline during GTN infusion for subjects administered with either NMI 861 or placebo were a decrease of 16.9 +/- 3.4 vs 13.6 +/- 2.4 mmHg (mean difference between treatments -3.3 mmHg, 95% CI -12.7, 6.0 mmHg (P = 0.460)) for SBP, a decrease of 14.7 +/- 2.0 vs 14.0 +/- 2.0 mmHg for DBP (mean difference -0.7 mmHg, 95% CI -8.2, 6.8 mmHg (P = 0.835)), and an increase of 11.8 +/- 1.9 vs 14.1 +/- 2.4 beats min(-1) for pulse, respectively (mean difference -2.3 beats min(-1), 95% CI -9.3, 4.5 beats min(-1) (P = 0.464)).
Conclusions: Acute oral administration of NMI 861 was found to be well tolerated and bioavailable in healthy male subjects and no significant hypotensive interaction with intravenous GTN was detected at the doses investigated.