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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Effect of the renin response during renin inhibition: oral Ro 42-5892 in normal humans.

The effect of the new renin inhibitor Ro 42-5892 was evaluated in healthy volunteers after both intravenous and oral administration. In a preliminary study, 14 subjects received a 10-min infusion of Ro 42-5892 at doses ranging from 0.001 to 1 mg/kg. Plasma renin activity (PRA) and angiotensin (Ang) II levels were maximally suppressed in a dose-dependent manner at the end of the infusion. Plasma active renin concentration increased up to threefold. In a second study, 24 volunteers received placebo or 100, 600, or 1,200 mg of Ro 42-5892 p.o. in a single-blind, randomized fashion. Within 30 min after drug intake, PRA and plasma Ang I and Ang II levels fell to their nadir. Both Ang I and Ang II were measured specifically after extraction on phenylsilylsilica and separation by isocratic HPLC. The degree as well as the duration of inhibition were dose related. The decrease in plasma Ang lasted maximally for 2 h. Active renin increased dose dependently and remained elevated for more than 8 h after the 1,200 mg dose. A theoretical generation rate of Ang I was calculated for individual plasma samples assuming Michaelis-Menten kinetics for competitive inhibition and steady-state conditions. This calculated Ang I generation rate, based on plasma active renin concentrations and drug levels, closely correlated with actually measured Ang I and Ang II levels (r = 0.90, n = 88) over the whole 8 h time period. Thus, a sustained renin inhibition by Ro 42-5892, as indicated by increased plasma active renin levels, induces a much shorter fall in plasma Ang I and II apparently because of a rise in renin secretion.[1]

References

  1. Effect of the renin response during renin inhibition: oral Ro 42-5892 in normal humans. Camenzind, E., Nussberger, J., Juillerat, L., Munafo, A., Fischli, W., Coassolo, P., van Brummelen, P., Kleinbloesem, C.H., Waeber, B., Brunner, H.R. J. Cardiovasc. Pharmacol. (1991) [Pubmed]
 
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