Allikmets No dose-dependent increase in the number of adverse effects and no signiﬁcant abnormalities in laboratory param- eters have been observed with aliskiren doses up to 300 mg (Stanton et al 2003; Weir et al 2006). However, higher doses of aliskiren (600 mg) seem to be associated with higher rate of diarrhoea when compared to placebo. In the meta-analysis by Weir et al (published so far only as abstract), the incidence of diarrhoea with aliskiren 600 mg was 9.5% versus 1.2% in the placebo group, there was no increase with aliskiren doses of 150 mg or 300 mg (1.2% and 2.3% respectively), and diarrhoea was not associated with patient discontinua- tions (Weir et al 2006). Aliskiren is a highly selective inhibitor of the RAS and does not interfere with the metabolism of bradykinin or substance P; therefore side-effects such as cough or angioedema that occur with ACE inhibitors are not likely to occur with aliskiren treatment. Aliskiren’s side effect proﬁle is rather comparable to that of ARBs (ie, similar to that of a placebo). Aliskiren was well tolerated in patients with hepatic imparment (Vaidyanathan et al 2007). This open-label, nonrandomized, single-center, parallel-group study com- pared the pharmacokinetics and safety of a single 300 mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. Pooled analysis across subgroups was performed, with no signiﬁcant differences detected between patients with hepatic impairment and healthy subjects in aliskiren AUC0–∞ (ratio of geometric means, 1.12; 90% conﬁdence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% con- ﬁdence interval, 0.84, 1.68). Also, there was no correla- tion between severity of hepatic impairment and either AUC0–∞ or Cmax. In conclusion, hepatic impairment had no signiﬁcant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjust- ment is unlikely to be needed in patients with liver disease (Vaidyanathan et al 2007). Although aliskiren appears to be safe, additional data would be needed to assess the effects of aliskiren on renal function and biochemistry, especially serum potassium levels in patients with renal impairment, heart failure and diabetes mellitus (Azizi et al 2006). The potential hazards of a complete RAAS inhibition with combination treatment (aliskiren combined with ACE inhibitor and/or ARB) require careful evaluation, especially in situations in which blood pressure and renal function are renin dependent (such as in elderly or salt-depleted patients), in patients receiving COX inhibitors, patients with renal artery stenosis and patients placed under anaesthesia (Azizi et al 2006). 814 In summary, aliskiren appears to be well tolerated and safe based on the available clinical data. Future studies should further conﬁrm the beneﬁcial side-effect proﬁle of aliskiren in speciﬁc patient populations such as patients with renal impairment or heart failure. The potential hazards of a complete RAAS inhibition when using aliskiren in combi- nation with ACE inhibitors or ARBs need to be evaluated, especially in populations in whom BP and renal function are renin dependent, such as elderly, salt-depleted patients and patients with renal artery stenosis. Conclusion Aliskiren offers a promising new approach to the blockade of the RAS. It is the ﬁrst representative of a new class of non-peptide, low molecular weight, orally active transition- state renin inhibitors. Its high potency against human renin compensates for its relatively low absolute bioavailability, its long half-life makes it suitable for once daily administra- tion. Aliskiren is effective in reducing blood pressure and is well tolerated, with a side-effect proﬁle similar to placebo or ARBs. It exhibits synergistic effects when combined with drugs that lead to a reactive increase in the plasma renin activity, such as diuretics, ACE inhibitors or ARB. Aliskiren has demonstrated target organ protection in animal models and in clinical trials, future studies must show whether these properties translate into beneﬁcial effects on long-term mor- bidity and mortality. References Azizi M, Menard J, Bissery A, et al. 2004. 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