The Experts below are selected from a list of 10167 Experts worldwide ranked by ideXlab platform
Joël Ménard - One of the best experts on this subject based on the ideXlab platform.
-
Renin Inhibitors and cardiovascular and renal protection an endless quest
Cardiovascular Drugs and Therapy, 2013Co-Authors: Michel Azizi, Joël MénardAbstract:Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) Inhibitors or angiotensin receptor blockers (ARBs) has become a major therapeutic approach in medicine since the end of the 1970’s. Although these molecules were the first RAS blockers to be developed, it would have been physiologically and pharmacologically more pertinent to selectively inhibit Renin itself. Indeed, the reaction between Renin and its unique substrate, angiotensinogen, is the highly regulated and rate-limiting step of the RAS. The development of direct Renin Inhibitors (DRI) has been a slow and complex process and the synthesis of the first orally active DRI, aliskiren, was only achieved in the 2000’s. Its pharmacological profile in patients with hypertension, diabetic nephropathy or heart failure, in addition to experimental evidence, suggests that aliskiren may be of value for the management of cardiovascular and renal diseases. However, the long-term, randomized, placebo-controlled, morbidity/mortality trial, ALTITUDE, which included 8,600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk already treated with ACE Inhibitors or ARBs was terminated in December 2011 because of futility and an increased incidence of serious adverse events in the aliskiren 300 mg arm. Other long-term studies are still ongoing to demonstrate the safety and efficacy of aliskiren to reduce cardiovascular morbidity and mortality in patients with heart failure and in elderly individuals (≥65 years) with systolic blood pressure of 130 to 159 mmHg, no overt cardiovascular disease, and a high cardiovascular risk profile. In the meantime, according to the European Medicines Agency recommendations, aliskiren should not be prescribed to diabetic patients in combination with ACE Inhibitors or ARBs.
-
conformational changes in proRenin during Renin inhibition in vitro and in vivo
Journal of Hypertension, 2006Co-Authors: Joël Ménard, Thantam Guyene, Severine Peyrard, Michel AziziAbstract:Background Some Renin Inhibitors induce changes in the conformation of proRenin in vitro and influence the quantification of active Renin by immunoradiometric assays. Whether such changes in Renin recognition by monoclonal antibodies exist after oral administration of aliskiren, the first orally available Renin inhibitor, is not known. Methods Two commercially available immunoradiometric assays (Cisbio and Nichols) were compared to determine immunoreactive active Renin concentrations in plasma samples collected in a single oral dose crossover study comparing the Renin inhibitor, aliskiren (300 mg), with the angiotensin II antagonist, valsartan (160 mg), in healthy male subjects. Results The addition of aliskiren to plasma samples in vitro, at concentrations of 1–100 μmol/l, increased active Renin immunoreactivity in both the Cisbio and Nichols assays. In the crossover study, the two assays gave similar values for the plasma immunoreactive active Renin concentration before treatment and following valsartan administration (intraclass coefficient for agreement between the two assays = 0.92). However, a Bland–Altman plot showed a systematic bias towards higher values (1.75-fold higher; 95% confidence interval = 1.02–3.01) in the Nichols than in the Cisbio assay following aliskiren administration. The difference between the results obtained with the two assays depended on incubation time. Conclusions Depending on incubation conditions, circulating Renin Inhibitors interfere with the recognition of active Renin molecules by the monoclonal antibodies used in commercially available assays. Careful consideration must therefore be given to the methodology used for quantifying immunoreactive plasma active Renin when patients are treated with Renin Inhibitors, to avoid an overestimation of the magnitude of active Renin release attributable to conformational changes in plasma proRenin.
-
aliskiren a novel orally effective Renin inhibitor lowers blood pressure in marmosets and spontaneously hypertensive rats
Journal of Hypertension, 2005Co-Authors: Jeanette Marjorie Wood, Joël Ménard, Christian Schnell, Frederic Cumin, Randy Lee WebbAbstract:Objectives Aliskiren is a new Renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans. Methods The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry. Results In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (−30 ± 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active Renin Inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). Conclusions Aliskiren is an orally effective, long-lasting Renin inhibitor that shows antihypertensive efficacy in animals superior to previous Renin Inhibitors and at least equivalent to angiotensin-converting enzyme Inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.
Alexander H. J. Danser - One of the best experts on this subject based on the ideXlab platform.
-
new Renin inhibitor vtp 27999 alters Renin immunoreactivity and does not unfold proRenin
Hypertension, 2013Co-Authors: Manne Krop, Maarten A D H Schalekamp, Jeanette M G Van Gool, Brian M Mckeever, Koen Verdonk, Richard Gregg, Alexander H. J. DanserAbstract:Renin Inhibitors like aliskiren not only block Renin but also bind proRenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a Renin-specific assay. Consequently, aliskiren can be used to measure proRenin. VTP-27999 is a new Renin inhibitor with an aliskiren-like IC 50 and t 1/2 , and a much higher bioavailability. This study addressed (pro)Renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased Renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher Renin immunoreactivity levels, confirming the presence of proRenin. Unexpectedly, this approach did not work in VTP-27999–treated subjects, although an assay detecting the prosegment revealed that their blood still contained proRenin. Subsequent in vitro analysis showed that VTP-27999 increased Renin immunoreactivity for a given amount of Renin by ≥30% but did not unfold proRenin. Yet, it did bind to acid-activated, intact proRenin and then again increased immunoreactivity in a Renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated proRenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999–induced rises in Renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases Renin immunoreactivity in Renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on proRenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.
-
evaluation of a direct proRenin assay making use of a monoclonal antibody directed against residues 32 39 of the prosegment
Journal of Hypertension, 2011Co-Authors: Manne Krop, Jeanette M G Van Gool, Norman K Hollenberg, Duane Day, Alexander H. J. DanserAbstract:BACKGROUND ProRenin is an early marker of microvascular complications in diabetes. However, it can only be measured indirectly (following its conversion to Renin), with a Renin immunoradiometric assay (IRMA). Unfortunately, treatment with a Renin inhibitor interferes with this assay, because Renin Inhibitors induce a conformational change in proRenin, thereby allowing its detection as Renin. METHODS We evaluated Molecular Innovation's new direct proRenin ELISA, which makes use of an antibody that recognizes an epitope near proRenin's putative cleavage site (R 43 L 44), thus no longer requiring proRenin activation. Plasma samples of 41 diabetic individuals treated with aliskiren (Renin inhibitor) or irbesartan were tested. Semi-purified recombinant proRenin was used as standard, because the ELISA standard yielded approximately 10-fold lower values in the Renin IRMA following its conversion to Renin. RESULTS The ELISA detected proRenin levels that were identical to those determined by the IRMA in untreated and irbesartan-treated individuals. Yet, it yielded higher proRenin levels in aliskiren-treated individuals. Aliskiren, at levels reached in plasma during treatment, did not interfere with the ELISA, but allowed the detection of up to 20-30% of proRenin as Renin in the IRMA, thereby resulting in a significant overestimation of Renin and an underestimation of proRenin. The ELISA rendered results within 2 h and did not require a pretreatment period of several days to convert proRenin to Renin. CONCLUSION The new direct assay allows rapid proRenin detection, is not hampered by aliskiren when used at clinically relevant doses, and might be used to identify diabetic patients developing retinopathy and/or nephropathy.
-
newly developed Renin and proRenin assays and the clinical evaluation of Renin Inhibitors
Journal of Hypertension, 2008Co-Authors: Maarten A D H Schalekamp, F H M Derkx, Jaap Deinum, Alexander H. J. DanserAbstract:BACKGROUND: The last decade has seen the introduction of Renin Inhibitors and new plasma Renin and proRenin assays, which has led to a better understanding of the tissue Renin-angiotensin system. AIM OF THE STUDY: To clarify the consequences of these developments for the methodology and interpretation of measurements of Renin and proRenin. METHODS: The principles and application of the newly developed immunosorbent assays (ISAs) are surveyed and the results are compared with those of enzyme-kinetic assays (EKAs). RESULTS AND CONCLUSIONS: Angiotensin (Ang) II in cardiac, renal and adrenal tissue is known to originate mainly from locally produced Ang I. Experimental evidence and theoretical considerations show that a simple relation between Ang II receptor occupancy, in tissue micromilieu, and the circulating levels of Ang II or Renin may not exist. This supports the clinicians' view that the plasma level of Renin tells more about the mechanisms regulating its release into the circulation than about the Ang II-dependency of hypertension. ISAs are a welcome addition to clinical studies of Renin Inhibitors. By comparing the results of ISAs with those of EKAs, the inhibitor-bound forms of Renin and proRenin can be distinguished from the unbound forms. ISAs also provide important information on the molecular basis of proRenin activation. We propose a single kinetic model to incorporate the conformational changes of proRenin induced by cryo-activation and acid-activation, and by binding to Renin Inhibitors. It explains why Renin ISAs can overestimate the rise of Renin in response to these drugs, and shows how to deal with this artefact.
A Jan H Danser - One of the best experts on this subject based on the ideXlab platform.
-
hypertension Renin angiotensin aldosterone system alterations
Circulation Research, 2015Co-Authors: Luuk Te Riet, Joep H M Van Esch, Anton J M Roks, Anton H Van Den Meiracker, A Jan H DanserAbstract:Blockers of the Renin-angiotensin-aldosterone system (RAAS), that is, Renin Inhibitors, angiotensin (Ang)-converting enzyme (ACE) Inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline Renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.
-
the angiotensin ii type 2 receptor for pain control
Cell, 2014Co-Authors: A Jan H Danser, P AnandAbstract:All well-known deleterious effects of angiotensin (Ang) II, including vasoconstriction, inflammation, water and salt retention, and vascular remodeling, are mediated via its type 1 (AT 1 ) receptor. This explains why AT 1 receptor blockers (ARBs) and Inhibitors of Ang II synthesis, such as ACE Inhibitors and Renin Inhibitors, are beneficial for cardiovascular disease. Yet, Ang II has a second receptor, the Ang II type 2 (AT 2 ) receptor, the function of which, even after over 20 years of research, remains largely unknown. In this issue, Marion et al. provide a new chapter to the AT 2 receptor story.
-
proRenin and pro Renin receptor a review of available data from in vitro studies and experimental models in rodents
Experimental Physiology, 2008Co-Authors: Genevieve Nguyen, A Jan H DanserAbstract:The discovery of a (pro)Renin receptor [(P)RR] and the introduction of Renin Inhibitors in the clinic have brought Renin and proRenin back into the spotlight. The (P)RR binds both Renin and its inactive precursor proRenin, and such binding triggers intracellular signalling that upregulates the expression of profibrotic genes, potentially leading to cardiac and renal fibrosis, growth and remodelling. Simultaneously, binding of Renin to the (P)RR increases its angiotensin I-generating activity, whereas binding of proRenin allows the 'inactive' Renin precursor to become fully enzymatically active. Therefore, the (pro)Renin receptor system could be considered as having two functions, an angiotensin-independent function related to (P)RR-induced intracellular signalling and its downstream effects and an angiotensin-dependent function related to the increased catalytic activity of receptor-bound (pro)Renin. A (P)RR blocker has already been described which blocks both functions, thus preventing diabetic nephropathy, cardiac fibrosis and ocular neovascularization. On-going experimental studies should now determine which of the two functions plays the more important role in pathological situations. The results of these studies are extremely important in view of the clinical use of Renin Inhibitors, since it is well known that their administration results in increased levels of both Renin and proRenin. Although this rise can be interpreted as evidence of effective Renin-angiotensin system blockade, it could also result in increased (P)RR activation.
Jeanette Marjorie Wood - One of the best experts on this subject based on the ideXlab platform.
-
aliskiren a novel orally effective Renin inhibitor lowers blood pressure in marmosets and spontaneously hypertensive rats
Journal of Hypertension, 2005Co-Authors: Jeanette Marjorie Wood, Joël Ménard, Christian Schnell, Frederic Cumin, Randy Lee WebbAbstract:Objectives Aliskiren is a new Renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans. Methods The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry. Results In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (−30 ± 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active Renin Inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). Conclusions Aliskiren is an orally effective, long-lasting Renin inhibitor that shows antihypertensive efficacy in animals superior to previous Renin Inhibitors and at least equivalent to angiotensin-converting enzyme Inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.
-
structure based design of aliskiren a novel orally effective Renin inhibitor
Biochemical and Biophysical Research Communications, 2003Co-Authors: Jeanette Marjorie Wood, Stefan Stutz, Jurgen Maibaum, Joseph Rahuel, Nissimclaude Cohen, Markus G Grutter, Vittorio Rasetti, Heinrich Ruger, Richard Goschke, Walter FuhrerAbstract:Abstract Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the Renin–angiotensin system (RAS) have proven to be successful treatments for hypertension. As Renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like Renin Inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design Renin Inhibitors lacking the extended peptide-like backbone of earlier Inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human Renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit Renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of Renin Inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.
-
structure based drug design the discovery of novel nonpeptide orally active Inhibitors of human Renin
Chemistry & Biology, 2000Co-Authors: Joseph Rahuel, Walter Fuhrer, Frederic Cumin, Stefan Stutz, Jurgen Maibaum, Nissimclaude Cohen, Vittorio Rasetti, Richard Goschke, Heinrich Rueger, Jeanette Marjorie WoodAbstract:Abstract Background: The aspartic proteinase Renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide Inhibitors of Renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide Inhibitors. Based on the available structural information concerning Renin–substrate interactions, we synthesized Inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in Renin. Results: Crystal structure analysis of Renin–inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed Inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3 sp sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3 sp were optimised. Conclusions: Our design approach led to compounds with high in vitro affinity and specificity for Renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These Renin Inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
Sujata Vaidyanathan - One of the best experts on this subject based on the ideXlab platform.
-
absorption distribution metabolism and elimination of the direct Renin inhibitor aliskiren in healthy volunteers
Drug Metabolism and Disposition, 2007Co-Authors: Felix Waldmeier, J Valencia, Ulrike Glaenzel, Bernard Wirz, Lukas Oberer, Dietmar Schmid, Michael Seiberling, Gillesjacques Riviere, Peter End, Sujata VaidyanathanAbstract:Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct Renin Inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (C(max)) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC(0-infinity)), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.
-
pharmacokinetics safety and tolerability of the oral Renin inhibitor aliskiren in patients with hepatic impairment
The Journal of Clinical Pharmacology, 2007Co-Authors: Sujata Vaidyanathan, Marienoelle Bizot, Hans Armin Dieterich, Ching Ming Yeh, Vance Warren, William P DoleAbstract:Aliskiren is the first in a new class of orally active, direct Renin Inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared 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. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC(0-infinity) (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC(0-infinity) or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.
-
aliskiren a novel orally effective Renin inhibitor exhibits similar pharmacokinetics and pharmacodynamics in japanese and caucasian subjects
British Journal of Clinical Pharmacology, 2006Co-Authors: Sujata Vaidyanathan, Marienoelle Bizot, Joanne Jermany, C M Yeh, Riccardo P CamisascaAbstract:Aims Aliskiren is the first in a new class of orally effective Renin Inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects. Methods In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4–10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma Renin concentration (PRC) and plasma Renin activity (PRA). Results Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: Cmax 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC0−72 h 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: Cmax 1.30 (90% CI 1.00, 1.70); AUC0–τ 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 ± 10.2 h and 32.0 ± 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration–time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups. Conclusions The oral Renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.