Abstract-Renin is the main determinant of angiotensin (Ang) II levels. It, therefore, always appeared desirable to reduce Ang II levels by direct inhibition of renin. So far, specific renin inhibitors lacked potency and/or oral availability. We tested the new orally active nonpeptidic renin inhibitor SPP100 (Aliskiren, an octanamide with a 50% inhibitory concentration [IC50] in the low nanomolar range) in 18 healthy volunteers on a constant 100 mmol/d sodium diet using a double-blind, 3-way crossover protocol. In 3 periods of 8 days, separated by wash-outs of 6 days, each volunteer received 2 dosage levels of Aliskiren (low before high; 40 and 80 or 160 and 640 mg/d) and randomized placebo or 20 mg enalapril. Aliskiren was well tolerated. Not surprisingly, blood pressure and heart rate remained unchanged in these normotensive subjects. There was a dose-dependent decrease in plasma renin activity, Ang I, and Ang II following single doses of Aliskiren starting with 40 mg. Inhibition was still marked and significant after repeated dosing with maximal decreases in Ang II levels by 89% and 75% on Days 1 and 8, respectively, when the highest dose of Aliskiren was compared with placebo. At the same time, mean plasma active renin was increased 16-and 34-fold at the highest dose of Aliskiren. Plasma drug levels of Aliskiren were dose-dependent with maximal concentrations reached between 3 to 6 hours after administration; steady state was reached between 5 and 8 days after multiple dosing. Less than 1% of dose was excreted in the urine. Plasma and urinary aldosterone levels were decreased after doses of Aliskiren Ն80 mg and after enalapril. Aliskiren at 160 and 640 mg enhanced natriuresis on Day 1 by ϩ45% and ϩ62%, respectively, compared with placebo (100%, ie, 87Ϯ11 mmol/24h) and enalapril (ϩ54%); kaliuresis remained unchanged. In conclusion, the renin inhibitor Aliskiren dose-dependently decreases Ang II levels in humans following oral administration. The effect is long-lasting and, at a dose of 160 mg, is equivalent to that of 20 mg enalapril. Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases. (Hypertension. 2002;39:e1-e8.)Key Words: renin Ⅲ angiotensin I Ⅲ angiotensin-converting enzyme Ⅲ aldosterone Ⅲ blood pressure Ⅲ hypertension, essential Ⅲ hypertension, renovascular Ⅲ heart failure O ver the last 3 decades, inhibition of the renin-angiotensin system was successfully used in the treatment of hypertension and heart failure. [1][2][3][4] Reduced activation of the Ang II receptor appears to be a key event to counteract increased blood pressure and sympathetic tone as well as harmful cardiovascular hypertrophy and renal lesions. Pharmacological blockade of the Ang II receptors of the AT1-subtype so far turns out to be clinically equally effective to the less specific ACE-inhibition, 5 but the generation of Ang II remains unopposed during ...

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Abstract-Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Key Words: renin Ⅲ blood pressure Ⅲ hypertension, essential Ⅲ blood pressure monitoring, ambulatory Ⅲ receptors, angiotensin Ⅲ losartan T he renin-angiotensin system (RAS) has well-established roles in both blood pressure (BP) regulation and atherogenesis. 1,2 Recent clinical trial evidence suggests that blockade of the RAS by angiotensin-converting enzyme inhibition or by angiotensin receptor blockade may influence largevessel atherosclerosis and cardiovascular morbidity and mortality independent of BP lowering. 3,4 As renin catalyzes the first and rate-limiting step of the system and has high specificity for angiotensinogen, blockade of the production of angiotensin (Ang) II by direct inhibition of renin has long been a therapeutic goal. Indeed, intravenous administration of the early renin inhibitors, such as enalkiren and remikiren, did reduce angiotensin levels and lower BP without any important adverse effects. 5-8 However, to date, due to relatively low potency, poor oral bioavailability (Ͻ1%), short durations of action, and high costs of synthesis, none of these peptide and peptidomimetic inhibitors has made it to the end of clinical trials. 9 Aliskiren, an octanamide, is the first known representative of a new class of completely nonpeptide, low-molecularweight, orally active transition-state renin inhibitors. 10 Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of Ϸ24 hours. 10 Aliskiren has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. 10 When administered orally to sodium-depleted marmosets, it caused significant and sustained reductions in arterial blood pressure (unpublished data). In single-dose and multiple-dose tolerability studies in healthy normotensive male volunteers, oral doses up to 640 mg daily for 8 days were well tolerated and did not result in any significant toxicity. 11 Micromolar plasma concentrations were achieved, and aliskiren was shown to cause a dose-dependent decrease in plasma renin activity (PRA), to effectively block the formation of both Ang I and Ang II, and to decrease plasma and urine aldosterone levels. 11 In this study, we studied for the first time the efficacy, safety, and tolerability of 4 weeks of treatment with 37.5, 75, 150 and 300 mg aliskiren in healthy individuals with mild to moderate hypertension. We compared...

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