Dose-Dependent Effects of the Renin Inhibitor Zankiren HCl After a Single Oral Dose in Mildly Sodium-Depleted Normotensive Subjects

Ménard, Joël; Boger, R.; Moyse, Danielle; Guyene, Thanh‐Tam; Glassman, Harriet N.; Kleinert, Hollis D.

doi:10.1161/01.cir.91.2.330

Cited by 43 publications

(33 citation statements)

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“…The methods and antibodies used for sampling and determining plasma and urine hormones were as described in a previous clinical investigation of renin inhibitors (16,17). Circulating levels of aliskiren and valsartan were determined by liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) (detection limits, 0.5 ng/ml and 20 ng/ml, respectively).…”

Section: Laboratory Methodsmentioning

confidence: 99%

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Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Azizi¹,

Ménard²,

Bissery³

et al. 2004

Journal of the American Society of Nephrology

221

182

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Abstract. Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150ϩV80) in 12 mildly sodium-depleted normotensive individuals. In this doubleblind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150ϩV80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150ϩV80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 ϩV80 combination had a synergistic effect on renin release. The A150ϩV80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.Numerous experimental and clinical studies have demonstrated that the combination of currently available angiotensin I-converting enzyme (ACE) inhibitors and AT1 receptor (AT1R) antagonists provides additive or synergistic effects on BP lowering (1) and on the prevention of cardiovascular (2) and renal lesions (3). These observations have previously been explained by AT1R blockers inhibiting the effects of non-ACE-dependent angiotensin II (Ang II) production (4,5) or by the bradykinin-NO-related effects of ACE inhibition (6). However, the additive effects of low doses of two different renin angiotensin system (RAS) inhibitors may be better explained by inhibition of the biologic effects of the reactive renin release that is triggered by single-site RAS blockade. The amount of compensatory renin release is proportional to the extent of decrease in the amount of Ang II generated or bound to the AT1R of the renal juxtaglomerular cells. This counterregulation may be overcome by using higher-than-usual or repeated doses of single-site RAS blockers (7,8) or by neutralizing the biologic effects of the counterbalancing rise in active renin by using a combined RAS blockade.Direct demonstration of the importance of renin in this counterregulatory mechanism has not previously been possible in humans because of the absence of convenient orally available renin inhi...

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Section: Laboratory Methodsmentioning

confidence: 99%

“…C max , concentration at peak; t max , time to peak; t 1/2 , plasma half-life; AUC 0 -48 , area under time curve up to the last measured time-point; AUC 0 -ϱ , AUC extrapolated to infinity. 15 (12)(13)(14)(15)(16)(17)(18)(19) c,d…”

Section: Combined Blockade Of the Ras By Aliskiren And Valsartanmentioning

confidence: 99%

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Azizi¹,

Ménard²,

Bissery³

et al. 2004

Journal of the American Society of Nephrology

221

182

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“…Another approach is to measure the residual enzymatic activity of plasma renin with the antibodycapture method of the PRA or ac-PRC assay (11,39 ). Given the increased ir-PRC values that accompany renin inhibition, one approach to estimating the degree of renin inhibition is to calculate the PRA/ir-PRC ratio or the ac-PRC/ir-PRC ratio, for which the PRA and the ac-PRC are measured by the antibody-capture method (65,66 ). The PRA/ir-PRC ratio has been referred to as the Ang I-production rate (65 ), whereas the ac-PRC/ ir-PRC ratio has been referred to as the renin-specific activity (67 ).…”

Section: Assessment Of Renin Inhibitionmentioning

confidence: 99%

“…Given the increased ir-PRC values that accompany renin inhibition, one approach to estimating the degree of renin inhibition is to calculate the PRA/ir-PRC ratio or the ac-PRC/ir-PRC ratio, for which the PRA and the ac-PRC are measured by the antibody-capture method (65,66 ). The PRA/ir-PRC ratio has been referred to as the Ang I-production rate (65 ), whereas the ac-PRC/ ir-PRC ratio has been referred to as the renin-specific activity (67 ). The PRA/ir-PRC and ac-PRC/ir-PRC ratios more accurately estimate the proportion of renin that is inhibited by a renin inhibitor than the activity assays alone, because PRA and ac-PRC are expressed as a ratio to a quantity that represents the total number of renin molecules, given that the ir-PRC assay measures both active and inhibited renin.…”

Section: Assessment Of Renin Inhibitionmentioning

confidence: 99%

Activity Assays and Immunoassays for Plasma Renin and Prorenin: Information Provided and Precautions Necessary for Accurate Measurement

et al. 2009

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BACKGROUND:Measurement of plasma renin is important for the clinical assessment of hypertensive patients. The most common methods for measuring plasma renin are the plasma renin activity (PRA) assay and the renin immunoassay. The clinical application of renin inhibitor therapy has thrown into focus the differences in information provided by activity assays and immunoassays for renin and prorenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement.CONTENT: Renin activity assays and immunoassays provide related but different information. Whereas activity assays measure only active renin, immunoassays measure both active and inhibited renin. Particular care must be taken in the collection and processing of blood samples and in the performance of these assays to avoid errors in renin measurement. Both activity assays and immunoassays are susceptible to renin overestimation due to prorenin activation. In addition, activity assays performed with peptidase inhibitors may overestimate the degree of inhibition of PRA by renin inhibitor therapy. Moreover, immunoassays may overestimate the reactive increase in plasma renin concentration in response to renin inhibitor therapy, owing to the inhibitor promoting conversion of prorenin to

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“…R enin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system (RAS) inhibition [1][2][3] because the decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by angiotensin I-converting enzyme (ACE) or renin inhibitors or the displacement of Ang II from Ang II type-1 (AT 1 ) receptors by antagonists interrupts the permanent feedback inhibition of renin release mediated by Ang II. 4 The use of renin release as a sensitive plasma biomarker of an acute RAS blockade has several advantages: (1) it can be used for all class of inhibitors, including the ACE inhibitor-AT 1 receptor antagonist combination 5 and renin inhibitors, 3 provided that renin concentration is measured by immunoradiometric assay; (2) the range of variation for this factor is large, at Ϸ2 orders of magnitude; and (3) it is a more precise measurement than blood pressure (BP), another marker used to quantify the intensity of RAS blockade, especially in sodium-depleted subjects.…”

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confidence: 99%

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

et al. 2004

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Abstract-Renin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system inhibition because it is proportional to the interruption of the permanent negative feedback loop of angiotensin II on renin secretion. We investigated the 24-hour between-subject differences in renin profiles by analyzing the time-dependence of individual renin responses in 16 mildly sodium-depleted normotensive subjects exposed in a 4-period crossover study to single oral doses of 8-and 16-mg (C8 and C16) candesartan cilexetil and 80-and 160-mg (V80 and V160) valsartan. C8 had a similar effect to V160 in terms of the increase in active renin concentration and decrease in blood pressure. C16 had the strongest effect and V80 the weakest effect on renin release. Within-and between-subject variability was more marked for valsartan pharmacokinetics than for candesartan pharmacokinetics and influenced variability in renin response. To eliminate some of the variability caused by the pharmacokinetics of each drug, we corrected the area under time curve of plasma renin levels by that of plasma drug levels to obtain an individual normalized index of renin release or "renin/pharmacokinetic index". In these experimental conditions, this index was found to be a reproducible individual characteristic affecting renin response, in addition to the pharmacokinetics and pharmacological properties of angiotensin II type-1 receptor antagonists. The pharmacokinetic-pharmacodynamic model of renin release described here could be of value for the identification and investigation of renin release abnormalities in patients with hypertension and for the comparison of renin-angiotensin system blockers. Key Words: blood pressure Ⅲ renin Ⅲ angiotensin antagonist R enin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system (RAS) inhibition 1-3 because the decrease in angiotensin II (Ang II) production at the level of juxtaglomerular cells induced by angiotensin I-converting enzyme (ACE) or renin inhibitors or the displacement of Ang II from Ang II type-1 (AT 1 ) receptors by antagonists interrupts the permanent feedback inhibition of renin release mediated by Ang II. 4 The use of renin release as a sensitive plasma biomarker of an acute RAS blockade has several advantages: (1) it can be used for all class of inhibitors, including the ACE inhibitor-AT 1 receptor antagonist combination 5 and renin inhibitors, 3 provided that renin concentration is measured by immunoradiometric assay; (2) the range of variation for this factor is large, at Ϸ2 orders of magnitude; and (3) it is a more precise measurement than blood pressure (BP), another marker used to quantify the intensity of RAS blockade, especially in sodium-depleted subjects. 5,6 In contrast to the increase in renin concentration observed after RAS blockade, the magnitude of the decrease in BP may be influenced by a placebo effect and offers a limited range of variation (5 to 15 mm Hg).We investigated in detail between-subject d...

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Dose-Dependent Effects of the Renin Inhibitor Zankiren HCl After a Single Oral Dose in Mildly Sodium-Depleted Normotensive Subjects

Abstract: Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.

Cited by 43 publications

References 30 publications

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Activity Assays and Immunoassays for Plasma Renin and Prorenin: Information Provided and Precautions Necessary for Accurate Measurement

Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans

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