BACKGROUND:Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.METHODS:In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo.RESULTS:Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg.CONCLUSIONS:Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

For several decades, the lack of oral availability and poor antihypertensive effects of renin inhibitors (RI), despite seemingly powerful inhibition of conventionally measured plasma renin activity (PRA), have discredited RI as cardiovascular drugs. Aliskiren is a novel orally effective RI with antihypertensive potency comparable to losartan or irbesartan. The present study investigated the effects of aliskiren and irbesartan on PRA, measured by the reliable antibody trapping technique, as well as on plasma active renin concentration (ARC) and sitting systolic blood pressure (SBP). In 569 patients with mild to moderate hypertension (baseline sphygmomanometric sitting blood pressure 152±12/99±4 mmHg, mean±SD), PRA and ARC, as well as SBP were measured before and after 8 weeks of treatment with once daily oral doses of aliskiren (150, 300 or 600mg), irbesartan 150mg or placebo. The effects of study treatments on PRA, ARC and SBP are summarized in the Table. PRA and ARC values are geometric means; SBP values are mean ± SD PRA and ARC values are geometric means; SBP values are mean ± SD Aliskiren reduced PRA by 69%, 71% and 75% at 150, 300 and 600mg respectively, while irbesartan doubled PRA. Most of the antihypertensive effect of aliskiren was obtained with the lowest dose, but higher doses slightly further decreased SBP. Aliskiren 150mg and irbesartan 150mg provided similar increases in ARC and hence comparably blocked the renin-angiotensin system (RAS), and the achieved SBP was also the same. Aliskiren 300mg and 600mg caused greater increases in ARC compared with irbesartan 150mg (p<0.05), and further decreases in SBP. The dose-dependent increases in ARC observed with aliskiren document increasing blockade of the RAS. In conclusion, aliskiren provides a parallel reduction in PRA and SBP, a dose-dependent blockade of the RAS and is at least as effective as irbesartan at comparable dosages (150mg).

Background—Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results—The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] ≥95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3±0.8, 11.8±0.8, and 11.5±0.8 mm Hg, respectively, versus 6.3±0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4±1.3, 15.8±1.2, and 15.7±1.2 mm Hg, respectively, versus 5.3±1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9±0.7 and 12.5±1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. Conclusions—Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

Aliskiren is the first in a new class of orally effective, non-peptide renin inhibitors. This dose-finding study compared the antihypertensive efficacy and safety of aliskiren with placebo and with the AT1-receptor blocker, irbesartan. The study was a randomized, multi-centre, double-blind, placebo-controlled, active comparator 8 week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] ≥95 and <110 mmHg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with either once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg, or placebo. The primary efficacy variable of the study was the change from baseline in trough mean sitting DBP. All doses of aliskiren significantly lowered mean sitting DBP and systolic BP (SBP) compared with placebo. Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting DBP by 9.5 ± 8.0, 12.0 ± 8.5 and 11.7 ± 8.8 mmHg respectively versus 6.5 ± 9.0 mmHg for placebo (p< 0.005 versus placebo). Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting SBP by 10.8 ± 12.4, 15.5 ± 13.1 and 15.6 ± 14.3 mmHg respectively versus 5.1 ± 16.2 mmHg for placebo (p< 0.001 versus placebo). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.0 ± 7.9 and 12.5 ± 14.2 mmHg reduction in mean sitting DBP and SBP respectively for irbesartan). The effects on mean sitting DBP of aliskiren 300 mg and 600 mg were significantly greater than those obtained with irbesartan 150 mg (p< 0.05). Aliskiren was comparable to placebo and irbesartan with respect to overall safety and tolerability. The percentage of patients reporting adverse events (AEs) was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg and 600 mg respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%). The results of this study show that once-daily oral treatment with aliskiren lowers blood pressure effectively and that aliskiren 150 mg is comparable in efficacy to irbesartan 150 mg, with an overall safety and tolerability profile comparable to irbesartan and placebo in patients with mild-to-moderate hypertension. Am J Hypertens (2004) 17, 108A–108A; doi: 10.1016/j.amjhyper.2004.03.279

The authors examined the effect of the cyclooxygenase‐2 (COX‐2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 daysina double‐blind, randomized, balanced, two‐period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11‐day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC (0‐∞ ), AUC (0–24) , and C max , the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median t max was 0.5 hours for both treatments. The harmonic mean elimination half‐life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (± 30.8) and 235.1 (± 39.1) μg/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment‐related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.

Objective: The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin.Methods: Two single-dose (12.5 or 50 mg of rofecoxib with 25 mg or 30 mg of oral warfarin, respectively, on day 7 of each period) trials (N = 12 men) and 1 steady-state warfarin trial (25 mg rofecoxib; N = 15, 13 men and 2 women) were completed as two-period, randomized, balanced, crossover, double-blind designs. The prothrombin time international normalized ratio (INR) and S(-) and R(+) warfarin enantiomers were assessed during 144 hours after the single warfarin doses. In the steady-state warfarin trial, after the attainment of a stable INR (1.4-1.7), the stable warfarin dose was co-administered with rofecoxib (25 mg) and placebo over two 21-day periods. After the dose of warfarin on day 21, INR and S(-) and R(+) warfarin were assessed during 24 hours.Results: Compared with placebo, rofecoxib slightly increased the INR by approximately 5% (90% confidence interval on the geometric ratio, 1.03, 1.08) and 11% (1.04, 1.19) for the two single-dose warfarin trials with 12.5 and 50 mg of rofecoxib, respectively. In the steady-state warfarin study with 25 mg of rofecoxib, the INR was increased by 8% (1.02, 1.15). Rofecoxib had no significant effect (versus placebo) on the pharmacokinetics of S(-) warfarin. However, in the 3 studies, treatment with 12.5, 25, and 50 mg of rofecoxib was associated with a 27%, 38%, and 40% increase in the area under the plasma concentration-time curve of the biologically less active R(+) warfarin.Conclusions: Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR The approximately 8% increase in INR at steady state with warfarin co-administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin.

We describe the first reported case of resistance to human recombinant erythropoietin (rhEPO) treatment caused by vitamin B12 deficiency in a chronic hemodialysis patient. Despite a normal B12 level before rhEPO treatment, resistant anemia together with a low B12 level and a megaloblastic bone marrow developed after only 8 months of rhEPO. There was a rapid reticulocyte response to B12 supplements, and transfusion requirements dropped from 2 units monthly to nothing. Atrophic gastritis was diagnosed through endoscopy and biopsy. Because of the fall in B12 level after 8 months of rhEPO treatment, we analyzed the results of routinely measured B12 levels in 30 hemodialysis patients treated with rhEPO, and found the mean B12 levels to be unchanged before and after rhEPO treatment. Although we found screening for B12 deficiency of little benefit, any patient with rhEPO resistance should have B12 levels tested, given the potentially serious extrahematological effects of B12 deficiency.