Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study

Background: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness.Objectives: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness.Methods: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5-10 mg/d) or candesartan (8-12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment.Results: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (−7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect.Conclusion: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT.     

Comparison of the Effects of Amlodipine and Losartan on Blood Pressure and Diurnal Variation in Hypertensive Stroke Patients: A Prospective,Randomized, Double-Blind,Comparative Parallel Study

Background

Lowering blood pressure (BP) and reducing diurnal variation are important for the prevention of stroke in patients with hypertension.

Objective

This study was conducted to compare the BP-lowering and diurnal BP variation effects of amlodipine and losartan on acute stroke patients.

Methods

Seventy-seven hypertensive patients with acute stroke were enrolled in this randomized, double-blind, single-center clinical trial. They were randomly assigned to receive either amlodipine or losartan daily. To evaluate whether amlodipine was noninferior to losartan, ambulatory BP monitoring was performed before the drugs were first administered and at the end of week 8. BP variables analyzed included the mean awake, sleep, morning, evening, and prewake BP values; the nocturnal dipping status; and the morning surge.

Results

Thirty-nine patients in the amlodipine group and 38 patients in the losartan group completed the follow-up. In the baseline characteristics, mean age was 63.6 years, and 68.8% were male. In the intention-to-treat analysis, the mean (SD) systolic BP decreased 14.82 (11.71) mm Hg in the amlodipine group and 13.11 (12.69) mm Hg in the losartan group, and amlodipine proved noninferior to losartan (mean difference, 1.71 mm Hg [95% CI, –3.83 to 7.26]). However, in the per-protocol analysis, noninferiority was not proven (BP reduction, 16.06 [11.33] vs 17.17 [11.85] mm Hg; mean difference, –1.11 mm Hg [95% CI, –6.88 to 4.65]). Amlodipine had a greater tendency than losartan to produce a blunt morning surge.

Conclusions

The noninferiority of amlodipine was not confirmed by the per-protocol analysis. However, amlodipine showed a favorable effect on the morning surge. ClinicalTrials.gov identifier: NCT01830517.     

Ambulatory Blood Pressure Response to Once-Daily Fimasartan: An 8-Week,Multicenter, Randomized,Double-Blind,Active-Comparator,Parallel-Group Study in Korean Patients With Mild To Moderate Essential Hypertension

Background

Fimasartan, a selective angiotensin II type 1 receptor blocker, was approved in Korea for the treatment of patients with mild to moderate hypertension.

Objective

The aim of this study was to evaluate the 24-hour blood pressure (BP) profiles before and after 8-week treatment with fimasartan and to compare them with those of valsartan.

Methods

A multicenter, randomized, double-blind, active-controlled, parallel-group study was conducted using ambulatory BP monitoring (ABPM). Korean patients with mild to moderate essential hypertension were enrolled and randomly received once-daily oral fimasartan 60 or 120 mg or valsartan 80 mg for 8 weeks. ABPM was performed before and after 8-week treatment, and clinic BP was also measured. Based on ABPM data, trough-to-peak ratio and smoothness index were derived. Tolerability was monitored throughout the study.

Results

Ninety-two patients were enrolled (mean [SD] age, 54.1 [8.2] years; weight, 67.9 [10.2] kg). After 8 weeks, 24-hour, daytime, and nighttime mean ambulatory systolic and diastolic BPs (SBP and DBP, respectively) were significantly decreased in all 3 treatment groups (range: SBP, –9.2 to –15.6 mm Hg; DBP, –5.0 to –10.7 mm Hg; P <0.0001–<0.05). The global trough-to-peak ratios of ambulatory DBP in the fimasartan groups were 0.74 (60 mg/d) and 0.81 (120 mg/d)—45.1% and 58.8% higher, respectively, than the ratio of 0.51 in the valsartan group. Fimasartan 60 mg/d was associated with 53.5% (SBP) and 68.3% (DBP) greater smoothness index scores compared with those with valsartan 80 mg/d (SBP, 1.52 vs. 0.99; DBP, 1.38 vs. 0.82). The decrease in clinic-measured DBP was significantly greater in the fimasartan 60-mg/d group compared with that in the valsartan 80-mg/d group (–14.0 vs –8.7 mm Hg; P = 0.0380). Fimasartan was well tolerated; headache was the most common adverse event.

Conclusion

Once-daily fimasartan effectively maintained a BP-reduction profile over the full 24-hour dosing interval; this profile was comparable to or slightly better than that of once-daily valsartan. Fimasartan was well tolerated; headache was the most common adverse event. ClinicalTrials.gov identifier: NCT00922441.     

Implementation of the Surviving Sepsis Campaign guidelines for severe sepsis and septic shock: We could go faster

Purpose

The aim of this study is to evaluate the feasibility of applying sepsis bundles in the intensive care unit (ICU) and their effect on outcomes.

Methods

In this prospective, observational study in a 31-bed capacity department of intensive care, we measured the time taken to perform sepsis bundle interventions in 69 consecutive patients with severe sepsis or septic shock.

Results

Compliance with the 6-hour bundle was obtained in 44 (72%) of 61 patients; these patients had a lower mortality rate (16% vs 41%, P = .04) and shorter ICU stay (median [range], 5 [3-10] vs 9 [6-19] days, P = .01) than other patients. Compliance with the 24-hour bundle was obtained in 30 (67%) of 44 eligible patients. The mortality rate and duration of ICU stay were not significantly lower in the 24-hour compliant as compared with the noncompliant group (23% vs 33% and 6 [4-11] vs 9 [6-25] days, respectively; P value is not significant). Patients who complied with the 24-hour sepsis bundle after only 12 hours had a lower mortality rate (10% vs 39%, P = .036) and shorter stay (6 [4-10] vs 9 [6-25] days, P = .055) than those who were compliant after 24 hours.

Conclusions

Correct application of the sepsis bundles was associated with reduced mortality and length of ICU stay. Earlier implementation of the 24-hour management bundle could result in better outcomes.     

Etamicastat,a Novel Dopamine β-Hydroxylase Inhibitor: Tolerability,Pharmacokinetics, and Pharmacodynamics in Patients With Hypertension

Background

Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.

Objective

This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension.

Methods

This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM).

Results

The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat T_max was 1 hour postdose, and mean t_½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine—30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, –11.66 mm Hg [–21.57 to –1.76; P < 0.05]; 100 mg, –14.92 mm Hg [–24.98 to –4.87; P < 0.01]; and 200 mg, –13.62 mm Hg [–22.29 to –3.95; P < 0.01]).

Conclusions

Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.     

Polymyxin B-immobilized fiber column hemoperfusion removes endotoxin throughout a 24-hour treatment period

Purpose

The purpose of this study was to evaluate the extent of endotoxin adsorption by polymyxin B-immobilized fiber column hemoperfusion (PMX) performed for a 24-hour treatment period in patients with septic shock.

Materials and methods

Nineteen patients with septic shock were retrospectively studied. The plasma endotoxin concentrations of blood drawn from the radial artery and from the outlet circuit of the PMX column were measured by kinetic turbidimetric limulus assay using an MT-358 Toxinometer (Wako Pure Chemical Industries, Ltd, Osaka, Japan) after 24 hours of PMX treatment. The endotoxin removal rate was defined by the following equation: ([radial artery endotoxin concentration − outlet circuit of PMX column endotoxin concentration]/radial artery endotoxin concentration) × 100%.

Results

The patients had a median Acute Physiology and Chronic Health Evaluation II score of 29 at intensive care unit admission and a 28-day mortality of 47%. Before the start of the PMX treatment, the median radial arterial plasma endotoxin concentration was 16.48 pg/mL. After 24 hours of PMX treatment, the median radial plasma endotoxin concentration had decreased to 1.857 pg/mL, and the concentration at the outlet circuit of the PMX column was further decreased to 0.779 pg/mL. The median endotoxin removal rate was 74.4%.

Conclusion

These findings suggest that 24-hour PMX treatment was effective in removing endotoxin continuously throughout the entire treatment period.     

Differential time effect profiles of amlodipine, as compared to valsartan, revealed by ambulatory blood pressure monitoring, self blood pressure measurements and dose omission protocol

Amlodipine and valsartan are once-daily antihypertensive agents. To date, no comparison between these agents given as monotherapies was reported. This study was aimed to evaluate the therapeutic coverage and safety of amlodipine and valsartan in mild-to-moderate hypertensive patients. Multicenter, double-blind, randomized, comparative study. After a 4-week placebo wash-out period, 246 outpatients with office diastolic blood pressure 95 < or = DBP < or =110 mmHg and systolic blood pressure (SBP) < 180 mmHg, in addition to a mean daytime SBP and/or DBP > 135/85 mmHg on 24-h ambulatory blood pressure monitoring (ABPM), were randomly allocated to once-daily amlodipine 5-10 mg or valsartan 40-80 mg, for 12 weeks. In a subgroup of patients, 48-h ABPM were performed at the end of the treatment period. Dose omission was simulated by a single-blind placebo dosing. The primary efficacy end-point was the 24-h trough office BP after 12 weeks of active therapy. The reductions in 24-h trough BP were more pronounced in amlodipine compared with valsartan group as well in office [SBP: -17.8 +/- 10.9 vs. -14.6 +/- 11.2, P = 0.025, DBP: -12.7 +/- 7.2 vs. -10.9 +/- 7.8 mmHg, P = 0.06) as in ambulatory BP (SBP/DBP: -13.0 +/- 13.7/-10.8 +/- 9.1 vs. -7.2 +/- 19.4/-4.9 +/- 13.4 mmHg, P < 0.05). Forty-eight hours after the last active dose, the slope of the morning BP surge (4-9 h) was less steep with amlodipine vs. valsartan [DBP (P < 0.04), SBP (n.s.)]. Ankle edema were more often reported in amlodipine group. These results suggest a superior BP lowering and a longer duration of action with amlodipine compared with valsartan.     

Hemodynamic Effects of l-Threo-3,4-Dihydroxyphenylserine (Droxidopa) in Hypotensive Individuals With Spinal Cord Injury

Objectives

To determine the effect of an escalating dose of droxidopa (100, 200, and 400mg) compared with placebo on seated blood pressure (BP) in hypotensive individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effect of droxidopa on (1) supine BP and heart rate, (2) the change in BP and heart rate when these individuals were transferred from the supine to the seated position, and (3) adverse event (AE) reporting.

Design

Open-label dose titration trial.

Setting

A Veterans Administration Medical Center.

Participants

Participants with SCI (C3-T12) (N=10) were studied during 4 laboratory visits. Subjects visited the laboratory for about 5 hours on each visit, which incorporated a 30-minute seated baseline, a 30- to 60-minute supine, and a 4-hour seated postdrug observation.

Interventions

Placebo on visit 1, droxidopa 100mg on visit 2, droxidopa 200mg on visit 3, and droxidopa 400mg on visit 4.

Main Outcome Measures

BP and heart rate changes from baseline to the postdrug period, orthostatic heart rate and BP responses, and subjective AE reporting.

Results

Seated BP was significantly elevated with 400mg droxidopa compared with placebo and 100mg droxidopa for 3 hours and was elevated for 2 hours compared with 200mg droxidopa. Increase in supine BP was not worsened following droxidopa, and the expected fall in BP when transferred to the seated position was prevented with droxidopa 200 and 400mg. There were no significant differences in the heart rate response or AE reporting among the study visits.

Conclusions

Our preliminary findings suggest that droxidopa, at the doses tested, does not cause excessive increases in supine BP and the 400-mg dose appears to be effective at increasing seated BP for up to 3 hours in persons with SCI.     

Diurnal variation in stature: Do those with chronic low-back pain differ from asymptomatic controls?

Background

Stature loss is a commonly used measure of spinal load. The aim of this study was to investigate the pattern of diurnal stature change in those with and without chronic low-back pain, over a 24-h period.

Methods

Eight participants with chronic low-back pain (age 24.6 (SD 4.3) years, height 1.76 (SD 0.08) m, body mass 72.8 (SD 11.1) kg) and eight controls (age 21.8 (SD 2.0) years, height 1.75 (SD 0.10) m, body mass 71.8 (SD 11.6) kg) participated in this investigation. Twenty-four stature measurements were performed over a 24-h period.

Findings

The trough to peak variation in stature of 17.9 mm (low-back pain group) and 17.6 mm (control group) did not differ between groups (P > 0.05). Both groups experienced greatest stature change in the 1st hour after rising (31.3% [low-back pain] and 44.6% [control] of total stature change). At approximately 18:00 h the LBP group reached a plateau whilst the control group continued to lose stature. Between 14:00 and 18:00 h both groups demonstrated a previously unreported recovery of stature. A significant correlation was found between low-back discomfort and stature change in the low-back pain group only.

Interpretation

No significant difference existed between groups in relation to total stature loss; however the low-back pain group appeared to reach their nadir earlier, possibly exposing other spinal structures to loading for a greater duration. This is supported by the relationship found between stature loss and discomfort. The reversal in stature loss in the afternoon may be of clinical significance and warrants further investigation.     

Prolonged sevoflurane administration in the off-pump coronary artery bypass graft surgery: Beneficial effects

Purpose

The benefits of intraoperative administration of halogenated agents in patients undergoing cardiac surgery have been shown by numerous studies. The mechanisms of preconditioning and postconditioning appear to be the cause of these benefits. The possibility of maintaining the early postoperative sedation with halogenated agents, after its intraoperative administration, can increase their benefits.

Patients and methods

This is a prospective trial with 60 patients undergoing coronary artery bypass graft surgery divided into 3 groups according to the administration of hypnotic drugs in the intraoperative and postoperative periods (sevoflurane, sevoflurane: SS, sevoflurane-propofol: SP, propofol-propofol: PP). For the first 48 hours, hemodynamic parameters, the need for inotropic drugs, N-terminal pro-brain natriuretic peptide, and troponin I plasmatic concentrations were obtained.

Results

There were significant differences between group SS and the other 2 groups in the levels of N-terminal pro-brain natriuretic peptide (SS [501 ± 280 pg/mL] compared with SP [1270 ± 498 pg/mL] and PP [1775 ± 527 pg/mL] [P < .05]) and troponin I (SS [0.5 ± 0.4 ng/mL] compared with SP [1.61 ± 1.30 ng/mL] and PP [2.27 ± 1.5 ng/mL] [P < .05]) and a lower number of inotropic drugs.

Conclusion

Sevoflurane administration in patients undergoing off-pump coronary artery bypass graft, in the operating room and the intensive care unit, decreases myocardial injury markers compared with patients who only received sevoflurane in the intraoperative period, but both were a better option to decrease levels of myocardial markers when compared with the propofol group.     

Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin,a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects

Background

Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action.

Objectives

These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China.

Methods

In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed.

Results

Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m² in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (T_max, ≤1.5 h), accumulation (defined as the geometric mean ratio of AUC_τ at day 10 to AUC_τ at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median T_max (≤2 h) but a similar plasma concentration–time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg–treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing.

Conclusions

Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited.     

Effect of Food on the Pharmacokinetic Properties of the Oral Sarpogrelate Hydrochloride Controlled-Release Tablet in Healthy Male Korean Subjects

Background

A new controlled-release formulation of sarpogrelate, a 5-hydroxytryptamine receptor subtype 2 antagonist that blocks serotonin-induced platelet aggregation, has been developed for once-daily administration.

Objective

This study evaluated the effect of food on the pharmacokinetic properties of controlled-release sarpogrelate (sarpogrelate CR) in healthy volunteers.

Methods

A randomized, open-label, two-period, two-treatment crossover study was performed in healthy male Korean subjects. Following an overnight fast, a single dose of sarpogrelate CR 300 mg was administered either in the fasted condition or immediately after a high-fat breakfast. Pharmacokinetic parameters were calculated using a noncompartmental analysis. Tolerability was determined using clinical laboratory testing and physical examination, including vital sign measurements, electrocardiography, and interviews with the volunteers regarding adverse events (AEs).

Results

A total of 24 healthy subjects were enrolled, 23 of whom completed the study (mean [range] age, 26 years [21–45]; weight, 68.1 kg [56.0–79.9]; body mass index, 22.1 kg/m² [18.8–25.0]). Sarpogrelate C_max and AUC_last were decreased In the fed condition compared with those in the fasted condition, with geometric mean ratios (90% CI) of 0.4868 (0.4041–0.5864) and 0.7394 (0.6809–0.8028), respectively. T_max was delayed from 0.75 to 4.0 hours after a high-fat meal, but the fed condition exhibited a similar elimination profile to that of the fasted condition. The most commonly reported AE was headache (n = 2), and other AEs were reported in 1 subject each. All of the AEs were considered mild in intensity, and the participants recovered without treatment.

Conclusions

Compared with the administration of sarpogrelate CR 300 mg in the fasted condition, administration with food was associated with a decreased rate and extent of absorption, as assessed by C_max and AUC_last, respectively. The drug was well-tolerated by the healthy subjects in this study.     

Effects of Hydrochlorothiazide on the Pharmacokinetics,Pharmacodynamics, and Tolerability of Canagliflozin,a Sodium Glucose Co-transporter 2 Inhibitor,in Healthy Participants

Background

Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.

Objective

This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.

Methods

This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.

Results

Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUC_τ,ss) and C_max at steady state (C_max,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUC_τ,ss and C_max,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.

Conclusions

Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.     

Comparison of the Efficacy and Safety Profile of Morning Administration of Controlled-release Simvastatin Versus Evening Administration of Immediate-release Simvastatin in Chronic Kidney Disease Patients With Dyslipidemia

Purpose

Evening administration of the conventional immediate-release (IR) formulation of simvastatin is recommended because of its short half-life (1.9 hours). In a healthy population, morning administration of a controlled-release (CR) formulation of simvastatin was shown to have equivalent lipid-lowering efficacy and a safety profile similar to that of evening doses of IR simvastatin. The present study aimed to verify noninferiority and to compare the safety of morning administration of CR simvastatin with that of evening administration of IR simvastatin in patients with chronic kidney disease (CKD) who have dyslipidemia.

Methods

The present study was a prospective, multicenter, double-blind, Phase IV trial with an active comparator. We randomly assigned 122 patients with CKD and dyslipidemia to 1 of 2 drug administration groups: morning administration of CR simvastatin 20 mg (test group) and evening administration of IR simvastatin 20 mg (control group). After 8 weeks, the treatment outcomes and adverse effects of the 2 treatments were compared.

Findings

The mean (SD) percentage of change in serum LDL-C at the end of treatment was –35.1% (15.7%) for the test group and –35.6% (14.6%) for the control group. The difference between the 2 groups was not significant (P = 0.858). The 95% CI of the difference in the percentage of change of LDL-C between the test and control groups was –6.0 to 5.0. There was no difference in the percentage of change of total cholesterol (–24.3% [12.5%] vs –26.5% [12.0%], P = 0.317), triglyceride (–10.6% [35.1%] vs –12.4% [33.2%], P = 0.575) and HDL-C (10.2% [20.7%] vs 4.5% [11.4%], P = 0.064). Treatment-related adverse events were similar in both groups (10 events in the test group vs 8 events in the control group, P = 0.691).

Implications

The efficacy of morning administration of CR simvastatin was noninferior to evening administration of IR simvastatin in patients with CKD. Furthermore, the safety profile analysis showed no significant difference between the 2 treatments. Morning administration of CR simvastatin is expected to increase patient compliance and therefore better control of dyslipidemia in CKD patients.     

The Antihypertensive Efficacy of the Triple Fixed Combination of Perindopril,Indapamide, and Amlodipine: The Results of the PETRA Study

Introduction

The etiology of essential hypertension is multifactorial. Therefore, treatment with combinations of antihypertensive agents acting on multiple targets is necessary for successful therapy in the majority of patients. According to the experience and clinical data accumulated so far, combination therapy with three agents from different pharmacological classes is required in approx. 30% of patients in order to achieve long-term blood pressure control. The primary objective of the PETRA study was to evaluate the efficacy of blood pressure (BP) control with once daily administration of the different dosage strengths of the once-daily, triple fixed combination of perindopril, indapamide, and amlodipine. The evaluation was based on office BP readings and ambulatory blood pressure monitoring (ABPM) data gathered in routine clinical practice.

Methods

Data from 11,209 hypertensive patients (the proportion of female subjects was 47.6%) were processed and interpreted in a 3-month-long prospective, observational, non-interventional, open-label study conducted in 997 centers in Hungary.

Results

Mean baseline office BP was 156.58 ± 16.10/91.56 ± 9.33 mmHg (mean ± SD), whereas the mean duration of hypertension was 9.48 ± 7.19 years. Mean office BP decreased by 24.81 ± 15.47/11.41 ± 9.90 mmHg after switching to the triple fixed combination of perindopril, indapamide, and amlodipine (p < 0.0001). At the final visit 45.1% of patients took the 5/1.25/5 mg, 33.5% of them 10/2.5/5 mg, and 21.4% of them 10/2.5/10 mg strength of the perindopril/indapamide/amlodipine triple fixed combination. The 24-h blood pressure was obtained in 76 subjects. The mean 24-h BP decreased from 155.51 ± 17.43/85.28 ± 11.48 to 134.63 ± 12.51/77.83 ± 8.99 mmHg (p < 0.0001). Statistically significant (p < 0.0001) and clinically relevant improvement of a number of metabolic parameters—including total cholesterol (?8.6%), LDL-cholesterol (?11.4%), triglyceride (?12.1%), and fasting blood glucose (?6.6%) levels—was observed over the 3-month study period.

Conclusions

During the 3 months of the PETRA study, the outstanding 24-h antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine was confirmed both by office BP readings and by ABPM recordings. This combination may offer a new therapeutic option for hypertensive patients who have failed to achieve the desired BP target on their previous dual combination therapy.

Funding

EGIS Pharmaceuticals PLC.

     

Impact of initial blood pressure on antihypertensive response in patients with acute hypertension

Introduction

The effect profile of differing antihypertensive agents is well studied, but minimal data regarding the interaction between hemodynamic response and presenting blood pressure (BP) exist.

Hypothesis

Achievement of target BP is less likely in patients with higher initial BPs.

Methods

This is a substudy of the multicenter safety and efficacy Evaluation of intravenous Cardene (nicardipine) and Labetalol Use in the Emergency department (CLUE) trial that randomized patients to Food and Drug Administration–recommended intravenous dosing of nicardipine or labetalol to reach a physician predefined systolic BP (SBP) and target range (TR) of ± 20 mm Hg within 30 minutes. The proportion achieving TR was assessed as a function of initial SBP, and dichotomized comparisons were made using median SBP. Likelihood of a final BP within TR was modeled using logistic regression with forced inclusion of initial BP as a categorical variable.

Results

A total 223 patients were enrolled; 115 (51.6%) had an initial SBP greater than the median 202 mm Hg. The median SBP (interquartile range) of the high BP group was 218 (210-228) mm Hg vs the low BP group 190 (182-197) mm Hg (P < 0.0001). No groupwise differences existed except that the high group had higher mean (SD) serum creatinine level at baseline (3.1 [3.9] vs 1.9 [2.3], P = .008). The proportion of patients achieving SBP within TR at 30 minutes did not differ (85.2% [98 of 115] vs 88.9% [96 of 108], P = .42). Randomization to nicardipine (odds ratio = 2.85; 95% confidence interval, 1.16-7.01), but not initial SBP (odds ratio = 0.60; 95% confidence interval, 0.25-1.44), was associated with achievement of target SBP at 30 minutes.

Conclusion

Initial SBP is not a predictor of the ability to achieve a prespecified target range SBP within 30 minutes.     

Electroencephalogram for prognosis after cardiac arrest

Background

In assessing neurologic prognosis after cardiac arrest (CA), electroencephalogram (EEG) reactivity has not been specifically included with EEG classifications. Most studies have divided recordings into benign and malignant; however, some patterns within these groups may have greater prognostic significance than such broad classifications. We sought to explore reactivity, with broad classifications and subclassifications for their prognostic significance.

Methods

All consecutive adults in coma who had an EEG recording performed at least 1 day after CA or during normothermia after a 24-hour mild hypothermia protocol. Outcomes were dichotomous: recovery of awareness or no recovery of awareness during hospitalization.

Results

Twenty-nine patients met the inclusion criteria. Of the 18 patients with no reactivity, only 1 recovered awareness; of the 11 patients who demonstrated reactivity, 10 recovered awareness (sensitivity of 90% [95% confidence interval, or CI, 0.57-1] and specificity of 94% [95% CI, 0.7-1]). Of those with benign patterns, 7 recovered awareness and 1 did not; however, those patients demonstrating malignant patterns, 4 recovered and 17 did not (sensitivity of 94% [95% CI, 0.7-1] and a specificity of 63% [95% CI, 0.32-0.88]). None of the 15 patients with suppression or generalized spikes recovered consciousness, and none of these patients demonstrated reactivity.

Conclusions

Electroencephalogram reactivity after CA is a relatively favorable EEG feature; generalized suppression or generalized epileptiform activity, without reactivity, is associated with lack of recovery of awareness.     

Diabetic peripheral neuropathy is associated with increased arterial stiffness without changes in carotid intima-media thickness in type 2 diabetes

OBJECTIVE

This study was conducted to investigate the association of diabetic peripheral neuropathy (DPN) with both arterial stiffness and intima–media thickness (IMT).

RESEARCH DESIGN AND METHODS

We conducted a cross-sectional analysis of 731 subjects with type 2 diabetes. DPN was diagnosed on the basis of neuropathic symptoms, insensitivity to a 10-g monofilament, abnormal pin-prick sensation, and abnormal current perception threshold. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI), and IMT was assessed by B-mode ultrasonography.

RESULTS

Patients with DPN had higher CAVI than those without DPN in multivariate-adjusted models, whereas no differences in IMT were observed between patients with and without DPN after adjustment for age and sex. In the multivariate analysis, CAVI was a significant determinant of DPN (odds ratio 1.36 [95% CI 1.13–1.65], P = 0.001).

CONCLUSIONS

DPN is significantly associated with arterial stiffness without carotid intimal changes in patients with type 2 diabetes.The leading cause of death in patients with diabetes is cardiovascular disease (CVD) (1); recent studies have reported that microvascular disease is also associated with excess mortality (2). Although the underlying mechanism is unclear, some evidence suggests that the effects of microvascular disease on mortality may be linked to subclinical atherosclerosis, considering atherosclerotic vascular changes in parallel with microvascular complications, including retinopathy (3), nephropathy (4), and autonomic neuropathy (5).Diabetic peripheral neuropathy (DPN) is a common microvascular complication with high mortality rates (6), but little is known about the association between DPN and atherosclerotic vascular changes. Thus, we investigated the association between DPN and vascular wall properties in patients with type 2 diabetes by measuring cardio-ankle vascular index (CAVI) and carotid intima–media thickness (IMT).     

Pharmacokinetic and Pharmacodynamic Responses of Insulin Degludec in African American,White, and Hispanic/Latino Patients With Type 2 Diabetes Mellitus

Background

Pharmacokinetic and pharmacodynamic profiles of exogenous insulin may be affected by intrinsic factors, such as age, ethnicity/race, and hepatic and renal function. Insulin degludec (IDeg) is a basal insulin with an ultralong duration of action and a flat and stable glucose-lowering effect profile.

Objective

The purpose of this study was to investigate whether the pharmacokinetic and pharmacodynamic responses to IDeg at steady state vary according to patient race/ethnicity.

Methods

This randomized, single-center, double-blind, 2-period crossover trial investigated responses to IDeg in 59 patients with type 2 diabetes mellitus from 3 groups: African American, Hispanic/Latino, and white. Patients were allocated randomly to a sequence of 2 treatment periods, separated by a 7- to 21-day washout period, with once-daily IDeg or insulin detemir dosing for 6 days at a predefined fixed dose level (0.6 U/kg). Differences in pharmacokinetic and pharmacodynamic variables among groups were analyzed using an ANOVA with treatment period, an interaction between race/ethnicity, and treatment as fixed factors, subject as a random effect, and residual variance, depending on treatment.

Results

Total exposure to IDeg during one dosing interval at steady state (AUC_IDeg,τ,SS) was similar among the racial/ethnic groups (ratio [95% CI]: African American vs white, 1.10 [0.91–1.31]; African American vs Hispanic/Latino, 1.13 [0.95–1.34]; and Hispanic/Latino vs white, 0.97 [0.82–1.16]). The total glucose-lowering effect of IDeg (AUC_GIR,τ,SS) was also similar among the groups, with no statistically significant difference in pairwise comparisons (1940, 1735, and 2286 mg/kg in African American, white, and Hispanic/Latino patients, respectively). Steady state was reached in all groups after 2 to 3 days of dosing. In all groups, both exposure and glucose-lowering effect for IDeg were evenly distributed between the first and second 12 hours of the 24-hour dosing interval at steady state (mean AUC_{IDeg,0–12h,SS}/AUC_IDeg,τ,SS = 53%–54%; AUC_{GIR,0-–12h,SS}/AUC_GIR,τ,SS = 47%–52%).

Conclusion

The similar pharmacokinetic and pharmacodynamic responses to IDeg in 3 racial/ethnic groups of patients with type 2 diabetes mellitus suggest that the flat, stable, and ultralong pharmacokinetic and pharmacodynamic profiles of IDeg are preserved irrespective of race/ethnicity. Although insulin doses must be adjusted on an individual basis, similar pharmacokinetic and pharmacodynamic responses to IDeg are observed in patients with differing race/ethnicity.     

Pharmacokinetic Comparison of 2 Fixed-Dose Combination Tablets of Amlodipine and Valsartan in Healthy Male Korean Volunteers: A Randomized,Open-Label, 2-Period,Single-Dose,Crossover Study

Background

Amlodipine and valsartan have different mechanisms of action, and it is known that the combination therapy with the 2 drugs increases treatment effects compared with the monotherapy with each drug. A fixed-dose combination (FDC) drug is a formulation including fixed amounts of active drug ingredients combined in a single dosage form that is expected to improve medication compliance.

Objective

The goal of this study was to compare the pharmacokinetic profiles of single administration of a newly developed FDC tablet containing amlodipine orotate 10 mg and valsartan 160 mg (test formulation) with the conventional FDC tablet of amlodipine besylate 10 mg and valsartan 160 mg (reference formulation) in healthy male Korean volunteers.

Methods

This was a randomized, open-label, single-dose, 2-way crossover study. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight. Each subject received a single dose of the reference and the test formulations, with a 14-day washout period between formulations. Blood samples were collected up to 144 hours after the dose, and pharmacokinetic parameters were determined for amlodipine and valsartan. Adverse events were evaluated based on subject interviews and physical examinations.

Results

Forty-eight of the 50 enrolled subjects completed the study. For both amlodipine and valsartan, the primary pharmacokinetic parameters were included in the range for assumed bioequivalence, yielding 90% CI ratios of 0.9277 to 0.9903 for AUC_0–last and 0.9357 to 1.0068 for C_max in amlodipine, and 0.9784 to 1.1817 for AUC_0–last and 0.9738 to 1.2145 for C_max in valsartan. Dizziness was the most frequently noted adverse event, occurring in 4 subjects with the test formulation, followed by oropharyngeal pain occurring in 1 subject with the test formulation and 3 subjects with the reference formulation. All other adverse events occurred in <3 subjects.

Conclusions

These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.