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Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.
Christopher, R, Morgan, M, Ferry, J, Rege, B, Tang, Y, Kristensen, A, Shanahan, W
Clinical therapeutics. 2016;(10):2227-2238.e4
Abstract
PURPOSE Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. METHODS We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. FINDINGS Compared with lorcaserin IR, the Tmax after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the Cmax was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, Tmax after a single dose was identical (median, 12 hours), but Cmax was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, Cmax and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. IMPLICATIONS Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation.
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Immediate administration of tolvaptan prevents the exacerbation of acute kidney injury and improves the mid-term prognosis of patients with severely decompensated acute heart failure.
Shirakabe, A, Hata, N, Yamamoto, M, Kobayashi, N, Shinada, T, Tomita, K, Tsurumi, M, Matsushita, M, Okazaki, H, Yamamoto, Y, et al
Circulation journal : official journal of the Japanese Circulation Society. 2014;(4):911-21
Abstract
BACKGROUND Tolvaptan, an oral selective vasopressin 2 receptor antagonist that acts on the distal nephrons to cause a loss of electrolyte-free water, is rarely used during the acute phase of acute heart failure (AHF). METHODS AND RESULTS We investigated 183 AHF patients admitted to the intensive care unit and administered tolvaptan (7.5mg) with continuous intravenous furosemide, and then additionally at 12-h intervals until HF was compensated. When intravenous furosemide was changed to peroral use, the administration of tolvaptan was stopped. The patients were assigned to tolvaptan (n=52) or conventional treatment (n=131) groups. The amount of intravenous furosemide was significantly lower (35.4 [16.3-56.0] mg vs. 80.0 [30.4-220.0] mg), the urine volume was significantly higher on days 1 and 2 (3,691 [3,109-4,198] ml and 2,953 [2,128-3,592] ml vs. 2,270 [1,535-3,258] ml and 2,129 [1,407-2,906] ml) and the numbers of patients with worsening-AKI (step-up RIFLE Class to I or F) and Class F were significantly fewer (5.8% and 1.9% vs. 19.1% and 16.0%) in the tolvaptan group than in the conventional group, respectively. One of the specific medications indicated worsening-AKI and in-hospital mortality was tolvaptan (odds ratio [OR] 0.155, 95% confidence interval [CI] 0.037-0.657 and OR 0.191, 95% CI 0.037-0.985). The Kaplan-Meier curves showed that the death rate within 6 months was significantly lower in the tolvaptan group. The same result was found after propensity matching of the data. CONCLUSIONS Early administration of tolvaptan could prevent exacerbation of AKI and improve the prognosis for AHF patients.
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Single dose ivabradine versus intravenous metoprolol for heart rate reduction before coronary computed tomography angiography (CCTA) in patients receiving long-term calcium channel-blocker therapy.
Celik, O, Atasoy, MM, Ertürk, M, Yalçın, AA, Aksu, HU, Diker, M, Aktürk, IF, Atasoy, I
Acta radiologica (Stockholm, Sweden : 1987). 2014;(6):676-81
Abstract
BACKGROUND In patients with contraindication for beta-blockers who are also under long-term calcium channel-blocker therapy for any reason, ivabradine may be used as an alternative treatment to achieve the target heart rate. PURPOSE To assess whether single dose oral ivabradine in patients referred for coronary computed tomography angiography (CCTA) is safe and can significantly decrease heart rate compared to intravenous (i.v.) metoprolol in patients receiving long-term calcium channel-blocker therapy. MATERIAL AND METHODS One-hundred and twenty patients who were under calcium channel-blocker therapy referred for CCTA were randomized to premedication with single dose (15 mg) ivabradine (n = 63) or i.v. metoprolol (5-10 mg) (n = 62). Hearth rate (HR) was assessed at admission (HR1), prescan (HR2), and during CCTA scan (HR3) for all patients. Blood pressure (BP) was measured before medication (BP1) and immediately before CCTA scan (BP2). RESULTS Although the HR averages of two groups were not significantly different before medication (HRIv1 = 80 ± 7 bpm vs. HRβ1 = 81 ± 7 bpm; P = 0.42), significant HR reduction was observed in the ivabradine group (HRIv3 = 62 ± 7 bpm) when compared to the metoprolol group (HRβ3 = 66 ± 6 bpm; P = 0.001). Decreases in HR forivabradine (18 ± 6 bpm) was significantly higher than for metoprolol (15 ± 4 bpm; P = 0.003) without relevant side-effects. Ivabradine showed no significant effect on either systolic BP or diastolic BP (siBPIv1, 139 ± 10; siBPIv2, 138 ± 10; P = 0.260; diBPIv1, 81 ± 7; diBPIv2, 81 ± 6; P = 0.59). Nevertheless, metoprolol group demonstrated significant reduction in both SiBP and DiBP (siBPβ1, 136 ± 11; siBPβ2 130 ± 11; P < 0.001; diBPβ1, 81 ± 6; diBPβ2, 78 ± 6; P < 0.001). CONCLUSION Single dose ivabradine is safe and significantly more effective than i.v. metoprolol in decreasing HR in patients under calcium channel-blocker therapy.
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Acute heart failure volume control multicenter randomized (AVCMA) trial: comparison of tolvaptan and carperitide.
Suzuki, S, Yoshihisa, A, Yamaki, T, Sugimoto, K, Kunii, H, Nakazato, K, Abe, Y, Saito, T, Ohwada, T, Suzuki, H, et al
Journal of clinical pharmacology. 2013;(12):1277-85
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Abstract
BACKGROUND [corrected] Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Diuresis is a major therapy for the reduction of congestive symptoms. However, most diuretics cause hyponatremia, which is a worsening factor of ADHF patients prognosis. The purpose of this study was to examine the efficacy and safety of tolvaptan, which is a selective vasopressin V2 receptor antagonist and produces water excretion without changes in sodium excretion, compared with carperitide. METHODS AND RESULTS One hundred and nine hospitalized ADHF patients were enrolled and randomly assigned to tolvaptan or carperitide treatment groups. Subjective symptoms and plasma BNP level were similarly improved by treatment in both groups. Urine volume was significantly higher in the tolvaptan group (P < .05), but volume of water intake was also higher in the tolvaptan group (P < .05). Blood pressure was significantly lower in the carperitide group than in the tolvaptan group after treatment (P < .05). Less adverse events such as worsening heart failure and hypotension requiring drug discontinuation were observed in the tolvaptan group (P = .027). The average drug cost of tolvaptan was lower than that of carperitide (P < .001). CONCLUSIONS Tolvaptan might be a novel promising agent for ADHF in terms of efficacy and safety compared to carperitide.
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[Is the combination of benazepril and amlodipine more effective in hypertension than the combination of benazepril and hydrochlorothiazide? Results of the ACCOMPLISH trial].
Preobrazhenskiĭ, DV
Kardiologiia. 2009;(2):81-2
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Comparison of ivabradine versus metoprolol in early phases of reperfused anterior myocardial infarction with impaired left ventricular function: preliminary findings.
Fasullo, S, Cannizzaro, S, Maringhini, G, Ganci, F, Giambanco, F, Vitale, G, Pinto, V, Migliore, G, Torres, D, Sarullo, FM, et al
Journal of cardiac failure. 2009;(10):856-63
Abstract
BACKGROUND beta-blockers in ST-segment elevation myocardial infarction (STEMI) are indicated for patients without a contraindication, particularly in patients with high heart rates (HR) or blood pressures. Epidemiological studies have shown that elevated HR represents a risk factor for cardiovascular morbidity. The study investigates the feasibility, tolerability, and the effects after 30 days of follow-up of ivabradine (IVA) versus metoprolol (METO) in early phases of anterior STEMI reperfused by percutaneous coronary intervention (PCI). METHODS AND RESULTS Patients with a first anterior STEMI, Killip class I-II, an acceptable echocardiographic window, and admitted within 4hours of the onset of symptoms, with an ejection fraction <50%. METO or IVA, 12hours after PCI (double blind), were administered twice per day. Blood pressure (BP), heart rate (HR), electrocardiogram (ECG), and laboratory parameters were monitored during the study. At entry, day 10, day 30, and day 60, by echocardiography, the ESV, EDV, E/A ratio, E wave deceleration time, isovolumetric relaxation time were measured. A total of 155 (50 females, 105 males) patients were randomized in 2 groups: a group received METO (76 patients) 12hours after PCI and a group received IVA (79 patients) 12hours after PCI. The 2 groups were similar for clinical characteristics. No difference was evidenced in HR, systolic blood pressure, diastolic blood pressure, age (range, 39-73 years), sex, ejection fraction (EF), creatine kinase peak, between the 2 groups at entry. Both groups were similar for time to angiography and interventional procedures and number of vessels diseased. IVA group: the 79 patients showed 2 side effects and 5 readmissions: 4 for ischemic events and 1 for heart failure, and 1 sudden death; METO group: the 76 patients had 4 ischemic events, 2 side effects, and 1 patient died during re-acute MI (intrastent thrombosis) and 8 readmissions for heart failure signs. The systolic blood pressure and diastolic blood pressure showed a significant reduction in both groups, P < .0001, respectively), and significant lower values were observed in METO group, P=.0001). The HR was significantly reduced in both groups, P < .0001). IVA group showed a significant increase in EF, P=.0001, with concomitant reduction in ESV and EDV (P=.0001, and .048, respectively). The diastolic parameters were similar in both groups during study period. CONCLUSIONS Our results suggest that ivabradine may be administered early (12hours after PCI) to patients with successful PCI for anterior STEMI with an impaired left ventricular function and high HR and sinus rhythm. A larger sample of patients and further studies are required to evaluate the effects of ivabradine on clinical end points.
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[Unexpected study data for treatment of hypertension. Combination therapy with a diuretic not imperative].
Aumiller, J
MMW Fortschritte der Medizin. 2008;(23):46-7
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An eight-week, multicenter, randomized, double-blind study to evaluate the efficacy and tolerability of fixed-dose amlodipine/benazepril combination in comparison with amlodipine as first-line therapy in chinese patients with mild to moderate hypertension.
Ueng, KC, Lin, LC, Voon, WC, Lin, MC, Liu, YB, Su, HM, Chang, PY, Lin, TH, Chen, WL, Wu, CC, et al
Blood pressure. Supplement. 2008;:24-31
Abstract
AIMS: This study sought to compare the antihypertensive efficacy and tolerability of a fixed-dose combination with amlodipine/benazepril with that of amlodipine monotherapy in Chinese hypertensive subjects. RESULTS This multicenter, double-blind, 8-week study randomized 111 patients to fixed-dose amlodipine besylate/benazepril HCl (2.5/5 mg/day titrated to 5/10 mg/day as needed at week 4 to reach goal blood pressure (BP) <140/90 mmHg) or amlodipine besylate monotherapy (5 mg/day titrated to 10 mg/day as needed). At week 8, patients randomized to combination therapy compared with monotherapy had a comparable BP control rate (56.0% vs. 46.2%; p = 0.32). Fixed-dose combination resulted in similar reductions in sitting systolic (SBP) and diastolic BP (DBP) compared with monotherapy (SBP: -19.3 +/- 12.5 vs. -20.9 +/- 13.3 mmHg; DBP: -9.2 +/- 10.4 vs. -11.3 +/-9.3 mmHg; both p=NS). Safety profiles did not differ between groups, but cough was more common in the combination group (11.0% vs. 0%; p = 0.013). CONCLUSIONS In this group of patients, comparable antihypertensive effects were seen with the fixed-dose combination therapy, compared with amlodipine monotherapy. Both treatments appeared well tolerated in the studied population, but cough was more common in the fixed-dose combination group.
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Benazepril slows progression of renal dysfunction in patients with non-diabetic renal disease.
Ishimitsu, T, Akashiba, A, Kameda, T, Takahashi, T, Ohta, S, Yoshii, M, Minami, J, Ono, H, Numabe, A, Matsuoka, H
Nephrology (Carlton, Vic.). 2007;(3):294-8
Abstract
AIM: The present study examined the effects of benazepril, an angiotensin-converting enzyme inhibitor, on the progression of renal insufficiency in patients with non-diabetic renal disease. METHODS Fifteen patients with non-diabetic renal disease whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dL were given either benazepril (2.5-5 mg) or placebo once daily for 1 year in a random crossover manner. In both periods, antihypertensive medications were increased if blood pressure was greater than 130/85 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study period. RESULTS Blood pressure was similar when comparing the benazepril and the placebo periods (128+/-12/83+/-6 vs 129+/-10/83+/-7 mmHg). Serum Cr significantly increased from 1.62+/-0.18 to 1.72+/-0.30 mg/dL (P=0.036) during the placebo period, while there was no statistically significant increase in serum Cr during the benazepril period (from 1.67+/-0.17 to 1.71+/-0.27 mg/dL). The slope of decrease of the reciprocal of serum Cr was steeper in the placebo period than in the benazepril period (-0.073+/-0.067 vs-0.025+/-0.096/year, P=0.014). Urinary protein excretion was lower during the benazepril period than during the placebo period (0.57+/-0.60 vs 1.00+/-0.85 g/gCr, P=0.006). Serum K was significantly higher in the benazepril period than in the placebo period (4.4+/-0.5 vs 4.2+/-0.5 mEq/L, P<0.001), but no patient discontinued benazepril therapy as a result of hyperkalemia. CONCLUSION Long-term benazepril treatment decreased the progression of renal dysfunction in patients with non-diabetic renal disease by a mechanism that is independent of blood pressure reduction.
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Vasopressin v(2) receptor blockade with tolvaptan versus fluid restriction in the treatment of hyponatremia.
Gheorghiade, M, Gottlieb, SS, Udelson, JE, Konstam, MA, Czerwiec, F, Ouyang, J, Orlandi, C, ,
The American journal of cardiology. 2006;(7):1064-7
Abstract
Hyponatremia is common and is associated with a poor prognosis. Traditional management with fluid restriction is difficult to maintain, and it is often ineffective. The objective of this study was to determine the effect of tolvaptan versus fluid restriction on serum sodium concentration. The study was a prospective, multicenter, randomized, active-controlled, open-label trial. Twenty-eight hospitalized subjects with serum sodium <135 mmol/L were enrolled in the study. After a 2-day run-in period, subjects were randomized 2:1 to tolvaptan alone (n = 17) or fluid restriction (1,200 ml/day) plus placebo (n = 11). Oral tolvaptan was started at 10 mg/day and increased to 60 mg/day as needed. Treatment was continued for up to 27 days, and follow-up continued for up to 65 days. The primary end point was the normalization of serum sodium, defined as >135 mmol/L or a > or =10% increase from baseline. At the last inpatient visit, serum sodium had increased by 5.7 +/- 3.2 mmol/L in the tolvaptan group and 1.0 +/- 4.7 mmol/L in the fluid restriction group (p = 0.0065). No differences in adverse events were observed between the groups. In conclusion, tolvaptan appears to be more effective than fluid restriction at correcting hyponatremia in hospitalized subjects, without an increase in adverse events.