The pharmacodynamic effect of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease in Japan

Background To evaluate the pharmacodynamic effect, efficacy, and safety of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease (NERD) in Japan. Methods A total of 37 patients were randomized to omeprazole 10 mg or omeprazole 20 mg once daily for 4 weeks. Eligible patients had a history of moderate-to-severe heartburn for 2 days or more per week during the last 1 month or longer prior to the study screening, grade M or grade N on Hoshihara's modification of the Los Angeles classification (i.e., no sign of mucosal break on esophagogastroduodenoscopy), and heartburn episodes for 2 days or more per week during the last week of the observation period while taking antacids. Ambulatory 24-h intraesophageal pH was monitored on the day before treatment and on the last day of treatment. The occurrence of a heartburn episode was recorded during pH monitoring. The primary endpoint was the change in the percentage of time with intraesophageal pH < 4 during the 24-h period before and after omeprazole treatment. Results Both omeprazole 10 mg and omeprazole 20 mg once daily reduced the percentage of time with intraesophageal pH < 4. The percentage reduction in time with intraesophageal pH < 4 after treatment with omeprazole was associated with a reduced number of heartburn episodes. Patients with grade M or grade N esophagus had similar pH profiles and NERD characteristics (e.g., pH holding time, symptom index) and comparable responses to omeprazole. No serious, drug-related adverse events were reported. Conclusions Omeprazole 10 mg or 20 mg reduces the percentage of time with intraesophageal pH < 4, is efficacious, and is well tolerated in patients with NERD in Japan, regardless of the patient's endoscopic classification.     

Should aspirin be used with angiotensin-converting enzyme inhibitors in patients with chronic heart failure?

Aspirin and angiotensin-converting enzyme (ACE) inhibitors are widely used in combination to treat a wide spectrum of cardiac disorders. Theoretically, a rationale for interaction between these two agents exists in the possible counterbalancing prostaglandin inhibiting actions of aspirin and the vasodilatory prostaglandin promoting effects of ACE inhibitors. Animal and human studies suggest such an interaction, but most are plagued by small numbers or retrospective designs. Large-scale trials are in progress to address this issue. Until then, the key factor in deciding whether a patient with ischemic heart disease on ACE inhibitor therapy should be placed on aspirin therapy may largely depend on the severity of heart failure. The more severe the heart failure, the more likely an appreciable interaction between aspirin and ACE inhibitors will occur. Treatment with either low-dose aspirin or with alternative agents, such as warfarin or clopidogrel, may be the best therapeutic approach for patients with severe systolic heart failure.     

Efficacy and Safety of Rosuvastatin 5 mg in Combination with Fenofibric Acid 135 mg in Patients with Mixed Dyslipidemia – A Phase 3 Study

Background

Patients with mixed dyslipidemia characterized by elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides (TG), and reduced high-density lipoprotein cholesterol (HDL-C) often require combination therapy to improve multiple lipid and nonlipid parameters. This phase 3, multicenter, randomized, double-blind study evaluated the efficacy and safety of rosuvastatin 5 mg coadministered with fenofibric acid 135 mg in patients with mixed dyslipidemia.

Methods

A total of 760 patients with TG?≥?150 mg/dL, HDL-C <40 mg/dL (<50 mg/dL for women), and LDL-C?≥?130 mg/dL were randomized for a 12-week treatment period to rosuvastatin 5 mg, fenofibric acid 135 mg, or rosuvastatin 5 mg + fenofibric acid 135 mg. The primary efficacy comparisons were mean percentage changes in HDL-C and TG (rosuvastatin + fenofibric acid vs. rosuvastatin monotherapy), and LDL-C (rosuvastatin + fenofibric acid vs. fenofibric acid monotherapy).

Results

Treatment with rosuvastatin + fenofibric acid resulted in statistically significant greater improvements in HDL-C (23.0% vs. 12.4%; P?P?P?Conclusion In conclusion, rosuvastatin 5 mg + fenofibric acid 135 mg resulted in comprehensive improvements in the lipid profile of patients with mixed dyslipidemia without unanticipated adverse events.     

Safety,tolerability, and feasibility of antifungal prophylaxis with micafungin at 2 mg/kg daily in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

Introduction

Micafungin (MCFG) is used for the prophylaxis of invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, the safety, efficacy, or optimal dosage/blood levels as prophylaxis is uncertain in pediatric HSCT-patients.

Methods

We prophylactically administered MCFG at 2 mg/kg once daily to 38 children and adolescents undergoing allogeneic HSCT.

Results

During MCFG prophylaxis, infusion reactions or adverse events (grades 2–5) related to MCFG use were not found in all the patients. Thus, MCFG prophylaxis was not discontinued and other antifungal agents were not added except for 2 patients in whom probable or possible IFDs developed (completion rate, 94.7 %). To elucidate the influence of HSCT-related complications/drugs on blood concentration of MCFG, we determined the plasma trough and peak levels in 13 and 10 among 38 patients, respectively. The mean trough and peak levels were 3.04 ± 1.21 μg/mL (569 samples) and 9.63 ± 3.62 μg/mL (44 samples), respectively. The peak levels were moderately correlated to the trough levels (R ² = 0.466). In a patient, the trough level of MCFG transiently increased up to 10.21 μg/mL during hepatic dysfunction due to acute graft-versus-host disease. The MCFG trough levels strongly correlated with T-Bil value (R ² = 0.894). There was no relationship between the trough levels of MCFG and the circulating concentrations of tacrolimus (R ² = 0.040). Additionally, MCFG levels were not influenced by treatment with cyclophosphamide or corticosteroids.

Conclusions

Prophylaxis with MCFG at 2 mg/kg once daily may be safe, tolerable, and feasible in pediatric HSCT-patients.     

Pharmacodynamic effects of a new fixed-dose clopidogrel–aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG^®). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, ?5 PRU; 90% confidence interval of difference, ?23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). “BASE” and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG^® measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel–aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.     

Angiographic and platelet reactivity outcomes with prasugrel 60?mg pretreatment and clopidogrel 600?mg pretreatment in primary percutaneous coronary intervention

Pretreatment with 60?mg of prasugrel is more effective than 300?mg of clopidogrel in reducing thrombotic complications with primary percutaneous coronary intervention (PCI). We compared angiographic outcomes and platelet reactivity between treatment with 60?mg of prasugrel and 600?mg of clopidogrel administered before primary PCI. In this single centre non-randomized study, 65 consecutive Asian patients with ST-elevation myocardial infarction (STEMI) received 60?mg of prasugrel before primary PCI. The pre- and post-PCI corrected thrombolysis in myocardial infarction frame count (CTFC) and the 8-h post-treatment platelet vasodilator-stimulated phosphoprotein (VASP) index was compared with a matched historical Asian STEMI cohort (n?=?65) receiving 600?mg of clopidogrel pretreatment. Comparing the prasugrel and clopidogrel groups, the mean age was 54.1?±?10.2 versus 55.5?±?11.8?years, P?=?0.238, and the mean body mass index was 24.6?±?2.0 versus 24.7?±?2.8?kg?m^?2, P?=?0.393. The mean pre-PCI CTFC was 82.1?±?30.2 versus 86.1?±?27.6, P?=?0.045, and the mean post-PCI CTFC was 21.1?±?13.9 versus 20.1?±?9.2, P?=?0.309. Pre-PCI coronary thrombi were visualised in 6.3 versus 18.1?%, P?=?0.038. The median VASP index was 22.2?±?24.5 versus 70.5?±?17.5?%, P?<?0.001, and high on-treatment platelet reactivity (VASP index?>?50?%) was observed in 13.8 versus 84.3?%, P?=?0.001. Rescue intracoronary glycoprotein inhibitors were administered to 29.7 versus 51.0?%, P?=?0.018, respectively. Treatment with 60?mg of prasugrel before primary PCI was associated with lower platelet reactivity, a modest trend towards better pre-PCI angiographic outcomes, less pre-PCI coronary thrombi and less rescue glycoprotein inhibitor use compared with 600?mg of clopidogrel. The very high frequency of high on-clopidogrel platelet reactivity with 600?mg of clopidogrel in this Asian STEMI cohort deserves further study.     

Evaluation of the efficacy and safety of etanercept 50 mg once weekly in Japanese patients with rheumatoid arthritis and comparison with 25 mg etanercept twice weekly

Objective

Tumor necrosis factor-α inhibitors have been available in recent years for treating early and established rheumatoid arthritis (RA). Twice-weekly administration of 25 mg etanercept (ETN) has demonstrated efficacy and safety. The objective of this study was to evaluate the efficacy of once-weekly administration of 50 mg ETN (ETN50), and to compare it with that of twice-weekly administration of 25 mg ETN (ETN25).

Methods

The ETN50 group comprised 29 patients and the ETN25 group 26. The analysis compared changes from baseline in Disease Activity Score in 28 joints (DAS28)–C reactive protein (CRP) and DAS28–erythrocyte sedimentation rate (ESR) between the ETN50 and ETN25 groups.

Results

Overall, 42.3 % of ETN50 patients achieved DAS28–ESR remission (<2.6), and 76.9 % experienced low disease activity at 24 weeks. Patients in the ETN50 group also experienced more significant improvement in DAS28–ESR at 4 weeks, higher DAS28–ESR remission rates, and lower disease activity rates than ETN25 group patients. No serious adverse events were experienced in the safety analysis set (ETN50 group).

Conclusion

These results suggest that ETN50 can lead to earlier remission and higher remission rates compared with ETN25 in patients with RA.     

Do changes in visceral sensory function determine the development of dyspepsia during treatment with aspirin?

BACKGROUND & AIMS: We hypothesized that the development of dyspeptic symptoms during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) would be linked to alterations in gastric mechanosensory function and gastric emptying. METHODS: In the first study, gastric mechanosensory thresholds (barostat technique) and gastric emptying ((13)C-octanoic breath test) were measured and endoscopy was performed at entry and after 5 days of treatment with aspirin (500 mg 3 times daily) in 8 patients with functional dyspepsia (initially without symptoms) and 8 healthy controls. In a second, double-blind, placebo-controlled, cross-over study, 6 new patients with functional dyspepsia and 6 controls were started with either placebo or aspirin for 5 days. Sensory thresholds were tested after the fifth day of aspirin or placebo treatment. Abdominal symptoms were assessed daily. RESULTS: In the first study, 6 of 8 patients and 3 of 8 controls, and in the second trial 6 of 6 patients and 1 of 6 healthy subjects, developed dyspepsia on aspirin (P < 0.005 patients vs. healthy subjects). No symptoms occurred during placebo treatment. Lanza scores were not associated with symptoms. After aspirin, sensory thresholds increased in both studies in subjects without development of symptoms (by 25.9% +/- 7.9%, and 31.0% +/- 4.1%, respectively, all P < 0.05), whereas there was no significant increase in subjects who developed symptoms (-11.2% +/- 5.3% and -3.4% +/- 13.4%, all P > 0.4). Neither thresholds nor symptoms were linked with the severity of mucosal damage, baseline gastric emptying (t1/2), or changes of gastric emptying (all P > 0.4). CONCLUSIONS: Failure to increase sensory thresholds during treatment with aspirin is associated with the development of dyspepsia.