Current Therapeutic Research

Advisory Board

2012-02-01

Cross-Sectional Survey to Assess the Status of Lipid Management in High-Risk Patients With Dyslipidemia: Clinical Impact of Combination Therapy With Ezetimibe

2012-02-01

Abstract: Background: Previous retrospective surveys have shown that lipid management goals are well achieved in patients with dyslipidemia at relatively low risk for atherosclerotic diseases. However, more than half of patients in high-risk groups have not achieved the management goals. Since these surveys, newer medications, including rosuvastatin and ezetimibe, have emerged in clinical practice that may influence lipid management. Objective: To assess the current status of lipid management in high-risk patients, we conducted a cross-sectional study between January and March 2010. Methods: Eligible patients were those with dyslipidemia who were classified into the primary prevention high-risk or secondary prevention groups according to the Japan Atherosclerosis Society guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases. Patient data were collected from 300 randomly selected physicians at hospitals and clinics across Japan if patients had been receiving the same statin with or without other lipid-lowering agents for ≥3 months. The main outcome was the percentage of patients who achieved the serum LDL-C goal according to the guideline. Results: Data were collected from 1720 patients. The LDL-C goal was achieved in 56.5% of patients (447 of 791) in the primary prevention high-risk group and in 24.5% (103 of 420) in the secondary prevention group by statin monotherapy. For patients who had not reached the LDL-C goal with statin therapy alone, 53.8% (113 of 210) in the primary prevention high-risk group and 63.8% (111 of 174) in the secondary prevention group achieved their lipid management goal with the addition of ezetimibe. Ezetimibe significantly lowered mean serum LDL-C levels by 17.9% to 34.6% when added to various statins (P < 0.001). Conclusions: Although strong statins are available, lipid management in high-risk patients remains unsatisfactory. More aggressive treatment is needed for these patients.

Clinical Efficacy and Tolerability of Ezetimibe in Combination With Atorvastatin in Japanese Patients With Hypercholesterolemia—Ezetimibe Phase IV Randomized Controlled Trial in Patients With Hypercholesterolemia

Tamio Teramoto, Teruo Sawada, Kazuya Iwamoto, Hiroyuki Daida — 2012-03-05

Abstract: Objective: The purpose of this study was to compare the efficacy and tolerability of combination therapy of ezetimibe and atorvastatin in patients with high LDL cholesterol that had not reached the lipid management target value with 10 mg atorvastatin monotherapy, against increasing the dose to 20 mg atorvastatin or switching to 2.5 mg rosuvastatin. Design, setting, and participants: This was an open-label, randomized, multicenter, 3-parallel-group comparison trial at 23 community hospitals and clinics in Japan (enrollment period March 2009 to May 2010) in 125 patients with high LDL cholesterol. Interventions: A total of 125 Japanese patients with high LDL cholesterol level were randomized to 1 of the following 3 treatment groups: the ezetimibe (10 mg/d) and atorvastatin (10 mg/d) group, the atorvastatin (20 mg/d) group, or the rosuvastatin (2.5 mg/d) group for 12 weeks after treatment with 10 mg atorvastatin alone for 4 weeks. Main outcome measure: Percent change in LDL cholesterol level from baseline (4 weeks after treatment with 10 mg atorvastatin alone) until study completion. Results: The percent change in LDL cholesterol level from baseline until study completion was statistically greater for the combination of 10 mg ezetimibe + 10 mg atorvastatin compared with increasing atorvastatin to 20 mg (−25.8% vs −15.1%; P < 0.0001). A similar result was observed for ezetimibe + atorvastatin compared with switching to 2.5 mgt rosuvastatin (−25.8% vs 0.8%; P < 0.0001). The proportion of patients who reached the target LDL cholesterol value with the combination of ezetimibe + atorvastatin was significantly higher than increasing atorvastatin and switching to rosuvastatin (78.7%, 41.3%, and 3.1%, respectively). Although 5 serious adverse experiences bearing no relation to the study medications were reported, there were no adverse reactions. Conclusions: The combination of 10 mg ezetimibe +10 mg atorvastatin was more effective than increasing atorvastatin to 20 mg or switching to 2.5 mg rosuvastatin in patients with hypercholesterolemia whose LDL cholesterol levels had not reached the recommended target value with 10 mg atorvastatin monotherapy for 4 weeks. Ezetimibe coadministration with atorvastatin was well tolerated. ClinicalTrials.gov identifier: NCT00871351.

Comparison of Effects of Low-Flow Sevoflurane and Desflurane Anesthesia on Neutrophil and T-Cell Populations

Lutfiye Pirbudak Cocelli, Mete Gurol Ugur, Hakan Karadasli — 2012-03-05

Abstract: Background: Numerous transient effects of anesthesia on postoperative immune status have been documented in the literature. Objective: This study was performed to test the hypothesis that the effects on neutrophil and T-cell populations differ with use of low-flow sevoflurane- and desflurane-induced anesthesia during abdominal surgery. Methods: Fifty adult patients (American Society of Anesthesiologists physical status I or II) aged 20 to 60 years were recruited for the study. Patients were randomly assigned to one of two study groups. Anesthesia was induced using fentanyl, propofol, and vecuronium. After intubation, patients in group 1 received sevoflurane, oxygen, and nitrous oxide at a flow rate of 6 L/min, and those in group 2 received desflurane, oxygen, and nitrous oxide at a flow rate of 6 L/min. Ten minutes after induction of anesthesia, the flow rate was decreased to 1 L/min in both groups. Total leukocyte, lymphocyte, and neutrophil counts, percentage of T helper lymphocytes (CD4), cytotoxic T lymphocytes (CD8), natural killer lymphocytes, and active T lymphocyte, CD4/CD8 ratio, and plasma cortisol values were assessed before and at 2 and 24 hours after induction of anesthesia. Results: In the desflurane group, at 2 hours after induction of anesthesia, a significant decrease was observed in the lymphocyte count, percentage of CD4 cells, and CD4/CD8 ratio, and a significant increase was noted in the neutrophil count and percentage of CD8 cells (P < 0.05). At 24 hours after induction of anesthesia, a significant increase was observed in the leukocyte and neutrophil counts, percentage of CD4 cells, and CD4/CD8 ratio (P < 0.05). There was no change in the other parameters studied. In the sevoflurane group, a significant decrease was observed in the lymphocyte count and percentage of natural killer cells. In addition, a significant increase was noted in the leukocyte and neutrophil counts at 24 hours after induction of anesthesia (P < 0.01). The increase in the neutrophil count in the desflurane group compared with that in the sevoflurane group was statistically significant (P < 0.05). Conclusions: With use of the low-flow anesthesia technique, compared with desflurane, sevoflurane exerts minimal effects on neutrophil and T-cell populations, which supports our hypothesis.

Quinacrine Inhibits Cell Growth and Induces Apoptosis in Human Gastric Cancer Cell Line SGC-7901

2012-02-01

Abstract: Background: Quinacrine (QC), an antimalarial drug, has been shown to possess anticancer effect both in vitro (cancer cell lines) and in vivo (mouse models). In the cancer cells, QC can simultaneously suppress nuclear factor-κB and activate p53 signaling, which results in the induction of the apoptosis in these cells. However, the experimental results come from a few limited cancer cell lines, and the detailed mechanisms remain unknown. Objective: This study investigated the tumor-killing effects of QC on gastric cancer cells as well as underlying molecular pathways. Methods: SGC-7901 cells were treated with or without QC at different concentrations for 24 hours. The effect of QC on the inhibition of SGC-7901 cell proliferation was assessed by Cell Counting Kit-8 assay. Apoptosis was detected by examining nuclear morphology and quantifying phosphatidylserine externalization. Alterations in cellular morphology were analyzed by laser scanning confocal microscopy for fluorescent analysis. Cell cycle analysis was performed by propidium iodide (PI) staining and flow cytometry. The enzyme activity changes of caspase-3 were detected by colorimetry expression method. Western blot analysis was used to detect the changes in the protein level of Bax, Bc1-2, p53, and cytochrome c in cytosol of SGC-7901 cells. Results: Our results showed that QC could significantly inhibit the growth of SGC-7901 cells in a dose-dependent manner, with the IC50 mean (SD) value of 16.18 (0.64) μM, compared with nontreated controls. QC treatment (15 μM) could also induce apoptosis in SGC-7901 cells (26.30% [5.31%], compared with control group of 3.37% [0.81%]; P < 0.01), and the increasing phosphatidylserine level and the accumulation of chromatin nucleation in QC-treated cells provided further evidence. In addition, cell cycle analysis with PI staining showed that a significant S enriches, increasing from 12.00% (1.24%) (control) to 20.94% (2.40%) (QC treatment) (P < 0.01). Furthermore, increased activities of caspase-3 (increasing from 0.108 [0.019] to 0.628 [0.068]; P < 0.01) were observed in SGC-7901 cells treated with 15 μM QC. Western blot analysis showed that QC treatment significantly increased the levels of proapoptotic proteins, including cytochrome c, Bax, and p53, and decreased the levels of antiapoptotic protein Bcl-2, thus shifting the ratio of Bax/Bcl-2 in favor of apoptosis. Conclusions: Our findings suggest that QC can significantly inhibit cell growth and induce apoptosis in SGC-7901 cells, which involves p53 upregulation and caspase-3 activation pathway.

Long-Term Tolerability and Efficacy of Single-Pill Combinations of Telmisartan 40–80 mg Plus Amlodipine 5 or 10 mg in Patients Whose Blood Pressure Was Not Initially Controlled by Amlodipine 5–10 mg: Open-Label, Long-Term Follow-Ups of the TEAMSTA-5 and TEAMSTA-10 Studies

2012-02-01

Abstract: Background: Two 8-week, randomized, double-blind, controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40–80 mg/amlodipine 5–10 mg (T40–80/A5–10) in patients with hypertension not at diastolic blood pressure (DBP) goal (DBP <90 mm Hg) after 6 weeks of amlodipine 5 mg monotherapy (A5) (TEAMSTA-5) or amlodipine 10 mg monotherapy (A10) (TEAMSTA-10). The long-term (≥6 months) tolerability and efficacy of single-pill combinations of T40–T80/A5–A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 (TEAMSTA-5 and TEAMSTA-10 Follow-Ups). Methods: In the TEAMSTA-5 Follow-Up, 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks, with consecutive uptitration to T80/A5 if DBP was ≥90 mm Hg. In TEAMSTA-10 Follow-Up, 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before randomization to T40/A10 or T80/A10; after 4 weeks, patients randomized to T40/A10 with DBP ≥90 mm Hg were uptitrated to T80/A10. In both studies, add-on antihypertensive medication was allowed if DBP was not at goal. Results: Treatment compliance in both follow-up studies was ≥98.4%. Single-pill combinations of T40–T80/A5–A10 resulted in additional clinically relevant blood pressure reductions and 67% to 93% of patients achieved DBP goal (<90 mm Hg); only 1% to 19% of patients received additional medication for hypertension, of whom 29% to 76% achieved DBP goal. Long-term treatment with T40–T80/A5–A10 was well tolerated, with comparable adverse event profiles for all telmisartan/amlodipine combinations. The most common drug-related adverse events were peripheral edema (1.9%–3.9%) and dizziness (1.5% in the T80/A5 group only); these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations. Overall treatment discontinuation rates due to adverse events were low (0.7%–1.5%). Conclusions: In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40–T80/A5–A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. ClinicalTrials.gov identifiers: NCT00614380 (TEAMSTA-5 Follow-up) and NCT00624052 (TEAMSTA-10 Follow-up).