ACE inhibitors in heart failure--switching from enalapril to perindopril

Although ACE inhibitors have demonstrated their beneficial effects in heart failure, whether different agents may induce different benefits remains unclear. We designed an open, sequential, prospective study switching heart failure patients receiving enalapril to perindopril which has been reported to be longer acting and better tolerated. The objective of the study was to find out if clinical and functional status could be further improved by changing from enalapril 30 mg daily to a perindopril 4 mg daily. Assessments of clinical status, echocardiography and nuclear ventriculography were performed at baseline under enalapril (30 mg mean dose (b.i.d.)), then 6 and 12 months after the switch to perindopril (4 mg/day mean dose). Thirty-one patients were included (90% men, aged 56.5 +/- 11.8 years, mean radionuclide left ventricular (LV) ejection fraction 22.4 +/- 8.5 %). After 6 months of treatment, NYHA functional class was significantly improved; the percentage of patients in class I increased to 57% after perindopril versus 20% at baseline (p < 0.001), and 50% of the total study population gained at least one NYHA class. After 12 months of treatment, 80% of the patients were in NYHA class I. Blood pressure decreased significantly with a good tolerance at 6 months and then remained stable. After 12 months of treatment, significant reductions of LV end-diastolic diameter (61.4 +/- 5.3 vs. 64.5 +/- 6.5 mm; p = 0.001) and LV mass index (143.3 +/- 21.5 vs. 164.2 +/- 40.2 g/m2; p < 0.001) were observed, reflecting a positive effect on the LV remodelling process. Despite some limitations, because it is of an open-label design with a small number of patients, our study found significant differences in clinical and objective parameters in heart failure patients switched from enalapril to perindopril. The prognostic significance of these findings remains to be investigated.     

Comparative Haemodynamic Responses to the First Dose of Short- and Long-acting ACE Inhibitors in Patients with Congestive Heart Failure

Summary

Background: Angiotensin Converting Enzyme inhibitors (ACEi's) confer significant mortality and morbidity benefits in all functional grades of chronic heart failure (CHF). However, physicians' concerns regarding the possible occurrence of first-dose hypotension appear to be a contributing factor to their under-utilisation in both hospital and primary care settings. We investigated whether long-acting and short-acting ACEi's differ in their haemodynamic responses to the first-dose in patients with CHF.

Method: This was a multicentre, randomised, open, two-parallel-group study of captopril 6.25?mg and perindopril 2mg. 240 patients with CHF, age 68.9?±?8.9 years, of whom 66% were male, NYHAII—IV, with average blood pressure baseline values of 132.2?±?16.2/78.5?±?10.5mmHg for systolic and diastolic blood pressure, and left ventricular ejection fraction (LVEF) of 31.3?±?7.4% received either captopril (n?=?124) or perindopril (n?=?116). Blood pressure was continuously monitored during the 8?h following drug intake. Minimum levels and maximum decreases in systolic, diastolic and mean arterial pressures were measured, along with the incidence of hypotensive episodes defined as mean blood pressure (MBP) fall?>?20mmHg, whether symptomatic or not. Subgroups of patients distributed according to age, baseline blood pressure (BP) and LVEF were subsequently analysed.

Results: Overall, a statistically significant treatment effect in favour of perindopril was observed. First-dose hypotension was observed more frequently following captopril than perindopril administration, with lower MAP minimal levels (78.0?±?8.9 vs. 84.5?±?10.1?mmHg, p?<?0.0001), greater maximum falls (17.6?±?8.3 vs. 12.8?±?7.3mmHg, p?<?0.0001) and more frequent hypotensive episodes (42% vs. 15%, p?<?0.0001). The incidence of at least one symptomatic episode was also significantly higher with captopril (10 patients vs. one patient, p?=?0.029). Subgroup analyses according to age (< 70 years or > 70 years) or LVEF (< 30% or > 30%) reflected the main result.

Conclusion: Initiation of treatment with ACE inhibitors is associated with different haemodynamic and clinical tolerances in CHF patients, regardless of their risk for hypotension, with possible clinical implications.     

Attaining United States and European Guideline LDL-C Levels with Simvastatin in Patients with Coronary Heart Disease (the GOALLS Study)

SUMMARY

Objectives: The primary objective was to assess the effects of rilmenidine monotherapy and in combination with perindopril on blood pressure (BP) in patients assessed with grade 1 or 2 essential hypertension. The study also examined the effects of 2-year rilmenidine monotherapy on left ventricular hypertrophy (LVH) and on diastolic function of the left ventricle, along with the effects of rilmenidine on left ventricular mass index in hypertensive patients with no LVH, and the relationship between BP reduction and any change in LVH.

Research design and methods: Mild-to-moderate hypertensive patients (n?=?500) were enrolled in a multicentre 2-year open study and treated with rilmenidine (1-2?mg per day) monotherapy or rilmenidine plus perindopril (2, 4 or 8?mg per day) if control of hypertension was not achieved with rilmenidine monotherapy within 12 weeks. Blood pressure was recorded at regular intervals by the investigators and LVH measured by centralised single-blind echocardiographic reading.

Results: Rilmenidine monotherapy (average dose 1.42?mg) produced a significant decrease in BPfrom the baseline of 163?±?10/100?±?5?mmHg to 134?±?10/86?±?7?mmHg at 1 year and to 136?±?10/84?±?7?mmHg at 2 years (p?2 at 2 years (p?Conclusions: Long-term rilmenidine monotherapy was shown to be efficient in controlling BP and in reducing LVH. The addition of perindopril to rilmenidine monotherapy proved to be effective and well tolerated in those patients who did not respond to rilmenidine alone.     

Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus

SUMMARY

Aim: This Swiss multicentre study examined the efficacy and safety of oral pioglitazone in patients with type 2 diabetes.

Methods: Patients were randomised to pioglitazone at once-daily doses of 30mg for 20 weeks (n?=?76), 30?mg for 12 weeks followed by 45?mg for 8 weeks (n?=?74), or 45?mg for 20 weeks (n?=?84); 94.9% of patients completed 12 weeks and 88.9% completed all 20 weeks. Almost all (96.6%) patients received pioglitazone in combination with other anti-diabetic treatments.

Results: Mean HbA1c at baseline was 8.8?±?1.2%, and changes to endpoint were ?1.1?±?1.1%, ?1.1?±?1.4% and ?0.9?±?1.6%, respectively for the three dose groups (p?<?0.001 for each group). Triglyceride concentrations decreased in each group and the overall mean change during the study was ?0.58?mmol/l (p?<?0.001 versus baseline). HDL-cholesterol increased, with an overall mean change of 0.10?mmol?l^?1 (p?<?0.001 versus baseline). Blood pressure decreased from baseline, particularly for hypertensive patients with mean changes: systolic -10mmHg, p?<?0.001, diastolic-8mmHg, p?<?0.001 versus baseline. Serum alanine aminotransferase and γ-glutamyl transferase concentrations were significantly (p?<?0.001 for each) reduced during the study.

Conclusions: The study demonstrates the efficacy of pioglitazone 30?mg?day^?1 and 45?mg?day^?1 in the treatment of type 2 diabetes, with an improved lipid profile and decreased blood pressure in addition to improved glycaemic control.     

Prevention of arsenic-mediated reproductive toxicity in adult female rats by high protein diet

Abstract

Context: The detrimental effects of arsenic on female reproductive functions may involve overt oxidative stress. Casein and pea [Pisum sativum Linn. (Fabaceae)] proteins have antioxidant properties.

Objective: To investigate the role of casein- and pea-supplemented high-protein diet (HPD) in utero-ovarian protection from arsenic toxicity.

Materials and methods: Adult female Wistar rats were orally gavaged with vehicle (Gr-I) or arsenic at 3?ppm/rat/d (Gr-II and Gr-III) for 30 consecutive days, when they were maintained on either regular diet containing 18% protein (Gr-I and Gr-II), or HPD containing 27% protein in the form of casein (20%) and pea (7%) (Gr-III). Reproductive functions were evaluated using a battery of biochemical and histological techniques.

Results: As compared to Gr-I, the Gr-II rats suffered from loss of estrous cyclicity, reduction in weight (mg/100?g body weight) of ovary (Gr-I: 54.3?±?4.2 versus Gr-II: 35.8?±?1.6; p?<?0.001) and uterus (Gr-I: 161.7?±?24.6 versus Gr-II: 94.44?±?13.2; p?<?0.05), utero-ovarian degeneration, attenuated ovarian activities (unit/mg tissue/h) of Δ⁵, 3β-hydroxysteroid dehydrogenase (Gr-I: 3.41?±?0.12 versus Gr-II: 2.31?±?0.09; p?<?0.01) and 17β-hydroxysteroid dehydrogenase (Gr-I: 3.82?±?0.57 versus Gr-II: 1.24?±?0.19; p?<?0.001), and decreased serum estradiol level (pg/ml) (Gr-I: 61.5?±?2.06 versus 34.1?±?2.34; p?<?0.001). Ovarian DNA damage was preponderant with blatant generation of malondialdehyde (nM/mg tissue; Gr-I: 15.10?±?2.45 versus Gr-II: 29.51?±?3.44; p?<?0.01) and attenuated superoxide dismutase activity (unit/mg tissue) (Gr-I: 2.18?±?0.19 versus Gr-II: 1.33?±?0.18; p?<?0.05). The Gr-III rats were significantly protected from these ill effects of arsenic.

Discussion and conclusion: HPD, by way of antioxidant properties, may find prospective role in the protection of reproductive damage caused by arsenic.     

Effectiveness of perindopril/amlodipine fixed dose combination in everyday clinical practice: results from the EMERALD study

Objective: The rates of blood pressure (BP) control worldwide are discouraging. This study had the purpose of assessing the effectiveness of perindopril/amlodipine fixed dose combination on BP-lowering efficacy, and recording adherence, safety and tolerability during a 4 month treatment period.

Research design and methods: In this multicenter, observational study 2269 hypertensive patients were prospectively enrolled. The data were recorded at 1 and 4 months of treatment.

Main outcome measures and results: Between the first and third visits mean BP values (systolic/diastolic) decreased from 158.4?±?13.6/89.9?±?8.7?mmHg to 130.0?±?7.9/77.7?±?6.3?mmHg (P?<?0.001). The magnitude of BP reduction depended on baseline blood pressure levels and total cardiovascular (CV) risk (P?<?0.001). Patients with grade 1, 2 and 3 showed a BP reduction of 21.9/10.0?mmHg, 34.4/14.2?mmHg and 51.4/21.2?mmHg, accordingly (P?<?0.001). Patients with very high, high, moderate and low added CV risk showed a BP reduction of 35.7/14.9?mmHg, 27.5/12.1?mmHg, 28.6/12.2?mmHg and 14.5/5.8?mmHg respectively (P?<?0.001). Adherence to treatment was high: 98.3% of the sample was taking the treatment “every day” or “quite often”, while only 15 patients (0.7% of the sample) prematurely discontinued treatment. Study interpretation may be limited by the fact that this is an observational study with no comparator and a short follow-up period.

Conclusions: A perindopril/amlodipine fixed dose combination significantly decreases BP levels. The degree of BP reduction is related to baseline BP levels and total CV risk.     

Patient characteristics,drug adherence patterns,and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine

ABSTRACT

Objective: Examine real-world effectiveness and hypoglycemia cost burden in patients with type?2 diabetes newly initiated on exenatide or insulin glargine.

Design and methods: Retrospective cohort study describing patient characteristics, drug adherence patterns, and 1-year hypoglycemia rates with associated costs using an administrative claims database. Adult subjects with type?2 diabetes had an initial claim for exenatide or insulin glargine between May?1, 2005 and June?30, 2007, and had continuous eligibility for ≥?6 months pre- and ≥?12 months post-initiation.

Results: The exenatide cohort (n?=?3262) was 53?±?10?years (±SD); 54% female. The insulin glargine cohort (n?=?3038) was 56?±?12?years; 41% female. The mean Deyo-Charlson comorbidity index score was 1.45 for exenatide versus 1.82 for insulin glargine (p?<?0.001). Baseline OAD use rates for exenatide and insulin glargine, respectively, were 77% versus 69% metformin; 47% versus 65% sulfonylurea; 50% versus 49% thiazolidinedione; 56% versus 60% multiple OAD. For patients with two or more pharmacy claims for exenatide or insulin glargine, the 12-month medication possession ratio (MPR) was 68?±?29% for exenatide and 58?±?28% for insulin glargine (p?<?0.001). MPR ≥?80% was higher for exenatide (p?<?0.001) and fewer patients discontinued therapy (p?<?0.001). The probability of a hypoglycemic event was significantly lower for exenatide (p?<?0.005), resulting in lower associated annual costs.

Conclusions: This study provides the first real-world observational comparison of type?2 diabetes patients newly initiated on exenatide or insulin glargine. Exenatide patients had a lower comorbidity burden, better drug adherence, and a lower rate of hypoglycemic events with associated costs. Retrospective database analyses examine medical care utilization in large populations using a relatively inexpensive and expedient approach. However, data are only representative of a commercial health-care plan with limited information on multiple variables usually collected during clinical trials.     

Epidemiology,clinical and economic outcomes of admission hyponatremia among hospitalized patients

ABSTRACT

Background: Hyponatremia, the most frequent electrolyte derangement identified among hospitalized patients, is associated with worsened outcomes in patients with pneumonia, heart failure and other disorders.

Research design and methods: We performed a retrospective cohort study of hospitalized patients to quantify the attributable influence of admission hyponatremia on hospital costs and outcomes. Data were derived from a large administrative database with laboratory components, representing 198,281 discharges from 39 US hospitals from January 2004 to December 2005. Hyponatremia was defined as admission serum [Na⁺]?<?135?mEq/L.

Results: The incidence of hyponatremia at admission was 5.5?%?(n?=?10,899). Patients with hyponatremia were older (65.7?±?19.6 vs. 61.5?±?21.8, p?<?0.001) and had a higher Deyo-Charlson Comorbidity Index score (1.8?±?2.1 vs. 1.3?±?1.8, p?<?0.001) than those with normal [Na⁺]. A higher proportion of hyponatremic patients required intensive care unit (ICU) (17.3?%?vs. 10.9?%?, p?<?0.001) and mechanical ventilation (MV) (5.0?%?vs. 2.8?%?, p?<?0.001) within 48?hours of hospitalization. Hospital mortality (5.9?%?vs. 3.0?%?, p?<?0.001), mean length of stay (HLOS, 8.6?±?8.0 vs. 7.2?±?8.2 days, p?<?0.001) and costs ($16,502?±?$28,984 vs. $13,558?±?$24,640, p?<?0.001) were significantly greater among patients with hyponatremia than those without. After adjusting for confounders, hyponatremia was independently associated with an increased need for ICU (OR 1.64, 95?%?CI 1.56–1.73) and MV (OR 1.68, 95?%?CI 1.53–1.84), and higher hospital mortality (OR 1.55, 95?%?CI 1.42–1.69). Hyponatremia also contributed an increase in HLOS of 1.0 day and total hospital costs of $2,289.

Conclusions: Hyponatremia is common at admission among hospitalized patients and is independently associated with a 55?%?increase in the risk of death, substantial hospital resource utilization and costs. Potential for bias inherent in the retrospective cohort design is the main limitation of our study. Studies are warranted to explore how prompt normalization of [Na⁺] may impact these outcomes.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients

ABSTRACT

Background: Despite the widespread notion that controlling hypertension is essential to improve cardiovascular outcome, uncontrolled hypertension rates remain high. Fixed-dose combinations are used routinely to reduce the impact of hypertension. Treatment with fixed-combination perindopril/indapamide, for example, at the currently approved doses (perindopril 2?mg/indapamide 0.625?mg [Per2/Ind0.625] and perindopril 4?mg/indapamide 1.25?mg [Per4/Ind1.25]), reduces blood pressure, end-organ damage, and cardiovascular morbidity and mortality in a wide range of hypertensive patients.

Aim and scope: This article reviews three published randomised trials that evaluated the efficacy and safety of the highest dose of perindopril/indapamide (perindopril 8?mg/indapamide 2.5?mg [Per8/Ind2.5]) in blood pressure lowering and end-organ protection studies.

Results: In the first (dose-finding) study, incremental reductions in SBP/DBP were observed with each dose doubling. After 8 weeks of treatment, decreases in supine SBP/DBP were statistically significant compared to placebo for all three doses, with incremental and progressive reductions with each dose doubling: ranging from SBP/DBP respectively ?14/?9?mmHg for Per2/Ind0.625 to ?23/?15?mmHg for Per8/Ind2.5 compared to ?5/?5?mmHg for placebo. In the PICXEL and PREMIER trials, SBP/DBP decreases of 16.3/8.1?mmHg (p?<?0.0001) and 2.5/2.6?mmHg, respectively, were noted when Per4/Ind1.25 was doubled to Per8/Ind2.5 (decreases from 167.7/101.7 to 151.4/93.6 in PICXEL and from 154.9/92.1 to 152.4/89.5 in PREMIER, respectively). As a consequence more patients had normalised blood pressure (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively. Additional end-organ benefits were also noted with Per8/Ind2.5. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5?g/m² decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5?g/m²?±?39.5 (mean?±?SD) to 131?g/m²; p?<?0.0001). In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was Per8/Ind2.5 (p?<?0.0001). When safety data, including potassium levels, were analysed, the increase in dose to Per8/Ind2.5 did not have a notable impact on the safety profile of perindopril/indapamide.

Conclusions: Based on data available from an evaluation of three randomised clinical trials, fixed-combination Per8/Ind2.5 provided a significant, incremental reduction in blood pressure as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.     

Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea

Objective The present study aimed to compare the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and saxagliptin on 24?hour acute glucose fluctuations in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with a combination of metformin and sulfonylurea.

Research design and methods This was a 24 week, prospective, randomized, open-label, active-controlled study. Patients (N?=?73) with T2DM who had inadequate glycemic control (HbA1c 7.0%–10.0%) with a stable dosage of metformin plus gliclazide for more than 3 months were randomized to receive either vildagliptin 50?mg twice daily (BID, n?=?37) or saxagliptin 5?mg once daily (QD, n?=?36). Change in mean amplitude of glycemic excursions (MAGE) was assessed at the end of 24 weeks.

Results At baseline, the mean (±SD) age was 62.9?±?6.55 years, disease duration was 7.0?±?2.33 years, and HbA1c was 8.4?±?0.68%. After 24 weeks of treatment, the MAGE decreased from 5.81?±?1.16?mmol/L to 4.06?±?0.86?mmol/L (p<0.001) in the vildagliptin group and from 5.66?±?1.14?mmol/L to 4.79?±?1.25?mmol/L (p?=?0.003) in the saxagliptin group. The mean change in MAGE in the vildagliptin group was significantly greater than that in the saxagliptin group (1.74?±?0.48?mmol/L vs. 0.87?±?0.40?mmol/L, p<0.001). The mean change in HbA1c, from baseline to the study endpoint, in the vildagliptin and saxagliptin groups, was 1.22?±?0.40% and 1.07?±?0.36%, respectively, with no significant difference between the groups (p?=?0.091). The overall safety and tolerability of vildagliptin and saxagliptin were similar. The limitations of the study were a small number of patients and open-label administration of the study drug.

Conclusion Vildagliptin produced a significantly greater reduction in acute glucose fluctuations compared with saxagliptin when added to a dual combination of metformin and sulfonylurea in Chinese patients with T2DM.

Chinese clinical trial registration number ChiCTR-TRC-13003858.     

Long-term treatment effect of atorvastatin on aortic stiffness in hypercholesterolaemic patients

Summary

Aim: To assess the effect of atorvastatin on aortic stiffness in hypercholesterolaemic patients free of arterial hypertension and diabetes mellitus.

Methods and Results: The study included 36 patients (25 men and 11 women, mean age 56?±?12 years); 18 patients had stable coronary heart disease (CHD) and 18 were free of CHD at baseline. All patients received atorvastatin (20mg/day) for a 2-year period. Aortic stiffness was assessed by transthoracic echocardiography at baseline and 2 years later. At baseline, total cholesterol, low density lipoprotein cholesterol (LDL-C) and LDL-C/high density lipoprotein cholesterol (HDL-C) ratio were positively related to aortic stiffness (p?<?0.001 for all). The mean change in lipid parameters during treatment was: total cholesterol ?38%, LDL-C ?46%, triglycerides ?29%, and HDL-C +6%, all significant (p?=?0.029 to <0.0001). After the 2-year treatment with atorvastatin, aortic stiffness was significantly reduced by 14% (p?=?0.019). An improvement of left ventricular (LV) ejection fraction by 13% (p?<?0.001) and a reduction of LV mass index by 9% (p?=?0.008) were also recorded. The change in aortic stiffness was similar in patients with or without CHD.

Conclusion: Long-term treatment with atorvastatin improves aortic stiffness; this index is related to total and coronary mortality. Moreover, assessment of aortic stiffness may be useful in identifying which hypercholesterolaemic patients should be treated aggressively, regardless of CHD. The aortic stiffness effect may eventually become an index of the efficacy of lipid lowering treatment.     

Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure

Objective: The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

Research design and methods: In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5?mg OD) began treatment with bisoprolol/amlodipine FDC 5/5?mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10?mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

Results: Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9?±?12.82?mmHg reduction; amlodipine monotherapy failure: 24.7?±?11.67?mmHg reduction; p?<?0.001 for both). Overall mean SBP decreased by 25.3?±?12.25?mmHg (p?<?0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6?±?9.67 bpm reduction; amlodipine monotherapy failure: 11.5?±?8.65 bpm reduction; p?<?0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5?mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

Conclusions: Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.     

Medical resource utilization among community-acquired pneumonia patients initially treated with levofloxacin 750 mg daily versus ceftriaxone 1000 mg plus azithromycin 500 mg daily: A US-based study*

ABSTRACT

Objective: The 2007 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines recommend that community-acquired pneumonia (CAP) patients admitted to hospital wards initially receive respiratory fluoroquinolone monotherapy or β-lactam plus macrolide combination therapy. There is little evidence as to which regimen is preferred, or if differences in medical resource utilization exist between therapies. Thus, the authors compared length of hospital stay (LOS) and length of intravenous antibiotic therapy (LOIV) for patients who received initial levofloxacin 750?mg daily versus ceftriaxone 1000?mg plus azithromycin 500?mg daily (‘combination therapy’).

Research design and methods: Adult hospital CAP cases from January 2005 to December 2007 were identified by principal discharge diagnosis code. Patients with a chest infiltrate and medical notes indicative of CAP were included. Direct intensive care unit admits and healthcare-associated cases were excluded. A propensity score technique was used to balance characteristics associated with initial antimicrobial therapy using multivariable regression to derive the scores. Propensity score categories, defined as propensity score quintiles, rather than propensity scores themselves, were used in the least squares regression model to assess the impact of LOS and LOIV.

Results: A total of 495 patients from six hospitals met study criteria. Of these, 313 (63%) received levofloxacin and 182 (37%) received combination therapy. Groups were similar with respect to age, sex, most comorbidities, presenting signs and symptoms, and Pneumonia Severity Index (PSI) risk class. Patients on combination therapy were more likely to have heart failure and receive pre-admission antibiotics. Adjusted least squares mean (±SE) LOS and LOIV were shorter with levofloxacin versus combination therapy: LOS, 4.6?±?0.17 vs. 5.4?±?0.22 days, p?<?0.01; and LOIV, 3.6?±?0.17 vs. 4.8?±?0.21 days, p?<?0.01. Results for PSI risk class III or IV patients were: LOS, 5.0?±?0.30 vs. 5.9?±?0.37 days, p?=?0.07; and LOIV, 3.7?±?0.33 vs. 5.2?±?0.39 days, p?<?0.01. Due to the retrospective study design, limited sample size, and scope (single health-network), the authors encourage replication of this study in other data sources.

Conclusions: Given the LOS and LOIV reductions of 0.8 and 1.2 days, respectively, utilization of levofloxacin 750?mg daily for CAP patients admitted to the medical floor has the potential to result in substantial cost savings for US hospitals.     

Recalculation of cardiovascular risk score as a surrogate marker of change in clinical care of diabetes patients: the Alphabet POEM project (Practice Of Evidence-based Medicine)

SUMMARY

Aims: To assess the impact of evidence-based strategies on the care of subjects with diabetes, in particular on their coronary heart disease (CHD) risk, using the Alphabet Strategy template and coronary heart disease (CHD) risk calculators as novel audit tools.

Methods: Diabetes and cardiovascular parameters were collected on 400 consecutive type 2 diabetes patients attending the outpatient clinic. The subjects were men and women aged 21-75 years with necessary follow-up data from referral or first chronological available letter in the notes (T0) to the most recent follow-up visit (Tfu). The average follow-up period was 5 years. Absolute CHD risk was calculated using the Framingham risk function and the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. The results were analysed using Student's paired t-test and chi-squared test.

Results (T0 vs.Tfu): Advice: smoking status improved 18.3 vs. 15.5%: p?=?0.3. Blood pressure: systolic blood pressure improved 145.8?±?21.1 vs. 140.1?±?20.5mmHg: p?<?0.0001. Diastolic blood pressure improved 82.0?±?12.2 vs. 76.5?±?11.0mmHg: p?<?0.0001. Cholesterol: total cholesterol improved 5.8?±?1.6 vs. 4.9?±?1.0 mmol/L: p?<?0.0001; high density lipoprotein (HDL) cholesterol improved 1.05 vs. 1.26 mmol/L: p?<?0.001. Diabetes control: glycated haemoglobin (HbA1c)% worsened 7.9?±?1.8 vs. 8.1?±?1.5: p?<?0.0001. However, when adjusted for duration of diabetes, this improved non-significantly by 12% overall. Eye examination: improved 86.5 vs. 97.5%: p?<?0.001. Feet examination: improved 69.8 vs. 83.5%: p?<?0.001. Guardian drugs: significantly more patients were on aspirin (29.0 vs. 83.5%: p?<?0.001), angiotensin converting enzyme (ACE) inhibitors (32.0 vs. 64.5%: p?<?0.001), and lipid lowering therapy (16.8 vs. 55.0%: p?<?0.001). Heart disease risk scores: a significant reduction in Framingham 10-year absolute cardiac risk was achieved (20.6?±?10.04% vs. 16.7?±?9.1%: p?=?0.001). Using the UKPDS risk engine, there was a non-significant reduction in absolute CHD risk over the follow-up period (23.8?±?14.8% vs. 23.7?±?15.5: p?=?NS). There were significant improvements between age-adjusted risk score (Tadj) and follow-up values (Tfu) (Framingham: 23.67% (Tadj) vs. 16.7% (Tfu); UKPDS 31.2% (Tadj) vs. 23.7% (Tfu)). For UKPDS stroke risk, a significant improvement was seen from Tadj to Tfu (19.0% (Tadj) vs. 16.4% (Tfu): p?<?0.001), with a significant deterioration noted between T0 and Tfu (11.5% (T0) vs. 16.4% (Tfu): p?<?0.0001).

Conclusions:The Alphabet Strategy is a novel evidence-based approach to clinical diabetes care, which produced a statistically significant improvement in most of the assessed parameters. The Alphabet Practice Of Evidence-based Medicine (POEM) template is a useful clinical tool for diabetes care and audit. It includes most of the components of diabetes audit required by the National Service Framework (NSF) and the United Kingdom GP contract.     

Effects of triptolide on pharmacokinetics of fenofibrate in rats and its potential mechanism

1. Triptolide and fenofibrate are often used together for the treatment of nephrotic syndrome in Chinese clinics.

2. This study investigates the effects of triptolide on the pharmacokinetics of fenofibrate in rats and it potential mechanism.

3. The pharmacokinetics of fenofibrate (20?mg/kg) with or without triptolide pretreatment (2?mg/kg/day for seven days) were investigated. Additionally, the inhibitory effects of triptolide on the metabolic stability of fenofibrate were investigated using rat liver microsome incubation systems.

4. The results indicated that the C_max (35.34?±?7.52 vs. 30.43?±?6.45?μg/mL), t_1/2 (6.17?±?1.15 vs. 4.90?±?0.82?h) and AUC_(0–t) (468.12?±?35.84 vs. 416.35?±?32.68?mg?h?L^?1) of fenofibric acid decreased significantly (p?<?.05). The T_max of fenofibric acid increased significantly (p?<?.05) from 5.12?±?0.36 to 6.07?±?0.68?h. Additionally, the metabolic stability of fenofibrate was prolonged from 35.8?±?6.2 to 48.6?±?7.5?min (p?<?.05) with the pretreatment of triptolide.

5. In conclusion, these results indicated that triptolide could affect the pharmacokinetics of fenofibric acid, possibly by inhibiting the metabolism of fenofibrate in rat liver when they were co-administered.

     

Bioactive peptide carnosin protects against lead acetate-induced hepatotoxicity by abrogation of oxidative stress in rats

Context Oxidative stress is a common mechanism of liver injury. Carnosine is a dipeptide having strong antioxidant effects.

Objectives We investigated the effects of carnosine on lead-induced hepatotoxicity and oxidative stress in rats.

Materials and methods Animals received an aqueous solution of lead acetate (500?mg Pb/L in the drinking water) and/or daily oral gavage of carnosine (10?mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical (commercial kits), molecular (standard chemical methods) and histological (microscopic) evaluations.

Results Lead-induced oxidative stress in liver tissue was indicated by a significant increase in the level of malondialdehyde (MDA) (8.25?±?0.15?nmol/mg) as well as decrease in the level of total antioxidant capacity (TAC) (1.72?±?0.25?μmol/g) and total thiol (SH) groups) 1.9?±?0.22?μmol/g). Carnosine treatment decreased MDA (4?±?0.08?nmol/mg), whereas it increased the contents of total thiol (3.25?±?0.04?μmol/g) and TAC (3.44?±?0.32?μmol/g) in the lead group. Carnosine also prevented the decreased body weight (p?<?0.001), albumin (p?<?0.05) and total protein levels (p?<?0.001) and increased liver weight (p?<?0.05) and activates of hepatic enzymes (p’s?<?0.001) (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase) in the lead group. Furthermore, histopathological study showed that carnosine attenuates liver damage by decreasing necrosis and infiltration of inflammatory cells.

Conclusion Carnosine prevented lead-induced hepatotoxicity, indicated by molecular, biochemical and histopathological analyses through inhibiting lipid peroxidation and enhancing antioxidant defence systems. Therefore, carnosine makes a good candidate to protect against the deleterious effect of chronic lead intoxication.     

In vitro inhibitory effects of thymol and carvacrol on dendritic cell activation and function

Context: Thyme has been used in traditional medicine for medicinal purposes since ancient times.

Objective: The objective of this study was to investigate the effects of thymol and carvacrol as two major constituents of thyme on dendritic cells (DCs) maturation and T cell activation.

Materials and methods: Splenic DCs were treated with non-cytotoxic concentrations of the components and then analyzed for MHC II, CD86, and CD40 expression by flow cytometry. The effects of compounds on mitogenic, as well as allogenic T cell responses in mixed lymphocyte culture (MLR) and the release of cytokines were investigated.

Results: At 0.1?µg/ml, reduced mean fluorescent intensity (MFI) of CD86 for thymol (80.3?±?0.2% of untreated control) and CD40 for carvacrol (79.5?±?0.14%) was observed (p?<?0.001). Decreased mitogenic T cell proliferation by thymol [proliferation index (PI) from 0.93?±?0.11 at 1?µg/ml to 0.42?±?0.16 at 100?µg/ml (p?<?0.01)] and carvacrol [PI from 1.08?±?0.3 at 1?µg/ml to 0.28?±?0.1 at 100?µg/ml (p?<?0.001)] was seen. Ten micrograms/ml thymol (PI, 0.85?±?0.04) and carvacrol (PI, 0.89?±?0.03) inhibited allogenic T cell response (p?<?0.05). Decreased IFN-γ level in MLR supernatant from 1441?±?27.7?pg/ml in untreated cells to 944?±?32.1 at 10?µg/ml of thymol and of carvacrol (886?±?31.7?pg/ml) (p?<?0.01) was found. IL-4 levels were decreased in the presence of both compounds (p?<?0.01).

Conclusion: These data showed the suppressive effects of thymol and carvacrol on DCs maturation and function, as well as T cell responses.     

Effect Of epigallocatechin-3-gallate on the pharmacokinetics of amlodipine in rats

1. This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats.

2. The pharmacokinetics of orally administered amlodipine (1?mg/kg) with or without EGCG pretreatment (30?mg/kg/day for 10?days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems.

3. The results indicated that when the rats were pretreated with EGCG, the C_max of amlodipine increased from 16.32?±?2.57 to 21.44?±?3.56?ng/mL (p?<?0.05), the T_max decreased from 5.98?±?1.25 to 4.01?±?1.02?h (p?<?0.05), and the AUC_0–t increased from 258.12?±?76.25 to 383.34?±?86.95?μg h L^?1 (p?<?0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3?±?5.6 to 52.6?±?7.9?min (p?<?0.05) with the pretreatment of EGCG.

4. It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.

     

Alteration of pentylenetetrazole-induced seizure threshold by chronic administration of ginger (Zingiber officinale) extract in male mice

Abstract

Context: Zingiber officinale Roscoe (Zingiberaceae), or ginger, used in traditional Chinese medicine, has antioxidant activity and neuroprotective effects. The effects of this plant on clonic seizure have not yet been studied.

Objective: The present study evaluated the anticonvulsant effect of ginger in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male mice.

Materials and methods: The anticonvulsant effect of Z. officinale was investigated using i.v. PTZ-induced seizure models in mice. Different doses of the hydroethanolic extract of Z. officinale (25, 50, and 100?mg/kg) were administered intraperitonal (i.p.), daily for 1 week before induction of PTZ. Phenobarbital sodium (30?mg/kg), a reference standard, was also tested for comparison. The effect of ginger on to the appearance of three separate seizure endpoints, e.g., myoclonic, generalized clonic, and tonic extension phase, was recorded.

Results: Hydroethanolic extract of Z. officinale significantly increased the onset time of myoclonic seizure at doses of 25–100?mg/kg (55.33?±?1.91 versus 24.47?±?1.33?mg/kg, p?<?0.001) and significantly prevented generalized clonic (74.64?±?3.52 versus 47.72?±?2.31?mg/kg, p?<?0.001) and increased the threshold for the forelimb tonic extension (102.6?±?5.39 versus 71.82?±?7.82?mg/kg, p?<?0.01) seizure induced by PTZ compared with the control group.

Discussion and conclusion: Based on the results, the hydroethanolic extract of ginger has anticonvulsant effects, possibly through an interaction with inhibitory and excitatory systems, antioxidant mechanisms, and oxidative stress inhibition.