Differences in Lipid Profiles of Patients Given Rosiglitazone Followed by Pioglitazone

Summary

To compare the effects of rosiglitazone and pioglitazone on patient lipid levels in a clinical practice setting, we retrospectively examined charts of 20 patients in our practice. The patients had been treated for type 2 diabetes for 3 or more months with rosiglitazone (4?mg b.i.d.) followed immediately by 3 or more month^s' treatment with pioglitazone (45?mg once daily). Glycaemic control was excellent and essentially equivalent during the two treatments. At baseline, the mean HbA1c level was 7.6%; it dropped to 6.6% and 6.3% with rosiglitazone and pioglitazone treatment, respectively. Lipid levels, however, differed with the two treatments. Triglyceride levels rose 13% with rosiglitazone treatment, but fell 14% below baseline levels with pioglitazone therapy - a 24% reduction overall (p?=?0.02). Rosiglitazone was associated with a significant increase in low-density

lipoprotein cholesterol (LDL-C) levels (35%, p?<?0.001 vs. baseline) and a significant increase in total cholesterol levels (22%, p?<?0.001 vs. baseline). When pioglitazone replaced rosiglitazone therapy, LDL-C fell 25% (p?<?0.001), and total cholesterol fell 19% (p?<?0.001 between treatments). HDL-C levels did not change significantly during either treatment. Both drugs were otherwise safe and well tolerated. One patient receiving rosiglitazone and one receiving pioglitazone developed oedema that resolved without therapy discontinuation. Liver enzyme levels and blood pressure were unaffected in this group of patients. Because patients with diabetes are at risk for coronary artery disease, physicians should consider each agent's effects on lipid levels when choosing a specific thiazolidinedione.     

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.     

Clinical effect of combination therapy of pioglitazone and an α-glucosidase inhibitor

SUMMARY

This study evaluated the efficacy of adding pioglitazone 30?mg to the therapy of patients with type 2 diabetes mellitus whose glycaemic control was poor on an α-glucosidase inhibitor (α-GI) alone or in combination with a sulphonylurea (SU).

The patients (n?=?20) had a HbA1c level between 7.0 and 12.0% and the fasting plasma glucose was 7.8?mmol?l^?1 or higher. They were treated with 30?mg pioglitazone once daily for 16 weeks.

The decrease in HbA1c at week 16 of treatment was 0.8% (7.8% at baseline dropping to 7.1% at week 16; p?<?0.01). An increase in leptin was observed 4 weeks after starting the post-study period (p?<?0.05). Tumour necrosis factor-α (TNF-α) and body fat percentage did not show any

significant alterations. Correlations between the decrease in HbA1c at week 16 and characteristic variables of patients were examined. A correlation with leptin (p?=??0.5632, p?<?0.05) levels was found. Five patients experienced adverse drug reactions, such as oedema, hypoglycaemia and increased creatine phosphokinase (CK), all of which were mild in severity.

The addition of pioglitazone in diabetics whose glycaemic control was poor on a α-GI alone or with a α-GI and SU combination resulted in a significant decrease in HbA1c, and the treatment was well-tolerated. Our findings also suggest that leptin levels could be useful for assessing responders to pioglitazone.     

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.     

ACE Inhibitors in Heart Failure-Switching from Enalapril to Perindopril

Summary

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 4mg daily.

Assessments of clinical status, echo-cardiography and nuclear ventriculography were performed at baseline under enalapril (30mg mean dose (b.i.d.)), then 6 and 12 months after the switch to perindopril (4mg/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?±?6.5mm; p?=?0.001) and LV mass index (143.3?±?21.5 vs. 164.2?±?40.2g/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.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n?=?23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.

Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (～1000).

Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We

evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.

Results: PIO 15, 30 and 45?mg enhanced HOMA-S compared with baseline (56.9-63.6%, p?=?0.0298); (53.7-64.7%, p?=?0.0008); (59.0-75.9%, p?<?0.0001), respectively. Only the 45?mg dose showed a difference from placebo (p?=?0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p?=?0.0026); (0.287-0.299, p?=?0.0001); (0.290-0.306, p?=?0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p?=?0.0005, p?<?0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p?=?0.0007; 53.2–68.4%, p?<?0.0001) and placebo plus SU (p?=?0.0129, p?<?0.0001, respectively). Likewise, PIO 15 and 30?mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p?=?0.0001; 0.287-0.305, p?=?0.0001, respectively). Both doses had different effects from placebo plus SU (p?=?0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p?<?0.0001) and placebo plus MET (p?=?0.0002).     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY

Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation.

Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500?mmol?day^?1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone).

Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean?±?SD body weight falling from 270?±?54?lbs (123?±?25?kg) to 244?±?61 lbs (111?±?28?kg) (p?<?0.01). The weight loss observed was no different from that observed

in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263?±?54?lbs (120?±?25?kg) to 239?±?52?lbs (109?±?24?kg); p?<?0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control.

Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

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.     

Inhibitory effect of TGF-β peptide antagonist on the fibrotic phenotype of human hypertrophic scar fibroblasts

Context: TGF-β plays a central role in hypertrophic scar (HS) formation and development.

Objective: This study investigated the role of a TGF-β antagonist peptide in inhibiting fibrotic behavior of human HS-derived fibroblasts (HSFs).

Materials and methods: HSFs were seeded at a density of 3.1?×?10⁴/cm² and were subjected to treatment of peptide antagonist (30?μM) or TGF-β receptor inhibitor LY2109761 (10?μM) or without treatment followed by the analyses of quantitative PCR, Elisa, in vitro wounding and fibroblast-populated collagen lattice (FPCL) assays.

Results: qPCR and Elisa analyses showed that the peptide could, respectively, reduce the gene (at 48?h) and protein (at 72?h) expression levels of collagen I (86?±?4.8%; 56.6?±?7.3%), collagen III (73?±?10.7%; 43.7?±?7.2%), fibronectin (90?±?8.9%; 21.1?±?2.8%), and TGF-β1 (85?±?9.3%; 25.0?±?9.4%) as opposed to the non-treated group (p?<?0.05), as the LY2109761 group similarly did. Cell proliferation was also significantly inhibited at day 5 (CCK-8 assay) by both peptide and LY2109761 treatments compared with the non-treated group (p?<?0.05). The peptide also significantly inhibited cell migration as opposed to blank control at 24?h (43?±?6.7% versus 60?±?2.1%, p?<?0.05) and at 48?h (63.9?±?3.1% versus 95?±?4.1%, p?<?0.05). Similar to LY2109761, the peptide antagonist significantly reduced HS FPCL contraction compared with the non-treated group with significant differences in surface area at 48?h (0.71?±?0.06?cm² versus 0.51?±?0.06?cm², p?<?0.05) and at 72?h (0.65?±?0.02?cm² versus 0.42?±?0.01?cm², p?<?0.05).

Conclusion: The TGF-β antagonist peptide may serve as an important drug for HS prevention and reduction given the obvious benefits of good biosafety, low cost, and easy manufacture and delivery.     

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.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.     

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.     

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.     

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.     

Efficacy,tolerability and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% in a broad patient population: multicenter,open-label observational study*

ABSTRACT

Objective: To evaluate intraocular pressure (IOP)-lowering efficacy, tolerability, and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort^?) among German patients.

Methods: Multicenter, observational, open-label study of patients with primary open angle glaucoma or ocular hypertension (n?=?606). As determined by participating physicians, patients had insufficient IOP control and required a medication change. They were switched to once-daily fixed-combination bimatoprost/timolol with no wash-out period. IOP was recorded at treated baseline, 4–6 weeks and 12 weeks after switching. Tolerability was measured using a 4-step scale (excellent, good, moderate, poor) and all adverse events were recorded.

Results: A total of 405 patients switched from monotherapy, 97 switched from other fixed combinations, and 104 switched from non-fixed combinations. Among all patients, 32.5% had used prostaglandin analog (PGA) monotherapy, 8.7% had been using a fixed combination that included a PGA, and 6.9% had been using an adjunctive combination of a PGA and a β-blocker. Mean treated baseline IOP (±SD) for all patients was 20.7?±?3.5?mmHg. Overall, changing medication to fixed-combination bimatoprost/timolol lowered IOP to 16.6?±?2.7?mmHg (p?<?0.001 vs. baseline) after 4–6 weeks and to 16.1?±?2.6?mmHg (p?<?0.001) after 12 weeks; reductions of 19.8% and 22.2%, respectively. Combined bimatoprost/timolol provided an additional IOP reduction versus baseline in most subgroups based on prior treatment. At week 12, patients who had previously used a β-blocker achieved an additional 25.8% decrease from baseline and IOP was reduced by 22.6% in former PGA monotherapy patients. At week 12, 84.6% of all eyes reached a target pressure less than or equal to 18?mmHg. Tolerability of bimatoprost/timolol was rated excellent or good by the physicians for 98.7% of patients and by 96.7% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of bimatoprost 0.03%/timolol 0.5% was effective, well tolerated, and safe in a broad patient population.     

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.     

Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary

Context: It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS?), as established medicines with dual anti-cytokine and anti-oxidant potential may be a therapeutic alternative approach to the current treatments.

Objective: The objective of this study is to study the protective effects of carvedilol and ANGIPARS? on inflammatory and oxidative response in hyperandrogenism-induced polycystic ovary (PCO).

Materials and methods: The murine model of PCO was induced by letrozole (1?mg/kg/d; orally) and effective doses of carvedilol (10?mg/kg/d; orally) and ANGIPARS? (2.1?mg/kg/d; orally) were administrated for 21?d in PCO and non-PCO healthy rats. Ovarian folliculogenesis, sex hormones concentrations, OS, inflammatory, and metabolic biomarkers were assessed in serum and ovaries.

Results: PCO rats exhibited ovarian cystogenesis which was preserved by the application of carvedilol and ANGIPARS?. In comparison with controls, decreased level of the total antioxidant power (TAP) and higher levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) in serum and ovaries (2.41?±?0.67 versus 0.72?±?0.11; and 0.17?±?0.04 versus 0.05?±?0.01; 5.48?±?1.30 versus 10.56?±?0.77; and 7.06?±?1.94 versus 17.98?±?0.98; p?<?0.05, respectively) were detected in PCO rats. Moreover, the PCO rats exhibited hyperandrogenism due to a 3.7-fold increase in serum testosterone concentration (35.04?±?3.17 versus 131.09?±?13.24; p?<?0.05) along with a 2.98-fold decrease in serum progesterone (6.19?±?0.40 versus 18.50?±?1.03; p?<?0.05) and 5.2-fold decrease in serum estradiol (9.30?±?0.61 versus 48.3?±?2.10; p?<?0.05) when compared with those of the control group. However, similar to the control group, normal levels of OS markers and sex hormones were detected in ANGIPARS? and carvedilol co-treated PCO rats. Besides, when compared with controls, increased levels of TNF-α (770.75?±?42.06 versus 477.14?±?28.77; p?<?0.05) and insulin (1.27?±?0.10 versus 0.36?±?0.05; p?<?0.05) in PCO rats were significantly inhibited by carvedilol and ANGIPARS? co-treatment.

Discussion and conclusion: We evidenced the beneficial effects of carvedilol and ANGIPARS? in PCO, which underpin the new alternative approach in using these kinds of medicines in female reproductive disorders.