Losartan reduces mortality in a genetic model of heart failure

Altered Ca²⁺ homoeostasis accompanies heart failure. As a model of heart failure, transgenic mice (TG) with selective overexpression of calsequestrin (CSQ) in the heart were used. CSQ is the main Ca²⁺ binding protein in the lumen of the junctional sarcoplasmic reticulum. Overexpression of CSQ leads to hypertrophy, fibrosis, heart failure, cardiac arrhythmias, and ultimately premature death compared to littermate controls (WT). In the present study, cardiac hypertrophy was noted at 2 months of age (relative heart weight 6.4?±?0.2 mg/g in WT and 11.2?±?0.3 mg/g in TG, n?=?7, p?<?0.05) which progressed at 5 months of age (relative heart weight 15.5?±?1.1 mg/g in TG, n?=?11). Furthermore, an increased degree of fibrosis (from 0.29?±?0.04 in WT to 0.77?±?0.06 in TG, n?=?8, p?<?0.05) was quantified by sirius red staining. Cardiac function was greatly impaired in TG as exemplified by reduced pressure development and cardiac arrhythmias. It is hypothesized that losartan, an inhibitor of angiotensin II receptors, might be able to attenuate these detrimental effects. Hence, TG and WT were treated for 1 or 4 months perorally with losartan (5 mg/kg/day) or solvent alone (control conditions) starting at 4 weeks of age. Under control conditions, none of the WT died within the observation period whereas all TG died within 9 months. Losartan treatment reduced the mortality of TG: Mean life span was raised from 116 to 193 days (n?=?18 end, p?<?0.05). Likewise, losartan reduced relative heart weight and the degree of fibrosis. In addition, losartan improved hemodynamic parameters, like left ventricular pressure and its first derivative. However, losartan treatment did not modify overexpression of CSQ in the heart of TG. These results imply that the angiotensin II receptor (type 1) contributes to heart failure due to CSQ overexpression, as its blockade improved survival.     

Fosinopril improves the electrophysiological characteristics of left ventricular hypertrophic myocardium in spontaneously hypertensive rats

This study investigated the effects of fosinopril on the electrophysiological characteristics of the left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHRs). Twenty-four 10-week-old male SHRs were divided into fosinopril and non-fosinopril groups (n?=?12 each). Twelve 10-week-old Wistar–Kyoto rats were used a control group. Left ventricular mass index and ventricular fibrillation threshold (VFT) were measured after 8 weeks of fosinopril or saline treatment. L-type calcium current (I _CaL), sodium current (I _Na), and transient outward potassium current (I _to) were measured in left ventricular myocytes after 8 weeks of fosinopril or saline treatment using the whole-cell patch-clamp technique. VFT was higher in the fosinopril group than in the non-fosinopril group (17.5?±?1.2 mA vs. 15.6?±?1.1 mA, P?<?0.01). The density of I _CaL was lower in the fosinopril group than in the non-fosinopril group (?7.17?±?0.13 pA/pF vs. ?7.87?±?0.13 pA/pF, P?<?0.05). The density of I _to was higher in the fosinopril group than in the non-fosinopril group (14.46?±?0.28 pA/pF vs. 12.66?±?0.25 pA/pF, P?<?0.05). I _to was positively correlated with VFT (r?=?0.90, P?<?0.001) and was found to be associated independently with VFT (P?<?0.001). Fosinopril improves the electrophysiological characteristics of the left ventricular hypertrophic myocardium in SHRs.     

Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug–drug interaction assessment in a mouse model

Sunitinib is a tyrosine kinase inhibitor for GIST and advanced renal cell carcinoma. Diclofenac is used in cancer pain management. Coadministration may mediate P450 toxicity. We evaluate their interaction, assessing biomarkers ALT, AST, BUN, creatinine, and histopathological changes in the liver, kidney, heart, brain, and spleen. ICR mice (male, n?=?6 per group/dose) were administered saline (group A) or 30 mg/kg diclofenac ip (group B), or sunitinib po at 25, 50, 80, 100, 140 mg/kg (group C) or combination of diclofenac (30 mg/kg, ip) and sunitinib (25, 50, 80, 100, 140 mg/kg po). Diclofenac was administered 15 min before sunitinib, mice were euthanized 4 h post-sunitinib dose, and biomarkers and tissue histopathology were assessed. AST was 92.2?±?8.0 U/L in group A and 159.7?±?14.6 U/L in group B (p?<?0.05); in group C, it the range was 105.1–152.6 U/L, and in group D, it was 156.0–209.5 U/L (p?<?0.05). ALT was 48.9?±?1.6 U/L (group A), 95.1?±?4.5 U/L (p?<?0.05) in group B, and 50.5–77.5 U/L in group C and 82.3–115.6 U/L after coadministration (p?<?0.05). Renal function biomarker BUN was 16.3?±?0.6 mg/dl (group A) and increased to 29.9?±?2.6 mg/dl in group B (p?<?0.05) and it the range was 19.1–33.3 mg/dl (p?<?0.05) and 26.9–40.8 mg/dl in groups C and D, respectively. Creatinine was 5.9 pmol/ml in group A; 6.2 pmol/ml in group B (p?<?0.01), and the range was 6.0–6.2 and 6.2–6.4 pmol/ml in groups C and D, respectively (p?<?0.05 for D). Histopathological assessment (vascular and inflammation damages) showed toxicity in group B (p?<?0.05) and mild toxicity in group C. Damage was significantly lesser in group D than group B (p?<?0.05). Spleen only showed toxicity after coadministration. These results suggest vascular and inflammation protective effects of sunitinib, not shown after biomarker analysis.     

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

Objective

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

Methods

Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment.

Results

At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28?±?12.62, 33.98?±?14.13, 50.08?±?12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49?±?15.27, 15.53?±?7.16, 32.12?±?15.23 pg/mL, respectively) (p's?<?0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2 weeks (48.02?±?16.00 pg/mL, p?<?0.01) and 1 month (44.70?±?16.63 pg/mL, p?<?0.001), but then gradually increased at 2 months (48.49?±?18.87 pg/mL), 3 months (50.59?±?18.48 pg/mL) and 6 months (53.64?±?16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p?=?0.001), but reached the levels comparable to baseline at 6 months (37.13?±?13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02?±?16.69 pg/mL, p?<?0.01) and 6 months (58.69?±?13.57 pg/mL, p?<?0.001); steady and significant weight gain was observed at each follow-up time point (p's?<?0.001), from 56.71?±?9.25 kg at baseline to 62.72?±?9.53 kg at 6 months.

Conclusions

Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.     

Ivabradine in patients with inappropriate sinus tachycardia

Inappropriate sinus tachycardia (IST) is characterized by paroxysmal tachycardia originating in the sinus nodal area. IST predominately affects young, female patients. Current antiarrhythmic drug treatment (ß-blockers, calcium antagonists), frequently complicated by side effects, is often not successful. Ivabradine, approved for angina pectoris, selectively reduces heart rate by blocking the “funny current” in the sinus node. We therefore evaluated the effect of ivabradine in patients with symptomatic IST. Ten female patients (median age 32.5 years, range 12–57) suffering from symptomatic IST who had either failed (n?=?8) or refused (n?=?2) conventional therapy were analyzed. Symptoms included palpitations, pre-syncope, syncope, dyspnea, and exercise intolerance. After obtaining informed consent for individual off-label therapy, patients were treated with ivabradine (5–7.5 mg bid) in addition to beta-blocker therapy (n?=?3) or as mono- therapy (n?=?7). Therapy was monitored by 72-h Holter ECG and a symptoms questionnaire. Ivabradine significantly reduced maximum and mean heart rate (baseline, maximal heart rate 176?±?45/min, mean heart rate 84?±?11/min; ivabradine, maximal heart rate 137?±?36/min, mean HR 74?±?8/min, both p?<?0.05, all values as mean ± SD). Minimum heart rate was not significantly changed. Three patients reported transient phosphene-like phenomena without discontinuation of ivabradine while on therapy. IST-associated symptoms were ameliorated (3 pts) or suppressed (5 pts) in all eight patients who could be contacted after a mean follow-up of 16?±?9 months. Ivabradine appears effective and safe in patients with symptomatic inappropriate sinus tachycardia.     

Decreased vancomycin clearance in patients with congestive heart failure

Purpose

Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.

Methods

After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.

Results

Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r ²?=?0.649).

Conclusions

Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.     

Protection of the right ventricle from ischemia and reperfusion by preceding hypoxia

We have previously shown that 2 weeks of hypoxia protect the right ventricle of the rat heart from subsequent ischemia and reperfusion (I/R). In the present study, we examined the following: (1) Do shorter periods of hypoxia protect from subsequent I/R? (2) Does intermittent normoxia increase the cardioprotective effect? (3) Is hypoxia-inducible factor-1α (HIF-1α), erythropoietin (EPO), or vascular endothelial growth factor (VEGF) involved in the protective effects? Preischemic cardiac work was followed by global ischemia, reperfusion, and postischemic cardiac work (15 min each). External heart work was determined at the end of both work phases. Four groups of hearts were investigated: hearts from normoxic rats (n?=?8), hearts from rats after 24 h of continuous hypoxia (10.5% inspired oxygen, n?=?7), hearts from rats after 24 h hypoxia with a single intermission of 30 min normoxia (n?=?9), and hearts from rats after 24 h hypoxia and multiple intermissions of 30 min normoxia (n?=?7). Protein levels of HIF-1α and mRNA levels of EPO and VEGF were determined in right ventricular tissue of normoxic and hypoxic hearts. Postischemic right heart recovery was better in all three hypoxic groups compared with normoxic hearts (61.8?±?5.9%, 65.6?±?3.0%, and 75.7?±?2.6% vs. 46.0?±?3.9%, p?p?p?=?0.02). No differences in EPO and VEGF mRNA levels were found between normoxic and hypoxic hearts. Twenty-four hours of continuous hypoxia protect the isolated working right heart from subsequent ischemia and reperfusion. When preceding hypoxia is interrupted by multiple reoxygenation periods, there is a further significant increase in cardiac functional recovery. HIF-1α may be involved in the protective effect.     

Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis

Objectives

To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs).

Methods

A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥?6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 <?3.2; and (2) patients without a response to DMARDs, with persistent DAS28?≥?3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression.

Results

Serum P-gp levels were significantly higher in RA patients (n?=?151) than in the controls (n?=?30) (158.70?±?182.71 ng/mL vs. 14.12?±?8.97 ng/mL, p?<?0.001). The P-gp level was correlated with the DAS28 score (r?=?0.39, p?<?0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206?±?21.47 ng/mL vs 120.60?±?15.70 ng/mL; p?=?0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54–7.27, p?=?0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29–5.40, p?=?0.01).

Conclusion

Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.

     

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

Rationale

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.

Objectives

To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D₂ receptor occupancy and changes in working memory.

Methods

Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [¹¹C]raclopride and [¹⁸?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [¹⁸?F]FDG scan.

Results

The mean (±SD) D₂ receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D₂ receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.

Conclusions

Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D₂ receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.     

Impaired social behavior in chicks exposed to sodium valproate during the last week of embryogenesis

Rationale and objectives

To evaluate direct exposure to sodium valproate (VPA) during embryogenesis, we administered VPA to chick embryos and examined their social behaviors after hatching.

Methods and results

Embryos treated with VPA (35 μmol/egg) on day 14 were similar to controls for hatching date (day 21) and hatchlings' abilities, such as motor, imprinting, and surface righting. However, these VPA chicks on posthatching day 3 scored significantly low in the chick's social separation stress (SSS) test as follows. Aggregation test evaluated the speed of four chicks, individually isolated by a cardboard in a box, to aggregate upon removal of the cardboards. Belongingness test evaluated the speed of a chick isolated at a corner to join the group of three chicks placed at the opposite corner. Vocalization test for each chick was performed in an isolated corner by using a sound level meter. The results demonstrated that compared with controls, VPA chicks were significantly slow in aggregation (12.7?±?2.5 s vs. 2.9?±?0.9 s, p?=?0.006) and belongingness (3.6?±?0.28 s/40 cm vs. 2.6?±?0.14 s/40 cm, P?=?0.003) and weak in vocalization (13.4?±?2.8 dB/30 s vs. 26.7?±?1.3 dB/30 s, P?=?0.001), respectively. Weight of cerebellum of VAP chick was 15 % lighter than controls (P?=?0.004).

Conclusions

Chick embryos exposed to VPA during the last week of embryogenesis had impaired social behaviors in spite of normal mortar and imprinting ability. The present method will be a useful animal model for assessing the effects of environment during embryogenesis on social behaviors in later life.     

Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study

Purpose

Contrast-enhanced ultrasonography (CEUS) is a novel approach used for measuring organ perfusion changes. Studies using CEUS to assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on renal blood flow (RBF) have not yet been conducted. We aimed to evaluate the effects of NSAIDs on the renal hemodynamics of healthy subjects with CEUS.

Methods

We performed CEUS using the bolus injection method in a total of 10 healthy subjects. Measurements were completed over two study days in a randomized, crossover manner. On each study day, CEUS was performed twice, before and after the administration of NSAIDs. Subjects received an injection of contrast medium and images were recorded. A region-of-interest (ROI) was selected within the renal cortex, signal intensity in the ROI of the kidney was measured and a time-intensity curve (TIC) was automatically generated with attached software.

Results

The mean (±SD) peak intensity decreased significantly after an administration of diclofenac sodium (from 26.0?×?10^?4?±?17.4?×?10^?4 AU to 19.2?×?10^?4?±?12.0?×?10^?4 AU; P?=?0.022), but not significantly with etodolac (from 26.5?×?10^?4?±?9.7?×?10^?4 AU to 25.9?×?10^?4?±?20.8?×?10^?4 AU; P?=?0.474). The mean (±SD) percent reduction in intensity following diclofenac sodium administration was significantly reduced compared with etodolac administration (22.2?±?20.5 % vs. 3.4?±?8.9 %, P?=?0.037).

Conclusions

These finding suggests that diclofenac sodium (P?=?0.022), but not etodolac (P?=?0.474), affects renal hemodynamics even in healthy subjects.     

The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs

Connexin 43 is located in the cardiomyocyte sarcolemma and in the mitochondrial membrane. Sarcolemmal connexin 43 contributes to the spread of myocardial ischemia/reperfusion injury, whereas mitochondrial connexin 43 contributes to cardioprotection. We have now investigated the antiarrhythmic dipeptide ZP1609 (danegaptide), which is an analog of the connexin 43 targeting antiarrhythmic peptide rotigaptide (ZP123), in an established and clinically relevant experimental model of ischemia/reperfusion in pigs. Pigs were subjected to 60 min coronary occlusion and 3 h reperfusion. ZP1609 (n?=?10) was given 10 min prior to reperfusion (75 μg/kg b.w. bolus i.v. + 57 μg/kg/min i.v. infusion for 3 h). Immediate full reperfusion (IFR, n?=?9) served as control. Ischemic postconditioning (PoCo, n?=?9; 1 min LAD reocclusion after 1 min reperfusion; four repetitions) was used as a positive control of cardioprotection. Infarct size (TTC) was determined as the end point of cardioprotection. Systemic hemodynamics and regional myocardial blood flow during ischemia were not different between groups. PoCo and ZP1609 reduced infarct size vs. IFR (IFR, 46?±?4 % of area at risk; mean?±?SEM; PoCo, 31?±?4 %; ZP1609, 25?±?5 %; both p?<?0.05 vs. IFR; ANOVA). There were only few arrhythmias during reperfusion such that no antiarrhythmic action of ZP1609 was observed. ZP1609 when given before reperfusion reduces infarct size to a similar extent as ischemic postconditioning. Further studies are necessary to define the mechanism/action of ZP1609 on connexin 43 in cardiomyocytes.     

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial

Rational

Autism is associated with activation of the inflammatory response system.

Objective

This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autism

Methods

In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C.

Results

Significant time?×?treatment interaction was observed for Irritability (F (1.658, 63.021)?=?13.580, P?<?0.001), Lethargy/Social Withdrawal (F (1.948, 74.032)?=?16.811, P?<?0.001), and Stereotypic Behavior (F(1.742, 66.198)?=?12.104, P?<?0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424)?=?1.469, P?=?0.232), and Inappropriate Speech subscales (F (1.607, 61.075)?=?0.173, P?=?0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P?<?0.001), Lethargy/Social Withdrawal (P?<?0.001), and Stereotypic Behavior (P?<?0.00) but not in Hyperactivity/Noncompliance (P?=?0.202) and Inappropriate Speech (P?=?0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ ² (1)?=?5.227, P?=?0.022). Frequency of side effects was similar between the two groups.

Conclusions

Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir; IRCT138711091556N2)     

Naphthalene Biomarkers and Relationship with Hemoglobin and Hematocrit in White, Black, and Hispanic Adults: Results from the 2003–2004 National Health and Nutrition Examination Survey

Naphthalene is an important contaminant in indoor and outdoor air. Acute overexposure can have toxic effects, resulting in hemolysis. There have been no studies evaluating the impact of environmental exposure on red blood cell indices. We examined 1- and 2-hydroxynaphthalene urinary metabolites (NAP1 and NAP2) in non-Hispanic White, non-Hispanic Black, and Mexican-American adults in the USA and their relationship with hemoglobin (Hb) and hematocrit (HCT). Using the 2003–2004 National Health and Nutrition Examination Survey data, weighted generalized linear regression analyses were used to examine the association between Hb (in grams per deciliter) and HCT (in percent) with NAP1 and NAP2 (per 100,000 ng/L). Beta coefficients ± SE are reported. NAP1 and NAP2 were highest in non-Hispanic Blacks, followed by non-Hispanic Whites, and lowest in Mexican-American adults. There was a positive association between NAP1 and Hb (0.39?±?0.11, p?=?0.0034) and HCT (1.14?±?0.28, p?=?0.0009) after adjusting for age, gender, race, education, and smoking. Stratified analysis by smoking showed similar results with the association being stronger for smokers (Hb 0.63?±?0.23, p?=?0.02; HCT 1.43?±?0.79, p?=?0.09) than nonsmokers (Hb 0.34?±?0.14, p?=?0.03; HCT 1.08?±?0.42, p?=?0.02). The association was also stronger for non-Hispanic blacks (Hb 0.54?±?0.20, p?=?0.02; HCT 1.43?±?0.55, p?=?0.02) than for non-Hispanic whites (Hb 0.37?±?0.18, p?=?0.06; HCT 1.20?±?0.51, p?=?0.03) and was not significant for Mexican-Americans (Hb 0.30?±?1.7, p?=?0.10; HCT 0.99?±?0.52, p?=?0.08). NAP2 was not significantly associated with Hb or HCT. The observed disparity in NAP1 and NAP2 levels by race/ethnicity is consistent with published literature. The origin of these differences in exposure is unclear but may reflect differences in environmental exposure as well as genetic susceptibility. The positive association between NAP1 with HCT and Hb is an unexpected finding. Further research is needed to understand the possible biological mechanisms or other explanations for this association.     

Oral Treatment with the NADPH Oxidase Antagonist Apocynin Mitigates Clinical and Pathological Features of Parkinsonism in the MPTP marmoset Model

This study evaluates the therapeutic efficacy of the NADPH oxidase inhibitor apocynin, isolated as principal bioactive component from the medicinal plant Picrorhiza kurroa, in a marmoset MPTP model of Parkinson’s disease (PD). The methoxy-substituted catechol apocynin has a similar structure as homovanillic acid (HVA), a metabolite of dopamine (DA). Apocynin acquires its selective inhibitory capacity of the reactive oxygen species generating NADPH oxidase via metabolic activation by myeloperoxidase (MPO). As MPO is upregulated in activated brain microglia cells of PD patients and in MPTP animal models, the conditions for metabolic activation of apocynin and inhibition of microglia NADPH oxidase are in place. Marmoset monkeys received oral apocynin (100 mg/kg; p.o.) (n?=?5) or Gum Arabica (controls; n?=?5) three times daily until the end of the study, starting 1 week before PD induction with MPTP (1 mg/kg?s.c. for 8 days). Parkinsonian symptoms, motor function, home-cage activity and body weight were monitored to assess the disease development and severity. Post-mortem numbers of the tyrosine hydroxylase expressing DA neurons in the substantia nigra were counted. During the MPTP injections, apocynin limited the body weight loss and relieved parkinsonian symptoms compared to controls (Linear regression, P?<?0.05) indicating a reduction of disease progression. During the last test week, apocynin also improved the hand-eye coordination performance compared with vehicle treatment (resp. 39.3?±?4.5 % and 17.7?±?6.7 %; P?=?0.048) and improved the home cage activity with 32 % (P?=?0.029), indicating anti-Parkinson efficacy. Apocynin also increased the number of surviving DA neurons in MPTP-treated marmosets with 8.5 % (P?=?0.059), indicating a tendency towards a neuroprotective efficacy. In conclusion, compensation for the loss of DA and its metabolite HVA by apocynin mitigates the PD progression and limits the parkinsonian signs and motor-function deterioration.     

Sorafenib Decreases Tumor Exposure to an Anti-carcinoembryonic Antigen Monoclonal Antibody in a Mouse Model of Colorectal Cancer

In this investigation, we test the hypothesis that treatment with sorafenib, an anti-angiogenic agent, decreases tumor vascularization and, consequently, hinders the delivery of monoclonal antibodies (mAb) to xenograft tumors. Severe combined immunodeficiency mice bearing carcinoembryonic antigen (CEA) expressing tumor xenografts were divided into control and sorafenib-treated groups. Sorafenib was administered to the latter group at 50 mg/kg IP every 48 h, starting 4 days post-tumor implantation. When tumors attained a size of 200–300 mm³, mice were evaluated for (a) tumor microvessel density (using immunohistochemical analysis), (b) tumor macromolecular extravasation (using Evans Blue Dye (EBD)), (c) pharmacokinetics of an anti-CEA mAb, T84.66, following an intravenous dose of 10 mg/kg, and (d) intra-tumoral spatial distribution of T84.66 (using autoradiography). Sorafenib treatment resulted in a substantial reduction in tumor growth rate, a visible reduction in tumor microvessel density, and in a 46.4% decrease in EBD extravasation in tumor tissue (p?<?0.0455). For control and treated mice, no significant difference was found for the area under the mAb plasma concentration-time curve (AUC_(0–7d): 1.67?×?10³?±?1.28?×?10² vs. 1.76?×?10³?±?1.75?×?10² nM?×?day, p?=?0.51). However, tumor AUC_(0–7d) was reduced by 40.8% in sorafenib-treated mice relative to that observed in control mice (5.61?×?10²?±?4.27?×?10¹ vs. 9.48?×?10²?±?5.61?×?10¹ nM?×?day, p?<?0.001). Sorafenib therapy was also found to markedly alter mAb tumor spatial distribution. The results collectively suggest that sorafenib treatment causes a significant reduction in mAb delivery to, and distribution within, solid tumors.     

Comparative extrapyramidal effects of Rauwolfia vomitoria, chlorpromazine and reserpine in mice

Most antipsychotics interfere with the dopaminergic system, resulting in extrapyramidal effects. This study compared the extrapyramidal effects of chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res), used as antipsychotics, in mice. Ninety age-matched male CD-1 strain of mice (25?C33?g body weight) were divided into 3 groups, each consisting of 5 subgroups (n?=?6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0?mg/kg, i.p.) was administered 30?min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0?mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6?mg/kg, i.p.) were administered 24?h before testing. Locomotor behaviour (open field test) and motor coordination (acceleratory rotarod) were assessed. Mice were also observed for 10?min for tremor and vacuous chewing movement (VCM). CPZ and Res dose-dependently decreased locomotor behaviour and impaired motor coordination (p?<?0.01). RV also decreased locomotor behaviour (4.0?mg/kg; p?<?0.05) but had minimal effect on motor coordination. VCM was lower in the RV group (0.17?±?0.16/10?min) than the Res (6.8?±?1.36/10?min) and Cpz groups (7.83?±?1.95/10?min): F _(4,25)?=?10.703; p?<?0.01. The frequency of bouts of tremor was also lower in the RV group (1.17?±?0.72/10?min) than the Res (21.2?±?5.63/10?min) and Cpz (7.83?±?1.59/10?min) groups: F _(4,25)?=?11.012; p?<?0.001. The root bark extract of R. vomitoria, therefore, has great potential in the management of psychotic disorders.     

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.     

EBHU18, a novel derivative of fatty acid bile acid conjugates, prevents cholesterol gallstone formation in experimental mice

In this study, we tested whether the oral administration of EBHU18, one of the newly synthesized fatty acid bile acid conjugates (FABACs), was able to prevent the development of cholesterol gallstones. In the first study, gallstone-susceptible C57BL/6 mice were fed a lithogenic diet for 8?weeks, and then treated with ursodeoxycholic acid (UDCA, 10?mg?kg^?1?day^?1, i.g.), EBHU18-L (0.5?mg?kg^?1?day^?1 i.g.), or EBHU18-H (3?mg?kg^?1?day^?1 i.g.). In the second study, C57BL/6 mice were fed the lithogenic diet for 8?weeks and then treated with EBHU18 at a daily dose of 3?mg (EBHU18-H) or 0.5?mg (EBHU18-L) or with 10?mg of UDCA for another 8?weeks. Pre-treatment or post-treatment with EBHU18 at 3?mg?kg^?1?day^?1 significantly decreased gallstone formation and the fatty liver score. In the first study, EBHU18-H significantly decreased gallstone formation compared with the control animals. The fatty liver score decreased from a mean of 1.6?±?1.02 in the controls to 0.5?±?0.67 in the EBHU18-L group (P?<?0.05) and 0.3?±?0.64 in the EBHU18-H group (P?<?0.01). In the second study, the drug significantly lowered the gallstone formation rate in the EBHU18-H group. The fatty liver score decreased from a mean of 1.6?±?0.98 in the controls to 0.67?±?0.90 in the EBHU18-L group (P?<?0.05) and 0.4?±?0.74 in the EBHU18-H group (P?<?0.01). EBHU18 can prevent and reduce gallstone formation and/or fatty liver and can be developed as a potential therapeutic candidate for anti-gallstone therapy.     

CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients

Purpose

Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice.

Methods

Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n?=?21) or in combination with metformin (n?=?135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110.

Results

The average duration of diabetes in the study group was 10.6?±?7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0?±?0.9). In total, 76 hypoglycemia events were observed (mean 0.48?±?1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n?=?103). Among them, carriers of two wild-type alleles suffered 0.36?±?0.98 events, while patients with one or two polymorphic alleles had 0.79?±?1.7 or 2.67?±?4.6 events, respectively (p?=?0.014).

Conclusions

Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.