Effect of pretreatment with coenzyme Q10 on isoproterenol-induced cardiotoxicity and cardiac hypertrophy in rats

Background: Coenzyme Q₁₀ (CoQ₁₀) is a lipid-soluble, vitamin-like substance found in the hydrophobic interior of the phospholipid bilayer of most cellular membranes. It appears to be involved in the coordinated regulation between oxidative stress and antioxidant capacity of heart tissue when the heart is subjected to oxidative stress in various pathogenic conditions.Objective: The objective of the present study was to investigate the effect of pretreatment with CoQ₁₀ (100 mg/kg) on isoproterenol (ISO)-induced cardiotoxicity and cardiac hypertrophy in rats.Methods: Albino male Wistar rats (250–300 g) were evenly divided by lottery method into 1 of the following 3 groups: the ISO group (olive oil 2 mL/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); the CoQ₁₀ + ISO group (CoQ₁₀ 100 mg/kg orally for 18 days and ISO 1 mg/kg IP from days 9–18); and the control group (olive oil 2 mL/kg orally for 18 days and water IP from days 9–18). Twenty-four hours after the last dose of water or ISO, the rats were anesthetized and an ECG was recorded. Blood was withdrawn by retro-orbital puncture for estimation of serum creatine kinase-MB (CK-MB) isoenzyme levels, lactate dehydrogenase (LDH) levels, and aspartate aminotransferase activities. The animals were euthanized using an overdose of ether. The hearts of 6 animals from each group were used for estimation of superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, lipid peroxidation (LPO), malondialdehyde (MDA), and total protein concentration. Histopathology of the 2 remaining hearts in each group was carried out by a blinded technician.Results: A total of 24 rats (8 in each group) were used in this study; all rats survived to study end. Compared with the control group, the ISO-treated rats had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly higher myocardial MDA concentration [P < 0.001]; significantly lower myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.01]); and significantly higher serum activities of marker enzymes (eg, CK-MB [P < 0.001] and LDH [P < 0.001]). Compared with the ISO group, the CoQ₁₀ + ISO group had a significant change in heart to body weight ratio (P < 0.001); significant changes in the endogenous antioxidants (ie, significantly lower MDA concentration [P < 0.05]; significantly higher myocardial GSH concentration [P < 0.001] and SOD activity [P < 0.05]); and significantly lower serum activities of marker enzymes (eg, CK-MB [P < 0.05] and LDH [P < 0.01]).Conclusion: Pretreatment with CoQ₁₀ (100 mg/kg) for 18 days was associated with moderate protection against ISO-induced cardiotoxicity and cardiac hypertrophy, and with lower myocardial injury by preserving endogenous antioxidants and reducing LPO in rat heart.     

Prognostic Value of Cardiac Magnetic Resonance Imaging in Acute Coronary Syndrome Patients With Troponin Elevation and Nonobstructive Coronary Arteries

ObjectiveTo define the diagnostic yield of cardiac magnetic resonance (CMR) in differentiating the underlying causes of myocardial infarction with nonobstructive coronary arteries (MINOCA) and to determine the long-term prognostic implications of such diagnoses.MethodsCardiac magnetic resonance evaluation was performed in 227 patients (mean age, 56.4±14.9 years; 120 [53%] female) with a “working diagnosis” of MINOCA as defined by presentation with a troponin-positive acute coronary syndrome (troponin I >0.04 μg/L) and nonobstructed coronary arteries between January 1, 2007, and February 28, 2013. Follow-up was performed to assess the primary composite end point of myocardial infarction, heart failure, and all-cause mortality.ResultsCardiac magnetic resonance identified nonstructural cardiomyopathies in 97 (43%) patients, myocardial infarction in 55 (24%) patients, structural cardiomyopathies in 27 (12%) patients, and pulmonary embolism in 1 patient. No CMR abnormalities were identified in the remaining patients. Kaplan-Meier analysis demonstrated the ability of a CMR diagnosis to predict the risk of the primary composite end point (P=.005) at 5-year follow-up. Worse outcomes were seen among patients with “true” MINOCA and a normal CMR image compared with those with CMR-confirmed myocardial infarction (P=.02). Use of antiplatelets (78% [37/45] vs 95% [52/55]; P=.01), beta blockers (56% [25/45] vs 82% [45/55]; P=.004), and statins (64% [29/45] vs 85% [47/55]; P=.01) was significantly lower in patients with true MINOCA with normal CMR imaging compared with those with CMR-confirmed myocardial infarction.ConclusionsCardiac magnetic resonance carries a high diagnostic yield in patients with MINOCA and predicts long-term prognosis. Patients with MINOCA with normal CMR imaging had an increased rate of major adverse cardiac events and lower use of guideline-recommended myocardial infarction therapy compared with those with CMR-confirmed myocardial infarction.     

Effects of β-glucan pretreatment on acetylsalicylic acid-induced gastric damage: An experimental study in rats

Background: NSAIDs have been found to induce gastrointestinal tract damage. Recently, it has been suggested that this might be mediated by lipid peroxidation.Objective: The aim of this study was to assess the potential protective effects of β-glucan against acetylsalicylic acid (ASA-induced gastric damage by means of its antioxidant capacity in an experimental rat model.Methods: Thirty-two male Wistar albino rats (200–250 g) were randomized into 4 groups consisting of 8 rats each. The β-glucan group received 50 mg/kg β-glucan once a day for 10 days and 30 minutes before anesthesia. The ASA group received saline once a day for 10 days and 300 mg/kg (20 mg/mL) ASA as a single dose, 4 hours before anesthesia. The ASA+β-glucan group was administered 50 mg/kg β-glucan once a day for 10 days and 30 minutes before anesthesia. Additionally, 300 mg/kg (20 mg/mL) ASA was administered as a single dose, 4 hours before anesthesia. The control group received saline once a day for 10 days and 30 minutes before anesthesia. All medications were administered by intragastric gavage. The stomach from each rat was dissected and divided into 2 parts for histologic and biochemical analysis. Gastric tissue malondialdehyde (MDA), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities were determined for oxidative parameter analysis.Results: The gastroprotective and antioxidant effects of β-glucan appeared to attenuate the ASA-induced gastric tissue damage. Compared with the control group, MDA and NO levels and CAT and GSH-Px activities were significantly increased in the stomachs of ASA-treated rats (MDA, 4.12 [0.44] to 13.41 [1.05] μmol/L; NO, 8.04 [7.25–9.10] vs 30.35 [22.34–37.95] μmol/g protein; CAT, 0.050 [0.004] to 0.083 [0.003] k/g protein; GSH-Px, 0.57 [0.42–0.66] to 1.55 [1.19–1.76] U/L; all, P < 0.001), whereas SOD activity was significantly decreased in the same group (291 [29] to 124 [6] U/mL; P < 0.001). In the ASA+β-glucan group, MDA and NO levels and CAT and GSH-Px activities were found to be significantly lower, while SOD activity was found to be significantly higher, in comparison with the ASA-treated group (all, P < 0.001).Conclusion: β-Glucan appeared to attenuate the gastric damage caused by ASA in these rats.     

Prospective,randomized, single-blind comparison of effects of 6 months of treatment with telmisartan versus enalapril on high-molecular-weight adiponectin concentrations in patients with coronary artery disease

Background: High-molecular-weight (HMW) adiponectin has important antiatherosclerotic properties.Objectives: This study compared circulating HMW adiponectin concentrations and other parameters between patients with coronary artery disease (CAD) and participants without CAD. We investigated whether treatment with statins and either telmisartan or enalapril might affect HMW adiponectin and other parameters in patients with CAD. Finally, adiponectin concentrations were compared after 6 months of treatment between CAD patients with versus without cardiac events.Methods: Consecutive patients with stable CAD admitted to our hospital (Iwate Medical University School of Medicine, Iwate, Japan) for percutaneous coronary intervention (PCI) and stent implantation and with no previous treatment with renin—angiotensin system blockers or statins were recruited. Patients with CAD who met all eligibility criteria were randomly assigned using computer-generated numbers in a 1:1 ratio to receive telmisartan (40 mg/d) or enalapril (5 mg/d) for 6 months. In addition, all patients with CAD were treated with atorvastatin (10 mg/d). The patients without CAD received no treatment with telmisartan, enalapril, or atorvastatin. Plasma concentrations of total and HMW adiponectin were measured using a highly sensitive ELISA system before PCI or drug treatment (ie, baseline) and after 6 months of treatment. In addition, high-sensitivity C-reactive protein (hs-CRP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. To evaluate cardiac events, follow-up coronary angiography was performed at least 6 months after PCI.Results: This study included 70 patients with stable CAD (mean [SD] age, 65.8 [10.9] years; male/female ratio, 55/15) and 25 participants with normal results on coronary angiography (non-CAD) (mean age, 63.5 [11.2] years; male/female ratio, 20/5). Baseline concentrations (mean [SD]) of HMW adiponectin were significantly lower in the CAD group than in the non-CAD group (2.0 [0.3] vs 9.2 [0.5] ug/mL; P < 0.01). The ratio of HMW to total adiponectin was also lower in the CAD group than in the non-CAD group (0.37 [0.02] vs 0.53 [0.02]; P < 0.01). Baseline concentrations of HMW adiponectin were negatively correlated with hs-CRP (r = ?0.60) and HOMA-IR (r = ?0.30) in patients with CAD. After 6 months of treatment, the telmisartan group showed significantly increased HMW adiponectin concentrations and HMW/total adiponectin ratio (HMW, 3.7 [0.7] vs 2.1 [0.5] ug/mL; P < 0.01 vs baseline; HMW/total, 0.44 [0.02] vs 0.39 [0.02]; P < 0.05 vs baseline), whereas HOMA-IR was significantly decreased (2.86 [1.93] vs 3.39 [1.77]; P < 0.05 vs baseline). HOMA-IR at follow-up was significantly lower in the telmisartan group than in the enalapril group (2.86 [1.93] vs 3.64 [1.45]; P < 0.05). In contrast, treatment with enalapril was not associated with any significant changes in total or HMW adiponectin concentrations, HMW/total adiponectin ratio, or HOMA-IR. Both the telmisartan and the enalapril groups showed significant decreases in hs-CRP after 6 months (P < 0.05 vs baseline). After 6 months of treatment with either telmisartan or enalapril, HMW adiponectin concentrations were 0.7 (0.2) μg/mL with cardiac events versus 3.2 (0.4) μg/mL without (P < 0.05); HMW/total concentrations were 0.25 (0.03) with cardiac events versus 0.43 (0.01) without (P < 0.01). In contrast, hs-CRP concentrations were higher in patients with cardiac events than in those without cardiac events (2.42 [0.52] vs 1.86 [0.45] log10 μg/dL; P < 0.01).Conclusion: This study found that treatment with telmisartan and statins (but not enalapril and statins) was associated with a significant increase in HMW adiponectin concentrations and a decrease in insulin resistance in these patients with CAD.     

Effect of equivalent doses of fentanyl, sufentanil, and remifentanil on the incidence and severity of cough in patients undergoing abdominal surgery: A prospective, randomized, double-blind study

Background: Fentanyl congeners have been found to induce cough during induction of general anesthesia. Studies of fentanyl and sufentanil have found incidence rates of 28% to 65% and 15%, respectively. However, no study has assessed the occurrence of cough induced by remifentanil.Objective: The aim of this study was to assess the effect of equivalent doses of fentanyl, sufentanil, and remifentanil on cough.Methods: Patients rated American Society of Anesthesiologists class I or II of either sex, aged 18 to 60 years, who were scheduled for elective abdominal surgery with general anesthesia were randomly and equally assigned to 3 groups using a computer-generated table of random numbers. The patients received equivalent doses of fentanyl 2 μg/kg, sufentanil 0.2 μg/kg, or remifentanil 2 μg/kg via IV push. Vital signs (systolic blood pressure [SBP], heart rate [HR], and oxygen saturation via pulse oximetry [SpO₂]) and the occurrence and severity of cough were recorded for 2 minutes after drug administration by an anesthesiologist who was blinded to the drug treatment. The severity of cough was graded as none (0), mild (1–2), moderate (3–5), or severe (>5).Results: A total of 315 Chinese patients (197 women, 118 men; mean [SD] age, 37.9 [10.4] years) were approached for enrollment and assigned to 3 groups of 105 patients each; all patients completed the study protocol. The 3 treatment groups were similar in terms of demographic characteristics and type of abdominal surgery. The incidence of cough was significantly greater in the remifentanil group (57 [54.3%] patients) than in the fentanyl group (35 [33.3%]; P < 0.01) or the sufentanil group (32 [30.5%]; P < 0.01). The severity of cough was significantly greater in the remifentanil group (severe, moderate, mild, none: 24, 7, 26, 48) than in the fentanyl (7, 9, 19, 70; P < 0.01) or sufentanil group (4, 2, 26, 73; P < 0.01). In all 3 groups, when the patients coughed, significant increases were observed in their SBP (128 [12]–139 [16] mm Hg; P < 0.01) and HR (74 [10]–87 [16] beats/min; P < 0.01). Within 2 minutes after drug administration, 62 patients (59%) in the remifentanil group experienced hypoxemia (SpO₂ <90%) necessitating manually assisted mask ventilation, while no patients experienced hypoxemia in the fentanyl or sufentanil group. Three patients (2.9%) in the remifentanil group experienced muscle rigidity and deterioration of SBP, HR, and SpO₂. No other adverse events were recorded.Cunclusion: Remifentanil was associated with a significantly greater incidence and severity of cough than equivalent doses of fentanyl or sufentanil. Fentanyl and sufentanil appeared comparable in these Chinese patients undergoing abdominal surgery.     

Efficacy and safety of solifenacin succinate 10 mg once Daily: A multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group trial in patients with overactive bladder

Background: Solifenacin succinate is an antimuscarinic drug with reported efficacy and tolerability at a recommended starting dose of 5 mg QD in patients with overactive bladder (OAB).Objective: The objective of this trial was to investigate the efficacy, safety, and tolerability of solifenacin 10 mg QD in patients with OAB.Methods: In this multicenter, Phase III, double-blind, placebo-controlled, parallel-group trial, patients aged ≥18 years with OAB were randomized at a 1:1 ratio to receive solifenacin 10 mg or placebo QD for 12 weeks. The patients were instructed to complete a micturition diary for the 3 days preceding each scheduled visit (weeks 4, 8, and 12). The primary end point was the change from baseline in the mean number of micturitions per 24 hours; secondary end points included the mean change from baseline in the number of episodes per 24 hours of urgency, incontinence, nocturnal voiding, and nocturia and the mean volume voided per micturition. Tolerability was monitored through adverse events (AEs), vital sign measurements, ECGs, laboratory assessments, and physical examination.Results: A total of 672 patients were randomized and received ≥1 dose of study drug (solifenacin, n = 340; placebo, n = 332). The mean (SE) decrease from baseline to study end in the number of micturitions per 24 hours was significantly greater in the solifenacin group compared with the placebo group (−3.0 [0.2] vs −1.5 [0.2], respectively; P < 0.001). The mean decrease in the number of episodes of incontinence was significantly greater in the solifenacin group compared with the placebo group (−2.0 [0.2] vs −1.1 [0.2]; P < 0.001), as was the mean decrease in the number of episodes of urgency (−4.1 [0.2] vs −2.1 [0.2]; P < 0.001). Of the patients with ≥1 incontinence episode per 24 hours at baseline, significantly more patients in the solifenacin group achieved complete continence at study end than did patients in the placebo group (119/225 [52.9%] vs 80/237 [33.8%]; P < 0.001). The change from baseline to study end in the mean volume voided per micturition increased significantly in the solifenacin group compared with the placebo group (47.2 vs 2.7 mL; P < 0.001). Most AEs were mild or moderate in intensity. The AEs that were most commonly reported in the solifenacin-treated group were anticholinergic in nature: dry mouth (91 [26.8%] vs 13 patients [3.9%] in the placebo group; P < 0.001); constipation (58 [17.1%] vs 11 [3.3%]; P < 0.001); and blurred vision (12 [3.5%] vs 4 [1.2%]; P < 0.05). Serious AEs (SAEs) were reported for 5 patients in the solifenacin group and 3 patients in the placebo group. In the solifenacin group, 2 patients experienced chest pain, 1 had cellulitis, 1 had dehydration, and 1 had colonic obstruction; only 1 SAE (colonic obstruction) was judged to be possibly related to the study drug. In the placebo group, 1 patient had chest pain, 1 had bacterial meningitis, and 1 had hemopericardium.Conclusions: This study found that solifenacin 10 mg QD for 12 weeks was associated with significantly reduced symptoms of OAB, including the frequency of micturition, and episodes of urgency and of incontinence. With solifenacin, the volume voided per micturition increased by 47.2 mL, and 53% of patients with ≥1 incontinence episode per 24 hours at baseline achieved complete continence. This efficacy was accompanied by a favorable safety and tolerability profile.     

Comparison of the pharmacokinetics of a new 15-mg modified-release tablet formulation of metoclopramide versus a 10-mg immediate-release tablet: a single- and multiple-dose, randomized, open-label, parallel-group study in healthy Mexican male volunteers

BackgroundMetoclopramide is a prokinetic and antiemetic agent.ObjectiveThe goal of this study was to assess the pharmacokinetics of a new, modified-release metoclopramide tablet and compare it with an immediate-release tablet to obtain marketing approval from the Mexican regulatory agency.MethodsThis was a single-center, randomized, open-label, parallel-group, single- and multiple-dose, pharmacokinetic study. Investigational products were administered to healthy Mexican male volunteers for 3 consecutive days: one 15-mg modified-release tablet every 12 hours or one 10-mg immediate-release tablet every 8 hours. Multiple blood samples were collected after the first and last doses of metoclopramide over a 24-hour period. Plasma metoclopramide concentrations were determined by using a validated HPLC method. Safety and tolerability were assessed by measurement of vital signs, clinical evaluations, and spontaneous reports from study subjects.ResultsAll 26 subjects were included in the analyses (mean [SD] age: 25 [6] years [range, 18–40 years]; body mass index, 23.44 [2.31] kg/m² [range, 18.26–27.49 kg/m2]). Peak plasma concentrations were lower (C_max, 33.13 [7.25] vs 46.04 [17.27] ng/mL after the first dose [P < 0.05]; C_max,ss, 48.60 [8.52] vs 75.23 [21.27] ng/mL after the last dose [P < 0.05]) and occurred later (P < 0.05) with the modified-release formulation. In terms of average plasma concentrations (C_avgτ, 20.98 [3.94] vs 23.38 [7.35] ng/mL after the first dose; C_avg,ss, 22.20 [5.64] vs 23.02 [7.77] ng/mL after the last dose), differences did not reach the level of statistical significance (P > 0.05). Four adverse events were reported in the test group (abdominal distention [n = 2], epigastric pain [n = 1], and somnolence [n = 1]), and 3 were reported in the reference group (epigastric pain [n = 1], diarrhea [n = 1], and hiccups [n = 1]).ConclusionsThis study in a sample of selected healthy Mexican male volunteers suggests that the metoclopramide15-mg modified-release tablets have features compatible with the slow-release formulation (lower C_max and longer T_max) compared with immediate-release tablets.     

Cardiac Amyloidosis Without Increased Left Ventricular Wall Thickness

ObjectivesTo determine how often left ventricular wall thickness (LVWT) is normal and to assess the effect of LVWT on clinical outcomes of patients with immunoglobulin light chain (AL) cardiac amyloidosis.Patients and MethodsA total of 117 patients with systemic AL amyloidosis were retrospectively categorized from April 1, 1995, to September 15, 2012; group A included cardiac amyloidosis patients with an LVWT greater than 12 mm (45 patients); group B, cardiac amyloidosis patients with an LVWT of 12 mm or less (25 patients); and group C, no evidence of cardiac amyloidosis (47 patients). We compared echocardiographic parameters and survival rates among the 3 groups.ResultsNo differences were found between groups A and B in the following parameters: left ventricular ejection fraction (median, 56% [interquartile range (IQR), 46%-63%] vs 56% [IQR, 49%-63%], P=.76), left arterial volume index (median, 44.5 [IQR, 38.5-59.7] vs 43.9 [IQR, 33.8-57.1] mL/m², P=.79), eˈ (median, 0.04 [IQR, 0.03-0.05] vs 0.05 [IQR, 0.04-0.06] m/s, P=.10), and E/eˈ (early diastolic mitral inflow velocity (E)/eˈ) (median, 18.4 [IQR, 12.0-23.3] vs 18.0 [IQR, 13.6-25.0], P=.98). Patients in group C exhibited significantly different values for these parameters (median, 65% [IQR, 61%-69%], 23.4 [IQR, 18.0-29.0] mL/m², 0.08 [IQR, 0.06-0.09] m/s, and 8.8 [IQR, 7.2-10.5], respectively; all P<.001). The survival rates were statistically different, with median survival times of 422, 729, and 2080 days in groups A, B, and C, respectively (P=.002). Using multivariate Cox proportional hazards regression analysis, we found that age, an N-terminal pro–B-type natriuretic peptide level of 1800 pg/mL or greater, E/eˈ, and complete hematologic remission were significant predictors of survival.ConclusionsA third of patients with AL cardiac amyloidosis were diagnosed as having an LVWT of 12 mm or less. Because appropriate therapy can improve the survival of patients with AL cardiac amyloidosis, early detection by sensitive diagnostic methods should be pursued even when LVWT is not increased.     

Effect of rosuvastatin on concentrations of plasma lipids, urine and plasma oxidative stress markers, and plasma high-sensitivity C-reactive protein in hypercholesterolemic patients with and without type 2 diabetes mellitus: A 12-week, open-label, pilot study

Background: Oxidative stress and inflammation of the arterial wall are now recognized as important factors in the progression of atherosclerosis. C-reactive protein (CRP) has been defined as a sensitive but not specific marker of inflammation. Statin therapy has been reported to decrease plasma high-sensitivity CRP (hs-CRP) concentration in hypercholesterolemic patients.Objective: The aim of this study was to examine the effect of rosuvastatin on concentrations of plasma lipids, urine and plasma oxidative stress markers, and plasma hs-CRP in hypercholesterolemic patients with and without type 2 diabetes mellitus.Methods: Patients with hypercholesterolemia with and without type 2 diabetes mellitus were enrolled in this pilot study after written informed consent was given. At baseline and after 12 weeks of open-label treatment with rosuvastatin 2.5 mg/d, concentrations of plasma lipids, urine and plasma oxidative stress markers, and plasma hs-CRP were measured. Urine 8-iso-prostaglandin F_2α (8-iso-PGF_2α) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations were also measured to asess whole-body oxidative stress. Plasma free-radical generation was estimated using a total reactive oxygen species (TROS) assay system. Adverse effects were assessed at each study visit (4-week intervals) through patient interviews and laboratory testing.Results: Thirty-five patients were enrolled with 1 dropping out prior to study completion; therefore, 34 patients (19 women, 15 men; mean [SE] age, 55.4 [13.6] years; range, 30–78 years) completed the study. Compared with baseline, significant decreases were found in serum concentrations of total cholesterol (TC) (252.3 [39.3] vs 187.8 [30.1] mg/dL; P < 0.001; Δ = 24.5%), LDL-C (162.0 [44.3] vs 98.5 [31.9] mg/dL; P < 0.001; Δ = 38.7%), and triglycerides (TG) (157.2 [93.6] vs 124.4 [69.9] mg/dL; P < 0.05; Δ = 11.7%) after 12 weeks of treatment with rosuvastatin. Serum HDL-C concentration did not change significantly from baseline (59.7 [20.5] vs 63.7 [19.3] mg/dL; Δ = 9.4%). The plasma LDL-C/HDL-C ratio decreased significantly after rosuvastatin treatment (3.03 [1.33] vs 1.72 [0.83]; P < 0.001; Δ = 43.2%). Compared with baseline, significant decreases were observed in urine concentrations of the oxidative stress markers after 12 weeks of rosuvastatin treatment: 8-iso-PGF_2α (342.8 [154.3] vs 300.6 [101.2] pg/mg; P < 0.05) and 8-OHdG (11.1 [4.53] vs 8.1 [2.7] ng/mg; P < 0.01). TROS decreased significantly (182.3 [29.0] vs 157.6 [17.3] U; P < 0.001), and plasma hs-CRP concentration also decreased significantly (0.107 [0.100] vs 0.054 [0.033] mg/dL; P < 0.05). When the patients' results were assessed according to the presence or absence of type 2 diabetes mellitus, urine 8-iso-PGF_2α concentration was significantly decreased from baseline only in the nondiabetic group. No adverse events were reported or observed during the course of the study.Conclusion: Rosuvastatin treatment was associated with significant reductions in plasma concentrations of TC, LDL-C, and TG, urine and plasma oxidative stress markers, and plasma hs-CRP in these hypercholesterolemic patients.     

Effects of aminoguanidine and melatonin on intestinal ischemia/reperfusion injury in rats: An assessor-blinded, controlled experimental study

Background: The reactive oxygen and nitrogen species generated during reperfusion of tissue are characteristic of intestinal ischemia and reperfusion (IIR) injury.Objective: This study was designed to assess whether the administration of aminoguanidine (AG), a selective nitric oxide synthase inhibitor, and/or melatonin has protective potential in IIR injury.Methods: Male Wistar albino rats (age, 3–4 weeks; weight, 100–150 g) were divided in a nonrandom fashion into 5 groups of equal size: group 1, IIR injury + AG 100 mg/kg; group 2, IIR injury + melatonin 10 mg/kg; group 3, IIR injury + AG 100 mg/kg + melatonin 10 mg/kg; group 4, sham operation; and group 5, IIR injury alone. Sixty minutes of intestinal ischemia and 4 hours of reperfusion were carried out in all but the sham-operation group. Ileal specimens were obtained from all rats to determine the extent of histologic changes, measure tissue concentrations of malondialdehyde (MDA) and protein carbonyl (PC), and assess the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Specimens were also assessed and scored by a pathologist blinded to the experiment and the data.Results: Forty rats were divided into 5 groups of 8 each; all 40 survived until study end. In the IIR injury-alone group, mean (SD) MDA concentration and PC content were significantly higher than that of the sham-operation group, and SOD and GPx activity were significantly lower: MDA concentration, 0.86 (0.03) versus 0.54 (0.01) mmol/g protein, respectively; PC content, 0.60 (0.02) versus 0.34 (0.01) mmol/g protein; SOD activity, 104.33 (43.14) versus 2954.72 (109.55) U/g protein; and GPx activity, 10.44 (0.63) versus 24.34 (1.77) U/g protein (all, P < 0.001). Administration of AG, melatonin, and the AG/melatonin combination was associated with significantly higher SOD (1802.31 [102.35], 1776.50 [58.41], and 1924.28 [98.10] U/g protein, respectively) and GPx (17.36 [1.23], 15.96 [1.08], and 18.06 [1.72] U/g protein) activity and significantly lower MDA concentration (0.62 [0.02], 0.64 [0.02], and 0.56 [0.01] mmol/g protein) and PC content (0.53 [0.03], 0.51 [0.01], and 0.49 [0.02] mmol/g protein) compared with the IIR injury-alone group (P < 0.001). Mean intestinal mucosal injury scores were significantly lower in the 3 treatment groups (2.12 [0.35], 1.75 [0.46], and 1.12 [0.35]) compared with the IIR injury-alone group (3.87 [0.35]; all, P < 0.001).Conclusion: In this study, AG, melatonin, or both administered in combination were associated with improvements in oxidative markers in this rat model of IIR injury.     

Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study

ObjectiveTo characterize the obese heart failure with preserved ejection fraction (HFpEF) phenotype in a multicenter cohort.Patients and MethodsThis was a secondary analysis of the randomized clinical trial RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) performed between October 1, 2008, and February 1, 2012. Patients with HFpEF were classified by body mass index (BMI) as obese (BMI≥35 kg/m²) and nonobese (BMI<30 kg/m²) for comparison.ResultsObese patients with HFpEF (n=81) were younger (median age, 64 [interquartile range (IQR), 67-79] years vs 73 [IQR, 56-70] years; P<.001) but had greater peripheral edema (31% [25] vs 9% [6]; P<.001), more orthopnea (76% [56] vs 53% [35]; P=.005), worse New York Heart Association class (P=.006), and more impaired quality of life (P<.001) as compared with nonobese patients with HFpEF (n=70). Despite more severe signs and symptoms, obese patients with HFpEF had lower N-terminal pro B-type natriuretic peptide level (median, 481 [IQR, 176-1183] pg/mL vs 825 [IQR, 380-1679] pg/mL [to convert to pmol/L, multiply by 0.118]; P=.007) and lower left atrial volume index (median, 38 [IQR, 31-47] mL/m² vs 54 [IQR, 41-63] mL/m²; P<.001). Serum C-reactive protein (median, 5.0 [IQR, 2.4-9.9] mg/dL vs 2.7 [IQR, 1.6-5.4] mg/dL [to convert to mg/L, multiply by 10^?3]; P<.001) and uric acid (median, 7.8 [IQR, 6.1-8.7] mg/dL vs 6.8 [IQR, 5.5-8.3] mg/dL; P=.03) levels were higher in obese HFpEF, indicating greater systemic inflammation, than in nonobese HFpEF. Peak oxygen consumption was impaired in obese HFpEF (median, 11.1 [IQR, 9.6-14.4] mL/kg per minute vs 13.1 [IQR, 11.3-14.7] mL/kg per minute; P=.008), as was submaximal exercise capacity (6-minute walk distance, 272 [IQR, 200-332] m vs 355 [IQR, 290-415] m; P<.0001).ConclusionObese HFpEF is associated with decreased quality of life, worse symptoms of heart failure, greater systemic inflammation, worse exercise capacity, and higher metabolic cost of exertion as compared with nonobese HFpEF. Further study is required to understand the pathophysiology and potential distinct treatments for patients with the obese phenotype of HFpEF.Trial Registrationclinicaltrials.gov Identifier: NCT00763867     

Effect of memantine on plasma concentrations of carbamazepine and phenytoin in rats: A controlled experimental study

Background: Elderly patients, especially those with Alzheimer's disease, may be prescribed memantine and an antiepileptic drug concurrently.Objective: The aim of this study was to compare the interaction of memantine with phenobarbital (an enzyme inducer) and chloramphenicol (an enzyme inhibitor) on plasma concentrations of carbamazepine (CBZ), CBZ-10,11-epoxide (CBZE), and phenytoin in an experimental model.Methods: Eight groups of rats (200-230 g) were treated for 14 days each. In groups 1 and 2, phenobarbital 50 mg/kg was administered daily as an enzyme inducer 60 minutes before CBZ 50 mg/kg or phenytoin 30 mg/kg administration, respectively. In groups 3 and 4, chloramphenicol 300 mg/kg was administered daily as an enzyme inhibitor 60 minutes before CBZ or phenytoin administration, respectively. In groups 5 and 6, memantine 20 mg/kg was administered daily 60 minutes before CBZ or phenytoin, respectively. In group 7, CBZ alone was administered daily; in group 8, phenytoin alone was administered daily. Two hours after the last intragastric gavage, animals were anesthetized with ether and 2 mL of blood was drawn from the heart into a syringe containing EDTA. A validated method developed in this study was used for simultaneous determination of CBZ, CBZE, and phenytoin concentrations in rat plasma.Results: The study comprised 8 groups of 9 male adult Wistar rats each. Compared with groups 7 and 8, concurrent use of CBZ or phenytoin with phenobarbital (groups 1 and 2) was associated with significantly lower mean (SEM) plasma concentrations of CBZ (3.45 [0.16] vs 2.20 [0.21] μg/mL; P < 0.001) and phenytoin (3.68 [0.09] vs 1.63 [0.15] μg/mL; P < 0.001) and a significantly higher plasma CBZE concentration (9.85 [0.29] vs 11.18 [0.29] μg/mL; P < 0.05). Concurrent use of CBZ or phenytoin with chloramphenicol (groups 3 and 4) was associated with significantly higher plasma concentrations of CBZ (4.81 [0.17] μg/mL; P < 0.001) and phenytoin (6.24 [0.22] μg/mL; P < 0.001) and a significantly lower plasma CBZE concentration (3.88 [0.25] μg/mL; P < 0.001). Concurrent use of CBZ or phenytoin with memantine (groups 5 and 6) was not associated with a significant change in the plasma concentration of CBZ, CBZE, or phenytoin.Conclusion: Memantine was not associated with a significant change in the plasma concentration of CBZ, CBZE, or phenytoin in this experimental model.     

[18F]-Fluorodeoxyglucose–Positron Emission Tomography in Patients With Active Myelopathy

ObjectiveTo report and compare spinal cord [¹⁸F]-fluorodeoxyglucose–positron emission tomography (FDG-PET) metabolism in 51 patients with active myelopathy.Patients and MethodsWe retrospectively identified patients from January 1, 2001, through December 31, 2011, with active myelopathy in whom FDG-PET was performed. Inclusion criteria were (1) intramedullary myelopathy, (2) neoplastic/inflammatory etiology, and (3) FDG-PET performed after myelopathy onset. Exclusion criteria were (1) extramedullary myelopathy, (2) radiation-associated myelopathy, (3) no pathological confirmation of neoplasm, and (4) inactive myelopathy. Diagnostic categories of nonsarcoid inflammatory, neoplastic, and neurosarcoid were based on their final myelopathic diagnosis. Two radiologists who independently assessed FDG-PET for spinal cord hypermetabolism and maximum standardized uptake value (SUVmax) were blinded to the underlying etiology.ResultsFifty-one patients (53% women) with a median age of 60 years (range, 20-82 years) were included. Inflammatory myelopathic diagnoses (n=24) were as follows: paraneoplastic (n=13), autoimmune/other (n=5), inflammatory demyelinating (n=4), and transverse myelitis (n=2). Neoplastic diagnoses (n=21) were as follows: intramedullary metastases (n=12), intramedullary lymphoma/leukemia (n=7), and primary intramedullary neoplasm (n=2). Six patients had neurosarcoid myelopathy. Spinal cord hypermetabolism was more common with neoplastic myelopathy than with nonsarcoid inflammatory myelopathy (17 of 21 [81%] vs 6 of 24 [25%]; P<.001). Agreement between radiologist’s assessments was excellent (κ=0.88). Median SUVmax was greater in neoplastic than in nonsarcoid inflammatory causes of myelopathy (3.3 g/mL vs 1.9 g/mL; P<.001). The FDG-PET hypermetabolism was seen in 3 of the 6 patients (50%) with neurosarcoid myelopathy (median SUVmax, 2.6 g/mL; range, 1.8-12.2 g/mL).ConclusionSpinal cord FDG-PET hypermetabolism in patients with active myelopathy may be reliably detected and was more common in neoplastic than in inflammatory myelopathies in this study. Future investigation of spinal cord FDG-PET is indicated to assess its potential contributions in evaluating active myelopathies.     

Effects of nebivolol on skin flap survival: A randomized experimental study in rats

Background: Skin flaps are among the basic treatment options in the reconstruction of soft tissue defects. To improve skin flap survival, a variety of methods, including pharmacologic agents, have been investigated. The effectiveness of anticoagulants, antioxidants, anti-inflammatory drugs, and vasodilatory drugs in improving flap survival has been studied. Nebivolol is a new-generation selective β₁-adrenoreceptor blocking agent that has vasodilatory, antithrombotic, antioxidative, and anti- inflammatory effects.Objective: The aim of this experimental study was to investigate the effects of nebivolol (50 mg/kg/d) on random pattern skin flap survival in rats.Methods: Male Wistar rats weighing 290 to 310 g were randomly divided into 2 groups—the nebivolol group and the control group. Random patterned, caudally-based, ~3 × 10-cm skin flaps were elevated on the back of each rat. In the nebivolol group, nebivolol 50 mg/kg/d (1 mL, of a racemic solution of nebivolol) was administered orally 2 days before surgery to reach steady-state drug blood concentrations and was continued for 6 days. In the control group, 1 mL/d of sterile saline solution was orally administered 2 days before surgery and was continued for 6 days. To observe the effects of nebivolol, cutaneous blood flow was examined using a laser Doppler flow-meter before and after surgery on days 1, 3, 5, and 7, and flap tissue, malondialdehyde (MDA) and glutathione (GSH) concentrations, and superoxide dismutase (SOD) activity were measured 7 days postsurgery. Flap viability was evaluated 7 days after surgery by measuring necrotic flap area and total flap area.Results: All 20 rats (nebivolol group, n = 10; control group, n = 10) survived throughout the study period. Mean (SD) MDA concentration was significantly lower in the nebivolol group than in the control group (69.25 [5.82] vs 77.67 [6.87] nmol/g tissue; P = 0.009). GSH concentration was significantly higher in the nebivolol group than in the control group (2.14 [0.15] vs 1.88 [0.22] nmol/mg tissue; P = 0.004). SOD activity was significantly greater in the nebivolol group than in the control group (49.28 [5.49] vs 42.09 [4.95] U/g tissue; P = 0.007). The percentage of the flap that was necrotic was significantly lower in the nebivolol group than in the control group (40.27 [4.08] vs 48.87 [6.35]; P = 0.007).Conclusions: This small, experimental, in vivo animal study found that nebivolol was associated with reduced necrotic random pattern skin flap area. Further studies are needed to clarify these findings.     

Comparison of the efficacy and safety profiles of two fixed-dose combinations of antihypertensive agents, amlodipine/benazepril versus valsartan/hydrochlorothiazide, in patients with type 2 diabetes mellitus and hypertension: a 16-week, multicenter, randomized, double-blind, noninferiority study

BackgroundHypertension is a prevalent condition that is closely associated with chronic complications in patients with diabetes. Fixed-dose combination therapy is currently recommended for the treatment of hypertension due to the advantage of reducing the pill burden. However, the effects of combination therapy may be diverse because of the different components.ObjectivesWe examined blood pressure reduction and metabolic alterations after amlodipine/benazepril and valsartan/hydrochlorothiazide treatment in patients with type 2 diabetes mellitus and hypertension and microalbuminuria.MethodsThis randomized, double-blind, parallel comparison, noninferiority clinical trial included patients with type 2 diabetes mellitus and hypertension and microalbuminuria detected within the past year. After a 2-week, placebo run-in period, patients were assigned to treatment with amlodipine/benazepril or valsartan/hydrochlorothiazide for 16 weeks. The primary end point was mean change in diastolic blood pressure. The prespecified boundary for noninferiority was 3.5 mm Hg of the mean change in diastolic blood pressure between treatments (amlodipine/benazepril minus valsartan/hydrochlorothiazide). If the upper limit of the 95% CI fell within 3.5 mm Hg, amlodipine/benazepril would be considered noninferior to valsartan/hydrochlorothiazide.ResultsOf the 226 patients assessed for eligibility, 169 satisfied the inclusion/exclusion criteria and were assigned to a treatment group; 83 patients (54.2% male, mean age of 60.5 [10.0] years) in the amlodipine/benazepril group and 84 patients (64.3% male, mean age of 59.0 [10.6] years) in the valsartan/hydrochlorothiazide group received at least 1 dose of study medication and were included in the intention-to-treat population. In the per-protocol population, amlodipine/benazepril (n = 74) was noninferior to valsartan/hydrochlorothiazide (n = 78) with regard to the mean change in diastolic blood pressure (difference, ?0.9 mm Hg; 95% CI, ?3.5 to 1.6). The mean change in systolic blood pressure was not significantly different (2.4 mm Hg; 95% CI, ?1.2 to 6.0) between study groups (P = 0.195) in the per-protocol population. However, data from the intention-to-treat population suggest that patients in the amlodipine/benazepril group may have better metabolic outcomes than those in the valsartan/hydrochlorothiazide group; specifically, a preservation of the estimated glomerular filtration rate (5.7 mL/min/1.73 m² [95% CI, 1.9 to 9.6]; P = 0.004) and improvements in glycosylated hemoglobin (?0.5% [95% CI, ?0.7 to ?0.2]; P < 0.001), fasting triglycerides (?0.4 mmol/L [95% CI, ?0.7 to ?0.2]; P = 0.002), HDL-C (0.07 mmol/L [95% CI, 0.01 to 0.12]; P = 0.022), and uric acid (?57.5 μmol/L [95% CI, ?74.8 to ?40.3]; P < 0.001). There were no significant differences in adverse effects between groups, with the exception of more respiratory disorders in the amlodipine/benazepril group than in the valsartan/hydrochlorothiazide group (17 vs 5; P = 0 .006).ConclusionsThe study results suggest that amlodipine/benazepril is noninferior to valsartan/hydrochlorothiazide with regard to blood pressure reduction and that this combination exerts beneficial effects on renal function, glucose control, HDL-C, and triglyceride levels compared with valsartan/hydrochlorothiazide. However, respiratory adverse events (particularly coughing) were more frequently reported in the amlodipine/benazepril group. ClinicalTrials.gov identifier: NCT01375322.     

Effect of Country of Origin,Age, and Body Mass Index on Prevalence of Vitamin D Deficiency in a US Immigrant and Refugee Population

ObjectiveTo determine the prevalence of vitamin D deficiency (VDD) (25-hydroxyvitamin D level <20 ng/mL) and severe VDD (25[OH]D level <10 ng/mL) in a Minnesota immigrant and refugee population.Patients and MethodsThis retrospective study evaluated a cohort of adult immigrants and refugees seen at Health Partners Center for International Health in St Paul, Minnesota. Study participants were all patients seen from August 1, 2008, through July 31, 2009, with a first vitamin D screen (N=1378). Outcomes included overall prevalence of VDD and severe VDD. Covariates included country of origin, sex, age, month of test, and body mass index (BMI).ResultsVitamin D deficiency was significantly more prevalent in our Minnesota clinic immigrant and refugee population than among US-born patients (827 of 1378 [60.0%] vs 53 of 151 [35.1%]; P<.001). Severe VDD was also significantly more prevalent (208 of 1378 [15.1%] vs 12 of 151 [7.9%]; P=.02). Prevalence of VDD varied significantly according to country of origin (42 of 128 Russian patients [32.8%] vs 126 of 155 Ethiopian patients [81.3%]; P<.001). The BMI correlated negatively with VDD (488 of 781 [62.5%] when BMI was ≥25 vs 292 of 520 [56.2%] when BMI was <25; P=.02). Vitamin D deficiency was present in 154 of 220 individuals (70.0%) 16 to 29 years old vs 123 of 290 (42.4%) in those older than 66 years (P<.001).ConclusionImmigrants and refugees in a Minnesota clinic have a substantially higher rate and severity of VDD when compared with a US-born population. Country of origin, age, and BMI are specific risk factors for VDD and should influence individualized screening practices.     

Hemodynamic effect of angiotensin II receptor blockade in postmenopausal women on a high-sodium diet: A double-blind, randomized, placebo-controlled study

Background: Hypertension becomes increasingly prevalent after menopause. Postmenopausal women are more responsive to salt than premenopausal women, and they have been reported to develop marked renal vasoconstriction on a high-sodium diet.Objective: The aim of this study was to assess whether angiotensin II receptor blockade can restore a normal pattern of renal response to salt in postmenopausal women on a high-sodium diet. We also assessed segmental renal sodium handling in that population.Methods: Normotensive and hypertensive postmenopausal women not receiving hormone replacement therapy were enrolled in this prospective, double-blind, placebo-controlled, crossover study. They were assigned to receive irbesartan 150 mg or placebo for 6 weeks; the sequence in which they received irbesartan or placebo was randomized. During the last week of treatment, they received a high-sodium diet (250 mmol/d). Ambulatory blood pressure (ABP), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) were measured using sinistrin and para-amino-hippurate clearances. Renal sodium handling was assessed by measuring endogenous lithium clearance on day 7 of the high-salt diet.Results: Nineteen women (mean age, 54.7 years; range, 43–72 years; 7 normotensive subjects [mean age, 53.4 years; range, 47–61 years] and 12 hypertensive subjects [mean age, 55.4 years; range, 43–72 years]) were included in the study. When the data for all 19 subjects were pooled, ABP was significantly lower with irbesartan than placebo both during the day (120 [3]/79 [2] vs 127 [3]/85 [2] mm Hg; both, P < 0.01) and at night (systolic BP, 107 [4] vs 111 [4] mm Hg [P < 0.01] and diastolic BP, 71 [2] vs 75 [2] mm Hg [P < 0.05]). Compared with placebo, irbesartan was not associated with a significant change in GFR in either the normotensive or the hypertensive women. When the data for all 19 subjects were pooled, irbesartan was associated with a significant increase in ERPF compared with placebo (372 [21] vs324 [18] mL/min · 1.73 m²; P < 0.05). When the hypertensive and normotensive women were considered separately, the effect was more pronounced in the hypertensive women than in the normotensive women, but the changes did not reach statistical significance. When the data for all subjects were pooled, irbesartan was associated with a significant increase in daytime urinary sodium excretion compared with placebo (135 [13] vs 106 [13] μmol/min; P < 0.05) and a significant decrease at night (109 [13] vs 136 [19] μmol/min; P < 0.05). Fractional excretion of lithium (FELi), an inverse marker of proximal sodium reabsorption, increased significantly during the daytime with irbesartan compared with placebo (47% [6.5%] vs 35% [4.7%]; P < 0.05). At nighttime, FELi was significantly higher in the hypertensive subjects receiving irbesartan compared with placebo (43% [7.2%] vs 29% [6.5%]; P < 0.05). The fractional distal reabsorption of sodium did not change significantly with irbesartan compared with placebo.Conclusions: The results from this study suggest that angiotensin II receptor blockade had a favorable impact on BP, renal hemodynamics, and renal sodium handling in these salt-replete postmenopausal women. Blockade of the renin-angiotensin system restored the normal pattern of renal response to high sodium intake in these women.     

Physician Identification Badges: A Multispecialty Quality Improvement Study to Address Professional Misidentification and Bias

ObjectiveTo evaluate whether providing resident physicians with “DOCTOR” role identification badges would impact perceptions of bias in the workforce and alter misidentification rates.Participants and MethodsBetween October 2019 and December 2019, we surveyed 341 resident physicians in the anesthesiology, dermatology, internal medicine, neurologic surgery, otorhinolaryngology, and urology departments at Mayo Clinic in Rochester, Minnesota, before and after an 8-week intervention of providing “DOCTOR” role identification badges. Differences between paired preintervention and postintervention survey answers were measured, with a focus on the frequency of experiencing perceived bias and role misidentification (significance level, α=.01). Free-text comments were also compared.ResultsOf the 159 residents who returned both the before and after surveys (survey response rate, 46.6% [159 of 341]), 128 (80.5%) wore the “DOCTOR” badge. After the intervention, residents who wore the badges were statistically significantly less likely to report role misidentification at least once a week from patients, nonphysician team members, and other physicians (50.8% [65] preintervention vs 10.2% [13] postintervention; 35.9% [46] vs 8.6% [11]; 18.0% [23] vs 3.9% [5], respectively; all P<.001). The 66 female residents reported statistically significantly fewer episodes of gender bias (65.2% [43] vs 31.8% [21]; P<.001). The 13 residents who identified as underrepresented in medicine reported statistically significantly less misidentification from patients (84.6% [11] vs 23.1% [3]; P=.008); although not a statistically significant difference, the 13 residents identifying as underrepresented in medicine also reported less misidentification with nonphysician team members (46.2% [6] vs 15.4% [2]; P=.13).ConclusionResidents reported decreased role misidentification after use of a role identification badge, most prominently improved among women. Decreasing workplace bias is essential in efforts to improve both diversity and inclusion efforts in training programs.