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Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored.Experimental Approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed.Key Results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers.Conclusions and Implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism. [ABSTRACT FROM AUTHOR]

Background: Conventional infiltration anaesthesia (CIA) is the most frequently used in paediatric oral health care. However, other techniques are available, such as intraosseous anaesthesia (IOA), that can beneficiate from newly developed technologies. Aim: To compare the pain caused by CIA and IOA delivered by the computerized system (QuickSleeper™) in children. Design: We used an innovative design consisting in simultaneously conducting a multicentre split‐mouth and parallel‐arm randomized controlled trial (RCT) to allow for increased power. The primary outcome was pain reported by the patient on a visual analogue scale (0‐10 cm) concerning the insertion of the needle and injection. Results: A total of 30 children were included in the split‐mouth RCT and 128 in the parallel‐arm RCT. We combined treatment effect estimates by using an inverse‐variance weighting meta‐analysis approach. Pain scores were significantly decreased with IOA vs CIA (mean difference −0.69 cm, 95% confidence intervals −1.13 to −0.25 cm). For each patient enrolled in the split‐mouth RCT, about five were enrolled in the parallel‐arm RCT, which allowed for not losing any eligible patients. Conclusion: Pain during the insertion of the needle and injection was less with IOA vs CIA in children. The design of this study allowed for increasing statistical power and using all generated evidence. (ClinicalTrials.gov NCT02084433). [ABSTRACT FROM AUTHOR]

Background: Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. Objective: To evaluate the efficacy of fremanezumab, a selective monoclonal CGRP ligand antibody, during the first 3 weeks of therapy in patients with high‐frequency episodic migraine (HFEM) to relieve migraine headaches and associated symptoms and to reduce use of acute migraine medications. Methods: In a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study, patients with HFEM who met inclusion criteria and were 80% compliant with daily headache diary entry were randomized and treated once every 28 days for 3 months with either placebo or fremanezumab 225 or 675 mg. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days in month 3 relative to baseline. Herein, we performed post‐hoc analyses to assess the efficacy of each dose during the first 3 weeks of treatment to reduce migraine headache parameters, associated migraine symptoms, and the consumption of acute migraine medications. Results: The sample consisted of 297 study participants. Compared to placebo, decreases in migraine days were seen during the first week of therapy for both fremanezumab doses with least square mean (LSM) differences between fremanezumab 225 mg and placebo of −0.93 (95% CI: −1.36, −0.49) and between 675 mg dose and placebo of −1.02 (95% CI: −1.46, −0.58), both P < .0001. This benefit was maintained through the second week of therapy for the 225 and 675 mg doses, respectively, (−0.76 (95% CI: −1.11, −0.40) P < .0001, −.79 (95% CI: −1.15, −0.44) P < .0001) and the third week of therapy (−0.64 (95% CI: −0.97, −0.30) P = .0003 and −0.64 (95% CI: −0.98, −0.30) P = .0003). Likewise in the first week, patients recorded reductions in associated migraine symptoms such as nausea, vomiting, photophobia, and phonophobia, which continued through weeks 2 and 3. There were also reductions in days with acute medication use to treat migraine for the 225 and 675 mg fremanezumab doses compared to placebo. In the first week, LSM differences between 225 mg and placebo were −1.02 (95% CI: −1.39, −0.64) and between 675 mg and placebo were −1.06 (95% CI: −1.39, −0.64) P < .0001); for the second and third weeks (−1.01 (95% CI: −1.14, −0.55) P < .0001; −.90 (95% CI: −1.04, −0.44) P < .0001; −.91 (95% CI: −0.92, −0.34) P < .0001; and −.83 (95% CI: −0.84, −0.26) P = .0002), respectively. Conclusion: Fremanezumab treatment resulted in a rapid preventive response in patients with HFEM, with reductions seen in several headache parameters and migraine symptoms within the first week after therapy initiation and continuing during the second and third weeks. Patients also were able to rapidly reduce their use of acute medications to treat migraine attacks. The trial is registered at Clinicaltrials.gov as NCT02025556. [ABSTRACT FROM AUTHOR]

Introduction: The role of the radioprotector amifostine in ameliorating radiotherapy side effects in head and neck squamous cell carcinoma (HNSCC) is controversial. This trial aimed to determine whether pretreatment with amifostine reduced the incidence of Radiation Therapy Oncology Group grade ≥2 acute and late xerostomia in patients receiving definitive or adjuvant radiotherapy for HNSCC, without reducing tumour control or survival.Methods: Between 14 September 2001 and 8 November 2004, 44 Royal Adelaide Hospital patients were randomized double-blind to receive amifostine (200 mg/m2 IV) or placebo (normal saline IV) 5 days/week, prior to standard radiotherapy (60-70 Gy), each having ≥75% of the parotids treated to ≥40 Gy. Side effects were assessed weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months until disease progression or death.Results: The accrual target was 200 patients over 4-5 years, but the trial closed prematurely when only 44 patients had been randomized after 3 years. Of 41 evaluable patients, 80% (16/20) in the amifostine arm had grade ≥2 acute radiation salivary toxicity versus 76% (16/21) in the placebo arm (P = 1.00). The rate of grade ≥2 late radiation salivary toxicity at 12 months was 66% in the amifostine arm and 82% in the placebo arm (estimated hazard ratio 1.61, 95% confidence interval 0.74-3.49, P = 0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3-4 skin 35% vs 5% and mucous membrane 40% vs 5%; grade ≥2 vomiting 35% vs 5%, hypocalcaemia 25% vs 5% and fatigue 85% vs 33%, with only the latter retaining statistical significance after adjusting for multiple comparisons. There were no significant differences in failure-free (P = 0.70) or overall survival (P = 0.86), with estimated 4-year rates of 48% vs 54% and 49% vs 59% for the amifostine vs placebo arms respectively.Conclusion: There was no clear evidence that pretreatment with amifostine made any difference to the incidence of grade ≥2 acute or late xerostomia. Other toxicity tended to be more severe with amifostine. There was no effect on failure-free or overall survival. Acknowledging the low statistical power, these results do not support the use of IV amifostine pre-radiotherapy in HNSCC. [ABSTRACT FROM AUTHOR]

Objective: To determine whether oral clindamycin reduces the risk of preterm birth (PTB) in women with abnormal vaginal microflora as evidenced by a vaginal pH ≥5.0.Design: Randomised double-blind placebo-controlled trial.Setting: Rural southern India.Population: Pregnant women with a singleton fetus between 13+0/7 weeks and 20+6/7 weeks.Methods: Pregnant women were recruited during prenatal visits in Karnataka, India, from October 2013 to July 2015. Women were required to have a singleton fetus between 13+0/7 weeks and 20+6/7 weeks and an elevated vaginal pH (≥5.0) by colorimetric assessment. Participants were randomised to either oral clindamycin 300 mg twice daily for 5 days or an identical-appearing placebo.Main Outcome Measures: The primary outcome was the incidence of PTB, defined as delivery before 37+0/7 weeks.Results: Of the 6476 screened women, 1727 women were randomised (block randomised in groups of six; clindamycin n = 866, placebo n = 861). The demographic, reproductive, and anthropomorphometric characteristics of the study groups were similar. Compliance was high, with over 94% of capsules being taken. The rate of PTB before 37 weeks was comparable between the two groups [clindamycin 115/826 (13.9%) versus placebo 111/806 (13.8%), between-group difference 0.2% (95% CI -3.2 to 3.5%, P = 0.93)], as was PTB at less than 34 weeks [clindamycin 40/826 (4.8%) versus placebo group 37/806 (4.6%), between-group difference 0.3% (95% CI -1.8 to 2.3%, P = 0.81)]. No differences were detected in the incidence of birthweight of<2500 g, <1500 g, miscarriage, stillbirth or neonatal death.Conclusion: In this setting, oral clindamycin did not decrease PTB among women with vaginal pH ≥5.0.Tweetable Abstract: Oral clindamycin between 13+0/7 and 20+6/7 weeks does not prevent preterm birth in women with a vaginal pH ≥5.0. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. Methods: We conducted a prospective, randomized, double‐blind, placebo‐controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high‐ or low‐risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. Results: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high‐risk proteomic pattern. Participants in the high‐risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low‐risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin‐angiotensin system‐blocking agents remained significant determinants of the CKD273 high‐risk group: area under the curve 0.72 (95% CI 0.68–0.75; P<0.01). Conclusions: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012‐000452‐34 and Clinicaltrials.gov: NCT02040441). [ABSTRACT FROM AUTHOR]

Aim: This pilot study investigated the use of acupuncture in the treatment of paediatric anxiety.Methods: Children with anxiety, aged 8-16, were randomised to either the acupuncture or waitlist control groups. Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A) for children and adolescents with generalised anxiety disorder and Multidimensional Anxiety Scale for Children 2nd Edition (MASC-2) self-rated and parent-rated forms.Results: Twenty participants were enrolled in the study and 19 completed all the questionnaires to be included in the analysis. There were no differences in socio-demographic characteristics at baseline between the two groups. At the second assessment, the mean MASC-parent score for the acupuncture group was significantly lower than the waitlist group (65.6 (SD 15.0) compared to 81.0 (SD 11.9), P = 0.025) with an effect size = 1.13. The pre- and post-treatment comparisons were also significantly lower for both groups in the anxiety measures. In the acupuncture group, MASC-parent (P = 0.008, effect size 0.75) and the HAM-A (P < 0.001, effect size 1.4). In the waitlist group, MASC-self (P = 0.022; effect size 0.4), MASC-parent (P = 0.048; effect size 0.75) and HAM-A (P = 0.007; effect size 1.21).Conclusions: This study provided promising results on the potential use of acupuncture to treat children and adolescents with general anxiety. Future research using a randomised control trial with a sufficient sample size to control for confounders and sham (placebo) comparators is warranted. [ABSTRACT FROM AUTHOR]

Elevated levels of reactive oxygen species under diabetic condition lead to vascular complications and inflammation. This study aimed to examine the effects of hesperidin supplement on blood pressure and inflammatory markers in type 2 diabetes. In this research, 64 patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on systolic blood pressure (SBP), diastolic blood pressure, serum total antioxidant capacity (TAC), tumor necrosis factor alpha, interleukin 6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) were collected at the baseline and at the end of the study. In the hesperidin group, SBP (122.7 ± 8.5 vs. 119.0 ± 7.4; p = .005), mean arterial blood pressure (94.2 ± 5.5 vs. 91.8 ± 5.5; p = .009), IL-6 (8.3 ± 2.1 vs. 7.4 ± 1.8; p = .001), and hs-CRP (1.9 ± 1.2 vs. 1.1 ± 0.9; p < .000) decreased whereas TAC increased (0.74 ± 0.1 vs. 0.82 ± 0.1; p < .000) in comparison to the baseline values. There was a significant difference in mean percent change of SBP, diastolic blood pressure, mean arterial blood pressure, serum TAC, and inflammatory markers (tumor necrosis factor alpha, IL-6, and hs-CRP) between hesperidin and control groups following intervention in adjusted models (p < .05). These results suggest that hesperidin may have antihypertensive and anti-inflammatory effects in type 2 diabetes. [ABSTRACT FROM AUTHOR]

At least 50% of infertile couple's problems are related to male factor infertility. This Randomized, Double-Blind, Placebo-Controlled Clinical Trial conducted in Urology unit of Infertility Clinic on 60 infertile men. Patients were randomly assigned to one of intervention and placebo (n = 30) groups. Finally, 28 subjects in each group completed the study. Participants in the intervention group took daily 80 mg curcumin nanomicelle and those in the placebo group took daily placebo for 10 weeks. Semen analysis, anthropometric, physical activity assessments, total antioxidant capacity, malondialdehyde, inflammatory factors, and reproductive hormones were measured at the baseline and at the end of the study. At the end of study, statistically significant differences were seen in the total sperm count, sperm concentration, and motility in the intervention group to the control group. In treatment group, the total sperm count, sperm concentration, and motility levels were also statistically increased at the end of study compared to the baseline values. Curcumin nanomicelle supplementation also resulted in a statistically significant improvement in plasma levels of total antioxidant capacity, malondialdehyde, C-reactive protein, and tumor necrosis factor a in comparison to the placebo. Medical therapy of asthenoteratospermia with curcumin nanomicelle supplement could improve quality of semen parameters. However, further investigation is suggested in this regard. [ABSTRACT FROM AUTHOR]

Background: Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia.Methods: This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results.Results: The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and -0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively (P < .0001). Changes from the baseline in LBM, body weight, and anorexia symptoms showed significant differences between the 2 treatment groups at all time points. Anamorelin increased prealbumin at weeks 3 and 9. No changes in HGS or 6MWT were detected between the groups. Twelve weeks' treatment with anamorelin was safe and well tolerated in NSCLC patients.Conclusions: Anamorelin significantly increased LBM and improved anorexia symptoms and the nutritional state, but not motor function, in Japanese patients with advanced NSCLC. Because no effective treatment for cancer cachexia is currently available, anamorelin can be a beneficial treatment option. Cancer 2018;124:606-16. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. [ABSTRACT FROM AUTHOR]

Objective: The ketones d-β-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite.Methods: Following an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY), and a three-measure visual analogue scale was used to measure hunger, fullness, and desire to eat.Results: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT.Conclusions: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat. [ABSTRACT FROM AUTHOR]

The relaxant effects of carvacrol, a phenolic monoterpene, on tracheal smooth muscle and its preventive effect on asthmatic animals were reported. The effect of carvacrol in asthmatic patients was examined in the placebo group (Group P, n = 11) receiving placebo and treatment group (Group C, n = 12), which received carvacrol capsule (1.2 mg/kg/day) for 2 months in a double-blind manner. Pulmonary function tests, respiratory symptoms, hematological indices, and high-sensitivity C-reactive protein (hs-CRP) were measured before, 1 and 2 months after starting treatment. At the end of treatment period, Pulmonary function tests values in Group C were significantly increased (p < .05 to p < .001). Most respiratory symptoms were also significantly reduced in Group C at the end of 2-month treatment (p < .05 to p < .001). Total and differential white blood cell (p < .05 to p < .001), as well as serum levels of hs-CRP in Group C were also significantly reduced after 2-month treatment with carvacrol (p < .001). Mean corpuscular hemoglobin concentration and hematocrit were changed in Group C (p < .05 and p < .01, respectively). However, in Group P, there was no significant changes in the evaluated parameters. Pulmonary function tests were increased but respiratory symptoms, inflammatory cells, and hs-CRP were reduced in asthmatic patients who received carvacrol that indicates its therapeutic effect on asthma. [ABSTRACT FROM AUTHOR]

Two studies showed an improvement in clinical outcomes after alcohol approach bias retraining, a form of Cognitive Bias Modification (CBM). We investigated whether transcranial direct current stimulation (tDCS) could enhance effects of CBM. TDCS is a neuromodulation technique that can increase neuroplasticity and has previously been found to reduce craving. One hundred alcohol-dependent inpatients (91 used for analysis) were randomized into three experimental groups in a double-blind parallel design. The experimental group received four sessions of CBM while receiving 2 mA of anodal tDCS over the dorsolateral prefrontal cortex (DLPFC). There were two control groups: One received sham stimulation during training and one received active stimulation at a different moment. Treatment outcomes were abstinence duration (primary) and relapse after 3 and 12 months, craving and approach bias (secondary). Craving and approach bias scores decreased over time; there were no significant interactions with experimental condition. There was no effect on abstinence duration after three months (χ2(2) = 3.53, p = 0.77). However, a logistic regression on relapse rates after one year (standard outcome in the clinic, but not-preregistered) showed a trend when relevant predictors were included; relapse was lower in the condition receiving active stimulation during CBM only when comparing to sham stimulation (B = 1.52, S.E. = .836, p = .07, without predictors: p = .19). No strong evidence for a specific enhancement effect of tDCS on CBM was found. However, in a post-hoc analysis, tDCS combined with CBM showed a promising trend on treatment outcome. Important limitations are discussed, and replication is necessary to find more reliable effects. [ABSTRACT FROM AUTHOR]

This study aimed to examine the effects of hesperidin supplement on the glycemic parameters, oxidative DNA damage, and lipid peroxidation in patients with type 2 diabetes. Sixty-four patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on glycemic parameters, total antioxidant capacity (TAC), 8-hydroxydeoxyguanosine (8-OHDG), and malondialdehyde (MDA) were collected at the baseline and at the end of the study. In hesperidin group, TAC increased (0.74 ± 0.16 vs. 0.82 ± 0.18), while serum froctoseamin (5.79 ± 5.86 vs. 5.01 ± 4.95; p = 0.001), 8-OHDG (14.32 ± 6.4 vs. 11.00 ± 7.0; p = 0.000), and MDA (5.78 ± 1.76 vs. 4.60 ± 0.75; p = 0.000) decreased in comparison with the baseline values. There was a significant difference in percent change of TAC (13.35 ± 19.21 vs. 3.13 ± 10.02; p = 0.043), froctoseamin (-10.10 ± 16.84 vs. 4.27 ± 34.646), 8-OHDG (-25.11 ± 28.23 vs. 8.69 ± 35.41; p = 0.000), and MDA (-16.46 ± 18.04 vs. -1.82 ± 22.63; p = 0.007) between hesperidin and control groups following intervention in adjusted models. These results suggest that hesperidin may improve TAC and alleviate serum froctoseamin, 8-OHDG, and MDA levels in type 2 diabetes. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity.Experimental Approach: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans.Key Results: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity.Conclusions and Implications: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity. [ABSTRACT FROM AUTHOR]

Background: The ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum-sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health-related quality of life (QOL) during the first year of treatment.Methods: Four hundred fifty-six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent-maintenance cediranib group.Results: The rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent-maintenance group (+4.5; 95% confidence interval, -2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self-reported diarrhea.Conclusions: The 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression-free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752-61. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. [ABSTRACT FROM AUTHOR]

Aim To examine the efficacy and safety of (1) midazolam-droperidol versus droperidol and (2) midazolam-droperidol versus olanzapine for methamphetamine-related acute agitation. Design and setting A multi-centre, randomized, double-blind, controlled, clinical trial was conducted in two Australian emergency departments, between October 2014 and September 2015. Participants Three hundred and sixty-one patients, aged 18-65 years, requiring intravenous medication sedation for acute agitation, were enrolled into this study. We report the results of a subgroup of 92 methamphetamine-affected patients. Intervention and comparator Patients were assigned randomly to receive either an intravenous bolus of midazolam 5 mg-droperidol 5 mg combined, droperidol 10 mg or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg or olanzapine 5 mg, respectively. Measurements The primary outcome was the proportion of patients sedated adequately at 10 minutes. Odds ratios with 95% confidence intervals (ORs, 95% CI) were estimated. Findings The baseline characteristics of patients in the three groups were similar. At 10 minutes, significantly more patients in the midazolam-droperidol group [29 of 34 (85.3%)] were sedated adequately compared with the droperidol group [14 of 30 (46.7%), OR = 6.63, 95% CI = 2.02-21.78] or with the olanzapine group [14 of 28 (50.0%), OR 5.80, 95% CI = 1.74-19.33]. The number of patients who experienced an adverse event (AE) in the midazolam-droperidol, droperidol and olanzapine groups was seven of 34, two of 30 and six of 28, respectively. The most common AE was oxygen desaturation. Conclusion A midazolam-droperidol combination appears to provide more rapid sedation of patients with methamphetamine-related acute agitation than droperidol or olanzapine alone. [ABSTRACT FROM AUTHOR]

Objective: To assess the short-term tolerability of lorcaserin alone or with two dose regimens of phentermine.Methods: This was a 12-week, randomized, double-blind, pilot safety study of N = 238 nondiabetic patients with obesity or overweight with ≥1 comorbidity randomized to lorcaserin 10 mg twice daily (BID; LOR BID) alone or with phentermine 15 mg once daily (QD; LOR BID+PHEN QD) or 15 mg twice daily (LOR BID+PHEN BID). Patients reporting ≥ 1 of 9 potentially serotonergic adverse events (AEs), mean weight loss (WL), and ≥5% WL are reported.Results: N = 238 were randomized, and N = 235 were treated. N = 94 reported potentially serotonergic AEs: 37.2% LOR BID, 42.3% LOR BID+PHEN QD, and 40.5% LOR BID+PHEN BID. AEs leading to discontinuation were reported approximately twice as often in the LOR BID+PHEN BID group versus the LOR BID group. Mean WL was 3.5 kg/3.3%, 7.0 kg/6.7%, and 7.6 kg/7.2% for LOR BID, LOR BID+PHEN QD, and LOR BID+PHEN BID, respectively. At least 5% WL was achieved by 28.2% LOR BID, 59.0% LOR BID+PHEN QD (P = 0.0002 vs. LOR BID), and 70.9% LOR BID+PHEN BID (P < 0.0001 vs. LOR BID) patients.Conclusions: Phentermine added to lorcaserin enhanced short-term weight loss but did not increase incidence of potentially serotonergic AEs; however, phentermine twice daily increased discontinuation compared to both lorcaserin alone and lorcaserin plus phentermine once daily. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of prebiotic supplementation on metabolic endotoxemia and systemic inflammation in adults with overweight and obesity.Methods: Samples from a previously conducted randomized, double-blind, placebo-controlled trial were used for analysis. Participants were randomized to 21 g of oligofructose (n = 20; BMI 30.4 kg/m2 ) or a maltodextrin placebo (n = 17; BMI 29.5 kg/m2 ) for 12 weeks. A total of 37 participants had samples available for the current analysis. Resistin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage chemoattractant protein-1 (MCP-1) were quantified using MILLIPLEX® assays. Lipopolysaccharide (LPS) was measured using PyroGene™ Recombinant Factor C Assay.Results: Plasma LPS concentrations were reduced by 40% in the oligofructose group over 12 weeks compared to a 48% increase in the placebo group (P = 0.04). PAI-1, a risk factor for thrombosis, was reduced to a greater extent in the oligofructose group (-17.3 ± 2.6 ng/ml) compared to the placebo group (-9.7 ± 1.8 ng/ml; P = 0.03). Oligofructose did not affect IL-6, TNF-α, MCP-1, adiponectin, or resistin.Conclusions: Oligofructose reduces metabolic endotoxemia and PAI-1. Incorporating prebiotics into the diet through supplements or functional foods may help mitigate some markers of obesity-associated inflammation. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the impact of resveratrol supplementation along with non-surgical periodontal treatment on blood glucose, insulin, insulin resistance, triglyceride (TG), and periodontal markers in patients with type 2 diabetes with periodontal disease. In this double-blind clinical trial study, 43 patients with diabetes with chronic periodontitis were participated. Subjects were randomly allocated to intervention and control groups. The intervention and control groups received either 480 mg/day of resveratrol or placebo capsules (two pills) for 4 weeks. Fasting blood glucose, insulin, insulin resistance (homeostasis model assessment of insulin resistance), TGs, and pocket depth were measured in all subjects' pre-intervention and post-intervention. The mean serum levels of fasting insulin and insulin resistance (homeostasis model assessment of insulin resistance) were significantly lower in the intervention group compared with control group (10.42 ± 0.28 and 10.92 ± 0.9; 3.66 ± 0.97 and 4.49 ± 1.56, respectively). There was a significant difference in the mean pocket depth between intervention and control groups (2.35 ± 0.6 and 3.38 ± 0.5, respectively) following intervention. No significant differences were observed in the mean levels of fasting blood glucose and TGs between two groups' post-intervention. It is recommended that resveratrol supplementation may be beneficial as adjuvant therapy along with non-surgical periodontal treatment in insulin resistance and improving periodontal status among patients with diabetes with periodontal disease. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: In the ENGAGE AF-TIMI 48 trial, edoxaban, a factor Xa inhibitor, was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with atrial fibrillation (AF) and was associated with significantly less bleeding. The higher-dose edoxaban regimen (HDER; 60 mg dose-reduced to 30 mg once daily) has been approved in various countries in Europe, the USA, and Japan. Among patients treated with vitamin K antagonists (VKAs), symptomatic heart failure (HF) is an independent risk factor for lower time-in-therapeutic range, which reduces the efficacy and safety of VKA therapy. We evaluated the efficacy and safety of edoxaban compared with warfarin across the spectrum of HF severity in the ENGAGE AF-TIMI 48 trial.Methods and Results: Of 14 071 patients randomized to well-controlled warfarin or the HDER, 5926 (42%) had no history of HF, 6344 (45%) were in New York Heart Association (NYHA) class I-II, and 1801 (13%) were in NYHA class III-IV. The efficacy of edoxaban compared with warfarin in preventing stroke/SEE was similar in patients without and with HF regardless of the severity of HF; [HDER vs. warfarin: No-HF: hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.69-1.11; NYHA class I-II: HR 0.88, 95% CI 0.69-1.12; NYHA class III-IV: HR 0.83, 95% CI 0.55-1.25; Pinteraction = 0.97]. Compared with warfarin, HDER was consistently associated with lower risk of major bleeding (No-HF: HR 0.82, 95% CI 0.68-0.99; NYHA class I-II: HR 0.79, 95% CI 0.65-0.96; NYHA class III-IV: HR 0.79, 95% CI 0.54-1.17; Pinteraction = 0.96).Conclusion: The relative efficacy and safety of HDER compared with well-managed warfarin in AF patients with HF were similar to those without HF. [ABSTRACT FROM AUTHOR]

Aims To examine the safety and effectiveness of buprenorphine + naloxone sublingual tablets (BUP, as Suboxone®) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol®) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. Methods This multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York and Washington DC, USA to one of three conditions provided with XR-NTX: 4 mg/day BUP (BUP4, n = 100), 16 mg/day BUP (BUP16, n = 100, or no buprenorphine (placebo; PLB, n = 102). Participants received pharmacotherapy for 8 weeks, with three clinic visits per week. Cognitive behavioral therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4 weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention and adverse events. Results No group differences were found between groups for the primary outcome (BUP4 versus PLB, P = 0.262; BUP16 versus PLB, P = 0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB [ P = 0.022, odds ratio (OR) = 1.71] but not for BUP4 ( P = 0.105, OR = 1.05). No secondary outcome differences across groups were found for adherence, retention or adverse events. Conclusions Buprenorphine + naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. [ABSTRACT FROM AUTHOR]

Aim: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion.Method: Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia.Results: Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01).Interpretation: There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis. [ABSTRACT FROM AUTHOR]

Background: This study's aims were to determine the efficacy and tolerability of rasagiline, a selective monoamine oxidase inhibitor B, for PD patients with mild cognitive impairment.Methods: Patients on stable dopaminergic therapy were randomized to adjunct rasagiline 1 mg/day or placebo in this 24-week, double-blind, placebo-controlled, multisite study. The primary endpoint was mean change from baseline to week 24 on the Scales for Outcomes of Parkinson's Disease-Cognition total score. Key secondary measures included changes in cognition, activities of daily living, motor scores, and Clinical Global Impression of Change, as well as safety and tolerability measures.Results: Of the 170 patients randomized, 151 (88.2%) completed the study. Change in Scales for Outcomes of Parkinson's Disease-Cognition scores were not significantly different in the rasagiline and placebo groups (adjusted mean: 1.6 [standard error {SE} = 0.5] vs. 0.8 [SE = 0.5] points; LS means difference = 0.8; 95% confidence interval: -0.48, 2.05; P = 0.22). There were no between-group differences in change in the MoCA (p=0.84) or Penn Daily Activities Questionnaire (P = 0.48) scores or in the distribution of Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change modified for mild cognitive impairment (P = 0.1). Changes in motor (UPDRS part III; P = 0.02) and activities of daily living (UPDRS part II; P < 0.001) scores favored rasagiline. Rasagiline was well tolerated; the most common adverse events in both groups were falls and dizziness.Conclusions: Rasagiline treatment in PD patients with mild cognitive impairment was not associated with cognitive improvement. Rasagiline did not worsen cognition, improved motor symptoms and activities of daily living, and was well tolerated in elderly cognitively impaired patients. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design.Methods: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection.Results: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups.Conclusions: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery. [ABSTRACT FROM AUTHOR]

Introduction: It has been suggested that creatine supplementation is safe and effective for treating idiopathic inflammatory myopathies, but no pediatric study has been conducted to date. The objective of this study was to examine the efficacy and safety of creatine supplementation in juvenile dermatomyositis (JDM) patients.Methods: In this study, JDM patients received placebo or creatine supplementation (0.1 g/kg/day) in a randomized, crossover, double-blind design. Subjects were assessed at baseline and after 12 weeks. The primary outcome was muscle function. Secondary outcomes included body composition, aerobic conditioning, health-related quality of life, and muscle phosphocreatine (PCr) content. Safety was assessed by laboratory parameters and kidney function measurements.Results: Creatine supplementation did not affect muscle function, intramuscular PCr content, or any other secondary outcome. Kidney function was not affected, and no side effects were reported.Conclusions: Twelve weeks of creatine supplementation in JDM patients were well-tolerated and free of adverse effects, but treatment did not affect muscle function, intramuscular PCr, or any other parameter. [ABSTRACT FROM AUTHOR]

Background and Objectives: The purpose of this study was to evaluate the efficacy of vilazodone, a selective serotonin receptor inhibitor and partial 5-HT1A agonist, for treatment of cannabis dependence.Methods: Seventy-six cannabis-dependent adults were randomized to receive either up to 40 mg/day of vilazodone (n = 41) or placebo (n = 35) for 8 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests; secondary outcomes included cannabis use self-report and cannabis craving.Results: Participants in both groups reported reduced self-reported cannabis use over the course of the study; however, vilazodone provided no advantage over placebo in reducing cannabis use. Men had significantly lower creatinine-adjusted cannabinoid levels and a trend for increased negative urine cannabinoid tests than women.Discussion and Conclusions: Vilazodone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes than men.Scientific Significance: Further medication development efforts for cannabis use disorders are needed, and gender should be considered as an important variable in future trials. [ABSTRACT FROM AUTHOR]

Background and Objective: Numerous studies have highlighted the possibility of modulating the excitability of cerebellar circuits using transcranial direct current stimulation. The present study investigated whether a single session of cerebellar anodal transcranial direct current stimulation could improve symptoms in patients with ataxia.Methods: Nineteen patients with ataxia underwent a clinical and functional evaluation pre- and post-double-blind, randomized, sham, or anodal transcranial direct current stimulation.Results: There was a significant interaction between treatment and time on the Scale for the Assessment and Rating of Ataxia, on the International Cooperative Ataxia Rating Scale, on the 9-Hole Peg Test, and on the 8-Meter Walking Time (P < 0.001). At the end of the sessions, all performance scores were significantly different in the sham trial, compared to the intervention trial.Conclusions: A single session of anodal cerebellar transcranial direct current stimulation can transiently improve symptoms in patients with ataxia and might represent a promising tool for future rehabilitative approaches. [ABSTRACT FROM AUTHOR]

Aims: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.Methods and Results: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.Conclusion: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have documented the clinical outcomes of laser therapy for untreated periodontitis, but very few have reported on lasers treating inflamed pockets during maintenance therapy. The aim of this study is to compare the effectiveness of scaling and root planing (SRP) plus the adjunctive use of diode laser therapy to SRP alone on changes in the clinical parameters of disease and on the gingival crevicular fluid (GCF) inflammatory mediator interleukin-1β (IL-1β) in patients receiving regular periodontal maintenance therapy.Methods: This single-masked and randomized, controlled, prospective study includes 22 patients receiving regular periodontal maintenance therapy who had one or more periodontal sites with a probing depth (PD) ≥ 5 mm with bleeding on probing (BOP). Fifty-six sites were treated with SRP and adjunctive laser therapy (SRP + L). Fifty-eight sites were treated with SRP alone. Clinical parameters, including PD, clinical attachment level (CAL), and BOP, and GCF IL-1β levels were measured immediately before treatment (baseline) and 3 months after treatment.Results: Sites treated with SRP + L and SRP alone resulted in statistically significant reductions in PD and BOP and gains in CAL. These changes were not significantly different between the two therapies. Similarly, differences in GCF IL-1β levels between SRP + L and SRP alone were not statistically significant.Conclusion: In periodontal maintenance patients, SRP + L did not enhance clinical outcomes compared to SRP alone in the treatment of inflamed sites with ≥ 5 mm PD. [ABSTRACT FROM AUTHOR]

Objectives To better understand the effectiveness of xylitol in caries prevention in adults and to attempt improved clinical trial efficiency. Methods As part of the Xylitol for Adult Caries Trial (X- ACT), non cavitated and cavitated caries lesions were assessed in subjects who were experiencing the disease. The trial was a test of the effectiveness of 5 g/day of xylitol, consumed by dissolving in the mouth five 1 g lozenges spaced across each day, compared with a sucralose placebo. For this analysis, seeking trial efficiency, 538 subjects aged 21-80, with complete data for four dental examinations, were selected from the 691 randomized into the 3-year trial, conducted at three sites. Acceptable inter- and intra-examiner reliability before and during the trial was quantified using the kappa statistic. Results The mean annualized noncavitated plus cavitated lesion transition scores in coronal and root surfaces, from sound to carious favoured xylitol over placebo, during the three cumulative periods of 12, 24, and 33 months, but these clinically and statistically nonsignificant differences declined in magnitude over time. Restricting the present assessment to those subjects with a higher baseline lifetime caries experience showed possible but inconsistent benefit. Conclusions There was no clear and clinically relevant preventive effect of xylitol on caries in adults with adequate fluoride exposure when non cavitated plus cavitated lesions were assessed. This conformed to the X- ACT trial result assessing cavitated lesions. Including non cavitated lesion assessment in this full-scale, placebo-controlled, multisite, randomized, double-blinded clinical trial in adults experiencing dental caries did not achieve added trial efficiency or demonstrate practical benefit of xylitol. Trial Registration: ClinicalTrials.Gov NCT00393055. [ABSTRACT FROM AUTHOR]

Background: Submassive pulmonary embolism (PE) has a low mortality rate but can degrade functional capacity. Objective: The present study aims to provide rationale, methodology, and initial findings of a multicentre, randomised trial of fibrinolysis for PE that used a composite end-point, including quality of life measures. Methods: This investigator-initiated study was funded by a contract between a corporate partner and the investigator's hospital (the prime site). The investigator was the Food and Drug Administration (FDA) sponsor. The prime site subcontracted, indemnified, and trained consortia members. Consenting, normotensive patients with PE and right ventricular strain (by echocardiography or biomarkers) received low-molecular-weight heparin and random assignment to a single bolus of tenecteplase or placebo in double-blinded fashion. The outcomes were: (i) in-hospital rate of intubation, vasopressor support, and major haemorrhage, or (ii) at 90 days, death, recurrent PE, or composite that defined poor quality of life (echocardiography, 6 min walk test and surveys). The planned sample size was n = 200. Results: Eight sites enrolled 87 patients over 5 years. The ratio of patients screened for each enrolled was 7.4 to 1, equating to 11 h screening time per patient enrolled. Primary barrier to enrolment was the cost of screening. Two patients died (2.5%, 95%CI [0-8%]), one developed shock, but 18 (22%, 95%CI: [13-30%]) had a poor quality of life. Conclusions: An investigator-initiated, FDA-regulated, multicentre trial of fibrinolysis for submassive PE was conducted, but was limited by screening costs and a low mortality rate. Quality of life measurements might represent a more important patient-centred end-point. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess the effectiveness and safety of the administration of misoprostol, an orally active prostaglandin, in addition to routine uterotonic therapy as part of the active management of the third stage of labor. Methods: The present study was a hospital-based, decentralized, multi-center, randomized, placebo-controlled, double-blind trial. We enrolled 1103 women (out of a target sample size of 1180) at 4 hospitals in South Africa, Uganda, and Nigeria. Participants received a sublingual dose of 400μg of misoprostol or a placebo, in addition to standard active management of the third stage of labor, after vaginal birth. Results: The baseline characteristics of the participants were comparable. The difference in the primary outcome of blood loss of 500mL or more within 1 hour of randomization was not significant between the 2 groups (misoprostol 22/546 [4.0%] versus placebo 35/553 [6.3%]; relative risk, 0.64; 95% confidence interval, 0.38–1.07). Shivering and pyrexia occurred more frequently in the misoprostol group. No maternal deaths occurred. Conclusion: The present study did not confirm a beneficial effect of administering 400μg of misoprostol, in addition to routine uterotonic therapy, during the third stage of labor, but was consistent with other trials showing a cumulative modest benefit. Where routine uterotonics are available for prophylactic use, any potential benefit of misoprostol might not outweigh the likelihood of adverse effects. Trial registered on clinical trials.gov: NCT 00124540. [Copyright &y& Elsevier]

Despite the success of opiate-agonist therapies such as methadone for the treatment of opiate addiction, treatment response is not complete. This study evaluates the efficacy of citalopram augmented with bupropion in the treatment of illicit opiate use in a methadone-stabilized population. We conducted a 12-week randomized, double-blind, outpatient clinical trial in which 60 subjects were randomized into one of three treatment groups: placebo, citalopram (40 mg/day) plus placebo, or citalopram (40 mg/day) plus bupropion (50 mg/day). The results indicate that neither citalopram nor citalopram augmented with bupropion were more effective than placebo in the treatment of opioid abuse. [ABSTRACT FROM AUTHOR]

Objectives: To study the use of drotaverine hydrochloride for acceleration of labor and relief of labor pains. Methods: In this double-blind placebo-controlled randomized study, 100 primigravidas in uncomplicated spontaneous labor at term were given drotaverine hydrochloride or placebo (distilled water) intramuscularly. Labor events, including pain (assessed by a visual analog scale and a verbal rating scale), neonatal outcome, and side effects of the drug were recorded. Student''s t-test was used for analysis. Results: Forty-four patients in the drug group and 40 in the placebo group had complete data for analysis after decoding. In drotaverine group, there was a mean 15% reduction in the duration of the first stage of labor and a mean 19% reduction in the second stage. The maximum shortening of the first stage (28%) was observed when drotaverine was administered when cervical dilatation was 4 cm (P=0.044). There were no adverse fetal effects, but atonic postpartum hemorrhage was more common in the drotaverine group. There was no relief of pain with the drug except in the fourth stage of labor. Conclusions: Drotaverine hydrochloride is safe and effective in accelerating labor, but not effective in lessening labor pain. [Copyright &y& Elsevier]

Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II–IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (−18.8% from baseline) vs. placebo (+6.9%). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure. [Copyright &y& Elsevier]

Aims: Drug-induced changes in QT dispersion may be a way of detecting harmful repolarisation abnormalities for patients receiving antiarrhythmic drugs affecting ventricular repolarisation. Methods and results: In 463 congestive heart failure (CHF) patients enrolled in the Danish Investigations Of Arrhythmia and Mortality On Dofetilide-CHF (DIAMOND-CHF) study, both pre-treatment and on-treatment day 2–6 QT dispersion was available from standard 12-lead ECGs. Patients were randomised in a double-blind manner to receive either placebo or dofetilide, a new class III antiarrhythmic drug. During a median follow-up of 19 months (minimum 1 year), 179 patients (39%) died (135 patients from cardiac causes). Changes in QT dispersion did not predict all-cause or cardiac mortality for patients treated with dofetilide in multivariate survival analysis (Risk ratio: 1.02, 95% confidence interval: 0.97–1.08, P>0.4). This finding was independent of pre-treatment QT dispersion. Dofetilide caused a small QT dispersion increment of 8 ms, not different from the changes seen in the placebo group (3 ms). Conclusion: For patients with CHF and reduced left ventricular systolic function, changes in QT dispersion following treatment with dofetilide do not predict all-cause or cardiac mortality. The dofetilide-induced QT dispersion changes are small and comparable to those seen in placebo treated patients. [Copyright &y& Elsevier]

Unlabelled: Immunological approaches have been considered as an alternative therapeutic option for the treatment of enteric infections over the past few years. Hyperimmune bovine colostrum (HBC) is a potentially innovative immunological option in the management of shigellosis together with traditional antibiotic therapy. Children aged 1-12 y with a history of bloody mucoid diarrhoea of less than 5 d duration were enrolled after their stool specimen was found to be positive for Shigella dysenteriae type I antigen by a rapid diagnostic fluorescent antibody staining test. They were randomized to receive either HBC containing very high titres of antibody against S. dysenteriae type I antigen or bovine colostrum (BC) without any antibody. The study group received 100 ml of HBC three times a day orally for 3 d and control group received BC. Children also received pivmecillinam in a dose of 50 mg kg(-1) d(-1) in four divided doses orally for 5 d. Admission characteristics of the 34 children in the HBC group and 35 in the BC group were comparable. No significant differences were observed in duration of diarrhoea, fever, anorexia, abdominal pain, tenesmus, stool frequency or visible blood in the stool between the groups. Two (6%) children in the study and five (14%) in the control group remained stool culture positive for S. dysenteriae type 1, even after 5 d of sensitive antimicrobial therapy.Conclusion: The results indicate that HBC as an adjuvant is unable to show any beneficial effect in reducing the stool frequency, duration or severity of childhood shigellosis due to S. dysenteriae type I infection. [ABSTRACT FROM AUTHOR]

A small, controlled study was conducted to assess whether pergolide mesylate has clinical promise as a treatment for cocaine abuse prior to embarking on a larger, randomized, double-blind, controlled trial. Fourteen individuals were placed on placebo for 2 weeks, followed by a 24-week single-blind study in which they were placed on pergolide for 12 weeks, followed by placebo for 12 weeks. Another 14 patients received single-blind placebo for two weeks and then were randomized into a 24-week double-blind, placebo-controlled, multiple baseline design. Initially, patients enrolled in the study were placed on risperidone (n = 9) or placebo (n = 5). During the first 12 weeks, retention was worse for those receiving pergolide compared to risperidone or placebo. Neither risperidone nor pergolide were more efficacious in reducing cocaine use than placebo. Although earlier open studies found pergolide to show promise as a treatment for cocaine abuse, this study did not support these earlier findings. Comparing an agent to both an active control and placebo group may better predict whether a promising new agent will have clinical utility compared to the standard open trial. [ABSTRACT FROM AUTHOR]