Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: A randomized,controlled, Phase III trial

Guanfacine extended-release (GXR), a selective α2A-adrenergic agonist, is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD). This study assessed the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo. Patients (6–17 years) were randomized at baseline to dose-optimized GXR (0.05–0.12 mg/kg/day – 6–12 years: 1–4 mg/day; 13–17 years: 1–7 mg/day), ATX (10–100 mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure was change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV). Key secondary measures were Clinical Global Impression-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P; learning and school, and family domains). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms and vital signs. A total of 272 (80.5%) patients from Europe, the USA and Canada completed the study. Significant differences were observed in least squares mean change from baseline in ADHD-RS-IV total score (placebo-adjusted differences) (GXR: [−8.9, p<0.001]; ATX: [−3.8, p<0.05]), the difference from placebo in the percentage of patients showing improvement (1 [‘very much improved’] or 2 [‘much improved’]) for CGI-I (GXR: [23.7, p<0.001]; ATX: [12.1, p<0.05]), WFIRS-P learning and school domain (GXR: [−0.22, p<0.01]; ATX: [−0.16, p<0.05]) and WFIRS-P family domain (GXR: [−0.21, p<0.01]; ATX: [−0.09, p=0.242]). Most common TEAEs for GXR were somnolence, headache and fatigue; 70.1% of GXR subjects reported mild-to-moderate TEAEs. GXR was effective and well tolerated in children and adolescents with ADHD.     

Frontal EEG predictors of treatment outcome in major depressive disorder

ObjectiveTo investigate the role of frontal EEG as predictor of clinical response to SSRIs or venlafaxine in major depressive disorder (MDD).Method82 subjects (age 35.9 ± 13.0; 47.6% female) meeting DSM-IV criteria for MDD entered an 8-week prospective treatment with SSRIs or venlafaxine. At baseline and week 1 we recorded serial, 4-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz). We evaluated prospectively the relative theta power as predictor of treatment outcome. We also developed an Antidepressant Treatment Response (ATR) index using EEG parameters assessed at baseline and week 1.Results45 subjects (54.9%) responded to treatment (HAM-D-17 reduction ≥ 50%). At baseline, frontal relative theta power (i.e., 4–8 Hz power/2–20 Hz power) was significantly (p = 0.017) lower (21%) in treatment responders than in non-responders (24%). Baseline relative theta power predicted treatment response with 63% accuracy [64% sensitivity, 62% specificity, 66% area under the receiver operator curve (AUROC) (p = 0.014)]. Relative theta power at week 1 predicted treatment response with 60% accuracy [62% sensitivity, 57% specificity, 61% AUROC (p = 0.089)]. ATR predicted response with 70% accuracy [82% sensitivity, 54% specificity, 72% AUROC (p = 0.001)].ConclusionUsing automated analysis of frontal EEG collected during the first week of antidepressant treatment it may be possible to facilitate prediction of SSRI or venlafaxine efficacy in MDD.     

Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data

Rationale Up to 60% of children with attention-deficit/hyperactivity disorder (ADHD) suffer from comorbid affective or behavioral impairments, the most common condition being oppositional defiant disorder (ODD), which occurs in 40–60% of children with ADHD.Objectives This post hoc meta-analysis was performed to determine the effect of the presence of comorbid ODD symptoms on clinical outcomes among pediatric and adolescent subjects being treated for ADHD.Methods Acute-phase data were analyzed from three randomized, double-blind, placebo-controlled studies in outpatients aged 6–16 and meeting the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for ADHD. Subjects received placebo or atomoxetine (max 1.8 mg/kg/day, daily) for 6–8 weeks. Patients were diagnosed with comorbid ODD on structured diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-aged Children—Present and Lifetime Versions).Results Of the 512 subjects studied, 158 were diagnosed with comorbid ODD. Relative to placebo, atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects irrespective of the comorbidity with ODD. ADHD subjects also showed significant improvements from baseline on most of the psychosocial measures of the child health questionnaire irrespective of the comorbidity with ODD. Reduction in ODD symptoms was highly related to the magnitude of ADHD response.Conclusions Atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects to similar extents, indicating that the presence of comorbid symptoms of oppositionality does not affect clinical outcomes of treatment of ADHD with atomoxetine.     

Effects of pantoprazole on dual antiplatelet therapy in stable angina pectoris patients after percutaneous coronary intervention

BackgroundOur aim was to prospectively assess the potential influence of pantoprazole therapy on the antiplatelet effects of acetylsalicylic acid (ASA) and clopidogrel (CLO) in stable angina pectoris (SAP) patients after percutaneous coronary intervention (PCI).MethodsForty-four patients with SAP (CCS I-III) and successful PCI with stent implantation were enrolled into the study. The patients were divided into group proton pump inhibitors (PPI): 23 patients with indications for PPI (F/M = 9/14; age = 64 ±  9; standard therapy + 20 mg pantoprazole) and the control group (group C): 21 patients (F/M = 6/15; age = 64 ±  8; standard therapy). The platelet function analysis in whole blood based on impedance aggregometry (ASPI, COL, ADP, TRAP tests) using Multiplate – V2.02.11 was performed 18–24 h after the PCI + CLO loading dose (600 mg) and 30 days after PCI.ResultsBoth baseline patient characteristics and clinical outcomes were comparable between the study groups. There were no differences in the mean values of the platelets (PTL) tests measured at the 30^th day after PCI between both groups (PPI vs. C: ASPI: 24.6 ±  10.0 vs. 42.1 ±  14.8U, COL: 32.9 ±  8.6 vs. 34.0 ±  7.7U, ADP: 26.8 ±  12.4 vs. 30.4 ±  8.1U, TRAP: 78.7 ±  16.6 vs. 78.1 ±  22.6U, p = ns). The mean delta values of the PTL tests (18–24 h post-PCI/30 days post-PCI) were also comparable between the groups. The PTL aggregometry results were related to time (ADP, ASPI, TRAP vs. time, p = 0.001; COL vs. time, p = 0.03) – the baseline values of ADP, ASPI, COL and TRAP tests were smaller than those measured after the one-month observation.ConclusionsPantoprazole treatment does not impair the efficacy of dual antiplatelet therapy in patients with SAP after PCI.     

High prevalence of substance use among heterosexuals living in communities with high rates of AIDS and poverty in Washington, DC

BackgroundThe degree to which distinct behavioral components of impulsivity predict alcohol consumption is as yet not well-understood. Further, the possibility that this relation might be more pronounced in groups characterized by heightened impulsivity (i.e., individuals with ADHD) has not been tested.MethodsThe current study examined the degree to which three specific behavioral components of impulsivity (i.e., poor response inhibition, poor attentional inhibition, and increased risk-taking) were associated with quantity and frequency of alcohol consumption in a group of young adult social drinkers with ADHD (n = 33) and in a comparison control group (n = 21). Participants performed the delayed ocular return task (attentional inhibition), the cued go/no-go task (behavioral inhibition), and the balloon analogue risk task (risk-taking).ResultsBoth poor behavioral inhibition and greater risk-taking were related to greater quantity of consumption in the entire sample, whereas poor attentional inhibition was related to greater quantity specifically among those with ADHD. By contrast, only risk-taking was associated with frequency of consumption, and this was found specifically in the control group.ConclusionsThese findings provide important information regarding the potential role of distinct behavioral components of impulsivity in drinking behavior, and highlight unique relevance of attentional impairments to drinking behavior in those with ADHD.     

A multi-centre,randomised, open-label study of atomoxetine compared with standard current therapy in UK children and adolescents with attention-deficit/hyperactivity disorder (ADHD)*

ABSTRACT

Objective: To assess the broader efficacy (i.e., improve­ments in quality of life/functional outcomes) of atomoxetine compared with standard current therapy (SCT) in UK paediatric patients with ADHD and to explore clinician/parent/child perceptions of ADHD.

Research design and methods: A total of 201 patients with ADHD were randomised into this multi-centre, open-label study to receive atomoxetine (n = 104) or SCT (n = 97) for 10 weeks. Broader efficacy was assessed using the parent-rated Child Health and Illness Profile-Child Edition (CHIP?CE) total (global) t-score. Secondary outcome measures included the five CHIP?CE domains; parent-rated Family Burden of Illness Module (FBIM); investigator-rated ADHD?Rating Scale; investigator-rated Clinical Global Impression (CGI)-Severity/Improvement scales; and child-rated Harter Self-Perception Profile (HSPP).

Results: Quality of life of children/adolescents with ADHD was extremely compromised at baseline (CHIP?CE total t-scores: atomoxetine, 23.2 ± 12.2; SCT, 23.9 ± 11.0), and improved during the 10-week study for both groups; the CHIP?CE score was statistically significantly higher for patients treated with atomoxetine (38.4 ± 1.3) compared with SCT (30.8 ± 1.3) at week 10 (?p < 0.001). ADHD?RS, CGI-Severity, and CGI-Improvement scores were significantly different between the groups in favour of atomoxetine (?p < 0.001). There was a statistically significant difference between the groups in the HSPP Social Acceptance domain in favour of atomoxetine, but not in the five other HSPP domains or FBIM total score. Atomoxetine was well-tolerated.

Conclusions: Results from this open-label trial show that atomoxetine is superior to SCT in addressing broader efficacy and functional outcomes in UK children/adoles­cents with ADHD. This study contributes to the under­standing of broader efficacy in children with ADHD, and is timely in light of recent NICE guidance.     

Normothermic and hypothermic models for studying the deleterious effects of hypoxia-reoxygenation on EDHF-mediated relaxation in isolated porcine coronary arteries

IntroductionThe vasomotor response of the coronary artery is altered by hypoxia–reoxygenation (H–R) induced damage. The aim of our study was to compare and evaluate normothermic and hypothermic models which are suitable for future drug studies of vasoprotective action against H–R injury.MethodsPorcine coronary arterial rings were isolated and placed in Krebs–Henseleit (K–H) solution. Rings were exposed to normoxic conditions (control group) and two different H–R conditions: the first induced by a 95% N₂–5% CO₂ gas mixture (40- and 60-min hypoxia) in a normothermic protocol, and the second induced by hypothermic (4 °C) hypoxia–reoxygenation in an air-tight beaker filled with K–H solution (24- and 48-hours hypoxia). Reoxygenation was applied by introducing K–H solution aerated with a 95% O₂–5% CO₂ mixture under normothermic (37 °C) conditions. To test the EDHF-mediated relaxation by substance P, rings were first incubated in L-NNA, nitric oxide synthase inhibitor, and indomethacin, cyclooxygenase inhibitor, and then pre-contracted with thromboxane analogue U-46619. Analysis of the maximum relaxation of the arterial rings was performed by one-way ANOVA, followed by Bonferroni's post-test.ResultsDistal segments of the coronary artery responded faster to contraction induced by U-46619 and were relaxed by substance P to a greater extent than proximal segments. Maximal relaxations of arterial rings induced by a 10 nM solution of substance P were significantly reduced (p < 0.001) from the values for normoxic rings (81.0 ± 1.0%, n = 30) after 40-min H–R (50.5 ± 5.3%, n = 30), 60-min H–R (32.1 ± 3.5%, n = 30), 24-hours hypothermic H–R (56.0 ± 2.3%, n = 30) and after 48-hours hypothermic H–R (38.5 ± 5.1%, n = 30).ConclusionsThe model employing 40-min normothermic H–R is as effective as 24-hours hypothermic H–R, and 60-min normothermic H–R as 48-hours hypothermic H–R for studying the deleterious effects of H–R on EDHF-mediated relaxation.     

Awareness of legal blood alcohol concentration limits amongst respondents of a national roadside survey for alcohol and traffic behaviours in Brazil

BackgroundIn Brazil the legal blood alcohol content (BAC) allowed for driving was changed to zero in 2008. If the BAC found is above 0.6 g/L, drivers may be arrested. However, there are limited data on drivers’ awareness of such limits.MethodsDrivers from 27 major metropolitan areas (n = 3397) were randomly asked to participate in roadside survey from 12 a.m. to 12 p.m. on Fridays and Saturdays. They were breathalized by highway patrol officers, and after consent interviewers collected data on drinking behaviours, knowledge about the law, and breath tests results.ResultsThe mean age was 37.3 ± 11.3 years; 94.3% were male and 26.5% had some college education. When asked about the BAC that could result in arrest, 34.5% of the subjects claimed to know it. However, only 23.5% (8.1% of the total sample) provided correct answers. Factors associated with the right answers were: male gender (p = 0.04; OR = 2.08; CI = 1.01–4.27); higher education (p < 0.0001); negative BAC or self-report of driving under the influence (DUI) (p = 0.02); higher family income (p = 0.01) and non-professional driving (p = 0.041). Age was not statistically different between groups. After multivariate analysis, male gender (p = 0.002), higher education (p < 0.0001) and negative BAC or DUI (p = 0.046) remained in the model.ConclusionsThe knowledge that BAC levels over 0.6 g/L may result in arrest is sparse amongst Brazilian drivers, notably amongst women, the less educated and those who drink and drive. Educational programmes targeted at those specific groups may be necessary in order to increase awareness about the legal BAC limit and its consequences.     

Granulocyte colony-stimulating factor improves early remodeling in isoproterenol-induced cardiac injury in rats

BackgroundGranulocyte colony-stimulating factor (G-CSF) has been used in some animal models and humans with wellestablished cardiovascular diseases. However, its effects in the initial stage of progressive non-ischemic heart failure are unknown.MethodsWistar rats (260–300 g) were divided into three groups: control (without any intervention), ISO (150 mg/kg isoproterenol hydrochloride sc, once a day for two consecutive days), and ISO-GCSF (50 μg/kg/d G-CSF for 7 days beginning 24 h after the last administration of ISO). Echocardiography was performed at baseline and after 30 days of follow-up. Subsequently, animals were anesthetized for hemodynamic analysis. The left ventricle was removed for analysis of interstitial collagen deposition and cardiomyocyte hypertrophy.ResultsIsoproterenol led to left ventricular dilation (control, 7.7 ± 0.14 mm; ISO, 8.7 ± 0.16 mm; ISO-GCSF 7.8 ± 0.09 mm; p < 0.05), myocardial fibrosis (control, 2.0 ± 0.18%; ISO, 9.1 ± 0.81%; ISO-GCSF 5.9 ± 0.58%; p < 0.05) and cardiomyocyte hypertrophy (control, 303 ± 10 μm²; ISO, 356 ± 18 μm²; ISO-GCSF 338 ± 11 μm²; p < 0.05). However, G-CSF partially prevented collagen deposition and left ventricular enlargement, with a slight effect on hypertrophy. Characterizing a compensated stage of disease, hemodynamic analysis did not change.ConclusionsG-CSF administered for 7 days was effective in preventing the onset of ventricular remodeling induced by high-dose isoproterenol with decreased collagen deposition and chamber preservation.     

Association between corneal temperature and mental status of treatment-resistant schizophrenia inpatients

IntroductionPreliminary point-prevalent data suggest that drug-free schizophrenia patients may exhibit increased body/corneal temperature, that antipsychotic drugs (APDs) may decrease body/core temperature and that patients' mental status might be associated with their body/corneal temperature. Hence, we hypothesized that treatment-resistant psychotic APD-treated schizophrenia patients' mental status may correlate with their corneal temperature during a continuous 6-week period.MethodsCorneal temperature of 12 treatment-resistant schizophrenia inpatients and 16 healthy volunteers was evaluated 2–3 times a week during 6 consecutive weeks using a flir thermal imaging camera.ResultsA significant and substantial correlation was found between inpatients' mean weekly Positive and Negative Syndrome Scale (PANSS)'s total scores and their mean weekly corneal temperature during the 6-week study period (r = 0.82; n = 6 weeks; p = 0.043). There was no significant difference in mean 6-week corneal temperature between the patient group and the healthy subjects (34.25 ± 0.64 °C vs. 34.39 ± 0.69 °C, respectively; t = 1.127, df = 131, p = 0.26).ConclusionsThis study indicates that treatment-resistant overtly psychotic schizophrenia inpatients' mental status (as assessed by the PANSS) correlates with their corneal temperature. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying corneal temperature alterations and the possible role of temperature-modulating drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis merits further large-scale investigation in both medicated- and drug-free schizophrenia patients compared to matched controls.     

Persistence of attentional bias toward alcohol-related stimuli in intoxicated social drinkers

This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants.DesignOne hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites.MethodsParticipants were stabilized on methadone during weeks 1–2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3–14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained.ResultsBaseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04).ConclusionsDisulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.     

The association of race, comorbid anxiety, and antidepressant adherence among Medicaid enrollees with major depressive disorder

BackgroundDepressed patients often have comorbid anxiety. African-Americans with depression are less likely to adhere to antidepressant treatment. Knowledge of the association between race, comorbid anxiety, and adherence among Medicaid enrollees with depression is limited.ObjectiveThe objective of this study was to evaluate the association of race, comorbid anxiety, and antidepressant adherence, and persistence among Medicaid enrollees with major depressive disorder (MDD).MethodsThe MarketScan^® Multi-State Medicaid Database (Thomson Reuters, Ann Arbor, MI) was used in this retrospective cross-sectional study. Medicaid enrollees aged between 18 and 64 years, with MDD but without bipolar disorders, and with a newly initiated antidepressant between January 1, 2004 and December 31, 2006 were identified. An index date was assigned corresponding to the newly initiated antidepressant. Patients having claims for any antidepressant refills during the 12 months before the index date were excluded. Eligible patients were then followed-up for 12 months after the index date. Adherence was measured by a modified medication possession ratio. Adherence was evaluated using multivariate logistic regression. Persistence was assessed based on treatment discontinuation and examined by Kaplan-Meier survival curves and Cox-propositional hazard regression models.ResultsA total of 3083 Medicaid patients with MDD were included. Approximately, 25% of patients had comorbid anxiety. The odds of adhering to antidepressants were 40% lower among African-Americans than Caucasians, adjusting for covariates (AOR [adjust odds ratio] = 0.60; 95% confidence interval [CI] = 0.51-0.72, P < .001). MDD patients with comorbid anxiety were more likely to adhere to antidepressants than patients with MDD alone (AOR = 1.55, 95% CI = 1.27-1.90, P < .001). African-Americans had a higher hazard of not persistently taking antidepressants (hazard ratio = 1.47, 95% CI = 1.30-1.65, P < .001). The interaction between race and comorbid anxiety was not associated with adherence or persistence.ConclusionsAmong Medicaid enrollees with MDD, race and comorbid anxiety disorders are significantly associated with antidepressant adherence and persistence. Physicians need to recognize comorbid anxiety and race as 2 important determinants of antidepressant use behaviors when they encounter Medicaid patients with MDD.     

Long-term inhibition of intestinal lipase by orlistat improves release of gut hormones increasing satiety in obese women

BackgroundReduced postprandial secretion of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin, and increased hunger was reported after a single dose of orlistat, an inhibitor of intestinal lipase. As yet, the influence of long-term therapy with orlistat on PYYand GLP-1 release has not been studied. Our study was aimed at assessing the influence of 8-week therapy with orlistat as a component of a weight loss program on pre-prandial circulating PYY and GLP-1 levels.MethodsForty obese women, without concomitant diseases, were randomly allocated to groups receiving orlistat or placebo during an 8-week weight management program. Body mass, body composition and plasma levels of PYY, GLP-1 and insulin (for QUICKI calculation) were determined prior to and at the end of therapy.ResultsWomen treated with orlistat obtained significantly greater body and fat mass loss than those receiving placebo (9.0 ± 3.1 vs. 5.9 ± 3.2% and 21.9 ± 10.9 vs. 7.4 ± 15.6%, respectively). Only in those treated with orlistat a slight, but significant increase of the QUICKI was found (8.0 ± 16.5 vs. –0.1 ± 12.7%, respectively).Weight loss was followed by a significant increase of plasma levels of PYY and GLP-1 in group treated with orlistat, and was about 2-times greater than receiving placebo. The increase was independent of body mass changes.ConclusionThe long-term inhibition of intestinal lipase by orlistat increases the pre-prandial levels of GLP-1 and PYY, independent of body mass changes. Therefore, it seems that long-term treatment with orlistat may exert hunger suppressing and insulin sensitizing incretin effect beyond weight reduction.     

Association between parental and individual psychiatric/substance use disorders and smoking stages among Puerto Rican adolescents

ObjectiveTo examine the associations between parental and individual psychiatric disorders and smoking stages among Puerto Rican youth from migrant and non-migrant families.MethodAnalyses were conducted drawing on data collected as part of a migrant family study examining youth at high and low risk for substance use disorders based on the presence or absence of a parental history of substance abuse or dependence. Parents and their offspring were recruited in San Juan, Puerto Rico (n = 450) and New Haven, CT, USA (n = 350).ResultsExperimental smoking among adolescent offspring was associated with parent proband disorders. In contrast, regular smoking behavior, defined as at least weekly smoking for a month or more, and DSM-IV nicotine dependence were more strongly associated with the adolescents’ own psychiatric disorders. With the exception of anxiety disorders, significant bivariate associations were shown between each psychiatric/substance use disorder and nicotine dependence. Once comorbidity was statistically controlled, only attention deficit hyperactivity disorder (ADHD), and alcohol and drug use disorders were significantly associated with nicotine dependence. After controlling for adolescents’ psychiatric comorbidity, there was an association between parental disorders and both experimental and regular smoking in their adolescent offspring.ConclusionsBy combining family and migrant research strategies within a single study, the present investigation was able to simultaneously examine familial, individual and sociocultural factors that may play a role in development and/or persistence of smoking behavior among Puerto Rican adolescents.     

A comparison of two fixed doses of aripiprazole with placebo in acutely relapsed,hospitalized patients with bipolar disorder I (manic or mixed) in subpopulations (CN138-007)

This study evaluated the efficacy and safety of two fixed doses of aripiprazole (15 mg/day, n = 131 and 30 mg/day, n = 136) compared with placebo (n = 134) in acutely manic or mixed bipolar I hospitalized patients. The mean change from baseline to Week 3 in the YMRS Total Scores was − 10.01 (95% CI: − 11.92, − 8.09) for aripiprazole 15 mg/day, − 10.80 (95% CI: − 12.71, − 8.90) for aripiprazole 30 mg/day, and − 10.12 (95% CI: − 12.01, − 8.24) for placebo. The most frequent adverse events (≥ 10% and greater than placebo) for either of the aripiprazole treatment groups were headache, nausea, dyspepsia, insomnia, agitation, constipation, akathisia, anxiety, lightheadedness, vomiting, diarrhea, asthenia and extremity pain. Aripiprazole 15 or 30 mg/day was not significantly more effective than placebo in the treatment of bipolar I disorder acute mania at endpoint (Week 3). A high placebo response rate may have accounted for the lack of separation between treatment groups.     

Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents—meta-analysis and meta-regression analysis

OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of atomoxetine in children and adolescents. MATERIALS AND METHODS: We searched for studies published between 1985 and 2006 through Medline, PubMed, PsychInfo and Cochrane Central Register of Controlled Trials (CENTRAL 2006 Issue 3) using keywords related to atomoxetine and attention-deficit/hyperactivity disorder (ADHD) and scanned though reference lists. We included nine randomized placebo-controlled trials (atomoxetine:placebo = 1,150:678). RESULTS: Atomoxetine was superior (p < 0.01) to placebo in reducing ADHD symptoms across different scales (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Conners' Parent and Teacher Rating Scales-Revised:Short Form, Clinical Global Impression-Severity) rated by different raters (parent, teacher, clinician). The number-needed-to-treat (NNTs) for treatment response and relapse prevention were 3.43 (95% CI, 2.79-4.45) and 10.30 (95% CI, 5.89-40.62), respectively. High baseline ADHD symptoms (p = 0.02) was associated with greater reduction in ADHD symptoms, whereas male gender (p = 0.02), comorbid oppositional defiant disorder (ODD) status (p = 0.01) and ADHD hyperactive/impulsive subtype (p = 0.01) were associated with smaller reductions. The commonest adverse events were gastrointestinal [appetite decrease, number-needed-to-harm (NNH) = 8.81; abdominal pain, NNH = 22.48; vomiting, NNH = 29.96; dyspepsia, NNH = 49.38] and sleep related (somnolence, NNH = 19.41). Young age (p = 0.03) and high baseline hyperactive/impulsive symptoms (p < 0.01) were associated with more adverse events, whereas ADHD inattentive subtype (p = 0.04) was associated with less adverse events. Quality of life using Child Health Questionnaire (CHQ) improved (p < 0.01) with atomoxetine treatment. Both ADHD and ODD symptoms (p < 0.01) were reduced in comorbid ADHD+ODD, and ODD status was not associated with more adverse events. Efficacy and side effects were not altered by comorbid general anxiety disorder or major depression. CONCLUSIONS: Atomoxetine is efficacious in reducing ADHD symptoms. It may have a role in treating comorbid ODD or depression, and probably in comorbid anxiety.     

Emergency department visits and admissions due to drug related problems at Riyadh military hospital (RMH), Saudi Arabia

ObjectivesAim of this study was to prospectively determine the incidence and types of emergency department (ED) visits and admissions due to drug related problems (DRPs) at Riyadh Military Hospital (RMH), to assess the severity and preventability of these drug related admissions or visits, and to identify the drugs and patient groups that are most commonly involved.MethodPatients (n = 300) were selected randomly from patients presented to the ED during the study period (one month). Computerized randomization program was used to select ten beds daily on different areas and times. Patient was eligible to be included if either visited ED or admitted through it due to DRPs.ResultsDuring the study period, 300 patients presented to ED were randomly selected with a mean age of 47.8 ± 27.7 years. One hundred and forty of them were females (46.67%) and 160 were male patients (53.33%). Of these 300 patients, 56 (18.7%) were presented to ED due to DRPs, and 244 (81.3%) patients were presented to ED due to non-drug related problems (NDRPs). About ninety-three percent (n = 52) of the DRP group were exposed to hospital admission while only 7.1% (n = 4) were ED visits (Fig. 2). Male to female ratio in ED visits was 3:1 while it was 9.7:8.9 in the ED admission group.ConclusionThe prospective design of this study, sample size, and randomization increases the likelihood that our estimates are accurate and increase the generalizability of our findings. Most DRPs attributed to hospital admissions or visits were avoidable. Direct patient contact with pharmacist and family physician was beneficial in providing a safe and effective therapy. Corrective, preventive and educational strategies should concentrate on the most frequently reported populations, diseases and medications. The study addresses the proper use of medications to ensure the best outcomes of pharmacological interventions. Finally, more studies with longer duration focusing on DRPs in Saudi Arabia are needed.     

Standardization of an ex vivo method for determination of intestinal permeability of drugs using everted rat intestine apparatus

IntroductionEverted gut sac of rat intestine is a paradigm widely employed for determination of absorption kinetics of drugs along with evaluation of effects of absorption enhancers. Since its inception in 1954, it has been optimized to enhance tissue survival and use, but it still suffers the limitation of small serosal compartment size and lack of validity of single experiment.MethodsThe aim of the present work was to standardize a new ex vivo model to study drug absorption using a specially designed glass apparatus, everted segment of rat intestine, and three absorption markers [paracellular (atenolol), transcellular (metoprolol and propranolol)]. To validate a single experiment phenol red was used as non-absorbable marker.ResultsThe mean apparent permeabilities (Papp) for the markers were found to be 0.054 ± 0.024 × 10^? 4 cm/s (atenolol), 0.84 ± 0.14 × 10^? 4 cm/s (metoprolol), and 1.64 ± 0.16 × 10^? 4 cm/s (propranolol); wherein data from only those experiment was used, which showed negligible absorption of phenol red.DiscussionThe model is simple to establish, gives excellent absorption kinetics, and most importantly provides a way to validate the experiment simultaneously. The proposed method can be used in all kinds of drug absorption studies, especially biopharmaceutical investigations studying absorption enhancement strategies.     

Immunomodulatory effect of pleuran (β-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections

ObjectivesRecurrent respiratory tract infections (RRTIs) represent a very important problem in daily clinical practice because of their significant contribution to morbidity in children. Several natural nutritional supplements have been used in the prevention of RRTIs, but the clinical efficacy of only a few preparations is supported by scientific evidence.Materials and methodsIn a double-blind, placebo-controlled, randomised, multicentre study, we have observed a group of 175 children (aged 5.65 ± 2.39 years) with more than 5 respiratory infections that occurred during the 12 months prior to the beginning of the study. Children were randomised into an active group, treated with Imunoglukan P4H® syrup (with pleuran-β-glucan from Pleurotus ostreatus and vitamin C), or a placebo group (vitamin C only). During the 3 visits, within a 12-month period, questionnaires were completed, and blood samples were examined for immune parameters.ResultsIn the active group, 36% of the children did not suffer from any respiratory infections throughout the treatment, compared to 21% in the placebo group (p < 0.05). Imunoglukan P4H® also significantly decreased the frequency of flu and flu-like disease and the number of lower respiratory tract infections. Imunoglukan P4H® treatment resulted in a statistically significant modulation of humoral and cellular immunity.ConclusionsResults from this study demonstrate that Imunoglukan P4H® is effective in the prevention of RRTIs in children. Furthermore, our results also revealed complex immunomodulatory activity of this product. This is the first double-blind, placebo-controlled study in children with RRTIs that has addressed the preventive effects of pleuran on morbidity caused by respiratory infections.     

Drug interaction between oral contraceptives and St. John's Wort: appropriateness of advice received from community pharmacists and health food store clerks.

ObjectiveTo estimate the extent to which community pharmacists and health food store clerks provide appropriate advice regarding a drug interaction between oral contraceptives and St. John's wort (SJW).DesignCross-sectional study.SettingThree community pharmacy chains and three health food store chains in four highly populated counties in California.ParticipantsCommunity pharmacists (n = 99) and health food store clerks (n = 184).InterventionInvestigators, posing as consumers, telephoned pharmacists and health food store clerks and asked the following question: "Is there a problem with taking SJW with birth control pills?"Main outcome measuresRespondents were classified based on their ability to correctly identify the drug interaction (yes or no) and on the overall appropriateness (i.e., the absence of incorrect advice) of their advice. Comparisons were made between men and women respondents and between pharmacists and health food store clerks.ResultsCommunity pharmacists were more likely than health food store clerks to correctly identify the drug interaction (50.5% versus 10.9%; χ²(1df) = 54.32,P < 0.001). Overall, 31.8% of respondents provided inappropriate advice that implied the absence of a drug interaction (26.3% of 99 pharmacists and 34.8% of 184 health food store clerks; χ²(1df) = 2.15,P = 0.14). Appropriateness of advice varied significantly among the three pharmacy chains (P < 0.001) and the three health food store chains (P < 0.05). Responses did not differ by gender of respondents (P = 0.18).ConclusionLack of awareness of the potentially serious drug interaction between SJW and oral contraceptives by those who sell these products places the public at risk. Training and education, more comprehensive product labeling, and policies to refer consumers to drug information centers are needed.