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The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM). A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys. Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects. The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

ObjectiveTo evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastro-oesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy.MethodsA double-blind, placebo-controlled, randomised, parallel-group, multicentre phase IIA study was carried out in outpatient clinics. The study group comprised 244 adult patients with persistent GORD symptoms (heartburn and/or regurgitation) of at least mild intensity and for 3 days of 7 days before enrolment, despite ≥6 weeks of continuous PPI therapy. Patients received either lesogaberan (65 mg twice daily) or placebo in addition to PPI therapy for a period of 4 weeks. Symptom intensity, based on the Reflux Disease Questionnaire, was recorded twice daily. Treatment response (defined as at most one 24 h period with heartburn or regurgitation of not more than mild intensity during the last 7 days of treatment). Time to response, proportion of symptom-free days and measures of tolerability were also analysed.ResultsA total of 232 (114 lesogaberan- and 118 placebo-treated patients) of the 244 randomised patients were analysed for efficacy. Treatment with lesogaberan, compared with placebo, resulted in a significantly larger proportion of responders to treatment (16% vs 8% of patients; p=0.026) and cumulative proportion of responders over time (log-rank p=0.0195). Lesogaberan was well tolerated: adverse events of mostly mild to moderate intensity were reported in 45% of patients on lesogaberan and in 37% on placebo.ConclusionsLesogaberan add-on therapy to PPIs significantly improved heartburn and regurgitation symptoms; however, the proportion of responders was small.Clinical trial numberNCT00394472.

Objective: The efficacy and tolerability of long-term treatment with atomoxetine for symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with autism spectrum disorder (ASD) has not been established. Methods: In this study, 88 patients 6–17 years of age, with ADHD and ASD, were treated with 1.2 mg/kg/day atomoxetine for 20 weeks as follow-up of an 8 week double-blind placebo-controlled period. Primary endpoint was the ADHD Rating Scale (ADHD-RS). Results: After 8 weeks of initial treatment, the mean total, inattention, and hyperactivity-impulsivity ADHD-RS further decreased significantly from 34.9 to 27.0 for the total ADHD-RS, from 18.3 to 14.5 for the ADHD-RS inattention subscale, and from 16.5 to 12.6 for the hyperactivity-impulsivity subscale. Adverse events were mild and tended to diminish over time during continued treatment, especially regarding nausea and fatigue. There were no serious adverse events. Conclusions: The results of the present analysis suggest that continued treatment with atomoxetine up to 28 weeks further improve ADHD symptoms in children and adolescents with ASD, while adverse events tend to subside. Future studies investigating the long-term efficacy of atomoxetine in children and adolescents with ASD should be randomized and placebo controlled. This study has been registered in ClinicalTrials.gov (www.clinicaltrials.gov) under registration number NCT00380692.

Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. Methods In this 9-week, double-blind, active-controlled study, patients aged 6–17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients <70 kg: 0.5–1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients ≥70 kg: 40, 80 or 100 mg/day). Treatment response was a secondary efficacy outcome and was predefined as a reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score of at least 25, 30 or 50 %. Sustained response was predefined as a reduction from baseline in ADHD-RS-IV total score (≥25, ≥30 or ≥50 %) or a Clinical Global Impressions (CGI)–Improvement (CGI–I) score of 1 or 2 throughout weeks 4–9. CGI–Severity (CGI–S) scores were also assessed, as an indicator of remission. Results A total of 267 patients were enrolled (LDX, n  = 133; ATX, n  = 134) and 200 completed the study (LDX, n  = 99; ATX, n  = 101). By week 9, significantly ( p  < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly ( p  < 0.05) higher among LDX-treated patients (ADHD-RS-IV ≥25, 66.1 %; ADHD-RS-IV ≥30, 61.4 %; ADHD-RS-IV ≥50, 41.7 %; CGI–I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV ≥25, 51.1 %; ADHD-RS-IV ≥30, 47.4 %; ADHD-RS-IV ≥50, 23.7 %; CGI–I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI–S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI–S category. Conclusions Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI–S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies.

Objectives The aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH). Methods This 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6–17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized daily dose of LDX (30, 50 or 70 mg) or ATX (patients <70 kg, 0.5–1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients ≥70 kg, 40, 80 or 100 mg). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment. Results Of 267 patients randomized (LDX, n  = 133; ATX, n  = 134), 200 (74.9 %) completed the study. The median time to first clinical response [95 % confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0–16.0)] than for those receiving ATX [21.0 days (15.0–23.0)] ( p  = 0.001). By week 9, 81.7 % (95 % CI 75.0–88.5) of patients receiving LDX had responded to treatment compared with 63.6 % (95 % CI 55.4–71.8) of those receiving ATX ( p  = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [−6.5 (−9.3 to −3.6); p  < 0.001; effect size 0.56], inattentiveness subscale score [−3.4 (−4.9 to −1.8); p  < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [−3.2 (−4.6 to −1.7); p  < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, −1.30 kg (1.806); ATX, −0.15 kg (1.434)]. Conclusions LDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from previous clinical trials.

Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.

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.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. There are at present three Food and Drug Administration-approved drugs based on the “one drug, one target” paradigm (donepezil, galantamine and rivastigmine) that improve symptoms by inhibiting acetylcholinesterase. However, apart from the beneficial palliative properties, cholinergic drugs have shown little efficacy to prevent the progression of the disease evidencing the unsuitability of this strategy for the complex nature of AD. By contrast, the multifactorial nature of this neurodegenerative disorder supports the most current innovative therapeutic approach based on the “one drug, multiple targets” paradigm, which suggests the use of compounds with multiple activities at different target sites. Accordingly, the also called multitarget-directed ligand (MTDL) approach has been the subject of increasing attention by many research groups, which have developed a variety of hybrid compounds acting on very diverse targets. The therapeutic potential of monoamine oxidase inhibitors (MAOI) in AD has been suggested due to their demonstrated neuroprotective properties besides their enhancing effect on monoaminergic transmission. Especially, those containing a propargylamine moiety are of particular interest due to their reported beneficial actions. Therefore, targeting MAO enzymes should be considered in therapeutic interventions. This review makes a special emphasis on MTDLs that commonly target MAO enzymes. There is at present an urgent need for real disease-modifying therapies for AD and the MTDL approach makes a breakthrough for the development of new drugs capable of addressing the biological complexity of this disorder.

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC 50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.

The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were T-DSM-IV-S, CGI-I and neuropsychological tests battery. Safety assessments included electrocardiogram, adverse events checklist and laboratory tests. According to the endpoint improvement scores of CGI and parents T-DSM-IV-S, treatment responses were not significantly different between the two study groups. OROS-MPH led to a significantly greater reduction in teacher T-DSM-IV-S scale scores. OROS-MPH was more effective than atomoxetine on Stroop-5 time and number of corrections. Significant decrease in the percentage of perseverative errors on WCST in the OROS-MPH group was seen ( p  = 0.005). The most frequently reported adverse events in the atomoxetine group were anorexia, nausea, nervousness, weight loss, abdominal pain, and somnolence. In the OROS-MPH group, patients most frequently reported anorexia, nervousness, insomnia, headache, nausea, and weight loss. When all these results are considered, although both drugs can be considered effective in ADHD treatment, more remarkable improvement is provided by OROS-MPH based on the rates across informant (i.e., teachers, clinicians) and neuropsychological evaluation.