Efficacy, Safety, and Systemic Exposure of Once-Daily Indacaterol Acetate in Pediatric Asthma: A Randomized, Double-Blind, Controlled Dose-Finding Study.

BACKGROUND: Indacaterol acetate (IND), a long-acting ß2-agonist in combination with mometasone furoate (MF), an inhaled corticosteroid (ICS), is being explored as a once-daily (od) treatment for asthma in children. This study examined the efficacy, safety, and systemic exposure of IND 75 µg and IND 150 µg in children with persistent asthma. METHODS: In this Phase IIb, multicenter, randomized, double-blind, parallel-group study, pediatric patients (aged ≥ 6 to < 12 years) with persistent asthma were randomized (1:1) to receive either IND 75 µg od or IND 150 µg od via Breezhaler® in combination with ICS background therapy. The primary endpoint was change from baseline in pre-dose trough forced expiratory volume in one second (FEV1) after two weeks of treatment. RESULTS: In total, 80 patients received IND 75 µg (n = 39) or IND 150 µg (n = 41). The study met its primary endpoint; both doses demonstrated improvements in pre-dose trough FEV1 from baseline to Day 14 (mean change [Δ]: 212 mL, IND 75 µg; 171 mL, IND 150 µg). The secondary spirometry parameters (post-dose FEV1 after 1-h, post-dose forced vital capacity; morning and evening peak expiratory flow) also improved. Overall, 36.1% in IND 75 µg group and 25% patients in IND 150 µg group achieved a decrease from baseline in Pediatric Interviewer-administered Asthma Control Questionnaire score of ≥ 0.5 units. A dose-dependent increase in plasma IND concentration was noted between the two groups. Both IND doses demonstrated an acceptable safety profile. CONCLUSIONS: Once-daily IND 75 µg and IND 150 µg via Breezhaler® in combination with background ICS therapy provided substantial bronchodilation in children with asthma and were well tolerated. Taken together, these clinical and systemic exposure findings support IND 75 µg as the most appropriate dose for evaluation in Phase III trials in combination with MF in pediatric asthma. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02892019; 08-Sep-2016).

Tail suspension test does not detect antidepressant-like properties of atypical antipsychotics.

The purpose of this study was to investigate the potency of atypical antipsychotics (clozapine, olanzapine, amisulpride, quetiapine, aripiprazole, risperidone) to reduce immobility time and to increase the fighting power, and the number of fights in an automated version of the tail suspension test in C57BL/6J mice. Antidepressant drugs, citalopram and imipramine were tested for comparison. Olanzapine (0.125-5 mg/kg), amisulpride (0.5-2 mg/kg), quetiapine (0.25-2 mg/kg), aripiprazole (0.25-1 mg/kg), and risperidone (0.005-0.05 mg/kg) did not produce any antidepressant-like effect. Only clozapine (0.156-2.5 mg/kg), administered at a dose of 0.312 mg/kg, significantly increased the number of fight episodes. As expected, citalopram (20-40 mg/kg) and imipramine (10-30 mg/kg) dose dependently produced antidepressant-like activity in the same procedure. The effect of antipsychotics on spontaneous locomotor activity and MK-801-induced or d-amphetamine-induced hyperactivity, were also tested in CD-1 mice to confirm the active doses of these drugs in tests commonly used to predict antipsychotic-like activity. Careful screening of potential antipsychotics for their antidepressant effects is considered to be an important part of modern drug development. Our data suggest that the tail suspension test in mice may be relatively insensitive to antidepressant-like activity of atypical antipsychotic drugs with antidepressant properties confirmed by clinical trials.

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

Behavioral phenotyping of Nestin-Cre mice: implications for genetic mouse models of psychiatric disorders.

Genetic mouse models based on the Cre-loxP system have been extensively used to explore the influence of specific gene deletions on different aspects of behavioral neurobiology. However, the interpretation of the effects attributed to the gene deletion might be obscured by potential side effects secondary to the Cre recombinase transgene insertion or Cre activity, usually neither controlled nor reported. Here, we performed a comprehensive behavioral analysis of endophenotypes of neuropsychiatric disorders in the extensively used Nestin(Cre) mouse line, commonly employed to restrict genetic modifications to the CNS. We observed no alterations in locomotion, general exploratory activity, learning and memory, sociability, startle response and sensorimotor gating. Although the overall response to stimuli triggering anxiety-like behaviors remained unaltered in Nestin(Cre) mice, a strong impairment in the acquisition of both contextual- and cued-conditioned fear was observed. These results underline the importance of adequately controlling the behavioral performance of the employed Cre-lines per-se in pre-clinical neurobehavioral research.

The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition.

In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.