Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial.

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Effects of fadolmidine, an α2 -adrenoceptor agonist, as an adjuvant to spinal bupivacaine on antinociception and motor function in rats and dogs.

α2 -Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2 -adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail-flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co-administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory-motor block and enables a reduction of the doses of both drugs. The results indicate that co-administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler® Device in Patients with Asthma.

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Microemulsion-based gel for the transdermal delivery of rasagiline mesylate: In vitro and in vivo assessment for Parkinson's therapy.

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD. Our in vitro skin permeation studies of RSM-MEG showed significantly higher (at least ~1.5-fold) permeation across rat skin compared to the conventional RSM hydrogel. Our skin irritation studies in rabbits showed that RSM-MEG is safe for transdermal application. Finally, using the rat model of rotenone-induced Parkinsonism, we demonstrated that the topical application of RSM-MEG was equally effective in reversing PD symptoms when compared to oral RSM therapy. Thus, our study confirmed the feasibility and potential of transdermal delivery of RSM via simple topical application of RSM-MEG, and this approach could be an alternative therapeutic intervention for the treatment of Parkinson's disease.

An Overview of the Efficacy and Safety of Ozanimod for the Treatment of Relapsing Multiple Sclerosis.

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.

Intracerebral Administration of a Ligand-ASO Conjugate Selectively Reduces α-Synuclein Accumulation in Monoamine Neurons of Double Mutant Human A30P*A53T*α-Synuclein Transgenic Mice.

α-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson's disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to the key affected neurons. Several experimental strategies for PD have been developed in recent years using oligonucleotide therapeutics. However, some of them have failed or even caused neuronal toxicity. One limiting step in the success of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations. Previously, we developed an indatraline-conjugated antisense oligonucleotide (IND-1233-ASO), that selectively reduces α-Syn synthesis in midbrain monoamine neurons of mice, and nonhuman primates. Here, we extended these observations using a transgenic male mouse strain carrying both A30P and A53T mutant human α-Syn (A30P*A53T*α-Syn). We found that A30P*A53T*α-Syn mice at 4-5 months of age showed 3.5-fold increases in human α-Syn expression in dopamine (DA) and norepinephrine (NE) neurons of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), respectively, compared with mouse α-Syn levels. In parallel, transgenic mice exhibited altered nigrostriatal DA neurotransmission, motor alterations, and an anxiety-like phenotype. Intracerebroventricular IND-1233-ASO administration (100 µg/day, 28 days) prevented the α-Syn synthesis and accumulation in the SNc and LC, and recovered DA neurotransmission, although it did not reverse the behavioral phenotype. Therefore, the present therapeutic strategy based on a conjugated ASO could be used for the selective inhibition of α-Syn expression in PD-vulnerable monoamine neurons, showing the benefit of the optimization of ASO molecules as a disease modifying therapy for PD and related α-synucleinopathies.

Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator.

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

BACKGROUND: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. METHODS: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 µg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 µg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. RESULTS: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. CONCLUSION: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.

Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients.

BACKGROUND: Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting ß2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 µg once daily (o.d.) and indacaterol acetate 150 µg o.d. in comparison with placebo. METHODS: This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 µg o.d., indacaterol acetate 150 µg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. RESULTS: Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). CONCLUSIONS: In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT03257995 June 06, 2017.

Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON).

BACKGROUND: The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. METHODS: Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting ß2-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 µg) or medium-dose (150/50/80 µg) o.d. or SAL/FLU high-dose (50/500 µg) b.i.d.+Tio 5 µg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. RESULTS: IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and -0.038, respectively; both p < 0.001). IND/GLY/MF high-dose improved ACQ-7 (Δ: -0.124; p = 0.004), trough FEV1 (Δ: 96 mL; p < 0.001), peak expiratory flow (morning [Δ: 9.56 L/min; p = 0.005], evening [Δ: 9.15 L/min; p = 0.006]) and SGRQ (Δ: -2.00; p = 0.04) versus SAL/FLU high dose + TIO. Improvements in these endpoints were comparable for IND/GLY/MF medium-dose and SAL/FLU high dose + TIO. Adverse events were generally comparable across treatments. CONCLUSIONS: IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.

OBJECTIVE: To better understand ozanimod's mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod's effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis. METHODS: An open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics. RESULTS: Ozanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined. CONCLUSION: Ozanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod's MOA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT02797015.

Accidental chlorophacinone exposure of lactating ewes: Clinical follow-up and human health dietary implications.

Anticoagulant rodenticides are widely used for rodent control in agricultural and urban settings. Their intense use can sometimes result in accidental exposure and even poisoning of livestock. Can milk, eggs or meat derived from such accidently exposed animals be consumed by humans? Data on the pharmacokinetics of chlorophacinone in milk of accidently exposed ewes were used to estimate the risk associated with its consumption. Three days after accidental ingestion, chlorophacinone was detected in plasma of 18 ewes, with concentrations exceeding 100 ng/mL in 11 animals. Chlorophacinone was detected in milk on day 2 post-exposure and remained quantifiable for at least 7 days in milk of these 11 ewes. Concentrations in milk were much lower than in plasma and decreased quickly (mean half-life of 2 days). This study demonstrated dose-dependent mammary transfer of ingested chlorophacinone. Variation in prothrombin time (PT) on Day 3 suggested that some of the ewes that ingested chlorophacinone may have been adversely affected, but PT did not facilitate estimation of the quantity of chlorophacinone consumed. Using safety factors described in the literature, consumption of dairy products derived from these ewes after a one-week withdrawal period would pose low risk to consumers.

Large nest building and high marble-burying: Two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention.

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study.

BACKGROUND: Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. METHODS: This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 µg, 150 µg) or medium-dose MF-IND (160 µg, 150 µg) once daily via Breezhaler; high-dose MF (800 µg [400 µg twice daily]) or medium-dose MF (400 µg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. FINDINGS: Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. INTERPRETATION: Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. FUNDING: Novartis Pharmaceuticals.