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Antonio R Anzueto,1,2 Claus F Vogelmeier,3 Konstantinos Kostikas,4 Karen Mezzi,4 Sebastian Fucile,5 Giovanni Bader,4 Steven Shen,5 Donald Banerji,5 Robert Fogel5 1University of Texas Health Science Center, 2South Texas Veterans Healthcare System, University of Texas, San Antonio, TX, United States; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients.Methods: Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George’s Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1.Results: Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P

Maria Vittoria Cossu,1 Dario Cattaneo,1 Serena Fucile,1 Paolo Pellegrino,1 Sara Baldelli,1 Valeria Cozzi,1 Amedeo Capetti,2 Emilio Clementi1,3 1Unit of Clinical Pharmacology, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital “Luigi Sacco”, Università di Milano, Milan, Italy; 2Unit of Infectious Diseases, University Hospital “Luigi Sacco”, Milan, Italy; 3Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy Abstract: We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs’ efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug’s pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0–t, and AUC0–∞). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5–1 hour – a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone. Keywords: coadministration, pharmacokinetic profile, adverse events, ibuprofen, isosorbide dinitrate

A cDNA coding for the human neuronal nicotinic [Alpha]7 receptor subunit with Leu-248 mutated to threonine was expressed in Xenopus oocytes. When activated by acetylcholine (AcCho), the receptors expressed generated currents that had low desensitization, linear current-voltage relation, and high apparent affinity for both AcCho and nicotine. These characteristics are similar to those already described for the chick threonine-for-leucine-247 [Alpha]7 nicotinic AcCho receptor (nAcChoR) mutant (L247T[Alpha]7). These properties were all substantially maintained when the human L248T[Alpha]7 mutant was transiently expressed in human Bosc 23 cells. Simultaneous whole-cell clamp and fluorescence measurements with the [Ca.sup.2+] indicator dye Fura-2 showed that nicotine induced a [Ca.sup.2+] influx in standard 2 mM [Ca.sup.2+] solution. The average fractional [Ca.sup.2+] current flowing through L248T[Alpha]7 nAcChoRs was 6.7%, which is larger than that flowing through muscle [Alpha][Beta][Epsilon][Delta] nAcChoRs (4.1%). The relative [Ca.sup.2+] permeability, determined in oocytes in the absence of [Cl.sup.-], was measured from the shift in reversal potential caused by increasing the external [Ca.sup.2+] concentration from 1 to 10 mM. The human wild-type [Alpha]7 nAcChoR was found to be more permeable than the L248T[Alpha]7 mutant to [Ca.sup.2+]. Our findings indicate that the [Ca.sup.2+] permeability of the homomeric [Alpha]7 nAcChoR is larger than that of the heteromeric neuronal nicotinic receptors studied to date and is possibly similar to that of the N-methyl-D-aspartate subtype of brain glutamate receptors.

Aim: To describe the clinical properties and psychometric soundness of pediatric oral motor feeding assessments. Methods: A systematic search was conducted using Medline, CINAHL, EMBASE, PsycInfo, and HAPI databases. Assessments were analyzed for their clinical and psychometric characteristics. Results: 12 assessment tools were identified to meet the inclusion/exclusion criteria. Clinical properties varied from assessments evaluating oral-motor deficits, screening to identify feeding problems, and monitoring feeding progress. Most assessments were designed for children with developmental disabilities or cerebral palsy. Eleven assessments had psychometric evidence, of these nine had reliability and validity testing (Ability for Basic Feeding and Swallowing Scale for Children, Behavioral Assessment Scale of Oral Functions in Feeding, Dysphagia Disorder Survey, Functional Feeding Assessment-modified, Gisel Video Assessment, Montreal Children's Hospital Feeding Scale, Oral Motor Assessment Scale, Schedule for Oral Motor Assessment, and Screening Tool of Feeding Problems Applied to Children). The Brief Assessment of Motor Function-Oral Motor Deglutition and the Pediatric Assessment Scale for Severe Feeding Problems had reliability testing only. The Slurp Test was not tested for any psychometric properties. Overall, psychometric evidence was inconsistent and inadequate for the evaluative tools. [ABSTRACT FROM AUTHOR]

This study assessed the effect of an oral stimulation program on the maturation of sucking skills of preterm infants. Thirty-two preterm infants (13 males, 19 females), appropriate size for gestational age (gestational age at birth 28 wks, SD 1.2wks; birthweight 1002g, SD 251g), were randomly placed into experimental and control groups. The experimental group received a daily 15-minute oral stimulation program, consisting of stroking the peri- and intra-oral structures, for 10 days before the start of oral feedings. Sucking measures were monitored with a specially-designed nipple-bottle apparatus. Results indicate that the experimental group achieved full oral feedings 7 days sooner than the control group, and demonstrated greater overall intake (%), rate of milk transfer (mL/min), and amplitude of the expression component of sucking (mmHg). There was no difference in sucking stage maturation, sucking frequency, and amplitude of the suction component of sucking. Endurance, defined as ability to sustain the same sucking stage, sucking burst duration, and suction and expression amplitudes throughout a feeding session, was not significantly different between the two groups. The stimulation program enhanced the expression component of sucking, resulting in better oral feeding performance. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4).Experimental Approach: The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours.Key Results: When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions.Conclusion and Implications: Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation. [ABSTRACT FROM AUTHOR]

We have shown that the provision of a nonnutritive oral motor therapy (NNOMT) or infant massage therapy (iMT) provided singly and in combination vs. no intervention shortens the number of days from start to independent oral feeding in very low birth weight infants. This study hypothesizes that infants who benefited from NNOMT and/or iMT will demonstrate enhanced maturation of their oral feeding skills (OFS) when compared to control counterparts. OFS levels were monitored using a recently developed scale that takes into account their nutritive sucking skills and endurance at time of assessment. It is a simple method that requires only the additional reading of the volume taken 5 minutes into the start of a feeding and information routinely recorded in patients' medical chart. Four OFS levels were identified, characterized by infant's proficiency (% volume taken during the first 5 min/volume prescribed) and rate of transfer monitored over the entire feeding session (ml/min); OFS level 1 being the most immature and 4 the most mature. In parallel with the benefits provided by NNOMT and/or iMT, we demonstrate the direct positive impact these interventions have on accelerating the maturation of infants' oral feeding skills. [ABSTRACT FROM AUTHOR]