The role of Veterinary Services in areas of conflict.

Armed conflict significantly impacts livestock production, animal health, public health, and the delivery of Veterinary Services by limiting resources, eroding border control, disrupting land use, impairing disease surveillance, and reducing food safety and quality. Those seeking to build capacity in animal health in areas of conflict should focus on strengthening resilience in animal production systems and animal health infrastructure to minimise the devastating effects of conflict. Methods for reconstructing Veterinary Service systems should be tailored to each country's specific needs. These can be determined through participatory assessment, with a focus on building sustainable relationships among all stakeholders. Although it is tempting for animal health professionals to focus primarily on improving animal health on individual farms or targeting specific diseases, attention should be centred on entire systems and on developing sustainable agricultural improvements that will enhance livelihoods on a national scale. Aiding economic growth can also help to lower the probability of future conflict.

Les conflits armés ont d'importantes répercussions sur l'élevage, la santé animale, la santé publique et les prestations des Services vétérinaires, car ils limitent les ressources, mettent à mal les contrôles aux frontières, perturbent l'utilisation des terres, nuisent à la surveillance des maladies et réduisent la sécurité sanitaire et la qualité des aliments. Les acteurs cherchant à renforcer les capacités en santé animale dans les zones de conflit devraient se centrer sur la consolidation de la résilience des systèmes de production animale et des infrastructures de santé animale afin de réduire au minimum les effets dévastateurs du conflit. Il convient d'adapter les méthodes de reconstruction des Services vétérinaires aux besoins spécifiques de chaque pays. Ceux-ci peuvent être estimés à partir d'évaluations participatives, qui mettent l'accent sur l'édification de relations durables entre tous les acteurs concernés. S'il peut être tentant pour les professionnels de la santé animale de s'attacher en premier lieu à l'amélioration de la santé animale dans des exploitations individuelles ou de cibler certaines maladies particulières, il faudrait plutôt centrer l'attention sur les systèmes dans leur ensemble et sur la mise sur pied d'améliorations agricoles durables qui finiront par renforcer les moyens de subsistance à l'échelle nationale. Les mesures favorisant la croissance économique peuvent également contribuer à réduire la probabilité d'un futur conflit.

Los conflictos armados inciden sustancialmente en la producción ganadera, la sanidad animal, la salud pública y la prestación de servicios veterinarios porque disminuyen los recursos disponibles, erosionan los controles de fronteras, desorganizan los usos del suelo, dificultan la vigilancia de enfermedades y merman los niveles de inocuidad y calidad de los alimentos. Quienes traten de potenciar los medios de acción zoosanitaria en zonas de conflicto deberían centrarse en conferir más resiliencia a los sistemas de producción animal y las infraestructuras zoosanitarias con el fin de reducir al mínimo los devastadores efectos de los conflictos. Los métodos para reconstruir los sistemas de prestación de servicios veterinarios deben estar adaptados a las necesidades específicas de cada país, necesidades que se pueden determinar con procesos de evaluación participativa, procurando especialmente forjar relaciones sostenibles entre todas las partes interesadas. Aunque para los profesionales de la sanidad animal resulte tentador centrarse primordialmente en la mejora de las condiciones zoosanitarias en las explotaciones o combatir selectivamente determinadas enfermedades, lo conveniente es prestar atención a los sistemas considerados en su conjunto e introducir en el mundo agropecuario mejoras sostenibles que potencien los medios de vida de la población de todo el país. El hecho de apuntalar el crecimiento económico también puede ser útil para reducir las probabilidades de conflicto en el futuro.

A Phase 3, Multicenter, Open-Label, 12-Month Extension Safety and Tolerability Trial of Lisdexamfetamine Dimesylate in Adults With Binge Eating Disorder.

BACKGROUND: A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). METHODS: Adults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. RESULTS: Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. CONCLUSIONS: In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.

The apparent role of climate change in a recent anthrax outbreak in cattle.

An anthrax outbreak recently occurred in cattle in a region that had previously been free of the disease for more than two decades. This event followed heavy springtime rains that had caused flooding, and a hot, dry summer. These temporally connected events may indicate a new link between climate change and an increased incidence of bacterial diseases with environmental reservoirs.

Récemment, un foyer de fièvre charbonneuse a affecté les bovins d'une région précédemment indemne de cette maladie depuis au moins deux décennies. De fortes précipitations printanières accompagnées d'inondations et suivies d'un été chaud et sec ont précédé cet événement. La relation chronologique entre ces événements semble indiquer un nouveau lien entre le changement climatique et l'incidence en hausse des maladies bactériennes ayant des réservoirs dans l'environnement naturel.

En fechas recientes se produjo un brote de carbunco bacteridiano que afectó al ganado vacuno de una región que hasta entonces llevaba más de dos décadas libre de la enfermedad. Ese episodio ocurrió después de intensas lluvias primaverales, que causaron inundaciones, y de un verano seco y caluroso. Estos fenómenos conectados en el tiempo podrían ser indicativos de la existencia de un nuevo vínculo entre el cambio climático y una mayor incidencia de enfermedades bacterianas que disponen de reservorios en el medio natural.

Lisdexamfetamine Dimesylate Effects on Binge Eating Behaviour and Obsessive-Compulsive and Impulsive Features in Adults with Binge Eating Disorder.

In a published 11-week, placebo-controlled trial, 50 and 70 mg/d lisdexamfetamine dimesylate (LDX), but not 30 mg/d LDX, significantly reduced binge eating days (primary endpoint) in adults with binge eating disorder (BED). This report provides descriptions of LDX effects on secondary endpoints (Binge Eating Scale [BES]; Three-Factor Eating Questionnaire [TFEQ]; Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE]; and the Barratt Impulsiveness Scale, version 11 [BIS-11]) from that study. Week 11 least squares mean treatment differences favoured all LDX doses over placebo on the BES (p ≤ 0.03), TFEQ Disinhibition and Hunger subscales (all p < 0.05), and Y-BOCS-BE total, obsessive, and compulsive scales (all p ≤ 0.02) and on BIS-11 total score at 70 mg/d LDX (p = 0.015) and the TFEQ Cognitive Restraint subscale at 30 and 70 mg/d LDX (both p < 0.05). These findings indicate that LDX decreased global binge eating severity and obsessive-compulsive and impulsive features of BED in addition to binge eating days.

A generalized estimating equation approach to analysis of maintenance of wakefulness testing in a study of lisdexamfetamine dimesylate, armodafinil, and placebo in sleep-deprived adults.

In a study of acute sleep deprivation in healthy male volunteers randomized to double-blind treatment with lisdexamfetamine dimesylate (20, 50, or 70 mg), placebo control, or an active control (armodafinil 250 mg), Maintenance of Wakefulness Test data were compared using a generalized estimating equation analysis to eliminate the need for unequivocal sleep latency imputation. Compared with placebo across all Maintenance of Wakefulness Tests, all active treatments were associated with lower risk of falling asleep (risk ratio [95% confidence interval]): 0.45 (0.27-0.76; P = 0.0026), 0.10 (0.05-0.20; P < 0.0001), and 0.05 (0.02-0.14; P < 0.0001) for 20, 50, and 70 mg lisdexamfetamine dimesylate, respectively, and 0.11 (0.06-0.21; P < 0.0001) for the active control. Sleep-risk ratios were similar for lisdexamfetamine dimesylate 50 or 70 mg and for the active control, but lisdexamfetamine 20 mg was associated with a greater risk of falling asleep compared with the active control (4.13 [1.97-8.67]; P = 0.0002). Generalized estimating equation analysis detected wake-promoting effects of active treatments and eliminating data imputation, suggesting model utility in future studies.

A randomized clinical trial of Cogmed Working Memory Training in school-age children with ADHD: a replication in a diverse sample using a control condition.

BACKGROUND: Cogmed Working Memory Training (CWMT) has received considerable attention as a promising intervention for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. At the same time, methodological weaknesses in previous clinical trials call into question reported efficacy of CWMT. In particular, lack of equivalence in key aspects of CWMT (i.e., contingent reinforcement, time-on-task with computer training, parent-child interactions, supportive coaching) between CWMT and placebo versions of CWMT used in previous trials may account for the beneficial outcomes favoring CWMT. METHODS: Eighty-five 7- to 11-year old school-age children with ADHD (66 male; 78%) were randomized to either standard CWMT (CWMT Active) or a well-controlled CWMT placebo condition (CWMT Placebo) and evaluated before and 3 weeks after treatment. Dependent measures included parent and teacher ratings of ADHD symptoms; objective measures of attention, activity level, and impulsivity; and psychometric indices of working memory and academic achievement (Clinical trial title: Combined cognitive remediation and behavioral intervention for the treatment of Attention-Deficit/Hyperactivity Disorder; http://clinicaltrials.gov/ct2/show/NCT01137318). RESULTS: CWMT Active participants demonstrated significantly greater improvements in verbal and nonverbal working memory storage, but evidenced no discernible gains in working memory storage plus processing/manipulation. In addition, no treatment group differences were observed for any other outcome measures. CONCLUSIONS: When a more rigorous comparison condition is utilized, CWMT demonstrates effects on certain aspects of working memory in children with ADHD; however, CWMT does not appear to foster treatment generalization to other domains of functioning. As such, CWMT should not be considered a viable treatment for children with ADHD.

Precocious mammary gland development in P-cadherin-deficient mice.

To investigate the functions of P-cadherin in vivo, we have mutated the gene encoding this cell adhesion receptor in mice. In contrast to E- and N-cadherin- deficient mice, mice homozygous for the P-cadherin mutation are viable. Although P-cadherin is expressed at high levels in the placenta, P-cadherin-null females are fertile. P-cadherin expression is localized to the myoepithelial cells surrounding the lumenal epithelial cells of the mammary gland. The role of the myoepithelium as a contractile tissue necessary for milk secretion is clear, but its function in the nonpregnant animal is unknown. The ability of the P-cadherin mutant female to nurse and maintain her litter indicates that the contractile function of the myoepithelium is not dependent on the cell adhesion molecule P-cadherin. The virgin P-cadherin-null females display precocious differentiation of the mammary gland. The alveolar-like buds in virgins resemble the glands of an early pregnant animal morphologically and biochemically (i.e., milk protein synthesis). The P-cadherin mutant mice develop hyperplasia and dysplasia of the mammary epithelium with age. In addition, abnormal lymphocyte infiltration was observed in the mammary glands of the mutant animals. These results indicate that P-cadherin-mediated adhesion and/or signals derived from cell-cell interactions are important determinants in negative growth control in the mammary gland. Furthermore, the loss of P-cadherin from the myoepithelium has uncovered a novel function for this tissue in maintaining the undifferentiated state of the underlying secretory epithelium.

Sequenced neurocognitive and behavioral parent training for the treatment of ADHD in school-age children.

The present study examines the potential of sequencing a neurocognitive intervention with behavioral parent training (BPT) to improve executive functions (EFs), psychiatric symptoms, and multiple indices of functional impairment in school-age children aged 7 to 11 years who have been diagnosed with attention-deficit/hyperactivity disorder (ADHD). Specifically, in a randomized controlled trial design, 85 children were assigned to either Cogmed Working Memory Training (CWMT) followed by an empirically supported, manualized BPT intervention, or to a placebo version of CWMT followed by the same BPT intervention. Working memory maintenance (i.e., attention control/short-term memory), working memory processing and manipulation, ADHD and oppositional defiant disorder (ODD) symptoms, impairment in parent-child dynamics, familial impairment, and overall functional compromise were evaluated as outcomes. The results suggest specific effects of the combined CWMT and BPT program on verbal and nonverbal working memory storage and nonverbal working memory processing and manipulation but no incremental benefits in regard to ADHD symptoms, ODD symptoms, and functional outcomes. The present findings do not support the hypothesis regarding the complementary and augmentative benefits of sequenced neurocognitive and BPT interventions for the treatment of ADHD. These results, the study's limitations, and future directions for research are further discussed.

12-O-tetradecanoylphorbol-13-acetate activation of the MDR1 promoter is mediated by EGR1.

P-glycoprotein, the product of the MDR1 gene (multidrug resistance gene 1), is an energy-dependent efflux pump associated with treatment failure in some hematopoietic malignancies. Its expression is regulated during normal hematopoietic differentiation, although its function in normal hematopoietic cells is unknown. To identify cellular factors that regulate the expression of MDR1 in hematopoietic cells, we characterized the cis- and trans-acting factors mediating 12-O-tetradecanoylphorbol-13-acetate (TPA) activation of the MDR1 promoter in K562 cells. Transient-transfection assays demonstrated that an MDR1 promoter construct containing nucleotides -69 to +20 conferred a TPA response equal to that of a construct containing nucleotides -434 to +105. TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. The -69/+20 promoter region contains an overlapping SP1/EGR site. The TPA-responsive element was localized to the overlapping SP1/EGR site by using a synthetic reporter construct. A mutation in this site that inhibited EGR protein binding blocked the -69/+20 MDR1 promoter response to TPA. The expression of a dominant negative EGR protein also blocked the TPA response of the -69/+20 promoter construct. Finally, the expression of EGR1 was sufficient to activate a construct containing tandem MDR1 promoter SP1/EGR sites. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells.

Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial.

Importance: The ability of pharmacotherapies to prevent relapse and maintain efficacy with long-term treatment in psychiatric conditions is important. Objective: To assess lisdexamfetamine dimesylate maintenance of efficacy in adults with moderate to severe binge-eating disorder. Design, Setting, and Participants: A multinational, phase 3, double-blind, placebo-controlled, randomized withdrawal study including 418 participants was conducted at 49 clinical research study sites from January 27, 2014, to April 8, 2015. Eligible adults met DSM-IV-R binge-eating disorder criteria and had moderate to severe binge eating disorder (≥3 binge-eating days per week for 14 days before open-label baseline; Clinical Global Impressions-Severity [CGI-S] scores ≥4 [moderate severity] at screening and open-label baseline). Following a 12-week, open-label phase (dose optimization, 4 weeks [lisdexamfetamine dimesylate, 50 or 70 mg]; dose maintenance, 8 weeks), lisdexamfetamine responders (≤1 binge eating day per week for 4 consecutive weeks and CGI-S scores ≤2 at week 12) were randomized to placebo or continued lisdexamfetamine during a 26-week, double-blind, randomized withdrawal phase. Interventions: Lisdexamfetamine administration. Main Outcomes and Measures: The primary outcome variable, time to relapse (≥2 binge-eating days per week for 2 consecutive weeks and ≥2-point CGI-S score increases from randomized withdrawal baseline), was analyzed using a log-rank test (primary analysis); the analysis was stratified for dichotomized 4-week cessation status. Safety assessments included treatment-emergent adverse events. Results: Of the 418 participants enrolled in the open-label phase of the study, 411 (358 [87.1%] women; mean [SD] age, 38.3 [10.4] years) were included in the safety analysis set. Of 275 randomized lisdexamfetamine responders (placebo, n = 138; lisdexamfetamine, n = 137), the observed proportions of participants meeting relapse criteria were 3.7% (5 of 136) for lisdexamfetamine and 32.1% (42 of 131) for placebo. Lisdexamfetamine demonstrated superiority over placebo on the log-rank test (χ21, 40.37; P < .001) for time to relapse; the hazard ratio, based on a Cox proportional hazards model for lisdexamfetamine vs placebo, was 0.09 (95% CI, 0.04-0.23). The treatment-emergent adverse events observed were generally consistent with the known profile of lisdexamfetamine. Conclusions and Relevance: Risk of binge-eating relapse over 6 months was lower in participants continuing lisdexamfetamine than in those randomized to placebo. The hazard for relapse was lower with lisdexamfetamine than placebo. Trial Registration: clinicaltrials.gov Identifier: NCT02009163.

Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs.

The accumulation of daunomycin in drug-sensitive and multidrug-resistant human KB cells was examined using light microscopy to detect the inherent fluorescence of daunomycin. Intracellular accumulation of fluorescent drug occurred rapidly in parental KB cells and was markedly reduced in several multidrug-resistant mutants. The addition of verapamil, which reverses multidrug resistance, resulted in increased accumulation of daunomycin in resistant cells. In living cells, most of the daunomycin was found in the nucleus, but significant amounts were detected associated with the plasma membrane, in the cytoplasm, in organelles of the Golgi region, and in lysosomes. The nuclear fluorescence was measured using a photometer system, and the loss of daunomycin from the cells was determined under various conditions. When sensitive cells were allowed to accumulate daunomycin for 5 min at 37 degrees C and then placed in medium without the drug, daunomycin remained inside the nuclei for longer than 1 day. When resistant cells were loaded in the presence of verapamil and the verapamil was removed, the resistant cells lost daunomycin with a half-time of about 1 min. The continuous presence of verapamil markedly inhibited the loss of daunomycin from the cells. Similar results were obtained in separate experiments using [3H]daunomycin. Vinblastine, vincristine, and quinidine were also effective in stimulating daunomycin accumulation in multidrug-resistant cells and in preventing the loss of daunomycin from these resistant cells. This effect required half-maximal concentrations of 1-2 microM for verapamil, vinblastine, and quinidine. Ouabain, lanthanum, colchicine, amiloride, probenecid, and 1-beta-D-arabinofuranosylcytosine had no effect on this process. Quinine was effective at 10 microM and nifedipine was effective at 50 microM. Depletion of cellular adenosine triphosphate levels by preincubation of cells with azide and 2-deoxyglucose partially inhibited daunomycin loss from resistant cells. These single-cell measurements indicate that diminished daunomycin accumulation in multidrug-resistant cells results from accelerated energy-dependent efflux across the plasma membrane, and this efflux is inhibited by verapamil, quinidine, vincristine, and vinblastine.

Lisdexamfetamine Dimesylate for Adults with Moderate to Severe Binge Eating Disorder: Results of Two Pivotal Phase 3 Randomized Controlled Trials.

The efficacy and safety of lisdexamfetamine dimesylate (LDX) vs placebo in binge eating disorder (BED) was evaluated in two multicenter, double-blind, placebo-controlled trials. Adults (study 1, n=383; study 2, n=390) meeting DSM-IV-TR BED criteria were randomized (1:1) to placebo or LDX (50 or 70 mg/day) dose titration; optimized doses were maintained to the end of double-blind treatment (week 12/early termination). Change from baseline in binge eating days/week at weeks 11-12 (primary efficacy endpoint) was assessed with mixed-effects models for repeated measures. Secondary endpoints related to binge eating and medical parameters, safety, and treatment compliance were also assessed. Least squares mean (95% CI) treatment differences for change from baseline binge eating days/week at weeks 11-12 significantly favored LDX (study 1: -1.35 [-1.70, -1.01]; study 2: -1.66 [-2.04, -1.28]; both P<0.001). In both studies, treatment-emergent adverse events (TEAEs) reported by ⩾10% of LDX participants were dry mouth, insomnia, and headache. Serious TEAEs occurred in two (1.1%) placebo participants in each study and in three (1.6%) and one (0.6%) LDX participants in study 1 and study 2, respectively. Across studies, mean increases from baseline at week 12/early termination with LDX for pulse and systolic and diastolic blood pressure ranged from 4.41-6.31 b.p.m. and 0.2-1.45 and 1.06-1.83 mm Hg, respectively. LDX (50 and 70 mg/day) was superior to placebo in decreasing binge eating days/week from baseline and improving binge eating-related key secondary endpoints. Safety results appear consistent with the known safety profile of LDX.

Inhibition of the adhesion of Chinese hamster ovary cells by the naphthylsulfonamides dansylcadaverine and N-(6-aminohexyl)-5-chloro-1-naphthylenesulfonamide (W7).

Treatment of Chinese hamster ovary cells with dansylcadaverine or N-(6-aminohexyl)-5-chloro-1-naphthylenesulfonamide (W7) reduced cell attachment in a reversible, dose-dependent manner. The concentration of dansylcadaverine required to produce 50% inhibition of adhesion was significantly higher than that of W7, 300 microM and 50 microM, respectively. Concentrations of dansylcadaverine and W7 which produced decreased adhesion also antagonized calmodulin-dependent activation of phosphodiesterase. Chlorpromazine, another calmoldulin antagonist also decreased cell attachment. Dansylcadaverine and W7 both interfere with cellular transglutaminase activity, but several other transglutaminase antagonists, such as methylamine, butylamine, putrescine and bacitracin, had no effect on CHO cell attachment. We conclude that naphthylsulfonamides such as dansylcadaverine and W7 may inhibit the attachment of CHO cells by a mechanism which could involve inhibition of calmodulin-dependent processes, although further studies are required to show a direct role of calmodulin in cell adhesion.

Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells.

Expression of the human multidrug resistance 1 gene (MDR1), which encodes the P-glycoprotein transmembrane efflux pump, has been associated with treatment failure of some leukemias, primarily acute myeloid leukemia (AML). To elucidate the epigenetic events associated with overexpression of MDR1 in AML, we analyzed the methylation status of a 2000 bp region within the MDR1 locus using a bisulphite genomic sequencing technique. A CpG-rich domain, approximately 1 kb in size, encompasses the promoter region, exon I, and intron I. This domain was found to be relatively unmethylated in five out of six primary and cultured human hematopoietic cells, as well as five out of six AML patient samples, independent of the MDR1 phenotype. The data suggest that the methylation status of the CpG-rich domain does not act as a 'switch' to regulate expression of the MDR1 gene. In addition, we found an upstream Alu repeat sequence to be unmethylated in three out of five cultured hematopoietic cell lines, both MDR1 expressing and non-expressing. However, analysis of primary CD8-positive T cells and AML patient samples revealed dense methylation of this region which is consistent with methylation of Alu repeat sequences observed in somatic tissues.

Studies on the effects of dansylcadaverine and related compounds on receptor-mediated endocytosis in cultured cells.

It has been suggested that cellular transglutaminases may play an important role in the process of receptor-mediated endocytosis. We have examined this premise by investigating the receptor-mediated endocytosis of two proteins, epidermal growth factor and alpha 2 macroglobulin in cells that are deficient in transglutaminases. We find that endocytic activity is normal in these cells, ruling out an obligatory role for transglutaminases in endocytosis. We do find, however, that dansylcadaverine is not an inhibitor of endocytosis in cells that lack transglutaminase activity. Immunofluorescent localization of dansylcadaverine in dansylcadaverine-treated cells demonstrates incorporation of the amino into endocytic vesicles. We believe that covalent coupling of dansylcadaverine to cellular membranes may account for its ability to interfere with endocytosis in certain susceptible cells.

Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: a randomized clinical trial.

IMPORTANCE: Binge-eating disorder (BED), a public health problem associated with psychopathological symptoms and obesity and possibly with metabolic syndrome, lacks approved pharmacotherapies. OBJECTIVE: To examine the efficacy and safety of lisdexamfetamine dimesylate, a dextroamphetamine prodrug, to treat moderate to severe BED. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012. Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively. INTERVENTIONS: Lisdexamfetamine dimesylate at dosages of 30, 50, or 70 mg/d or placebo were provided to study participants (1:1:1:1). Dosages were titrated across 3 weeks and maintained for 8 weeks. We followed up participants for a mean (SD) of 7 (2) days after the last dose. MAIN OUTCOMES AND MEASURES: We assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1. Secondary measures included BE cessation for 4 weeks. Safety assessments included treatment-emergent adverse events, vital signs, and change in weight. RESULTS: At week 11, log-transformed BE days per week decreased with the 50-mg/d (least squares [LS] mean [SE] change, -1.49 [0.066]; P = .008) and 70-mg/d (LS mean [SE] change, -1.57 [0.067]; P < .001) treatment groups but not the 30-mg/d treatment group (LS mean [SE] change, -1.24 [0.067]; P = .88) compared with the placebo group. Nontransformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/d treatment groups by -3.3 (2.04), -3.5 (1.95), -4.1 (1.52), and -4.1 (1.57), respectively. The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3%) compared with the 50-mg/d (42.2% [P = .01]) and 70-mg/d (50.0% [P < .001]) treatment groups. The incidence of any treatment-emergent adverse events was 58.7% for the placebo group and 84.7% for the combined treatment group. In the treatment groups, 1.5% of participants had serious treatment-emergent adverse effects. Events with a frequency of at least 5% and changes in heart rate were generally consistent with the known safety profile. The mean (SD) change in body weight was -0.1 (3.09), -3.1 (3.64), -4.9 (4.43), -4.9 (3.93), and -4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/d treatment groups, and the combined treatment groups, respectively (P < .001 for each dose vs placebo group comparison in post hoc analysis). CONCLUSIONS AND RELEVANCE: The 50- and 70-mg/d treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement. The safety profile was generally consistent with previous findings in adults with attention-deficit/hyperactivity disorder. Further investigation of lisdexamfetamine in BED is ongoing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01291173.

Immunocytochemical localization of P170 at the plasma membrane of multidrug-resistant human cells.

P170 (P-glycoprotein) is a membrane protein found in high levels in multidrug-resistant cultured cell lines. We have localized this protein using monoclonal antibody MRK16 by immunofluorescence and electron microscopy in the multidrug-resistant human carcinoma cell line KB-C4. The P170 determinant recognized by antibody MRK16 was found on drug-resistant KB-C4 cells, but not on parental drug-sensitive KB-3-1 cells. The determinant was present on the external surface of the plasma membrane and on the luminal side of Golgi stack membranes. P170 was excluded from coated pits at the plasma membrane and absent from endocytic vesicles and lysosomes. This determinant was detected only in small amounts in the endoplasmic reticulum. The high protein concentration of P170 in the plasma membrane is consistent with a role of this protein as a drug efflux pump at the cell surface.

Analysis of structural features of dihydropyridine analogs needed to reverse multidrug resistance and to inhibit photoaffinity labeling of P-glycoprotein.

Synthetic dihydropyridine analogs were screened to determine whether they would reverse multidrug resistance of a multidrug-resistant human KB carcinoma cell line, KB-C1. Among twenty-four dihydropyridine analogs examined, thirteen almost completely overcame drug resistance (group A), nine partially overcame resistance (group B) and two did not reverse resistance (group C). The twenty-two compounds that reversed drug-resistance (groups A and B) were hydrophobic dihydropyridine derivatives. Three compounds that reversed resistance, NK-113, NK-138 and NK-194, increased the accumulation of [3H]vincristine in the resistant KB-C1 cells, but not in the parental KB cells, nor in a revertant cell line, KB-C1-R2. NK-101 (group C), which did not reverse resistance, had no effect on drug accumulation. Enhanced efflux of vincristine from the resistant cells was inhibited completely by NK-194, but NK-194 did not affect vincristine influx. Nine of the twenty-four compounds were screened to determine whether they inhibited photoaffinity labeling of the cell surface protein gp170 (P-glycoprotein) in KB-C1 cells by N-(p-azido-[3-125I]-salicyl)-N'-beta-aminoethylvindesine [( 125I]NASV). All five compounds of group A, NK-138, NK-194, NK-200, NK-203 and NK-220, inhibited the photoaffinity labeling of gp170 at less than 10-100 microM, whereas NK-113 and NK-196 of group B inhibited the labeling at 100-200 microM. By contrast, NK-101 and NK-102 of group C did not inhibit labeling even at 2000 microM. These studies confirm the relationship among reversal of multidrug resistance, decreased efflux of vincristine, and inhibition of [125I]NASV labeling of P-glycoprotein.

Multifocality in the earliest detectable breast carcinomas.

A prospective study (protocol SG 89-150) was undertaken to determine the role of mammographically guided fine-needle aspirations in the diagnosis and subsequent surgical treatment of nonpalpable, mammographically detected breast cancers. During this study, once a diagnosis of cancer based on mammographically guided fine-needle aspiration was established, a wide segmental excision was performed to attempt to eradicate local disease. Surgical margins free of tumor were obtained in all cases. Total excision of these small lesions permitted in-depth histopathologic evaluation of the specimens. This led to the discovery that even the earliest detectable breast cancers may have extensive involvement of the surrounding breast tissue, which is vital information for planning complete therapy for the patient with breast cancer.