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Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score ≥ 28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95% confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95% CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score.
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Clorhidrato de Atomoxetina/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Dimesilato de Lisdexanfetamina/uso terapéutico , Metilfenidato/uso terapéutico , Adolescente , Atención , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
The production of new knowledge in augmentative and alternative communication (AAC) requires effective processes to leverage the different perspectives of researchers and knowledge users and improve prospects for utilization in clinical settings. This article describes the motivation, planning, process, and outcomes for a novel knowledge translation workshop designed to influence future directions for AAC outcomes research for children with complex communication needs. Invited knowledge users from 20 pediatric AAC clinics and researchers engaged in the collaborative development of research questions using a framework designed for the AAC field. The event yielded recommendations for research and development priorities that extend from the early development of language, communication, and literacy skills in very young children, to novel but unproven strategies that may advance outcomes in transitioning to adulthood.
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Equipos de Comunicación para Personas con Discapacidad , Trastornos de la Comunicación/rehabilitación , Evaluación de Resultado en la Atención de Salud , Investigación , Investigación Biomédica Traslacional , Adolescente , Canadá , Niño , Preescolar , Congresos como Asunto , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: In the context of developmental trajectories, the association between adaptive functioning and core autism symptomatology remains unclear. The current study examines the associations of adaptive behavior with autism symptom sub-domains and with different facets of symptom expression. METHODS: Participants include 36 children with a recent diagnosis of autism (33 males; mean age = 56.4 months; SD = 9 months). Families were recruited in the context of the Pediatric Autism Research Cohort (PARC) project. Parents filled out questionnaires at two time points, six months apart, regarding their child's autism symptoms and adaptive functioning. The longitudinal relationship between adaptive functioning and autism symptoms was investigated using Mixed Linear Model analyses: one assessing the relationship between general symptom levels and adaptive functioning, and another examining the associations between symptom frequency and impact with adaptive functioning. We conducted Pearson correlation tests at both time points to assess the associations between symptom sub-domains and adaptive functioning. RESULTS: Findings showed that higher autism symptoms associated with lower adaptive behavior skills, and that this association remained stable over time. Autism impact scores did not significantly relate to adaptive skills, as opposed to frequency scores. Associations between adaptive functioning and autism symptom sub-domains strengthened over time. CONCLUSION: These findings suggest that adaptive functioning is associated with parent-report autism symptomatology, and that this association changes and, on average, becomes stronger over time. Findings may indicate that frequency and impact of symptoms have differential roles in the development of adaptive skills and are worthy of further exploration.
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Parents (n = 135) were surveyed in relation to administering antipyretic/analgesic medications to their children (2 months-6 years) at home. Parents usually chose acetaminophen, calculated dosages based on weight but did not always know the child's weight, administered medications with a dropper, and reported having a sick child was moderately stressful. Many children were medicated for pain and/or fever during the week prior to immunization and many weighed more than the age/weight recommended dosages on the label. Community health nurses can facilitate safe administration of medications by integrating knowledge of parents' pain and fever management practices into discussions and anticipatory planning during clinic visits.
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Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Medicamentos sin Prescripción/uso terapéutico , Padres , Adulto , Analgésicos/uso terapéutico , Antipiréticos/uso terapéutico , Niño , Preescolar , Centros Comunitarios de Salud/estadística & datos numéricos , Femenino , Fiebre/tratamiento farmacológico , Humanos , Lactante , Masculino , Persona de Mediana Edad , Dolor/tratamiento farmacológico , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUNDSevere coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune response, which can result in cytokine-release syndrome and acute respiratory distress syndrome (ARDS). Patients with COVID-19-associated ARDS have elevated free serum levels of the cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT; also known as TNFSF14). Such patients may benefit from LIGHT-neutralization therapy.METHODSThis randomized, double-blind, multicenter, proof-of-concept trial enrolled adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS. Patients received standard of care plus a single dose of a human LIGHT-neutralizing antibody (CERC-002) or placebo. The primary endpoint was the proportion of patients receiving CERC-002 who remained alive and free of respiratory failure through day 28. Safety was assessed via adverse event monitoring.RESULTSFor most of the 83 enrolled patients, standard of care included systemic corticosteroids (88.0%) or remdesivir (57.8%). A higher proportion of patients remained alive and free of respiratory failure through day 28 after receiving CERC-002 (83.9%) versus placebo (64.5%; P = 0.044), including in patients 60 years of age or older (76.5% vs. 47.1%, respectively; P = 0.042). Mortality rates were 7.7% (CERC-002) and 14.3% (placebo) on day 28 and 10.8% and 22.5%, respectively, on day 60. Treatment-emergent adverse events were less frequent with CERC-002 than placebo.CONCLUSIONFor patients with COVID-19-associated ARDS, adding CERC-002 to standard-of-care treatment reduces LIGHT levels and might reduce the risk of respiratory failure and death.TRIAL REGISTRATIONClinicalTrials.gov NCT04412057.FUNDINGAvalo Therapeutics.
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Anticuerpos Monoclonales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , SARS-CoV-2/metabolismo , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/antagonistas & inhibidores , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Corticoesteroides/administración & dosificación , Adulto , Alanina/administración & dosificación , Alanina/análogos & derivados , COVID-19/sangre , COVID-19/mortalidad , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/mortalidad , Tasa de Supervivencia , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangreRESUMEN
Objective: The day-to-day experience of families with an Autistic child may be shaped by both, child characteristics and available resources, which often are influenced by the socioeconomic context of the family. Using a socioecological approach, this study explored the quantitative associations between child autistic symptoms, family socioeconomic status, and family life. Methods: Data came from the Pediatric Autism Research Cohort-PARC Study (pilot). Parents of children with a recent diagnosis of autism completed a set of assessments, including the Autism Family Experience Questionnaire, Autism Impact Measure, and a Sociodemographic Questionnaire. A series of multiple, iterative linear regression models were constructed to ascertain quantitative associations between child autistic symptoms, socioeconomic context, and family life. Results: A total of 50 children (mean age: 76 months; SD: 9.5 months; and 84% male) with data on the variables of interest were included in the analysis. The frequency of child autistic symptoms was associated with family life outcomes (p = 0.02 and R 2 = 24%). Once autistic symptom frequency, symptom impact, and sociodemographic variables were considered, parents of higher educational attainment reported worse family life outcomes compared to their lesser-educated counterparts. This cumulative regression model had considerable explanatory capability (p = 0.01, R 2 = 40%). Conclusion: This study demonstrates the utility of using a socioecological approach to examine the dynamic interplay between child characteristics and family circumstances. Our findings suggest that family life for parents (of an autistic child) who have obtained higher education is reported (by the parents themselves) as less satisfactory compared to that of parents without higher education, once adjusted for the autistic symptom frequency of child, symptom impact, and income. These findings can inform the design and delivery of more family-centered care pathways during the years following a diagnosis of autism.
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PURPOSE: This study was carried out to determine the meaning of an established intervention called 'Friday afternoon tea' for family members and patients on a palliative care unit. METHOD: A mini-ethnographic study was undertaken in a rural hospital in Newfoundland, Canada, to explore the meaning of 'Friday afternoon tea' as a sub-culture of the palliative care unit. Data were collected using semi-structured, audio-taped interviews with eight family members whose loved ones were receiving end-of-life or symptom management treatment. Data collection also included participant observation and field notes. Thematic analysis of the narratives revealed three themes: more than a cup of tea, a welcomed distraction, and caring and comfort. DISCUSSION AND CONCLUSION: The degree of distress experienced by family members reinforced the importance of the type of supportive intervention that 'Friday afternoon tea' provides. It was found that this bedside care provided additional opportunities for social interaction for family caregivers. This study contributes to evidence-based knowledge concerning the benefits of a cost-effective intervention which can easily be replicated by other palliative care units. This study acknowledges the importance of healthcare team members carrying out informal social initiatives.
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Cuidadores , Cuidados Paliativos , Apoyo Social , Humanos , TéRESUMEN
This report describes an innovative cooperative education model for promoting the integration of oral health and primary care in a safety-net setting for homeless populations. The model situates health sciences students as change agents within the health care team to facilitate interprofessional collaboration and medical-dental integration.
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Conducta Cooperativa , Atención Odontológica/organización & administración , Promoción de la Salud/organización & administración , Personas con Mala Vivienda , Modelos Educacionales , Atención Primaria de Salud/organización & administración , Humanos , Estados UnidosRESUMEN
Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D-dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C12 myoblasts arrested in G(1) phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G(1) cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G(1) arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma.
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Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Mioblastos Esqueléticos/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Rabdomiosarcoma/enzimología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Fase G1/efectos de los fármacos , Humanos , Ratones , Mioblastos Esqueléticos/citología , Mioblastos Esqueléticos/enzimología , Piperazinas/metabolismo , Piridinas/metabolismo , Células Tumorales CultivadasRESUMEN
OBJECTIVES: To engage users in the design of a regional child and youth health center. BACKGROUND: The perspective of users should be an integral component of a patient-centered, evidence-based approach to the design of health facilities. METHODS: We conducted a discrete choice conjoint experiment (DCE), a method from marketing research and health economics, as a component of a strategy to engage users in the preconstruction planning process. A sample of 467 participants (290 staff and 177 clients or community stakeholders) completed the DCE. RESULTS: Latent class analysis identified three segments with different design preferences. A group we termed an enhanced design (57%) segment preferred a fully featured facility with personal contacts at the start of visits (in-person check-in, personal waiting room notification, volunteer-assisted wayfinding, and visible security), a family resource center with a health librarian, and an outdoor playground equipped with covered heated pathways. The self-guided design segment (11%), in contrast, preferred a design allowing a more independent use of the facility (e.g., self-check-in at computer kiosks, color-coded wayfinding, and a self-guided family resource center). Designs affording privacy and personal contact with staff were important to the private design segment (32%). The theme and decor of the building was less important than interactive features and personal contacts. CONCLUSION: A DCE allowed us to engage users in the planning process by estimating the value of individual design elements, identifying segments with differing views, informing decisions regarding design trade-offs, and simulating user response to design options.
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Instituciones de Atención Ambulatoria , Arquitectura y Construcción de Instituciones de Salud , Hospitales Pediátricos , Adulto , Conducta de Elección , Defensa del Consumidor , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ontario , Personal de Hospital/psicologíaRESUMEN
Evaluate lisdexamfetamine dimesylate (LDX) augmentation of antidepressant monotherapy for executive dysfunction in partially or fully remitted major depressive disorder (MDD). This randomized, placebo-controlled study (NCT00985725) enrolled 143 adults (18-55 years) with mild MDD (Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤ 18) and executive dysfunction (Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) Self-Report Global Executive Composite (GEC) T score ≥ 60) on stable antidepressant monotherapy for ≥ 8 weeks. After 2 weeks of screening, participants were randomized to 9 weeks of double-blind LDX (20-70 mg/day) or placebo augmentation, followed by 2 weeks of single-blind placebo. The primary end point was change from baseline to week 9/end of study (EOS) in BRIEF-A Self-Report GEC T score; secondary assessments included the BRIEF-A Informant Report, MADRS, and treatment-emergent adverse events (TEAEs). Of 143 randomized participants, 119 completed double-blind treatment (placebo, n=59; LDX, n=60). Mean ± standard deviation (SD) BRIEF-A GEC T scores decreased from baseline (placebo, 74.2 ± 8.88; LDX, 76.8 ± 9.66) to week 9/EOS (placebo, 61.4 ± 14.61; LDX, 55.2 ± 16.15); the LS mean (95% CI) treatment difference significantly favored LDX (-8.0 (-12.7, -3.3); P=0.0009). The LS mean (95% CI) treatment difference for MADRS total score also significantly favored LDX (-1.9 (-3.7, 0.0); P=0.0465). TEAE rates were 73.6% with placebo and 78.9% with LDX; serious TEAE rates were 4.2 and 2.8%. In this trial, LDX augmentation significantly improved executive dysfunction and depressive symptoms in participants with mild MDD. The safety profile of LDX was consistent with prior studies in adults with attention-deficit/hyperactivity disorder.
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Antidepresivos/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Dextroanfetamina/uso terapéutico , Función Ejecutiva/efectos de los fármacos , Psicotrópicos/uso terapéutico , Adulto , Antidepresivos/efectos adversos , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/fisiopatología , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/fisiopatología , Dextroanfetamina/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Dimesilato de Lisdexanfetamina , Masculino , Escalas de Valoración Psiquiátrica , Psicotrópicos/efectos adversos , Inducción de Remisión , Método Simple Ciego , Resultado del TratamientoRESUMEN
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.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Dextroanfetamina/uso terapéutico , Propilaminas/uso terapéutico , Adolescente , Clorhidrato de Atomoxetina , Niño , Dextroanfetamina/administración & dosificación , Dextroanfetamina/efectos adversos , Método Doble Ciego , Esquema de Medicación , Humanos , Dimesilato de Lisdexanfetamina , Propilaminas/administración & dosificación , Propilaminas/efectos adversos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design. METHOD: European and US patients (6-17 years; N = 276) with ADHD were entered into a 26-week open-label trial of LDX treatment. Those who completed the open-label period (n = 157) were randomized 1:1 to their optimized dose of LDX (30, 50, or 70 mg per day) or placebo for a 6-week randomized-withdrawal period (RWP). The primary efficacy measure was the proportion of patients meeting treatment failure criteria (≥50% increase in ADHD Rating Scale IV total score and ≥2-point increase in Clinical Global Impressions-Severity of Illness [CGI-S] score, compared with RWP start point). Safety and tolerability were also evaluated. RESULTS: During the RWP (LDX, n = 78; placebo, n = 79), significantly fewer patients receiving LDX met treatment failure criteria (15.8%) compared with those receiving placebo (67.5%; difference = -51.7%; 95% confidence interval = -65.0, -38.5; p < .001 ). Most treatment failures occurred at or before the week 2 visit after randomization. Treatment-emergent adverse events were reported in 39.7% and 25.3% of patients receiving LDX and placebo, respectively, during the RWP. CONCLUSIONS: These data demonstrate the maintenance of efficacy of LDX during long-term treatment in children and adolescents with ADHD. The rapid return of symptoms on LDX withdrawal demonstrates the need for continuing treatment. The safety profile of LDX was consistent with that of other stimulants. Clinical trial registration information-Double-Blind, Placebo-Controlled, Randomized Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17; http://clinicaltrials.gov; NCT00784654.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Resultado del Tratamiento , Privación de Tratamiento/normas , Adolescente , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Dextroanfetamina/administración & dosificación , Dextroanfetamina/efectos adversos , Método Doble Ciego , Femenino , Humanos , Dimesilato de Lisdexanfetamina , Masculino , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems. METHODS: We have established a first cell line, BT183, from a case of ETMR and characterized its molecular and cellular features. LIN28 knockdown was performed in BT183 to examine the potential role of Lin28 in regulating signaling pathway gene expression in ETMR. Cell line findings were corroborated with immunohistochemical studies in ETMR tissues. A drug screen of 73 compounds was performed to identify potential therapeutic targets. RESULTS: The BT183 line maintains C19MC amplification, expresses C19MC-encoded microRNAs, and is tumor initiating. ETMRs, including BT183, have high LIN28 expression and low let-7 miRNA expression, and show evidence of mTOR pathway activation. LIN28 knockdown increases let-7 expression and decreases expression of IGF/PI3K/mTOR pathway components. Pharmacologic inhibition of the mTOR pathway reduces BT183 cell viability. CONCLUSIONS: BT183 retains key genetic and histologic features of ETMR. In ETMR, Lin28 is not only a diagnostic marker but also a regulator of genes involved in growth and metabolism. Our findings indicate that inhibitors of the IGF/PI3K/mTOR pathway may be promising novel therapies for these fatal embryonal tumors. As the first patient-derived cell line of these rare tumors, BT183 is an important, unique reagent for investigating ETMR biology and therapeutics.
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Cromosomas Humanos Par 19/genética , Amplificación de Genes , MicroARNs/metabolismo , Neoplasias de Células Germinales y Embrionarias/metabolismo , Proteínas de Unión al ARN/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Técnicas de Cultivo de Célula , Preescolar , Variaciones en el Número de Copia de ADN , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/metabolismo , Tumores Neuroectodérmicos Primitivos/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6-17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score ≥ 28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70 mg/day), OROS-MPH (18, 36, or 54 mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -18.6 (95% confidence interval [CI]: -21.5 to -15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -13.0 (95% CI: -15.9 to -10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70-86), 14% (8-21), and 61% (51-70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD.
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Conducta del Adolescente/efectos de los fármacos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Conducta Infantil/efectos de los fármacos , Dextroanfetamina/uso terapéutico , Conducta Impulsiva/prevención & control , Adolescente , Regulación del Apetito/efectos de los fármacos , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Dextroanfetamina/administración & dosificación , Dextroanfetamina/efectos adversos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Medicamentos , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Conducta Impulsiva/etiología , Dimesilato de Lisdexanfetamina , Masculino , Metilfenidato/administración & dosificación , Metilfenidato/efectos adversos , Metilfenidato/química , Metilfenidato/uso terapéutico , Pacientes Desistentes del Tratamiento , Escalas de Valoración Psiquiátrica , Índice de Severidad de la EnfermedadRESUMEN
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.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Dextroanfetamina/uso terapéutico , Propilaminas/uso terapéutico , Adolescente , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/uso terapéutico , Clorhidrato de Atomoxetina , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Niño , Dextroanfetamina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Dimesilato de Lisdexanfetamina , Masculino , Propilaminas/efectos adversos , Resultado del TratamientoRESUMEN
INTRODUCTION: There are limited head-to-head data comparing the efficacy of long-acting amfetamine- and methylphenidate-based psychostimulants as treatments for individuals with attention-deficit hyperactivity disorder (ADHD). This post hoc analysis provides the first parallel-group comparison of the effect of lisdexamfetamine dimesylate (lisdexamfetamine) and osmotic-release oral system methylphenidate (OROS-MPH) on symptoms of ADHD in children and adolescents. STUDY DESIGN: This was a post hoc analysis of a randomized, double-blind, parallel-group, dose-optimized, placebo-controlled, phase III study. SETTING: The phase III study was carried out in 48 centres across ten European countries. PATIENTS: The phase III study enrolled children and adolescents (aged 6-17 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for a primary diagnosis of ADHD and who had a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score of 28 or higher. INTERVENTION: Eligible patients were randomized (1:1:1) to receive a once-daily, optimized dose of lisdexamfetamine (30, 50 or 70 mg/day), placebo or OROS-MPH (18, 36 or 54 mg/day) for 7 weeks. MAIN OUTCOME MEASURES: In this post hoc analysis, efficacy was assessed using the ADHD-RS-IV and Clinical Global Impressions-Improvement (CGI-I) scale. Responders were defined as those achieving at least a 30% reduction from baseline in ADHD-RS-IV total score and a CGI-I score of 1 (very much improved) or 2 (much improved). The proportion of patients achieving an ADHD-RS-IV total score less than or equal to the mean for their age (based on normative data) was also determined. Endpoint was the last on-treatment visit with a valid assessment. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Of the 336 patients randomized, 332 were included in the safety population, 317 were included in the full analysis set and 196 completed the study. The mean (standard deviation) ADHD-RS-IV total score at baseline was 40.7 (7.31) for lisdexamfetamine, 41.0 (7.14) for placebo and 40.5 (6.72) for OROS-MPH. The least-squares (LS) mean change (standard error) in ADHD-RS-IV total score from baseline to endpoint was -24.3 (1.16) for lisdexamfetamine, -5.7 (1.13) for placebo and -18.7 (1.14) for OROS-MPH. The difference between lisdexamfetamine and OROS-MPH in LS mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of lisdexamfetamine (-5.6 [-8.4 to -2.7]; p < 0.001). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with a CGI-I score of 1 or 2 at endpoint was 17.4 (5.0-29.8; p < 0.05; number needed to treat [NNT] 6), and the difference in the percentage of patients (95% CI) achieving at least a 30% reduction in ADHD-RS-IV total score and a CGI-I score of 1 or 2 was 18.3 (5.4-31.3; p < 0.05; NNT 6). The difference between lisdexamfetamine and OROS-MPH in the percentage of patients (95% CI) with an ADHD-RS-IV total score less than or equal to the mean for their age at endpoint was 14.0 (0.6-27.4; p = 0.050). The overall frequency of TEAEs and the frequencies of decreased appetite, insomnia, decreased weight, nausea and anorexia TEAEs were greater in patients treated with lisdexamfetamine than in those treated with OROS-MPH, whereas headache and nasopharyngitis were more frequently reported in patients receiving OROS-MPH. CONCLUSIONS: This post hoc analysis showed that, at the doses tested, patients treated with lisdexamfetamine showed statistically significantly greater improvement in symptoms of ADHD than those receiving OROS-MPH, as assessed using the ADHD-RS-IV and CGI-I. The safety profiles of lisdexamfetamine and OROS-MPH were consistent with the known effects of stimulant medications.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/administración & dosificación , Dextroanfetamina/administración & dosificación , Metilfenidato/administración & dosificación , Adolescente , Estimulantes del Sistema Nervioso Central/efectos adversos , Niño , Dextroanfetamina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Dimesilato de Lisdexanfetamina , Masculino , Metilfenidato/efectos adversosRESUMEN
The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by ;abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous (PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor beta2 (Tgfbeta2) might control Arf expression, as we show that mice lacking Tgfbeta2 have primary vitreous hyperplasia similar to Arf(-/-) mice. Consistent with a potential linear pathway, Tgfbeta2 induces Arf transcription and p19(Arf) expression in cultured mouse embryo fibroblasts (MEFs); and Tgfbeta2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by beta-galactosidase activity in Arf(lacZ/+) mice, we show that Tgfbeta2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgfbeta receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1beta. In summary, Tgfbeta2 and p19(Arf) act in a linear pathway during embryonic development. We present the first evidence that p19(Arf) expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta2/fisiología , Animales , Células Cultivadas , Embrión de Mamíferos/fisiología , Anomalías del Ojo/embriología , Anomalías del Ojo/genética , Anomalías del Ojo/metabolismo , Fibroblastos/fisiología , Ratones , Ratones Transgénicos , Fosforilación , Activación Transcripcional , Factor de Crecimiento Transformador beta2/genéticaRESUMEN
OBJECTIVE: To assess the quality of life (QOL) in adults with attention-deficit/hyperactivity disorder (ADHD) given triple-bead mixed amphetamine salts (MAS), a long-acting amphetamine formulation designed for a duration of action of up to 16 hours. METHOD: 274 adults with ADHD (DSM-IV-TR criteria) were randomly assigned to 7 weeks of double-blind treatment with an optimal dose of triple-bead MAS (12.5 mg to 75 mg) (N = 137) or placebo (N = 137). As a secondary objective of this study, QOL was assessed on the basis of self-reported Adult ADHD Impact Module (AIM-A) scores, describing ADHD-specific QOL in 6 domains and global QOL (questions 1-4). To assess safety, data were collected on adverse events, vital signs, electrocardiograms, laboratory tests, and sleep quality. The trial was conducted from January 2005 to June 2005. RESULTS: Statistically significant improvement between triple-bead MAS and placebo was observed in all 6 ADHD-specific AIM-A subscales. In addition, statistically significant improvement in global QOL between triple-bead MAS and placebo was seen, based on AIM-A question 1 (p = .0006) and question 4 (p = .0001). Patients' age, gender, race, and prior use of stimulant medication were not found to significantly affect AIM-A subscale scores. The most common treatment-emergent adverse events with triple-bead MAS (insomnia, dry mouth, decreased appetite, headache, and weight decreased) were consistent with amphetamine treatment, and their incidence generally decreased with time. CONCLUSIONS: Adults with ADHD showed significantly improved QOL for both ADHD-specific and global measures with triple-bead MAS in comparison to placebo, based on AIM-A scores. Treatment-emergent adverse events were mostly mild to moderate in intensity and were consistent with amphetamine treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00150579.
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Anfetamina/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/administración & dosificación , Calidad de Vida , Adulto , Anfetamina/efectos adversos , Estimulantes del Sistema Nervioso Central/efectos adversos , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To compare the single-dose pharmacokinetics of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation, with MAS extended release (MAS XR) (Adderall XR) + MAS immediate release (MAS IR) administered 8 h later. METHODS: This was a phase I, randomized, open-label, single-dose, single-center, two-period, crossover study in healthy adult volunteers designed to evaluate the bioavailability of triple-bead MAS over the course of a full day. Subjects were randomized to triple-bead MAS 37.5 mg or MAS XR 25 mg + MAS IR 12.5 mg administered 8 h later (MAS XR + MAS IR). The reference treatment was designed to mimic the clinical practice of providing extended coverage by supplementing a morning dose of MAS XR with a dose of MAS IR 8 h later in order to increase the duration of action. Plasma was assayed for d-amphetamine and l-amphetamine. Treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and laboratory data were also collected for safety evaluation. RESULTS: Exposure to d- and l-amphetamine was equivalent between triple-bead MAS and MAS XR + MAS IR based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). For Cmax, least-squares mean ratios comparing triple-bead MAS with MAS XR + MAS IR were 101.0% and 90.9% for d-amphetamine and l-amphetamine, respectively, and for AUC(0-infinity) were 104.4% and 95.3% for d-amphetamine and l-amphetamine, respectively. Median time to maximum observed plasma concentration (Tmax) values for d-amphetamine and l-amphetamine were 8.0 h for triple-bead MAS and 10.0 h for MAS XR + MAS IR. There were no clinically meaningful differences between the study formulations for TEAEs or laboratory values. One subject experienced an ECG abnormality (asymptomatic premature ventricular contractions) leading to early termination from the study. CONCLUSIONS: In healthy adults, the exposure observed with triple-bead MAS 37.5 mg was bioequivalent to MAS XR 25 mg supplemented by MAS IR 12.5 mg administered 8 h later. These data demonstrate that a single morning dose of triple-bead MAS provides equivalent plasma concentrations to those observed with a dose-augmentation strategy of MAS XR in the morning followed by MAS IR in the afternoon, while minimizing peak-to-trough fluctuations. Triple-bead MAS was also generally well-tolerated in this study.