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1.
J Pediatr Gastroenterol Nutr ; 58(1): 12-7, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24121142

RESUMEN

OBJECTIVES: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. METHODS: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. RESULTS: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. CONCLUSIONS: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Mesalamina/uso terapéutico , Evaluación de Resultado en la Atención de Salud , Fenilhidrazinas/uso terapéutico , Colitis Ulcerosa/complicaciones , Humanos , Infliximab
2.
Clin Neurophysiol ; 144: 50-58, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36242948

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment to improve motor symptoms in Parkinson's disease (PD). The Globus Pallidus (GPi) and the Subthalamic Nucleus (STN) are the most targeted brain regions for stimulation and produce similar improvements in PD motor symptoms. However, our understanding of stimulation effects across targets on inhibitory action control processes is limited. We compared the effects of STN (n = 20) and GPi (n = 13) DBS on inhibitory control in PD patients. METHODS: We recruited PD patients undergoing DBS at the Vanderbilt Movement Disorders Clinic and measured their performance on an inhibitory action control task (Simon task) before surgery (optimally treated medication state) and after surgery in their optimally treated state (medication plus their DBS device turned on). RESULTS: DBS to both STN and GPi targets induced an increase in fast impulsive errors while simultaneously producing more proficient reactive suppression of interference from action impulses. CONCLUSIONS: Stimulation in GPi produced similar effects as STN DBS, indicating that stimulation to either target increases the initial susceptibility to act on strong action impulses while concomitantly improving the ability to suppress ongoing interference from activated impulses. SIGNIFICANCE: Action impulse control processes are similarly impacted by stimulating dissociable nodes in frontal-basal ganglia circuitry.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Núcleo Subtalámico/fisiología , Globo Pálido/fisiología , Enfermedad de Parkinson/terapia , Resultado del Tratamiento
3.
Ann Clin Transl Neurol ; 8(3): 613-622, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33596331

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) improves motor symptoms in Parkinson's disease (PD), but it can also disrupt verbal fluency with significant costs to quality of life. The current study investigated how variability of bilateral active electrode coordinates along the superior/inferior, anterior/posterior, and lateral/medial axes in the subthalamic nucleus (STN) or the globus pallidus interna (GPi) contribute to changes in verbal fluency. We predicted that electrode location in the left hemisphere would be linked to changes in fluency, especially in the STN. METHODS: Forty PD participants treated with bilateral DBS targeting STN (n = 23) or GPi (n = 17) completed verbal fluency testing in their optimally treated state before and after DBS therapy. Normalized atlas coordinates from left and right active electrode positions along superior/inferior, anterior/posterior, and lateral/medial axes were used to predict changes in fluency postoperatively, separately for patients with STN and GPi targets. RESULTS: Consistent with prior studies, fluency significantly declined pre- to postsurgery (in both DBS targets). In STN-DBS patients, electrode position along the inferior to superior axis in the left STN was a significant predictor of fluency changes; relatively more superior left active electrode was associated with the largest fluency declines in STN. Electrode coordinates in right STN or GPi (left or right) did not predict fluency changes. INTERPRETATION: We discuss these findings in light of putative mechanisms and potential clinical impact.


Asunto(s)
Disfunción Cognitiva/etiología , Estimulación Encefálica Profunda , Globo Pálido , Neuroestimuladores Implantables , Enfermedad de Parkinson/tratamiento farmacológico , Complicaciones Posoperatorias , Núcleo Subtalámico , Anciano , Estimulación Encefálica Profunda/efectos adversos , Femenino , Lateralidad Funcional , Humanos , Neuroestimuladores Implantables/efectos adversos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas
4.
Neurosurgery ; 86(6): 792-801, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31814011

RESUMEN

BACKGROUND: Stereotactic electroencephalography (SEEG) is a minimally invasive neurosurgical method to localize epileptogenic brain regions in epilepsy but requires days in the hospital with interventions to trigger several seizures. OBJECTIVE: To make initial progress in the development of network analysis methods to identify epileptogenic brain regions using brief, resting-state SEEG data segments, without requiring seizure recordings. METHODS: In a cohort of 15 adult focal epilepsy patients undergoing SEEG, we evaluated functional connectivity (alpha-band imaginary coherence) across sampled regions using brief (2 min) resting-state data segments. Bootstrapped logistic regression was used to generate a model to predict epileptogenicity of individual regions. RESULTS: Compared to nonepileptogenic structures, we found increased functional connectivity within epileptogenic regions (P < .05) and between epileptogenic areas and other structures (P < .01, paired t-tests, corrected). Epileptogenic areas also demonstrated higher clustering coefficient (P < .01) and betweenness centrality (P < .01), and greater decay of functional connectivity with distance (P < .05, paired t-tests, corrected). Our functional connectivity model to predict epileptogenicity of individual regions demonstrated an area under the curve of 0.78 and accuracy of 80.4%. CONCLUSION: Our study represents a preliminary step towards defining resting-state SEEG functional connectivity patterns to help localize epileptogenic brain regions ahead of neurosurgical treatment without requiring seizure recordings.


Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/fisiopatología , Electroencefalografía/métodos , Epilepsias Parciales/fisiopatología , Descanso , Técnicas Estereotáxicas , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/cirugía , Estudios de Cohortes , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/cirugía , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos
5.
Cereb Cortex Commun ; 1(1): tgaa083, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33381760

RESUMEN

Patients with Parkinson's disease (PD) often experience reductions in the proficiency to inhibit actions. The motor symptoms of PD can be effectively treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN), a key structure in the frontal-striatal network that may be directly involved in regulating inhibitory control. However, the precise role of the STN in stopping control is unclear. The STN consists of functional subterritories linked to dissociable cortical networks, although the boundaries of the subregions are still under debate. We investigated whether stimulating the dorsal and ventral subregions of the STN would show dissociable effects on ability to stop. We studied 12 PD patients with STN DBS. Patients with two adjacent contacts positioned within the bounds of the dorsal and ventral STN completed two testing sessions (OFF medication) with low amplitude stimulation (0.4 mA) at either the dorsal or ventral contacts bilaterally, while performing the stop task. Ventral, but not dorsal, DBS improved stopping latencies. Go reactions were similar between dorsal and ventral DBS STN. Stimulation in the ventral, but not dorsal, subregion of the STN improved stopping speed, confirming the involvement of the STN in stopping control and supporting the STN functional subregions.

6.
Pediatr Infect Dis J ; 27(11): 955-7, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18833025

RESUMEN

We reviewed information about the safety and plasma pharmacokinetic data for amoxicillin, specifically related to its potential use for postexposure inhalational anthrax. Amoxicillin (45 mg/kg/d) given orally in 3 divided doses to pediatric patients <40 kg should yield an adequate time above the MIC for susceptible Bacillus anthracis (< or =0.5 microg/mL) over most of the dosing interval (75-100%). Doses <45 mg/kg/d and dosing intervals longer than 8 hours should not be used for postexposure inhalational anthrax.


Asunto(s)
Amoxicilina/administración & dosificación , Carbunco/prevención & control , Bacillus anthracis , Exposición por Inhalación , Amoxicilina/efectos adversos , Amoxicilina/farmacocinética , Amoxicilina/uso terapéutico , Carbunco/tratamiento farmacológico , Bacillus anthracis/efectos de los fármacos , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Pruebas de Sensibilidad Microbiana
7.
Pediatr Infect Dis J ; 21(3): 193-6, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12005080

RESUMEN

INTRODUCTION: Recent advances in the diagnosis and treatment of influenza virus infections include: (1) rapid bedside diagnosis methods with simple commercially available tests; and (2) Food and Drug Administration approval of treatment for children 1 year of age and older with neuraminidase inhibitor drugs. For proven benefit antivirals should be used within 2 days of onset of symptoms. OBJECTIVES: We conducted a performance improvement exercise comparing the sensitivity and specificity of four rapid tests for influenza viruses: (1) Flu OIA (Biostar); (2) Quickvue Influenza Test (Quidel); (3) Z Stat Flu (ZymeTx); and (4) Directigen Flu A (Becton Dickinson). METHODS: During the 1999 to 2000 epidemic, symptomatic patients seen at the private practice of one of the authors provided specimens collected and processed according to the manufacturer's directions. Throat swabs only were used to collect the specimens for the Z Stat Flu Kit. Directigen was performed immediately, and the others were run in parallel within 12 to 24 h. Specimens were frozen first at -20 degrees C for up to 3 days and shipped in transport medium to the Virology Research Laboratory of the Virginia State Health Department for culture where they were stored at -60 degrees C until cultured. Some of the samples were processed by a commercial laboratory. RESULTS: Specimens from 116 patients were available for influenza culture; for 88 of these culture was performed at the State Health Department Laboratory, and for 28 culture was performed at a local commercial medical laboratory. Influenza virus (A) was detected in 58 of 116 (50%) specimens, 10 (17%) of these only by direct fluorescent antigen samples. Viral culture-direct fluorescent antigen results were used as the standard. Of the 4 tests Biostar and Z Stat Flu required more technician time (by an average of 2-fold). The 4 tests had sensitivities ranging from 72 to 95%. Z Stat differed significantly in sensitivity from the other three (P = 0.001). The specificities of Directigen, Quickvue, Flu OIA and Z Stat Flu were similar (76 to 86%). The positive predictive value of Directigen, Quickvue and FluOIA and Z Stat ranged from 80 to 86%. The negative predictive value of all 4 tests ranged from 75 to 94%. Z Stat Flu had a lower negative predictive value than the other 3 tests (75%; P = 0.001. CONCLUSION: In this first head-to-head comparison of four rapid diagnostic tests for influenza, Directigen Flu A, Quickvue and Flu OIA appear equivalent in sensitivity, specificity, positive predictive value and negative predictive value. Z Stat Flu was not as sensitive or as efficient as the other three tests.


Asunto(s)
Gripe Humana/diagnóstico , Juego de Reactivos para Diagnóstico/normas , Adolescente , Adulto , Niño , Preescolar , Reacciones Falso Negativas , Reacciones Falso Positivas , Femenino , Humanos , Lactante , Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/virología , Masculino , Sensibilidad y Especificidad , Factores de Tiempo
8.
Pediatrics ; 134(2): e512-8, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25022732

RESUMEN

BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials.


Asunto(s)
Industria Farmacéutica/economía , Etiquetado de Medicamentos , Quimioterapia , Mercadotecnía , Selección de Paciente , Sujetos de Investigación , Ensayos Clínicos como Asunto , Aprobación de Drogas , Humanos , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration
9.
ISRN Orthop ; 2013: 471695, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24959360

RESUMEN

There is a high prevalence of hypovitaminosis D in patients with back pain regardless of whether or not they require surgical intervention. Furthermore, the risk of hypovitaminosis D is not limited to individuals with traditional clinical risk factors. Vitamin D plays an essential role in bone formation, maintenance, and remodeling, as well as muscle function. Published data indicate that hypovitaminosis D could adversely affect bone formation and muscle function in multiple ways. The literature contains numerous reports of myopathy and/or musculoskeletal pain associated with hypovitaminosis D. In terms of spinal fusion outcomes, a patient may have a significant decrease in pain and the presence of de novo bone on an X-ray, yet their functional ability may remain severely limited. Hypovitaminosis D may be a contributing factor to the persistent postoperative pain experienced by these patients. Indeed, hypovitaminosis D is not asymptomatic, and symptoms can manifest themselves independent of the musculoskeletal pathological changes associated with conditions like osteomalacia. It appears that vitamin D status is routinely overlooked, and there is a need to raise awareness about its importance among all healthcare practitioners who treat spine patients.

10.
Pediatrics ; 130(6): e1583-91, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23129087

RESUMEN

OBJECTIVE: To examine the characteristics of pediatric trials conducted under US legislation and to compare results with data from 2002 to 2007. METHODS: We reviewed all pediatric trials provided to the US Food and Drug Administration in submissions that were approved between September 28, 2007 and December 21, 2010. We extracted data for each trial including age range, therapeutic indication, design, duration, and patient and center enrollment by location. RESULTS: Overall 346 studies on 113 drugs and biologicals enrolled 55 819 pediatric patients. The United States participated in 86% of the studies, providing 71% of the centers and 74% of the patients. Corresponding percentages for non-US countries were 43%, 29%, and 26% respectively. Developing or transition countries participated in 22% of the studies, providing 12% of the centers and 10% of the patients; our earlier analysis found corresponding percentages of 38%, 12%, and 23%. The most common therapeutic areas studied in the latter countries were infectious, neurologic, and pulmonary diseases. Seventy-eight vaccine studies enrolled 147 692 patients. The United States participated in 40% of the studies, providing 39% of the centers and 22% of the patients. Corresponding percentages for non-US countries were 74%, 61%, and 78% respectively. Developing or transition countries participated in 27% of the studies, providing 15% of the centers and 52% of the patients. CONCLUSIONS: The United States remains an important location for pediatric trials. Developing country involvement in pediatric drug development is not increasing, although these countries participate significantly in vaccine trials.


Asunto(s)
Ensayos Clínicos como Asunto/tendencias , Internacionalidad , Pediatría/tendencias , Productos Biológicos/uso terapéutico , Niño , Estudios de Cohortes , Comparación Transcultural , Países en Desarrollo , Predicción , Humanos , Medicamentos bajo Prescripción/uso terapéutico , Estados Unidos , United States Food and Drug Administration , Vacunas/uso terapéutico
11.
Pediatrics ; 128(5): e1242-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22025597

RESUMEN

OBJECTIVES: In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. METHODS: We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. RESULTS: Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation. CONCLUSIONS: Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.


Asunto(s)
Interpretación Estadística de Datos , Cálculo de Dosificación de Drogas , Quimioterapia/normas , Preparaciones Farmacéuticas/administración & dosificación , United States Food and Drug Administration , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Diseño de Fármacos , Quimioterapia/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Lactante , Masculino , Pediatría , Desarrollo de Programa , Control de Calidad , Estudios Retrospectivos , Estados Unidos , United States Food and Drug Administration/organización & administración
12.
J Pediatr Gastroenterol Nutr ; 37 Suppl 1: S40-5, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14685077

RESUMEN

Pediatric studies have resulted in changes in the dose of many medications given to children and an increased awareness of safety issues. An additional 6 months of pediatric exclusivity legislated under the Food and Drug Administration (FDA) Modernization Act of 1997 for pediatric studies undertaken in response to written requests from the FDA have stimulated the conduct of a large number of studies.


Asunto(s)
Control de Medicamentos y Narcóticos , Enfermedades Gastrointestinales/tratamiento farmacológico , Pediatría/normas , United States Food and Drug Administration , Niño , Quimioterapia/normas , Control de Medicamentos y Narcóticos/legislación & jurisprudencia , Humanos , Legislación de Medicamentos/tendencias , Pediatría/legislación & jurisprudencia , Seguridad , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudencia
13.
J Infect Dis ; 190(5): 975-8, 2004 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15295704

RESUMEN

Premature infants and those with chronic lung disease or congenital heart disease are at high risk of severe respiratory syncytial virus (RSV) disease. Palivizumab (Synagis), a humanized anti-RSV monoclonal antibody, has been used extensively since 1998 to prevent severe RSV disease in high-risk infants. To monitor for possible palivizumab-resistant mutants, an immunofluorescence binding assay that predicts palivizumab neutralization of RSV was developed. RSV isolates were collected at 8 US sites from 458 infants hospitalized for RSV disease (1998-2002). Palivizumab bound to all 371 RSV isolates able to be evaluated, including 25 from active-palivizumab recipients. The palivizumab epitope appears to be highly conserved, even in infants receiving prophylaxis with palivizumab.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antivirales/farmacología , Farmacorresistencia Viral , Hospitalización , Mutación , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antivirales/uso terapéutico , Línea Celular , Técnica del Anticuerpo Fluorescente , Humanos , Lactante , Pruebas de Sensibilidad Microbiana , Pruebas de Neutralización , Palivizumab , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/virología
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