Asthma medications should be available for over-the-counter use: con.

The United States Food and Drug Administration recently considered a policy to transfer inhaled short-acting bronchodilators to over-the-counter status if conditions of safe use can be established. The American Thoracic Society filed a comment in opposition to the proposal. This article examines the negative consequences that might result from allowing nonprescription access to bronchodilators and other inhaled asthma medications. Such a proposed policy change conflicts directly with current guidelines for asthma management and would undermine efforts to achieve adequate asthma control in patients. In addition, a policy change to convert asthma medications to over-the-counter status could result in increased costs to patients as well as increased health care costs to society overall due to a worsening of asthma control in the population.

Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.

Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.

Standardized procedure for measurement of nasal potential difference: an outcome measure in multicenter cystic fibrosis clinical trials.

Patients with cystic fibrosis (CF) can be discriminated from healthy subjects by measurement of the nasal potential difference, which has become a useful outcome measure for therapies directed toward correcting defective electrolyte transport in CF. A standard operating procedure was developed by a CF Foundation clinical trials network, to be followed by all sites performing collaborative studies. Key variables in the measurement included type of voltmeter, exploring probe, reference electrodes, and solutions used to assess both sodium transport and chloride conductance. Eight sites submitted data on 3-8 normal and 4-5 CF subjects. Baseline voltage, an index of sodium transport, was -18.2 +/- 8.3 mV (mean +/- SD) for normals, and -45.3 +/- 11.4 mV for CF patients. There was no CFTR-mediated chloride secretion in CF subjects, as evidenced by the lack of response to perfusion with zero chloride + beta agonist solutions (+3.2 +/- 3.5 mV) vs. that in normals (-23.7 +/- 10.2 mV). The standardized nasal potential difference measurement minimizes variability between operators and study sites. Valid and consistent results can be attained with trained operators and attention to technical details. These data demonstrate the procedure to be sufficient for multicenter studies in the CF Foundation network.

Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution.

A double-blind, dose escalation gene transfer trial was conducted in subjects with cystic fibrosis (CF), among whom placebo (saline) or compacted DNA was superfused onto the inferior turbinate of the right or left nostril. The vector consisted of single molecules of plasmid DNA carrying the cystic fibrosis transmembrane regulator- encoding gene compacted into DNA nanoparticles, using polyethylene glycol-substituted 30-mer lysine peptides. Entry criteria included age greater than 18 years, FEV1 exceeding 50% predicted, and basal nasal potential difference (NPD) isoproterenol responses (> or = -5 mV) that are typical for subjects with classic CF. Twelve subjects were enrolled: 2 in dose level I (DLI) (0.8 mg DNA), 4 in DLII (2.67 mg), and 6 in DLIII (8.0 mg). The primary trial end points were safety and tolerability, and secondary gene transfer end points were assessed. In addition to routine clinical assessments and laboratory tests, subjects were serially evaluated for serum IL-6, complement, and C-reactive protein; nasal washings were taken for cell counts, protein, IL-6, and IL-8; and pulmonary function and hearing tests were performed. No serious adverse events occurred, and no events were attributed to compacted DNA. There was no association of serum or nasal washing inflammatory mediators with administration of compacted DNA. Day 14 vector polymerase chain reaction analysis showed a mean value in DLIII nasal scraping samples of 0.58 copy per cell. Partial to complete NPD isoproterenol responses were observed in eight subjects: one of two in DLI, three of four in DLII, and four of six in DLIII. Corrections persisted for as long as 6 days (1 subject to day 28) after gene transfer. In conclusion, compacted DNA nanoparticles can be safely administered to the nares of CF subjects, with evidence of vector gene transfer and partial NPD correction.

A multicenter study of the effect of solution temperature on nasal potential difference measurements.

BACKGROUND: Nasal potential difference (PD) measurement quantifies the abnormal sodium and chloride transport that is characteristic of cystic fibrosis (CF) and has gained acceptance as both a diagnostic tool and outcome measure for new CF therapies. Because small changes in nasal PD-measured chloride transport are often an important component in evaluating new CF therapies, techniques to maximize sensitivity and reproducibility are essential. STUDY OBJECTIVE: To determine if administration of warmed nasal PD solutions (37 degrees C), instead of room temperature solutions (22 degrees C), results in significant increase in nasal PD-measured transepithelial chloride transport. DESIGN: Multicenter, prospective, cross-over trial of repeated measurements of nasal PD at 22 degrees C and 37 degrees C. RESULTS: Thirty-two healthy volunteers completed the study (four centers, each with 8 subjects). For 22 degrees C vs 37 degrees C, baseline (+/- SD) nasal PD (- 19.3 +/- 6.9 millivolts [mV] vs - 18.8 +/- 7.7 mV, p = 0.76), amiloride-sensitive PD (Delta PD, 10.4 +/- 5.6 mV vs 11.0 +/- 6.1 mV, p = 0.60), and low chloride response (Delta PD, - 10.0 +/- 8.0 mV vs - 8.0 +/- 7.1 mV, p = 0.13) were not statistically significantly affected by warming of solutions. Warming solutions to 37 degrees C dramatically increased the chloride transport response to isoproterenol (Delta PD, - 6.9 +/- 6.4 mV vs - 13.3 +/- 8.8 mV, p < 0.01) and the combined total response to low chloride and isoproterenol (Delta PD, - 16.9 +/- 9.5 mV vs - 21.3 +/- 11.9 mV, p = 0.01). The average increases observed with warming in isoproterenol and combined total responses were - 6.4 mV (95% confidence interval [CI], - 8.5 to - 4.3) and - 4.4 mV (95% CI, - 7.6 to - 1.1), respectively. CONCLUSIONS: Performing nasal PD studies with solutions at 37 degrees C instead of 22 degrees C increases the observed total chloride response by approximately 25% and the isoproterenol-dependent chloride response by approximately 95%. The Cystic Fibrosis Foundation Therapeutics Development Network now recommends warming of solutions as a standard procedure for nasal PD protocols. Utilization of warmed solutions will standardize nasal PD techniques across centers and potentially increase the ability to identify therapies that result in small incremental improvements in CF transmembrane conductance regulator function.

Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis.

Inhaled recombinant human deoxyribonuclease (rhDNase) delivered by nebulizer improves pulmonary function and reduces the rate of pulmonary exacerbations in cystic fibrosis subjects. Standard jet nebulizers are relatively inefficient and require a delivery time of 10-20 min. We conducted an open-label, proof-of-concept study to evaluate whether bolus inhalation of rhDNase with a more efficient delivery system was safe and effective in cystic fibrosis subjects. The AERx system used for this study aerosolized 1.35 mg of rhDNase in three inhalations at a single sitting. The predicted AERx lung dose was approximately 0.68 mg, a dose consistent with lung doses of rhDNase given by jet nebulizer. In our 16 subjects with cystic fibrosis, a mean relative increase in FEV(1) of 7.8% (p < or = 0.001) was observed after 15 days of bolus delivery of rhDNase with the AERx system. The safety profile of rhDNase given as a bolus was similar to that observed with traditional nebulizer delivery. This study demonstrated that bolus inhalation of rhDNase was feasible, reasonably well-tolerated, and associated with improvement in pulmonary function in this small group of cystic fibrosis subjects.

Adolescencia, vínculos familiares ¿ qué valor se le da hoy al encuentro familiar alrededor de la mesa ? / Adolescence, family bons. What is value of the family encounter around the table nowdays

El sostén familiar es imprescindible para el pasaje de la dependencia a la autonomía en la adolescencia e incluye atención, cuidados, permisos y límites.Pareciera que la mesa familiar es el escenario privilegiado para la reunión en el hogar donde quedan en evidencias encuentros y desencuentros.Objetivos : Conocer las características de los encuentros familiares entre adolescentes y alumnos.Analizar el valor que le dan a la mesa familiar como espacio de encuentro. Evaluar si el análisis del encuentro alrededor de lamesa familiar sirve como recurso semiológico para conocer aspectos de los vínculos que podrían incidir en el proceso adolescente.Población, material y métodos : 1. Taller con 50 profesionales de diferentes disciplinas y construcción de categorías de análisis. 2. Encuestas a 50 adolescentes y 50 familiares sobre la base de esas categorías . 3. Talleres intergeneracionales con adolescentes y sus familiares. 4. Encuestas a 50 profesionales de salud y educación de La Plata para comparar la información obtenida entre ambas poblaciones. Estudio exploratorio cualitativo del material de los talleres y análisis de frecuencias de las encuestas. Resultados : Mas de la mitad de los 100 encuestados refirió que el mejor momento en casa es con la familia ; sin embargo 25 por ciento de los adolescente preferian estar solos. Ambos momentos son necesarios para el logro de la identidad. El encuentro mas frecuente fue la cena ; el 25 por ciento de los adultos y el 13 por ciento de los adolescentes rescataron el fin de semana. Alrededor de la mesa se habla de lo cotidiano y se despliegan diversidad de afectos. Aparecen conflictos por malestar entre los padres, discusiones entre hermanos y enfrentamiento generacionales. En los talleres se describió a la madre como aglutinadora del encuentro y al padre, inaccesible o ausente. Y en ello se relató el impacto de lo social. Obstaculizan el encuentro diferencias horarias, escasez de comida y la violencia. Conclusiones : Existen supuestos que la mesa familiar ha perdido vigencia como situación de encuentro. Sin embargo, padres e hijos valoran estas reuniones. Este espacio intrafamiliar contribuiría a dar sostén al proceso de autonomía del adolescente. La indagación de su dinámica en la consulta pareciera ser un importante recurso semiológico y operativo

Análisis del estado de la salud bucal de una población adolescente / Analysis of the oral health in an adolescent population

La prevalencia de caries, pérdida de piezas dentarias y enfermedad gingival en los adolescentes es elevada.El nivel socioeconómico, los hábitos de higiene y alimentación constituyen factores de riesgo. Las medidas de prevención y educación para la salud en controles clínicos, odontológicos e institucionales (escuelas, clubes etc) podrían evitar la aparición de estas patologías. Objetivos : Evaluar el estado de salud bucal de adolescente que concurren al Hospital "Ricardo Gutierrez", los factores de riesgo que la afecta y establecer estrategias de prevención en función de los resultados obtenidos. Población, material y métodos : Estudio analítico de un grupo de adolescentes (n=253) de 12 a 13 años que concurren a los consultorios de Adolescencia en forma espontánea o programada. Criterios de inclusión : adolescentes sanos, sin medicación o patología crónica que afecte la salud bucal. Los médicos pediatras recolectaron los datos mediante : observaciones clínicas del estado bucal (pérdida de piezas dentarias, obturación, caries visibles, patología gingival) y encuesta al adolescente y acompañante (nivel socioeconómico, hábitos de higiene bucal, ingesta de hidratos de carbono, educación para el cuidado de la salud). Los datos se procesaron en el programa estadístico EPI-info versión 6.04 y para el análisis multivariado se utilizó el programa SPSS 7.5. Resultados : Se observaron caries visibles en el 47,2 por ciento de los pacientes, gingivitis en el 60,6 por ciento, piezas obturadas en el 50 por ciento, y pérdida de piezas en el 15,4 por ciento. Se evaluaron el OR y la asociación de las variables encuestadas con el hecho en estudio (estado de la salud bucal). Se trabajó con un intervalo de confianza del 95 por ciento. Se observó asociación entre el hábito de cepillado con técnica inadecuada o ausente y la presencia de caries(OR:5,34) y gingivitis (OR:3,39). El 76,2 por ciento nunca había recibido información previa por parte del pediatra acerca del cuidado de la salud bucal. Conclusiones : Según las observaciones en esta población, el hábito de cepillado con técnica inadecuada constituiría un factor de riesgo para la aparición de caries y enfermedad gingival. La consulta del adolescente constituye una oportunidad para la educación en acciones preventivas para el cuidado de la salud bucal

Adolescencia, vínculos familiares ¿ qué valor se le da hoy al encuentro familiar alrededor de la mesa ? / Adolescence, family bons. What is value of the family encounter around the table nowdays

El sostén familiar es imprescindible para el pasaje de la dependencia a la autonomía en la adolescencia e incluye atención, cuidados, permisos y límites.Pareciera que la mesa familiar es el escenario privilegiado para la reunión en el hogar donde quedan en evidencias encuentros y desencuentros.Objetivos : Conocer las características de los encuentros familiares entre adolescentes y alumnos.Analizar el valor que le dan a la mesa familiar como espacio de encuentro. Evaluar si el análisis del encuentro alrededor de lamesa familiar sirve como recurso semiológico para conocer aspectos de los vínculos que podrían incidir en el proceso adolescente.Población, material y métodos : 1. Taller con 50 profesionales de diferentes disciplinas y construcción de categorías de análisis. 2. Encuestas a 50 adolescentes y 50 familiares sobre la base de esas categorías . 3. Talleres intergeneracionales con adolescentes y sus familiares. 4. Encuestas a 50 profesionales de salud y educación de La Plata para comparar la información obtenida entre ambas poblaciones. Estudio exploratorio cualitativo del material de los talleres y análisis de frecuencias de las encuestas. Resultados : Mas de la mitad de los 100 encuestados refirió que el mejor momento en casa es con la familia ; sin embargo 25 por ciento de los adolescente preferian estar solos. Ambos momentos son necesarios para el logro de la identidad. El encuentro mas frecuente fue la cena ; el 25 por ciento de los adultos y el 13 por ciento de los adolescentes rescataron el fin de semana. Alrededor de la mesa se habla de lo cotidiano y se despliegan diversidad de afectos. Aparecen conflictos por malestar entre los padres, discusiones entre hermanos y enfrentamiento generacionales. En los talleres se describió a la madre como aglutinadora del encuentro y al padre, inaccesible o ausente. Y en ello se relató el impacto de lo social. Obstaculizan el encuentro diferencias horarias, escasez de comida y la violencia. Conclusiones : Existen supuestos que la mesa familiar ha perdido vigencia como situación de encuentro. Sin embargo, padres e hijos valoran estas reuniones. Este espacio intrafamiliar contribuiría a dar sostén al proceso de autonomía del adolescente. La indagación de su dinámica en la consulta pareciera ser un importante recurso semiológico y operativo[AU]

Análisis del estado de la salud bucal de una población adolescente / Analysis of the oral health in an adolescent population

La prevalencia de caries, pérdida de piezas dentarias y enfermedad gingival en los adolescentes es elevada.El nivel socioeconómico, los hábitos de higiene y alimentación constituyen factores de riesgo. Las medidas de prevención y educación para la salud en controles clínicos, odontológicos e institucionales (escuelas, clubes etc) podrían evitar la aparición de estas patologías. Objetivos : Evaluar el estado de salud bucal de adolescente que concurren al Hospital "Ricardo Gutierrez", los factores de riesgo que la afecta y establecer estrategias de prevención en función de los resultados obtenidos. Población, material y métodos : Estudio analítico de un grupo de adolescentes (n=253) de 12 a 13 años que concurren a los consultorios de Adolescencia en forma espontánea o programada. Criterios de inclusión : adolescentes sanos, sin medicación o patología crónica que afecte la salud bucal. Los médicos pediatras recolectaron los datos mediante : observaciones clínicas del estado bucal (pérdida de piezas dentarias, obturación, caries visibles, patología gingival) y encuesta al adolescente y acompañante (nivel socioeconómico, hábitos de higiene bucal, ingesta de hidratos de carbono, educación para el cuidado de la salud). Los datos se procesaron en el programa estadístico EPI-info versión 6.04 y para el análisis multivariado se utilizó el programa SPSS 7.5. Resultados : Se observaron caries visibles en el 47,2 por ciento de los pacientes, gingivitis en el 60,6 por ciento, piezas obturadas en el 50 por ciento, y pérdida de piezas en el 15,4 por ciento. Se evaluaron el OR y la asociación de las variables encuestadas con el hecho en estudio (estado de la salud bucal). Se trabajó con un intervalo de confianza del 95 por ciento. Se observó asociación entre el hábito de cepillado con técnica inadecuada o ausente y la presencia de caries(OR:5,34) y gingivitis (OR:3,39). El 76,2 por ciento nunca había recibido información previa por parte del pediatra acerca del cuidado de la salud bucal. Conclusiones : Según las observaciones en esta población, el hábito de cepillado con técnica inadecuada constituiría un factor de riesgo para la aparición de caries y enfermedad gingival. La consulta del adolescente constituye una oportunidad para la educación en acciones preventivas para el cuidado de la salud bucal [AU]

A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis.

CPX (8-cyclopentyl-1,3-dipropylxanthine) is a novel compound currently under development as a potential treatment for cystic fibrosis (CF). The drug has been shown to increase chloride efflux and CFTR trafficking in vitro in CF airway cells. This phase I multicenter, single-dose, placebo-controlled trial was performed at four institutions. Thirty-seven subjects homozygous for the Delta F(508) allele were studied in an escalating dose protocol of seven single-dose cohorts (1, 3, 10, 30, 100, 300, and 1,000 mg) to evaluate the safety, pharmacokinetics, and efficacy of CPX. Efficacy was determined using nasal transepithelial potential difference and sweat chloride measurements prior to dosing and at 1, 2, and 4 hr postdose. The incidence of adverse events in the treatment group was similar to that with placebo, indicating safety of the single doses studied. One serious adverse event (an acute pulmonary exacerbation) occurred 13 days after dosing, and was not considered related to the study drug. The maximal plasma CPX concentration and total amount of CPX absorbed appeared to be linearly related to dose, but was highly variable throughout the dose range studied, suggesting inconsistent absorption. There was no apparent effect of single-dose administration on either nasal transepithelial potential difference or sweat chloride measurements. The positive safety and pharmacokinetic findings of this study support continued development of CPX as a potential therapeutic for CF.

Use of nasal potential difference and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis.

One of the goals of current research in cystic fibrosis (CF) is to develop treatments that correct or compensate for defects in function of the cystic fibrosis transmembrane regulator (CFTR) gene. The use of outcome measures that assess CFTR function such as nasal potential difference (NPD) measurements and sweat chloride determinations will be required to evaluate the efficacy of such treatments in multicenter clinical trials. The purpose of this work was to identify the sources and magnitude of variability in NPD and sweat chloride measurements when performed at multiple centers. For the variance component analysis presented here, we used NPD and sweat chloride measurements from 37 subjects with CF participating in a phase I, four-center clinical trial of CPX (8-cyclopentyl-1,3-dipropylxanthine), a drug intended to enhance trafficking of Delta F508 CFTR to the cell membrane. The specific techniques used to measure these outcomes were not standardized, and varied between the four sites. Variability of both NPD measurements (baseline potential difference during infusion with Ringer's solution; change in response to addition of 0.1 mM amiloride; and subsequent change in response to perfusion with low chloride solution containing 0.1 mM amiloride and 0.01 mM isoproterenol) and sweat chloride measurements differed significantly between study sites. For change in NPD, one study site had significantly greater variability (lower reproducibility) of measurement than the other three sites. For sweat chloride measurements, reproducibility was lower at two of the sites relative to the other two sites. Sample size calculations showed that lower reproducibility at one or more sites can substantially reduce the power of studies using NPD or sweat chloride determinations as outcome measures. Standardization of measurement protocols, careful operator training and certification, and ongoing monitoring of individual operator performance may help to improve reliability in multicenter trials.