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Introduction: The ideal contrast agents for ventilation SPECT and MRI are Technegas and 129Xe gas, respectively. Despite increasing interest in the clinical utility of ventilation imaging, these modalities have not been directly compared. Therefore, our objective was to compare the ventilation defect percent (VDP) assessed by Technegas SPECT and hyperpolarized 129Xe MRI in patients scheduled to undergo lung cancer resection with and without pre-existing obstructive lung disease. Methods: Forty-one adults scheduled to undergo lung cancer resection performed same-day Technegas SPECT, hyperpolarized 129Xe MRI, spirometry, and diffusing capacity of the lung for carbon monoxide (DLCO). Ventilation abnormalities were quantified as the VDP using two different methods: adaptive thresholding (VDPT) and k-means clustering (VDPK). Correlation and agreement between VDP quantified by Technegas SPECT and 129Xe MRI were determined by Spearman correlation and Bland-Altman analysis, respectively. Results: VDP measured by Technegas SPECT and 129Xe MRI were correlated (VDPT: r = 0.48, p = 0.001; VDPK: r = 0.63, p < 0.0001). A 2.0% and 1.6% bias towards higher Technegas SPECT VDP was measured using the adaptive threshold method (VDPT: 23.0% ± 14.0% vs. 21.0% ± 5.2%, p = 0.81) and k-means method (VDPK: 9.4% ± 9.4% vs. 7.8% ± 10.0%, p = 0.02), respectively. For both modalities, higher VDP was correlated with lower FEV1/FVC (SPECT VDPT: r = -0.38, p = 0.01; MRI VDPK: r = -0.46, p = 0.002) and DLCO (SPECT VDPT: r = -0.61, p < 0.0001; MRI VDPK: r = -0.68, p < 0.0001). Subgroup analysis revealed that VDP measured by both modalities was significantly higher for participants with COPD (n = 13) than those with asthma (n = 6; SPECT VDPT: p = 0.007, MRI VDPK: p = 0.006) and those with no history of obstructive lung disease (n = 21; SPECT VDPT: p = 0.0003, MRI VDPK: p = 0.0003). Discussion: The burden of ventilation defects quantified by Technegas SPECT and 129Xe MRI VDP was correlated and greater in participants with COPD when compared to those without. Our observations indicate that, despite substantial differences between the imaging modalities, quantitative assessment of ventilation defects by Technegas SPECT and 129Xe MRI is comparable.
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Body size influences bone mineral density (BMD) in health. Relationships of BMD with body mass index, fat mass (FM), fat-free mass, and appendicular lean mass were explored in acute lymphoblastic leukemia (ALL) survivors (n=75; 41 males; 45 standard risk ALL) >10 years from diagnosis. Dual energy radiograph absorptiometry performed body composition analysis. Relationships were assessed by regression analyses and Pearson correlation coefficients (r). Twenty subjects (26.3%) were osteopenic; lumbar spine (LS) BMD Z score <-1.00. Age at diagnosis, sex, ALL risk-category, type of post-induction steroid or cranial radiation did not correlate with LS or whole body (WB) BMD. Body mass index correlated significantly with LS BMD (r=0.333, P=0.004) and WB BMD (r=0.271, P=0.033). FM index (FM/height²) Z score showed no significant correlation with LS or WB BMD. Fat-free mass index Z score correlated strongly with LS BMD (r=0.386, P=0.013) and WB BMD (r=0.605, P<0.001) in males but not in females. The appendicular lean mass index, a surrogate for skeletal muscle mass, correlated significantly with LS BMD (r=0.367, P=0.018) and WB BMD (r=0.604, P<0.001) in males but not in females. Future studies to evaluate interventions to enhance BMD focused on improving body composition particularly skeletal muscle mass are warranted.
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Adiposidad , Composición Corporal , Índice de Masa Corporal , Densidad Ósea , Supervivientes de Cáncer/estadística & datos numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/rehabilitación , Sobrevivientes/estadística & datos numéricos , Adolescente , Adulto , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Diagnosing pulmonary embolism (PE) in the emergency department (ED) can be challenging because its signs and symptoms are non-specific. OBJECTIVE: We compared the efficacy and safety of using age-adjusted D-dimer interpretation, clinical probability-adjusted D-dimer interpretation and standard D-dimer approach to exclude PE in ED patients. DESIGN/METHODS: We performed a health records review at two emergency departments over a two-year period. We reviewed all cases where patients had a D-dimer ordered to test for PE or underwent CT or VQ scanning for PE. PE was considered to be present during the emergency department visit if PE was diagnosed on CT or VQ (subsegmental level or above), or if the patient was subsequently found to have PE or deep vein thrombosis during the next 30â¯days. We applied the three D-dimer approaches to the low and moderate probability patients. The primary outcome was exclusion of PE with each rule. Secondary objective was to estimate the negative predictive value (NPV) for each rule. RESULTS: 1163 emergency patients were tested for PE and 1075 patients were eligible for inclusion in our analysis. PE was excluded in 70.4% (95% CI 67.6-73.0%), 80.3% (95% CI 77.9-82.6%) and 68.9%; (95% CI 65.7-71.3%) with the age-adjusted, clinical probability-adjusted and standard D-dimer approach. The NPVs were 99.7% (95% CI 99.0-99.9%), 99.1% (95% CI 98.3-99.5%) and 100% (95% CI 99.4-100.0%) respectively. CONCLUSION: The clinical probability-adjusted rule appears to exclude PE in a greater proportion of patients, with a very small reduction in the negative predictive value.
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Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Embolia Pulmonar/diagnóstico , Adulto , Factores de Edad , Anciano , Angiografía por Tomografía Computarizada , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Gammagrafía de Ventilacion-PerfusiónRESUMEN
BACKGROUND: The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. METHODS: A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. RESULTS: The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. CONCLUSIONS: Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.
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Antineoplásicos/efectos adversos , Composición Corporal/efectos de los fármacos , Obesidad/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Sarcopenia/epidemiología , Absorciometría de Fotón , Adolescente , Adulto , Densidad Ósea/efectos de los fármacos , Supervivientes de Cáncer , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Músculo Esquelético/diagnóstico por imagen , Obesidad/diagnóstico , Obesidad/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prevalencia , Calidad de Vida , Sarcopenia/diagnóstico , Sarcopenia/etiología , Factores de Tiempo , Adulto JovenRESUMEN
INTRODUCTION: Success in the treatment of young people with cancer, as measured conventionally by survival rates, is mitigated by late effects of therapy that impose a burden of morbidity and limit life expectancy. Among these adverse sequelae are altered body composition, especially obesity, and compromised bone health in the form of osteoporosis and increased fragility. These outcomes are potentially reversible and even preventable. This study will examine measures of body composition and bone health in long-term survivors of acute lymphoblastic leukaemia (ALL) in childhood and adolescence. These measures will be complemented by measures of physical activity and health-related quality of life (HRQL). METHODS AND ANALYSIS: Survivors of ALL who are at least 10â years from diagnosis, following treatment on uniform protocols, will undergo measurements of body mass index; triceps skin fold thickness and mid-upper arm circumference; fat mass, lean body mass, skeletal muscle mass and bone mineral density by dual energy X-ray absorptiometry; trabecular and cortical bone indices and muscle density by peripheral quantitative CT; physical activity by the Habitual Activity Estimation Scale; and HRQL by Health Utilities Index instruments. Descriptive measures will be used for continuous variables and number (percent) for categorical variables. Associations between variables will be assessed using Fisher's exact t test and the χ(2) test; correlations will be tested by the Pearson correlation coefficient. ETHICS AND DISSEMINATION: The study is approved by the institutional research ethics board and is supported by a competitive funding award. Dissemination of the results will occur by presentations to scientific meetings and publications in peer-reviewed journals, and by posting summaries of the results on websites accessed by adolescent and young adult survivors of cancer.
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Composición Corporal , Densidad Ósea , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Sobrevivientes , Absorciometría de Fotón , Adolescente , Adulto , Índice de Masa Corporal , Niño , Estudios de Cohortes , Estudios Transversales , Ejercicio Físico , Femenino , Estado de Salud , Humanos , Masculino , Músculo Esquelético/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Calidad de Vida , Análisis de Regresión , Grosor de los Pliegues Cutáneos , Adulto JovenRESUMEN
BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.
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Bocio Nodular/tratamiento farmacológico , Bocio Nodular/radioterapia , Radioisótopos de Yodo/administración & dosificación , Tirotropina Alfa/administración & dosificación , Anciano , Quimioterapia Adyuvante , Preparaciones de Acción Retardada , Femenino , Bocio Nodular/patología , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/efectos de la radiación , Proteínas Recombinantes/administración & dosificación , Método Simple Ciego , Pruebas de Función de la Tiroides , Resultado del TratamientoRESUMEN
Inhalation of salmeterol xinafoate (SX) and fluticasone propionate (FP) from a combination product is reported to produce superior clinical outcomes in comparison to the concurrent administration of 'similar' doses via separate single-active inhalers. For bioequivalence determination across different products, emphasis is currently placed on the assessment of drug deposition within inertial impactors on a 'stage-by-stage' basis as stipulated in a recent European Medicines Agency guidance. The aim of this study was to compare the stage-by-stage deposition of drugs aerosolised from the single-active Accuhaler® products Serevent® (SX) and Flixotide® (FP) with the SX-FP combination product Seretide® Accuhaler® in vitro. Drug deposition on a stage-by-stage basis was assessed using the next generation impactor (NGI). Significant differences in drug deposition profiles were obtained following aerosolisation from the single-active versus combination products. The concurrent administration of the two single-active products: Serevent® and Flixotide® Accuhaler® may not be bioequivalent to inhalation of the combination product Seretide® Accuhaler®. The observed differences may have resulted from different characteristics of the active pharmaceutical ingredient (APIs) and the carrier alpha-lactose monohydrate between the single-active and combination inhalers and/or a change in the drug-carrier inter-particulate interaction as a consequence of the presence of a second active.
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Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Inhaladores de Polvo Seco/métodos , Administración por Inhalación , Albuterol/administración & dosificación , Albuterol/química , Androstadienos/química , Antiasmáticos/administración & dosificación , Broncodilatadores/administración & dosificación , Química Farmacéutica/métodos , Combinación de Medicamentos , Inhaladores de Polvo Seco/instrumentación , Fluticasona , Combinación Fluticasona-Salmeterol , Humanos , Xinafoato de SalmeterolRESUMEN
Inhalation particles can be produced by various techniques such as milling, controlled crystallisation and spray-drying, but current methods cannot, to-date, precisely control the aerodynamic size distribution of produced powders. The aim of this study was to develop and validate a novel preparative technique whereby the efficient and reproducible aerodynamic fractionation of drug and excipient powders could be achieved. Salmeterol xinafoate (SX), fluticasone propionate (FP) and fine α-lactose monohydrate (FL) were chosen as model compounds. Powders were aerosolised using a dry powder feeder into a Next Generation Impactor operated at 60 L min(-1). Powders deposited on NGI stages were then collected and analysed. The fractionation process was successful for all powders producing significant linear correlations between the pre-set aerodynamic cut-off limits and geometric size measurements. For each of SX, FP and FL, sufficient powder quantities were recovered from NGI stages 1-6 producing six fractions with sequential aerodynamic and geometric particle size distributions. The fractionation technique was efficient and reproducible for all powders studied. The method can be equally applied to various drugs and excipients regardless of their previous production/processing history. Therefore, the aerodynamic fractionation technique may be used to compare and contrast samples produced by different processes.
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Albuterol/análogos & derivados , Androstadienos , Broncodilatadores , Fraccionamiento Químico , Composición de Medicamentos , Administración por Inhalación , Aerosoles , Albuterol/administración & dosificación , Albuterol/química , Androstadienos/administración & dosificación , Androstadienos/química , Antialérgicos/química , Antialérgicos/farmacocinética , Broncodilatadores/química , Broncodilatadores/farmacocinética , Cristalización , Excipientes , Fluticasona , Humanos , Lactosa , Nebulizadores y Vaporizadores , Tamaño de la Partícula , Polvos , Xinafoato de SalmeterolRESUMEN
Positron emission tomography (PET) has shown potential benefits when used in therapeutic clinical trials for children with cancer. However, existing trials are limited in scope with small numbers of patients and varied observations, making accurate conclusions about the usefulness of PET scanning impossible. This review examines PET and its applications in pediatric oncology. While evidence is limited, there appears to be a basis for rigorous evaluation of this imaging modality before widespread application without validation from clinical trials.
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Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones , Niño , Ensayos Clínicos como Asunto , Fluorodesoxiglucosa F18 , Humanos , RadiofármacosRESUMEN
PURPOSE: To describe the lymphatic drainage patterns of the human eyelids. METHODS: Twenty-eight consenting patients who underwent unilateral eyelid surgery at McMaster University between March 2001 and July 2003 had their contralateral eyelids injected with 0.2 ml (0.250 mCi) of Tc 99 m sulphur colloid. The patients were divided into 1 of 5 injection sites of the eyelid, namely upper lateral, upper medial, medial canthus, lower medial, and lower lateral. Lymphoscintigraphy was performed between 2 and 6 hours later with a conventional planar gamma camera. Nodes in the head and neck were identified. In 15 patients, the right eye was injected, and in 13 patients, the left eye was injected. RESULTS: Three patients had no nodes that were identifiable. The remaining 25 patients had at least one node identified. In 11 patients, more than one node was identified. In 18 patients, the preauricular node was most intense and recognized first. Regardless of location on the eyelid, the sentinel node was most commonly the preauricular node. CONCLUSIONS: These results conflict with previously described classic drainage patterns of the eyelid lymphatics. In 72% (18/25) of cases, the first-order sentinel node was the preauricular node, regardless of location of the injection site on the eyelid. Many individuals did not fit the classic drainage patterns.
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Párpados/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Radiofármacos , Azufre Coloidal Tecnecio Tc 99m , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Sistema Linfático , Persona de Mediana Edad , CintigrafíaRESUMEN
Inertial impaction is generally regarded as the 'gold standard' for the in vitro assessment of aerodynamic deposition of inhaled formulations. Despite the availability of several impactors, few studies have compared measurements of aerodynamic deposition using multiple impactors and none employed a combination formulation. The aerodynamic deposition of the combination dry powder inhaler (DPI) Seretide Accuhaler, which contains salmeterol xinafoate (SX) and fluticasone propionate (FP), was assessed using the Andersen cascade impactor (ACI), multi-stage liquid impinger (MSLI) and next generation impactor (NGI) and the results were compared. Two Seretide products were tested at flow rates of 30 and QLmin(-1), the latter corresponding to a pressure drop of 4kPa across the device. Significant differences in the particle size distributions were observed when the same formulation was tested using various impactors. The ACI was found to be less suitable for DPI testing at flow rates considerably higher than 28.3Lmin(-1) due to the significant overlap in the cut-off curves of the pre-separator and stage 0. This was not the case with the MSLI but the data derived were limited by the relatively small number of stages. Deposition data determined by the three impactors were significantly different. The NGI produced good resolution and minimal inter-stage overlap and was regarded as the impactor of choice for DPI testing.
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Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Broncodilatadores/administración & dosificación , Nebulizadores y Vaporizadores , Administración por Inhalación , Aerosoles , Albuterol/administración & dosificación , Albuterol/química , Androstadienos/química , Broncodilatadores/química , Combinación de Medicamentos , Fluticasona , Tamaño de la Partícula , Polvos , Xinafoato de Salmeterol , Tecnología Farmacéutica/métodosRESUMEN
Direct crystallization of active pharmaceutical ingredient (API) particles in the inhalable size range of 1-6 microm may overcome surface energization resulting from micronization. The aerosolization of fluticasone propionate (FP) and salmeterol xinafoate (SX) microcrystals produced by aqueous crystallization from poly(ethylene glycol) solutions was investigated using a twin stage impinger following blending with lactose. Fine particle fractions from SX formulations ranged from 15.98 +/- 2.20% from SX crystallized from PEG 6000 to 26.26 +/- 1.51% for SX crystallized from PEG 400. The FPF of microcrystal formulations increased as the particle size of microcrystals was increased. The aerosolization of SX from DPI blends was equivalent for the microcrystals and the micronized material. FP microcrystals, which had a needlelike morphology, produced similar FPFs (PEG 400: 17.15 +/- 0.68% and PEG 6000: 15.46 +/- 0.97%) to micronized FP (mFP; 14.21 +/- 0.54). The highest FPF (25.66 +/- 1.51%) resulted from the formulation of FP microcrystals with the largest median diameter (FP PEG 400B: 6.14 +/- 0.17 microm). Microcrystallization of SX and FP from PEG solvents offers the potential for improving control of particulate solid state properties and was shown to represent a viable alternative to micronization for the production of particles for inclusion in dry powder inhalation formulations.
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Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Androstadienos/química , Broncodilatadores/química , Administración por Inhalación , Agonistas Adrenérgicos beta/administración & dosificación , Aerosoles , Albuterol/administración & dosificación , Albuterol/química , Androstadienos/administración & dosificación , Broncodilatadores/administración & dosificación , Química Farmacéutica , Cristalización , Composición de Medicamentos , Fluticasona , Lactosa/química , Nebulizadores y Vaporizadores , Tamaño de la Partícula , Polietilenglicoles/química , Polvos , Xinafoato de SalmeterolRESUMEN
Milling processes are known to cause polymorphic transition in enantiotropic systems and the micronization process employed to produce microparticles for inhalation formulations has been reported to result in solid-state damage. The aim of the current work was to investigate the polymorphism of salmeterol xinafoate (SX) following antisolvent micronization from poly(ethylene glycol) (PEG) solvents and compare this to the properties of SX conventionally crystallized and micronized. Powder X-ray diffraction revealed that SX crystallized predominantly as the SX form I polymorph following rapid precipitation from PEG solvents and cooling crystallization from propan-2-ol. Thermo-kinetic analysis using a modified Avrami-Erofe'ev equation was applied to differential scanning calorimetric thermographs of crystallized and micronized SX. The kinetic analysis revealed that SX crystallized from PEG solvents underwent significantly less or no re-crystallization of SX form II from the melt. A polymorphic transition was identified upon heating ball-milled SX, although the untreated material was resistant to such transformation. The thermal behaviour of SX crystallized from PEG solvents was consistent with a lower degree of crystal lattice disorder and higher enantiotropic purity than SX crystallized from propan-2-ol; the same was also true when comparing SX before and after micronization.
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Albuterol/análogos & derivados , Broncodilatadores/química , Microesferas , 2-Propanol/química , Administración por Inhalación , Albuterol/química , Rastreo Diferencial de Calorimetría , Química Farmacéutica/métodos , Cristalización , Tamaño de la Partícula , Polietilenglicoles/química , Difracción de Polvo , Xinafoato de Salmeterol , Solventes/químicaRESUMEN
PURPOSE: To investigate the aerosolization and behaviour of microparticles of salmeterol xinafoate (SX) and fluticasone propionate (FP) suspended in hydrofluoroalkane (HFA) propellant. METHODS: Microcrystals of SX and FP were produced from poly(ethylene glycol) by antisolvent crystallization. The suspension behaviour and aerosolization of the microcrystals when formulated as metered dose inhalers (MDIs) in HFA 134a propellant was compared with that of microparticles produced by micronization (mSX and mFP) using a glass twin stage impinger and by laser light diffraction using a pressurized cell. RESULTS: FP microparticles underwent non-reversible aggregation in suspension as seen by a doubling in the volume median diameter compared to the raw material. The degree of aggregation of SX particles in suspension was found to decrease as the particle size of the original particles increased. However, because the SX aggregate size was lowest for the particles with the smallest initial size (mSX), the highest fine particle fraction (FPF) of SX was obtained from a suspension of mSX. The FPFs following aerosolization of FP suspensions were similar although the FPF was lowest for particles with the largest original size. CONCLUSIONS: The size of the aggregates in the HFA suspensions was found to correlate directly with the FPFs determined by impaction.
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Albuterol/análogos & derivados , Androstadienos/química , Broncodilatadores/química , Inhaladores de Dosis Medida , Administración por Inhalación , Propelentes de Aerosoles , Aerosoles , Albuterol/administración & dosificación , Albuterol/química , Androstadienos/administración & dosificación , Broncodilatadores/administración & dosificación , Química Farmacéutica , Cristalización , Estabilidad de Medicamentos , Fluticasona , Hidrocarburos Fluorados/química , Tamaño de la Partícula , Polietilenglicoles/química , Presión , Reproducibilidad de los Resultados , Xinafoato de Salmeterol , Tecnología Farmacéutica/métodosRESUMEN
In recent years, 6-l-18F-fluorodihydroxyphenylalanine (18F-DOPA) PET has emerged as a new diagnostic tool for the imaging of neuroendocrine tumors. This application is based on the unique property of neuroendocrine tumors to produce and secrete various substances, a process that requires the uptake of metabolic precursors, which leads to the uptake of 18F-DOPA. This nonsystematic review first describes basic aspects of 18F-DOPA imaging, including radiosynthesis, factors involved in tracer uptake, and various aspects of metabolism and imaging. Subsequently, this review provides an overview of current clinical applications in neuroendocrine tumors, including carcinoid tumors, pancreatic islet cell tumors, pheochromocytoma, paraganglioma, medullary thyroid cancer, hyperinsulinism, and various other clinical entities. The application of PET/CT in carcinoid tumors has unsurpassed sensitivity. In medullary thyroid cancer, pheochromocytoma, and hyperinsulinism, results are also excellent and contribute significantly to clinical management. In the remaining conditions, the initial experience with 18F-DOPA PET indicates that it seems to be less valuable, but further study is required.
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Dihidroxifenilalanina/análogos & derivados , Tumores Neuroendocrinos/diagnóstico por imagen , Tomografía de Emisión de Positrones , Adenoma de Células de los Islotes Pancreáticos/diagnóstico por imagen , Humanos , Hiperinsulinismo/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Feocromocitoma/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico por imagenRESUMEN
The production of microparticles for inhalation has relied on jet-milling while the potential for crystallization of microparticles has remained underexplored until relatively recently. Aqueous antisolvent crystallization of salmeterol xinafoate (SX) from poly(ethylene glycol) (PEG) and other organic (co)solvent systems was compared in order to evaluate factors determining the resultant microparticle properties. SX was crystallized by the addition of water to solutions of SX in PEG 400, PEG 6000, propan-2-ol, acetone and methanol. Crystalline particles were characterized by laser diffraction sizing, scanning electron microscopy and differential scanning calorimetry; PEG-media were characterized by viscometry. Crystallization of SX from PEG 400 produced crystals that exhibited a narrower size distribution than those crystallized from other conventional organic solvents. SX crystallized from PEG 6000 demonstrated a smaller median particle size (D(v,0.5)=0.92+/-0.04 microm) than PEG 400 crystallized SX (D(v,0.5)=4.50+/-0.61 microm). Crystals produced from PEG 400 (Span=2.49+/-0.10) possessed a narrower particle size distribution (PSD) than those produced from PEG 6000 (Span=10.42+/-0.85). SX crystals displayed a plate-like habit with growth limited to two dimensions irrespective of the initial solvent employed. The importance of the rate of generation of SX supersaturation on the PSD was determined using HPLC analysis. DSC showed PEG-crystallized SX to be free from metastable crystal phases in contrast to SX crystallized from propan-2-ol. Crystallization of SX from PEG was shown to follow classical nucleation theory and the crystallization method represents a viable alternative to the use of conventional solvents for the production of microparticles.
Asunto(s)
Albuterol/análogos & derivados , Broncodilatadores/química , Cristalización , Microesferas , Albuterol/química , Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión , Portadores de Fármacos , Rayos Láser , Tamaño de la Partícula , Polietilenglicoles/química , Reología , Xinafoato de Salmeterol , Solubilidad , Solventes/química , Tecnología Farmacéutica/métodos , TermodinámicaRESUMEN
The production of microparticles for inhalation typically employs jet-milling which can be destructive to the solid-state properties of the particles. The objective of the current work was to develop a crystallization process for the production of respirable microparticles of salmeterol xinafoate (SX) with a controlled particle size distribution (PSD). Solvation of SX in aqueous poly(ethylene glycol) 400 (PEG 400) was investigated using HPLC and FTIR. SX was crystallized from PEG 400 solutions by the addition of water under a variety of conditions of supersaturation, addition rate of antisolvent and stirring speed. The crystals were filtered, dried at 50 degrees C and their PSDs were determined by laser diffraction. A logarithmic increase in solubility of SX was observed with increasing concentration of PEG 400 in water enabling the aqueous antisolvent crystallization of SX from PEG. Similar to antisolvent crystallization from conventional solvents, a 2(4) factorial study showed the particle size to decrease with increasing supersaturation. The PSD also depended on the balance of meso- and micromixing determined by the crystallization conditions. In particular a high addition rate (200 g min(-1)) and low stirrer speed (400 rpm) minimized the median diameter (2.54+/-0.40 microm) and produced a narrow PSD (90%<8.67+/-0.77 microm) of SX particles. Amphiphilic crystallization provided a novel, environmentally benign method to produce microparticles of SX with a controlled size range.
Asunto(s)
Química Farmacéutica/métodos , Microesferas , Tecnología Farmacéutica/métodos , Albuterol/análogos & derivados , Albuterol/química , Cromatografía Líquida de Alta Presión/métodos , Cristalización , Sistemas de Liberación de Medicamentos , Pulmón/efectos de los fármacos , Tamaño de la Partícula , Polietilenglicoles/química , Análisis de Regresión , Xinafoato de Salmeterol , Solubilidad , Solventes/química , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
This study was designed to analyse the two enantiomers of abuterol in urine after the inhalation of a single dose of racemic albuterol from three dry powder inhalers by human volunteers. Urine samples were collected over 24h and analysed by HPLC-with fluorescence detection. Albuterol and its metabolites in urine could only have resulted from pulmonary absorption because gastrointestinal absorption was prevented. Unchanged albuterol and its conjugated metabolites were detected in the urine of healthy volunteers at much higher levels than in the urine of the asthmatics. Also, the amount of S-(+)-isomer excreted in urine was higher than that of the R-(--)-isomer. These differences did not arise as a consequence of either the formulation or the inter-conversion of two isomers in the urine. There is a relationship between the improvement of mid-expiratory flow (FEF(25-75)) and the amount of R-(--)-albuterol remaining to be excreted. The elimination rate constants of the parent drug in healthy volunteers of both R-(--)- and S-(+)-isomers were higher than those of the respective conjugated metabolites. The mean S/R ratio of the parent drug was about unity initially and increased to about 1.5 in the urine collected between 12 and 24h. The values of S/R ratio of the conjugated metabolites in the healthy volunteers were in the range 1.2-2.4, with the value increasing over the time of collection before reaching a plateau. This also occurred with the asthmatics, but the ratios were higher, in the range of 2.0-4.5. In summary, the urinary level of albuterol following in vivo inhalation was found to correlate with in vitro deposition data from the dry powder inhaler.
Asunto(s)
Albuterol/farmacocinética , Asma/tratamiento farmacológico , Administración por Inhalación , Adulto , Albuterol/química , Albuterol/orina , Asma/fisiopatología , Asma/orina , Disponibilidad Biológica , Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Semivida , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Fenilefrina/análisis , Polvos , Estereoisomerismo , Sulfatos/orinaRESUMEN
On 27 occasions, radiation doses were measured for a family member designated as the 'caregiver' for a patient receiving high-dose radioiodine outpatient therapy for differentiated thyroid carcinoma. For 25 of the administrations, patients received 3.7 GBq of (131)I. Radiation doses for the designated caregivers were monitored on an hourly basis for 1 week using electronic personal dosemeters. The average penetrating dose was 98 +/- 64 microSv. The maximum penetrating dose was 283 microSv. Measured dose rate profiles showed that, on average, one-third of the caregiver dose was received during the journey home from hospital. The mean dose rate profile showed rapid clearance of (131)I with three distinct phases. The corresponding clearance half-times were <1 h, 21 h and approximately 8 d. These components were associated, respectively, with the drive home, the clearance of radioiodine from an athyreotic patient and small quantities of (131)I contaminating the home.
Asunto(s)
Cuidadores , Radioisótopos de Yodo/uso terapéutico , Pacientes Ambulatorios , Dosis de Radiación , Traumatismos por Radiación , Protección Radiológica , Neoplasias de la Tiroides/radioterapia , Exposición a Riesgos Ambientales , Humanos , Concentración Máxima Admisible , Monitoreo de RadiaciónRESUMEN
PURPOSE: The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 microm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. MATERIALS AND METHODS: Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63-90 microm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler. RESULTS: Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min(-1) s(-1) although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R (2) = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler, increasing FIR from 120 to 600 l min(-1) s(-1) for a constant peak flow rate (PFR) of 60 l min(-1) increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. CONCLUSION: Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.