RESUMEN
Leukotrienes can be generated from a wide variety of cells including mast cells and eosinophils. The biological properties of these products include bronchial smooth muscle contraction, stimulation of mucous production, enhancement of vascular permeability, and recruitment of eosinophils. These properties can contribute significantly to the pathobiology of asthma. Recently, zafirlukast and montelukast, and zileuton, leukotriene D4 receptor antagonists and 5-lipoxygenase inhibitors, respectively, have been developed and are available for treating asthma. Studies have found these compounds modify bronchospasm with exercise, the pulmonary reaction to aspirin in sensitive subjects, and the airway response to inhaled antigen. Furthermore, in patients with chronic asthma, leukotriene modifiers improve airflow obstruction, decrease the need for rescue medication, and diminish symptoms. Moreover, these drugs can prevent asthma exacerbations. However, there is little evidence that these medications have potent anti-inflammatory activity. Nonetheless, leukotriene modifiers represent new, and effective, therapeutics in the treatment of asthma; at present, the positioning of these products in relationship to inhaled corticosteroids, for example, in the treatment of asthma has not been fully defined but will emerge with further study and use in the clinic setting.
Asunto(s)
Asma/tratamiento farmacológico , Antagonistas de Leucotrieno/uso terapéutico , Leucotrieno D4/antagonistas & inhibidores , Inhibidores de la Lipooxigenasa/uso terapéutico , Enfermedades Pulmonares Obstructivas/tratamiento farmacológico , HumanosRESUMEN
OBJECTIVE: Asthma is a significant cause of morbidity and mortality in children. The objective of this study was to determine whether the federal program Head Start in Dane County, Wisconsin, could be used as a mechanism to identify preschool-aged children with asthma. DESIGN: Five-year, cross-sectional survey of parents with children enrolled in Head Start. METHODS: Investigator-administered asthma screening questionnaire to parents of enrolling Head Start children in Dane County, Wisconsin. MEASUREMENTS: Asthma prevalence and asthma-related health care use, including emergency department visits, hospitalizations, and medication usage, were measured using an asthma screening questionnaire developed by investigators. RESULTS: Information was gathered on 2215 children. The prevalence of physician-diagnosed asthma in the screened children was 15.8%. Parental reports of physician-diagnosed asthma were validated in a subset of 133 children, with a 98.5% confirmation rate. Independent risk factors for asthma included male gender (relative risk, 1.4) and African-American ethnicity (relative risk, 1.4). Asthma-related morbidity was substantial with 26.7% of identified children hospitalized for asthma and 54.5% with an emergency department visit during their lifetime. The majority of children (46.4%) were treated with intermittent, quick relief medications (beta-agonists) alone, whereas only 6.1% were on daily, long-term controller medications. CONCLUSIONS: Asthma screening through a Head Start program provides an effective means of targeting preschool-aged children from socioeconomic groups at high risk for asthma. Identification of children early in the disease course and those at high risk for asthma provides an ideal opportunity for the implementation of preventive and therapeutic interventions.
Asunto(s)
Asma/epidemiología , Intervención Educativa Precoz/estadística & datos numéricos , Tamizaje Masivo/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Asma/diagnóstico , Servicios de Salud del Niño/estadística & datos numéricos , Preescolar , Estudios Transversales , Femenino , Humanos , Incidencia , Masculino , Factores de Riesgo , Factores Socioeconómicos , Wisconsin/epidemiologíaAsunto(s)
Asma/tratamiento farmacológico , Antagonistas de Leucotrieno , Animales , Asma/etiología , Asma/fisiopatología , Humanos , Hidroxiurea/efectos adversos , Hidroxiurea/análogos & derivados , Hidroxiurea/uso terapéutico , Indoles , Leucotrienos/fisiología , Inhibidores de la Lipooxigenasa/efectos adversos , Inhibidores de la Lipooxigenasa/uso terapéutico , Fenilcarbamatos , Sulfonamidas , Compuestos de Tosilo/efectos adversos , Compuestos de Tosilo/uso terapéuticoRESUMEN
Ticlopidine is a novel antiplatelet drug reported to cause significant inhibition of several drugs metabolized by the hepatic cytochrome P-450 enzyme system, including antipyrine and theophylline. Warfarin, a racemic mixture of two enantiomers (R and S), is extensively metabolized by the CYP-450 system. S-Warfarin is five to eight times as active as R-warfarin. The effects of ticlopidine on the pharmacokinetics and pharmacodynamics of warfarin were examined in nine elderly men (69 +/- 4 years) receiving long-term warfarin therapy. Steady-state warfarin enantiomer concentrations and International Normalized Ratios (INRs) were determined at baseline and after 14 days of treatment with oral ticlopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chiral derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations (+25.7%, p < 0.05), while no significant difference in S-warfarin concentrations was noted (+0.8%). Mean INR values were not significantly different from the baseline (+8.3%), although substantial interindividual variability was noted. We conclude that ticlopidine co-medication does result in an enantioselective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients.
Asunto(s)
Anticoagulantes/farmacología , Ticlopidina/farmacología , Warfarina/farmacocinética , Anciano , Anticoagulantes/efectos adversos , Anticoagulantes/sangre , Cromatografía Líquida de Alta Presión , Interacciones Farmacológicas , Humanos , Masculino , Cooperación del Paciente , Tiempo de Protrombina , Estereoisomerismo , Ticlopidina/efectos adversos , Ticlopidina/sangre , Warfarina/efectos adversos , Warfarina/sangreRESUMEN
Pig kidney microvillar proteins were extracted with octyl beta-glucoside and reconstituted in liposomes prepared from microvillar lipids of known composition. Four peptidases, namely endopeptidase (EC 3.4.24.11), aminopeptidases N (EC 3.4.11.2) and A (EC 3.4.11.7) and dipeptidyl peptidase IV (EC 3.4.14.5), were shown to be reconstituted. At lipid/protein ratios greater than 4:1, about half the detergent-solubilized protein and nearly all of the activity of the four peptidases were reconstituted. Dissolution of the liposomes with Triton X-100 did not increase the activity of any of these peptidases, a result consistent with an asymmetric, 'right-side-out', orientation of these enzymes. When purified, endopeptidase was subjected to the same procedure; the two amphipathic forms of the enzyme (the detergent form and the trypsin-treated detergent form) were fully reconstituted. The amphiphilic form, purified after toluene/trypsin treatment, failed to reconstitute. Electron microscopy of microvilli showed that the appearance of the surface particles was profoundly altered by treatment with papain. Before treatment, the microvilli were coated with particles of stalk lengths ranging from 2.5 to 9 nm. After papain treatment nearly all the particles had stalks of 2-3 nm. Reconstituted microvillar proteins in liposomes showed the same heterogeneity of stalk length. In contrast, liposomes containing reconstituted endopeptidase revealed a very homogeneous population of particles of stalk length 2 nm. Since the smallest dimension of a papain molecule is 3.7 nm, the ability of papain, and other proteinases of similar molecular size, to release microvillar enzymes is crucially affected by the length of the junctional peptide that constitutes the stalk of this type of membrane protein.
Asunto(s)
Endopeptidasas , Riñón/enzimología , Proteínas de la Membrana , Aminopeptidasas , Animales , Riñón/ultraestructura , Lípidos/análisis , Liposomas , Microvellosidades/efectos de los fármacos , Microvellosidades/enzimología , Microvellosidades/ultraestructura , Papaína/farmacología , PorcinosRESUMEN
A population of sarcoplasmic-reticulum vesicles, all of which were sealed with their cytoplasmic side outwards, was obtained by density-gradient centrifugation after loading the vesicles with calcium oxalate. The calcium oxalate could subsequently be removed from the vesicles by the reverse action of the calcium-transport system. Measurements of the catalysed exchange of the phosphatidylcholine in the sarcoplasmic-reticulum cytoplasmic monolayer with an exogenous phosphatidylcholine pool suggested that phosphatidylcholine is symmetrically distributed across the sarcoplasmic-reticulum membrane. A similar result was obtained for phosphatidylethanolamine when sarcoplasmic-reticulum lipids were labelled with trinitrobenzenesulphonic acid. Further catalysed lipid-exchange reactions showed that the transverse movement of phosphatidylcholine across the membrane was exceedingly slow (t 1/2 greater than 15 days).
Asunto(s)
Membrana Dobles de Lípidos/metabolismo , Retículo Sarcoplasmático/metabolismo , Animales , Calcio/metabolismo , Citoplasma/metabolismo , Cinética , Microscopía Electrónica , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Conejos , Retículo Sarcoplasmático/ultraestructura , Ácido Trinitrobencenosulfónico/metabolismoAsunto(s)
Adenosina Trifosfatasas/metabolismo , Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Fosfolípidos/metabolismo , Retículo Sarcoplasmático/ultraestructura , Proteínas Portadoras/metabolismo , Membranas Artificiales , Fosfolipasas/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMEN
Pure complexes of dipalmitoyllecithin (DPL, 16:0) which Ca2+, Mg2+ dependent ATPase from sarcoplasmic reticulum are unusual in retaining significant ATPase activity down to about 30 degrees C, well below the transition temperature of the pure lipid at 41 degrees C. A minimum of about 35 lipid molecules per ATPase is required to maintain maximal ATPase activity, but the complexes are progressively and irreversibly inactivated at lower lipid to protein ratios. Complexes containing more than the minimum lipid requirement show very similar temperature profiles of activity about 30 degrees C over a wide range of lipid to protein ratios, up to 1500:1. Spin-label studies indicate that, at lipid to protein ratios of less than about 30 lipids per ATPase, no DPL phase transition can be detected, but at all higher ratios, a phase transition occurs at about 41 degrees C. In all of these complexes there are breaks in the Arrhenius plots of ATPase activity at 27--32 degrees C and at 37.5--38.5 degrees C. Experiments with perturbing agents, such as cholesterol and benzyl alcohol which have well-defined effects on the DPL phase transition, indicate that these breaks in the Arrhenius plots of ATPase activity cannot be attributed to a depressed and broadened phase transition in the lipids near the protein molecules. These results are interpreted as evidence for a phospholipid annulus of at least 30 lipid molecules with interact directly with the ATPase and cannot undergo a phase transition at 41 degrees C. This structural interaction of the ATPase with the annular DPL molecules has a predominant effect in determining the form of the temperature-activity profiles. However, the perturbation of the DPL phase transition does not extend significantly beyond the annulus since a phase transition which starts at 41 degrees C can be detected as soon as extraannular lipid is present in the complexes. We suggest that it may be a general feature of membrane structure that penetrant membrane proteins interact with their immediate lipid environment so as to cause only a minimal perturbation of the lipid bilayer.