RESUMO
G-protein-coupled receptors (GPCRs) mediate a wide range of human physiological functions by transducing extracellular ligand binding events into intracellular responses. GPCRs can activate parallel, independent signaling pathways mediated by G proteins or ß-arrestins. Whereas "balanced" agonists activate both pathways equally, "biased" agonists dominantly activate one pathway, which is of interest for designing GPCR-targeting drugs because it may mitigate undesirable side effects. Previous studies demonstrated that ß-arrestin activation is associated with transmembrane helix VII (TM VII) of GPCRs. Here, single-molecule fluorescence spectroscopy with the ß2-adrenergic receptor (ß2AR) in the ligand-free state showed that TM VII spontaneously fluctuates between one inactive and one active-like conformation. The presence of the ß-arrestin-biased agonist isoetharine prolongs the dwell time of TM VII in the active-like conformation compared with the balanced agonist formoterol, suggesting that ligands can induce signaling bias by modulating the kinetics of receptor conformational exchange.
Assuntos
Isoetarina/farmacologia , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , beta-Arrestinas/metabolismo , Sítios de Ligação/efeitos dos fármacos , Humanos , Cinética , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Transdução de Sinais , Imagem Individual de Molécula , Espectrometria de FluorescênciaRESUMO
Discovering biased agonists requires a method that can reliably distinguish the bias in signalling due to unbalanced activation of diverse transduction proteins from that of differential amplification inherent to the system being studied, which invariably results from the non-linear nature of biological signalling networks and their measurement. We have systematically compared the performance of seven methods of bias diagnostics, all of which are based on the analysis of concentration-response curves of ligands according to classical receptor theory. We computed bias factors for a number of ß-adrenergic agonists by comparing BRET assays of receptor-transducer interactions with Gs, Gi and arrestin. Using the same ligands, we also compared responses at signalling steps originated from the same receptor-transducer interaction, among which no biased efficacy is theoretically possible. In either case, we found a high level of false positive results and a general lack of correlation among methods. Altogether this analysis shows that all tested methods, including some of the most widely used in the literature, fail to distinguish true ligand bias from "system bias" with confidence. We also propose two novel semi quantitative methods of bias diagnostics that appear to be more robust and reliable than currently available strategies.
Assuntos
Agonistas Adrenérgicos/metabolismo , Bioensaio , Cromograninas/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , beta-Arrestinas/metabolismo , Agonistas Adrenérgicos/farmacologia , Viés , Cromograninas/genética , Clembuterol/metabolismo , Clembuterol/farmacologia , Dopamina/metabolismo , Dopamina/farmacologia , Epinefrina/metabolismo , Epinefrina/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Expressão Gênica , Células HEK293 , Humanos , Isoetarina/metabolismo , Isoetarina/farmacologia , Isoproterenol/metabolismo , Isoproterenol/farmacologia , Ligantes , Método de Monte Carlo , Ligação Proteica , Receptores Adrenérgicos beta 2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Regressão , beta-Arrestinas/genéticaRESUMO
Extracellular ligand binding to G protein-coupled receptors (GPCRs) modulates G protein and ß-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the ß(2)-adrenergic receptor (ß(2)AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein-specific active state of helix VI. In contrast, ß-arrestin-biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of ß(2)AR in partial and biased agonist signaling.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Arrestinas/metabolismo , Sítios de Ligação , Carbazóis/química , Carbazóis/metabolismo , Carbazóis/farmacologia , Carvedilol , Citoplasma/química , Agonismo Parcial de Drogas , Flúor , Isoetarina/química , Isoetarina/metabolismo , Isoetarina/farmacologia , Isoproterenol/metabolismo , Ligantes , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Propanolaminas/química , Propanolaminas/metabolismo , Propanolaminas/farmacologia , Conformação Proteica , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , beta-ArrestinasRESUMO
We studied the dose-dependent effects of inhaled isoetharine HCl, a beta-adrenergic bronchodilator (2.5, 5.0, 10.0, and 20.0 mg), on bronchial blood flow (Qbr) in anesthetized sheep. Isoetharine resulted in a dose-dependent increase in Qbr. With a total dose of 17.5 mg, Qbr increased from baseline values of 22 +/- 3.4 (SE) to 60 +/- 16 ml/min (P < 0.001), an effect independent of changes in cardiac output and systemic arterial pressure. To further study whether synthesis of endogenous nitric oxide (NO) affects beta-agonist-induced increases in Qbr, we administered isoetharine (20 mg) by inhalation before and after the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Intravenous L-NAME (30 mg/kg) rapidly decreased Qbr by approximately 80% of baseline, whereas L-NAME via inhalation (10 mg/kg) resulted in a delayed and smaller (approximately 22%) decrease. Pretreatment with L-NAME via both routes of administration attenuated bronchial arterial vasodilation after subsequent challenge with isoetharine. We conclude that isoetharine via inhalation increases Qbr in a dose-dependent manner and that beta-agonist-induced relaxation of vascular smooth muscle in the bronchial vasculature is partially mediated via synthesis of NO.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Artérias Brônquicas/efeitos dos fármacos , AMP Cíclico/fisiologia , Vasodilatação/efeitos dos fármacos , Administração por Inalação , Agonistas alfa-Adrenérgicos/farmacologia , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hemodinâmica/efeitos dos fármacos , Injeções Intravenosas , Isoetarina/administração & dosagem , Isoetarina/farmacologia , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Consumo de Oxigênio/efeitos dos fármacos , Fenilefrina/farmacologia , OvinosRESUMO
In anesthetized sheep, we measured bronchial blood flow (Qbr) by an ultrasonic flow probe to investigate the interaction between inhaled nitric oxide (NO; 100 parts/million) given for 5 min and 5 ml of aerosolized isoetharine (1.49 x 10(-2) M concentration). NO and isoetharine increased Qbr from 26.5 +/- 6.5 to 39.1 (SE) +/- 10.6 and 39.7 +/- 10.7 ml/min, respectively (n = 5). Administration of NO immediately after isoetharine further increased Qbr to 57.3 +/- 15.1 ml/min. NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME; 30 mg/kg, in 20 ml saline given i.v.) decreased Qbr to 14.6 +/- 2.6 ml/min. NO given three times alternately with isoetharine progressively increased Qbr from 14.6 +/- 2.6 to 74.3 +/- 17.0 ml/min, suggesting that NO and isoetharine potentiate vasodilator effects of each other. In three other sheep, after L-NAME three sequential doses of isoetharine increased Qbr from 10.2 +/- 3.4 to 11.5 +/- 5.7, 11.7 +/- 4.7, and 13.3 +/- 5.7 ml/min, respectively, indicating that effects of isoetharine are predominantly mediated through synthesis of NO. When this was followed by three sequential administrations of NO, Qbr increased by 146, 172, and 185%, respectively. Thus in the bronchial circulation, there seems to be a close interaction between adenosine 3',5'-cyclic monophosphate- and guanosine 3',5'-cyclic monophosphate-mediated vasodilation.
Assuntos
Artérias Brônquicas/efeitos dos fármacos , Isoetarina/farmacologia , Óxido Nítrico/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , OvinosAssuntos
Albuterol/farmacocinética , Asma/tratamento farmacológico , Broncodilatadores/farmacocinética , Isoetarina/farmacocinética , Doença Aguda , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Humanos , Isoetarina/administração & dosagem , Equivalência TerapêuticaRESUMO
PURPOSE: To compare the magnitudes of the immediate effects of the nebulized beta-agonists isoetharine and albuterol in the treatment of acute severe asthma. PATIENTS AND METHODS: Fifty-one adults presenting with severe asthma exacerbations (forced expiratory volumes in the first second of exhalation [FEV1] <40% of predicted) to the emergency department were randomized (double-blind) to receive hourly inhaled nebulization treatment with either isoetharine (5 mg) or albuterol (2.5 mg). The FEV1 was measured immediately before and after each nebulized treatment. Any side effects were recorded. RESULTS: Immediately after the first nebulized treatment, the isoetharine group improved its mean FEV1 (+/-SEM) by a significantly greater amount than did the albuterol group: 60% +/- 11% versus 39% +/- 5%, respectively (P <0.05). One hour later the mean FEV1 were equivalent. This pattern repeated itself after the second hourly treatment. The two groups did not differ in any outcome parameters (FEV1 at discharge, number of nebulized treatments required, the number of inpatient admissions, number of clinical relapses after discharge). More patients treated with isoetharine had side effects (36% versus 4% for albuterol, P <0.01), 1 of whom required discontinuation from the study. CONCLUSIONS: Both medications were equally effective in alleviating bronchospasm. The immediate effect of isoetharine was significantly greater, but equalized that of albuterol within an hour after treatment. There were more side effects with isoetharine.
Assuntos
Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Volume Expiratório Forçado/efeitos dos fármacos , Isoetarina/uso terapêutico , Doença Aguda , Administração por Inalação , Adulto , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Isoetarina/administração & dosagem , Isoetarina/efeitos adversos , Masculino , Resultado do TratamentoRESUMO
STUDY OBJECTIVE: Metered-dose inhalers (MDIs) may contain as much as 38% ethanol. We evaluated the effects of ethanol-containing MDIs on breath alcohol testing. DESIGN: Prospective, single-blind, crossover, controlled study. PARTICIPANTS: Three healthy male volunteers 29 to 36 years old. INTERVENTION: We studied three brands: Tornalate, (38% ethanol), Bronkometer, (30% ethanol), and Alupent, (0% ethanol). The effects of each MDI on breath and blood ethanol measurements were evaluated separately. Two puffs of each brand of MDI were administered. Breath ethanol measurements were obtained at baseline and .25, .5, 1, 2, 3, 5, and 10 minutes after MDI use. Blood ethanol measurements were obtained at baseline and 1 and 10 minutes after MDI use. RESULTS: Overall, Tornalate had the highest breath ethanol readings, with a mean ethanol level of 189 mg/dL recorded just after MDI use. Breath ethanol levels subsequently decreased rapidly over time. Mean breath ethanol concentrations were lower after the use of Bronkometer and undetectable after the use of Alupent. Blood ethanol levels were undetectable at all times tested. CONCLUSION: MDIs may cause elevations of breath alcohol above the legal criteria for intoxication. These effects are transient and may be prevented by a 10-minute interval between the use of an MDI and breath alcohol testing.
Assuntos
Testes Respiratórios/métodos , Broncodilatadores/administração & dosagem , Etanol/análise , Administração por Inalação , Adulto , Estudos Cross-Over , Etanol/sangue , Etanolaminas/administração & dosagem , Humanos , Isoetarina/administração & dosagem , Masculino , Metaproterenol/administração & dosagem , Nebulizadores e Vaporizadores , Estudos Prospectivos , Valores de Referência , Método Simples-Cego , Fatores de TempoRESUMO
OBJECTIVE: To determine whether airway hyperresponsiveness contributes to the development of lower airway obstruction in infants recovering from severe meconium aspiration syndrome treated with extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective comparison study of the response to bronchodilator during the acute and convalescent phase of severe meconium aspiration. SETTING: Pediatric/neonatal intensive care unit in a tertiary care hospital. PATIENTS: Seven neonates with severe meconium aspiration syndrome that was refractory to conventional mechanical ventilation, requiring ECMO treatment. INTERVENTIONS: Evaluation of the effect of bronchodilator treatment on the airway function at a postnatal age of 14 +/- 2.7 (SEM) days, after the patients had been off ECMO for 4.6 +/- 1.4 days, and comparison with the response the same patients had shown at a postnatal age of 2.7 +/- 0.6 days, when they had been on ECMO for 1.3 +/- 0.6 days. Lung mechanics and lower airway function were measured and compared before and after administration of aerosolized isoetharine early in the course of ECMO and again several days after ECMO. Maximum expiratory flow-volume curves produced by the deflation flow-volume curve technique were used for evaluating the lower airway function, and partial passive flow-volume curves were used for measuring respiratory system compliance and resistance. MEASUREMENTS AND MAIN RESULTS: During the first test, isoetharine produced a mild increase in maximum expiratory flows at 25% (MEF25) of forced vital capacity (FVC) (48 +/- 27% compared with baseline values), without significant change in the MEF25 to FVC ratio. During the second test approximately 2 wks later (post-ECMO), isoetharine increased MEF25 by 123 +/- 29% and increased the MEF25/FVC by 40 +/- 13% compared with baseline values. The percent change in both indices was significantly higher during the second test (p < .05) than in the first test. CONCLUSIONS: Airway obstruction in infants recovering from severe meconium aspiration syndrome is partially reversible with aerosolized isoetharine, indicating that airway hyperresponsiveness contributes to the pathogenesis of airway obstruction.
Assuntos
Obstrução das Vias Respiratórias/fisiopatologia , Hiper-Reatividade Brônquica , Oxigenação por Membrana Extracorpórea , Síndrome de Aspiração de Mecônio/fisiopatologia , Obstrução das Vias Respiratórias/etiologia , Resistência das Vias Respiratórias , Humanos , Recém-Nascido , Isoetarina/uso terapêutico , Complacência Pulmonar , Fluxo Expiratório Máximo , Síndrome de Aspiração de Mecônio/complicações , Síndrome de Aspiração de Mecônio/terapia , Estudos Prospectivos , Capacidade VitalRESUMO
To assess the role of albuterol powder in testing for reversibility of airflow obstruction during routine pulmonary function testing, spirometric data from subjects with baseline FEV1/FVC less than 70 percent and FEV1 less than 80 percent predicted who received inhaled albuterol powder (n = 42) were compared with those who received isoetharine aerosol via metered dose inhaler (n = 49). Prebronchodilator lung function was comparable for the albuterol and isoetharine groups. With albuterol powder, 14 (33 percent) of 42 subjects showed reversibility of airflow obstruction (defined as a 15 percent or greater improvement in either FEV1 or FVC) as compared with 30 (61 percent) of 49 subjects with isoetharine aerosol. The significantly (p less than 0.01) lower rate of improvement with albuterol powder was especially prominent in subjects with moderate airflow obstruction (FEV1/FVC of 45 to 59 percent). These data do not support the substitution of inhaled albuterol powder for isoetharine aerosol in assessing for reversibility of airflow obstruction during routine pulmonary function testing.
Assuntos
Albuterol , Testes de Função Respiratória/métodos , Aerossóis , Albuterol/administração & dosagem , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Isoetarina/administração & dosagem , Pós , Capacidade Vital/efeitos dos fármacosRESUMO
To determine the extent of pulmonary dysfunction following primary closure of an abdominal wall defect, we obtained pulmonary function tests (PFT) in 11 newborn infants with gastroschisis and 6 with large omphaloceles admitted to a newborn ICU in a children's hospital. Patients were 1 to 30 days of age at the time of the PFT; all required endotracheal intubation and mechanical ventilation for operative procedures or for postoperative ventilatory support. Full-term infants (n = 21) undergoing minor surgical procedures provided comparative measurements. Flow-volume curves were obtained with manual inflation of the lungs followed by forced deflation using negative pressure, or by passive expiration, under sedation and pharmacologic paralysis. Deflation flow-volume curves gave measurements of forced vital capacity (FVC) and maximal expiratory flow at 25% of vital capacity from residual volume (MEF25). Modified passive mechanics technique gave passive expiratory curves that provided measurements of respiratory system compliance (Crs) and resistance (Rrs). Tests were done: within 48 h (period A), 3-7 days (period B), and 8-30 days after surgical repair (period C). Pulmonary function testing after nebulized 0.1% isoetharine (a bronchodilator), to test for bronchial reactivity, began midway during the study period in 15 patients. Preoperative and postoperative tests were obtained in 5 patients. Closure of an abdominal wall defect decreased FVC, Crs, and MEF25 by up to 50% of normal, reference values after surgery (P less than 0.05). FVC and MEF25 approached values of normal infants by 4 weeks, whereas Crs remained 50% lower.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Músculos Abdominais/anormalidades , Hérnia Umbilical/cirurgia , Isoetarina/uso terapêutico , Pneumopatias/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Músculos Abdominais/cirurgia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Isoetarina/farmacologia , Pneumopatias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Mecânica Respiratória/efeitos dos fármacosRESUMO
STUDY OBJECTIVES: To determine the benefit of the addition of ipratropium bromide to beta-agonist therapy of acute exacerbations of chronic obstructive pulmonary disease. DESIGN: The trial was randomized and double blinded. SETTING: The study was conducted in the emergency department of Parkland Memorial Hospital, a busy, inner-city, county hospital. INTERVENTIONS: Patients were treated in the medicine emergency department with either the standard regimen of nebulized isoetharine, 0.5 mL of a 1% solution (5.0 mg) diluted to 2.0 mL with normal saline every hour (control group) or with the same regimen plus ipratropium bromide, 54 micrograms (three puffs) after the first isoetharine treatment and 36 micrograms (two puffs) after the second and fourth (experimental group). A placebo metered-dose inhaler used in the same manner as the ipratropium blinded the study to both the patients and medical personnel. MEASUREMENTS AND MAIN RESULTS: The group treated with the addition of ipratropium (30) was discharged from the ED an average of 91 minutes (P less than .05) sooner than the control group (25) and required on the average one less isoetharine treatment (P less than .05). The pulmonary functions tested, forced expiratory volume in the first second, and the forced vital capacity were the same in the two groups initially and on discharge, as identical discharge criteria were used in each group. CONCLUSION: The addition of ipratropium to standard beta-agonist treatment of chronic obstructive pulmonary disease exacerbations shortens the duration of treatment required in the ED.
Assuntos
Ipratrópio/uso terapêutico , Isoetarina/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Pneumopatias Obstrutivas/tratamento farmacológico , Doença Aguda , Administração por Inalação , Adulto , Idoso , Método Duplo-Cego , Avaliação de Medicamentos , Quimioterapia Combinada , Serviço Hospitalar de Emergência , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Ipratrópio/administração & dosagem , Ipratrópio/farmacologia , Isoetarina/administração & dosagem , Isoetarina/farmacologia , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
STUDY OBJECTIVE: To determine whether treatment of acute asthma with repeated doses of nebulized albuterol leads to greater bronchodilation and lower hospital admission rate than treatment with nebulized isoetharine. DESIGN: Randomized, double-blinded, controlled trial of albuterol and isoetharine. TYPE OF PARTICIPANTS: Patients between 18 and 50 years old presenting with acute asthma. Patients were excluded if they had a history of sensitivity to the study drugs, had congestive heart failure or chronic-obstructive pulmonary disease, or were unable to perform spirometry. One hundred three patients were entered into the study. INTERVENTIONS: All patients received oxygen and methylprednisolone in addition to administration of either isoetharine or albuterol. The nebulized aerosol was given at hourly intervals for a total of three doses. MEASUREMENTS AND MAIN RESULTS: Spirometry was performed before treatment and again at 90 and 180 minutes. Initial forced expiratory volume at one minute (FEV1) was 38.1% of predicted normal for the albuterol group and 36.0% of predicted normal for the isoetharine group. At 180 minutes, FEV1 was 55.6% of predicted normal for the albuterol group and 57.1% of predicted for the isoetharine group (NS). Twenty-eight percent of the albuterol group required admission compared with 26% of the isoetharine group (NS). There was no difference in occurrence of side effects between the two groups. CONCLUSION: Repeated doses of albuterol do not lead to a greater improvement in pulmonary function or a lower hospital admission rate than treatment with isoetharine.
Assuntos
Albuterol/uso terapêutico , Asma/tratamento farmacológico , Isoetarina/uso terapêutico , Adolescente , Adulto , Albuterol/efeitos adversos , Feminino , Volume Expiratório Forçado , Humanos , Isoetarina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , EspirometriaRESUMO
Acute asthma is a potentially life-threatening disorder, recognizable to the prehospital care provider. While therapies are available to the prehospital care provider for treating acute asthma, no previous controlled studies have been performed demonstrating the treatment in the field is efficacious and safe. The authors conducted a controlled trial of the prehospital use of nebulized isoetharine in an urban emergency medical services system. Fifty-two patients with acute asthma were studied. Patients were initially evaluated with a peak flow meter. Half of the patients received isoetharine, while the control group received basic life support only. There was no difference in baseline values. Peak expiratory flow increased from 138 L/min to 148 L/min in the control group, while it increased from 149 L/min to 218 L/min in the treatment group (P less than .001). The authors conclude that paramedic treatment of acute asthma with nebulized isoetharine is effective in improving pulmonary function and clinical status during transport.
Assuntos
Asma/tratamento farmacológico , Isoetarina/uso terapêutico , Doença Aguda , Adolescente , Adulto , Asma/fisiopatologia , Serviços Médicos de Emergência , Feminino , Humanos , Isoetarina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pico do Fluxo Expiratório/efeitos dos fármacosRESUMO
Seventeen hospitalized children with acute asthma, ages 7 to 15 years, were studied to determine the efficacy of simultaneous administration of atropine sulfate and isoetharine. Combination therapy was superior in 11/17 (65%) patients while isoetharine alone was superior in 4/17 (23%) patients (P = .037). We conclude that simultaneous administration of combination therapy is safe and beneficial in some children with acute asthma.
Assuntos
Amino Álcoois/administração & dosagem , Asma/tratamento farmacológico , Atropina/administração & dosagem , Isoetarina/administração & dosagem , Doença Aguda , Administração por Inalação , Adolescente , Aerossóis , Atropina/uso terapêutico , Criança , Quimioterapia Combinada , Humanos , Isoetarina/uso terapêutico , Testes de Função RespiratóriaRESUMO
Previous studies have found that between 0 and 95% of patients with cystic fibrosis (CF) have a significant response to bronchodilators. These studies have been limited by small numbers and the measurement of response at one point in time. We analyzed the response to bronchodilators of patients with CF in a longitudinal and cross-sectional manner using pulmonary function data from 1980 to 1988. Overall, the proportion of patients with a positive response to bronchodilators was relatively large but not consistent over time. Of 573 tests in 127 persons, a positive response occurred in 68 tests of 51 patients. A negative response occurred in 19 tests of 17 patients. Only nine patients had a positive response in more than one third of their tests. The cross-sectional analysis showed variability similar to previous cross-sectional studies. Although a large proportion of patients with CF had a response to bronchodilators, the response was not consistent and may have been related to the number of tests performed. Continued longitudinal testing is necessary for valid decisions for bronchodilator use and for documenting the length, variability, and clinical significance of these responses.
Assuntos
Broncodilatadores/uso terapêutico , Fibrose Cística/fisiopatologia , Pulmão/efeitos dos fármacos , Aerossóis , Broncodilatadores/administração & dosagem , Estudos Transversais , Feminino , Fluxo Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Isoetarina/administração & dosagem , Isoetarina/uso terapêutico , Isoproterenol/administração & dosagem , Isoproterenol/uso terapêutico , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Capacidade Vital/efeitos dos fármacosRESUMO
Airway reactivity and the effects of bronchodilators in infants are controversial. We studied the response to bronchodilator treatment in 14 mechanically ventilated infants (mean age, 2.74 months; range, 0.6-5.9) in respiratory failure caused by respiratory syncytial virus (RSV)-associated bronchiolitis. Sixteen infants without lung disease, undergoing elective surgery, provided normal values. Maximum expiratory deflation flow-volume (DFV) curves were produced by manual inflation of the lungs with an anesthesia bag to a predetermined static airway pressure followed by rapid deflation with a negative airway pressure before and after administration of bronchodilator. At baseline, the bronchiolitis group had a forced vital capacity (FVC) of 34.5 +/- 3.6 ml/kg compared with 41.8 +/- 1.5 ml/kg in the normal group; maximum expiratory flow rate at 25% of FVC (MEF25) was 10.2 +/- 2.0 ml/kg/s compared with 27.3 +/- 2.0 ml/kg/s in the normal group. The clinical and radiologic impression was severe lower airway obstruction and air trapping. After administration of bronchodilator, FVC did not increase significantly, but MEF25isov increased by over 30% in 13 of 14 infants. Mean MEF25 increased by 148 +/- 43.2% to 21.7 +/- 3.9 ml/kg/s (P less than 0.02). These findings indicate that during the acute phase of severe RSV-positive bronchiolitis most infants have airway reactivity that responds positively to bronchodilator treatment.
Assuntos
Bronquiolite Viral/fisiopatologia , Ventilação Pulmonar , Insuficiência Respiratória/fisiopatologia , Infecções por Respirovirus/fisiopatologia , Doença Aguda , Bronquiolite Viral/complicações , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Isoetarina/farmacologia , Masculino , Estudos Prospectivos , Ventilação Pulmonar/efeitos dos fármacos , Insuficiência Respiratória/etiologia , Infecções por Respirovirus/complicaçõesRESUMO
Beta-adrenergics are used frequently in the management of asthma. Tremor has been found to be a limiting side effect with the oral or the inhaled forms. We describe one child who developed gross tremors necessitating an extensive neurologic evaluation to eliminate any other cause. With the results of a normal work-up and the reappearance of tremor when challenged again, the diagnosis of increased sensitivity to the tremorogenic effect of beta-adrenergics was made.
Assuntos
Agonistas Adrenérgicos beta/efeitos adversos , Tremor/induzido quimicamente , Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/efeitos adversos , Criança , Humanos , Isoetarina/efeitos adversos , Masculino , Metaproterenol/efeitos adversos , Exame Neurológico , Estado Asmático/tratamento farmacológico , Tremor/fisiopatologiaRESUMO
Since parenteral beta 2-adrenergic stimulation can induce hypokalemia, we postulated that administration of beta 2 adrenoreceptor agonists by inhalation could induce the same. We administered the usual clinical doses of three commonly used bronchodilators to each of six subjects receiving assisted mechanical ventilation in line with the ventilator: two beta 2-adrenoreceptor agonists, metaproterenol, 5 percent solution, and isoetharine, 1 percent solution; and the anticholinergic agent atropine as a control. Each bronchodilator was nebulized over 10 to 15 minutes in random order, four hours apart, and given to every subject. Plasma potassium was measured at five-minute intervals and arterial blood gases at 15-minute intervals, for a total of 50 minutes after administration of each bronchodilator. Following administration of each drug, plasma potassium showed an average decline. The mean decline in plasma potassium from baseline was statistically significant for metaproterenol (p = 0.04) and atropine (p = 0.001) but not for isoetharine (p = 0.09). Although there were no statistically significant differences among the declines in plasma potassium induced by the three drugs, metaproterenol caused the greatest decline (-0.6 mEq/L).