RESUMO
OBJECTIVES: To assess the serum and lower respiratory tract tobramycin concentrations (C(T)) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients with cystic fibrosis (CF) 6 months to 6 years of age. STUDY DESIGN: We performed a dose escalation study of serum C(T) measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) C(T) was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. RESULTS: A 180-mg dose of inhaled tobramycin produced a mean peak serum C(T) of 0.5 microg/mL (SD 0.4; range, <0.2 to 1.4 microg/mL). A 300-mg dose produced a mean peak serum C(T) of 0.6 microg/mL (SD 0.5; range, <0.2 to 1.2 microg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 microg/mL). The target ELF C(T) was 20 microg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 microg/mL). Mean ELF C(T) was 90 microg/mL (SD 54; range, 16 to 204 microg/mL) and exceeded the target concentration in 11 patients. CONCLUSION: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/metabolismo , Fibrose Cística/metabolismo , Mucosa Respiratória/metabolismo , Tobramicina/administração & dosagem , Tobramicina/metabolismo , Administração por Inalação , Lavagem Broncoalveolar , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Nebulizadores e VaporizadoresRESUMO
OBJECTIVES: To determine the effect of repeated doses of aerosolized recombinant human deoxyribonuclease (rhDNase) on the development of anti-rhDNase antibodies, acute allergic reactions, and pulmonary function in patients with cystic fibrosis. DESIGN: A multicenter, open-label study in which 184 patients received 10 mg aerosolized rhDNase twice a day for 14 days followed by a 14-day washout period for a total of 6 treatment cycles. Serial determinations of anti-rhDNase antibodies and pulmonary functions were performed. RESULTS: Detectable anti-rhDNase antibodies developed in 16 (8.7%) patients. These patients had no changes in their symptoms from the time they entered the trial. Antibodies detected were all of the IgG isotype. Increases in both forced expired volume in 1 second and forced vital capacity were noted from the beginning to the end of each cycle of treatment returning to baseline during the off-treatment period of each cycle. Seropositivity to rhDNase was not associated with allergic reactions and had no relationship on improvement in pulmonary function. CONCLUSIONS: Development of anti-rhDNase antibodies occurred in a small number of patients and was not associated with side effects. Intermittent administration of rhDNase for 24 weeks to patients with cystic fibrosis was well tolerated and was not associated with anaphylaxis in any patient. Pulmonary function improved significantly during the 14-day cycles while rhDNase was administered and returned to baseline when rhDNase was discontinued.
Assuntos
Fibrose Cística/tratamento farmacológico , Desoxirribonucleases/uso terapêutico , Adolescente , Adulto , Aerossóis , Idoso , Formação de Anticorpos , Hiper-Reatividade Brônquica/induzido quimicamente , Criança , Fibrose Cística/imunologia , Fibrose Cística/fisiopatologia , Desoxirribonucleases/administração & dosagem , Desoxirribonucleases/imunologia , Esquema de Medicação , Hipersensibilidade a Drogas/etiologia , Dispneia/tratamento farmacológico , Feminino , Seguimentos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Imunoglobulina G/biossíntese , Isotipos de Imunoglobulinas/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes , Segurança , Capacidade Vital/efeitos dos fármacosRESUMO
To further investigate the early course of cystic fibrosis (CF), specifically to examine factors contributing to energy imbalance, we examined resting energy expenditure (REE) (by indirect calorimetry) per unit body weight and metabolically active body cell mass (by total body potassium), in relation to CF genotype (by genomic DNA analysis), CF pancreatic phenotype, and markers of pulmonary inflammation (from bronchoalveolar lavage fluid). Eighteen subjects with presymptomatic CF who were less than 2 years of age (n = 11, delta F508/ delta F508 genotype; n = 15, pancreatic insufficiency phenotype), identified by newborn screening, were compared with age-, sex-, and length-matched control subjects (n = 13). Those with the delta F508/ delta F508 genotype had significantly higher mean REE expressed per unit body weight (125%) and body cell mass (115%; p < 0.03). Those with other genotypes (n = 7) did not, as a group, have significantly different mean REEs, but individuals with known "severe" genotypes had REEs in the high range and those with a pancreatic-sufficient phenotype had significantly lower REE than those with a pancreatic-insufficient phenotype (p < 0.05), and REEs were in the normal range. Examination of bronchoalveolar lavage fluid revealed positive culture results (7/10) but variable colony counts, neutrophil percentages, and concentrations of interleukin-8 and interleukin-1 beta equally in both CF genotype groups. These markers of pulmonary inflammation were not correlated, individually or collectively, with REE or genotype. We conclude that genotypic variations in energy balance are detectable early in CF unrelated to lung inflammation. Subclinical defects in body composition and pulmonary integrity occur early in CF and, in combination with increased cellular metabolic activity, have important clinical implications with respect to early diagnosis and management.
Assuntos
Fibrose Cística/fisiopatologia , Metabolismo Energético , Genótipo , Pulmão/patologia , Composição Corporal , Peso Corporal , Líquido da Lavagem Broncoalveolar/citologia , Calorimetria Indireta , Pré-Escolar , Estudos Transversais , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Humanos , Lactente , Inflamação , Masculino , Pâncreas/fisiopatologia , Fenótipo , Potássio/análiseRESUMO
Pulmonary function tests were performed on 19 patients with homozygous beta-thalassemia ranging in age from 10 to 29 years. These included patients who had and had not received transfusions. None of the 19 subjects had completely normal pulmonary function. Residual volume (in 16 of 19 patients), ratio of residual volume to total lung capacity (12 of 19), and airway resistance (16 of 19) were abnormally increased; maximum expiratory flow (15 of 19) and peak flow (10 of 19) were abnormally reduced. Single-breath carbon monoxide diffusion was normal in 16 of 19. These results indicate that mild to moderate small airway obstruction and hyperinflation are common in thalassemia and that patient age, transfusion history, and iron accumulation are not important factors in the genesis of these pulmonary abnormalities.