RESUMEN
BACKGROUND: Chlorofluorocarbons (CFCs) have traditionally been used as propellants in pressurized metered-dose inhalers (pMDIs), which are often used to deliver drugs to the lungs for the treatment of reversible obstructive airways diseases. However, CFCs are harmful to the environment and need to be phased out. In response to that phase-out of environmentally harmful CFCs, the pharmaceutical industry is developing a new generation of pMDI formulations for the inhaled treatment of asthma. These formulations contain hydrofluoroalkanes (HFAs) in redesigned metered-dose inhalers. OBJECTIVES: This study primarily sought to establish clinical equivalence between a new HFA-formulated formoterol pMDI and the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma. METHODS: We enrolled 51 patients aged 18-70 years old who had stable persistent asthma. All patients were randomized to receive a single dose of each of the following 4 treatments in a double-blind, crossover manner: formoterol HFA pMDI 24 microg, formoterol HFA pMDI 12 microg, formoterol DPI 24 microg or placebo. RESULTS: Of the 51 patients randomised, 46 were evaluable for efficacy. The 12-hour average FEV1 was 2.885, 2.746, 2.916 and 2.353 liters in the HFA 24-microg, HFA 12-microg, DPI 24-microg and placebo groups, respectively. Assessment of 95% CIs revealed that the HFA pMDI 24-microg and DPI formulations were equivalent and that both were significantly superior to placebo (p < 0.001). Improvements in lung function were also significantly superior to placebo in the HFA 12-microg group, but the effect was more moderate than that observed in the higher dose groups. CONCLUSIONS: This study indicates that the formoterol HFA-formulated pMDI provides equivalent bronchodilating effect to the formoterol DPI at the 24-microg dose.
Asunto(s)
Propelentes de Aerosoles , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Etanolaminas/administración & dosificación , Hidrocarburos Fluorados , Adulto , Aerosoles , Asma/fisiopatología , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Etanolaminas/efectos adversos , Etanolaminas/uso terapéutico , Femenino , Fumarato de Formoterol , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Polvos , Índice de Severidad de la Enfermedad , Equivalencia Terapéutica , Resultado del TratamientoRESUMEN
BACKGROUND: Chlorofluorocarbons (CFCs) have traditionally been used as propellants in pressurized metered-dose inhalers (pMDIs), which are often used to deliver drugs to the lungs for the treatment of reversible obstructive airways diseases. However, CFCs are harmful to the environment and need to be phased out. Hydrofluoroalkanes (HFAs), such as HFA-134a, represent a safe alternative to CFC propellants for use with pMDIs. Formoterol fumarate has been recently formulated in an HFA-134a-containing pMDI and is undergoing clinical testing with the aim of providing an effective, safe and environmentally-friendly alternative to currently existing formulations. OBJECTIVES: The study objective was to demonstrate the non-inferiority (clinical equivalence) of the HFA-134a-propelled formoterol pMDI versus the formoterol Aerolizer dry powder inhaler (DPI). METHODS: The study was a single dose, double-blind, double-dummy, randomized, placebo and reference product controlled, three-periods, crossover trial in 49 patients with moderate-to-severe stable asthma. The active treatments involved a single 12-microg dose of formoterol delivered from an HFA-134a-propelled pMDI and an Aerolizer DPI. The primary efficacy parameter was the average 12-hour forced expiratory volume in 1 s (FEV1), calculated as area under the 12-hour post-morning dose FEV1 time curve divided by time (hours). RESULTS: Mean 12-hour average FEV1 was 2.28 liters for placebo, 2.60 liters for formoterol pMDI and 2.60 liters for the formoterol DPI. Contrast analysis showed that the HFA-propelled formoterol pMDI was significantly superior to placebo in terms of 12-hour average FEV1. Further statistical analysis confirmed bronchodilation with the pMDI formoterol formulation which was clinically equivalent to that seen with the DPI formoterol formulation. All treatments were well tolerated. CONCLUSIONS: The bronchodilatory effect of a 12-microg dose of formoterol inhaled from a CFC-free, HFA-propelled pMDI is significantly superior to placebo and equivalent to a commercially available formoterol DPI.
Asunto(s)
Propelentes de Aerosoles , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Etanolaminas/administración & dosificación , Hidrocarburos Fluorados , Adulto , Aerosoles , Anciano , Broncodilatadores/efectos adversos , Broncodilatadores/química , Broncodilatadores/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Etanolaminas/efectos adversos , Etanolaminas/química , Etanolaminas/uso terapéutico , Femenino , Fumarato de Formoterol , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Polvos , Equivalencia Terapéutica , Factores de TiempoRESUMEN
BACKGROUND: Pressurized metered-dose inhalers (pMDIs) have traditionally used CFCs as propellants. However, the worldwide phase-out of CFCs has necessitated the development of new pMDIs that use alternative propellants. One such replacement is the hydrofluoroalkane HFA-134a. OBJECTIVES: This study sought to establish the clinical non-inferiority of a new HFA-134a-containing pMDI to a conventional dry powder inhaler (DPI) in the administration of formoterol to adult patients with moderate-to-severe, stable persistent asthma. The secondary aim was to collect safety data in a multiple-dose long-term study. METHODS: During this multicenter, double-blind, parallel study, 500 patients were randomized to receive 12 microg of formoterol twice daily for 12 weeks via either an HFA pMDI or a DPI. If necessary, the dose could be increased to 24 microg twice daily. At baseline, all patients (aged 18-70 years) had an FEV1 40-80% of predicted and a documented positive response to the reversibility test. RESULTS: After 12 weeks' therapy, the adjusted mean morning PEFR was 343.69 l/min in the formoterol HFA pMDI group and 344.56 l/min in the formoterol DPI group. Because the lower limit of the 95% CI for the between-group difference (-11.64 l/min) was well within the non-inferiority margin (-20 l/min), the HFA device was deemed clinically non-inferior to the DPI device. This finding was confirmed when evening PEFR and FEV1 were assessed. Both formulations of formoterol were well tolerated during prolonged multiple dosing. CONCLUSIONS: This study provides evidence that the new HFA-formulated formoterol pMDI has a similar efficacy and safety profile to the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma.
Asunto(s)
Propelentes de Aerosoles , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Etanolaminas/administración & dosificación , Hidrocarburos Fluorados , Adulto , Anciano , Asma/fisiopatología , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Etanolaminas/efectos adversos , Etanolaminas/uso terapéutico , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Fumarato de Formoterol , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Ápice del Flujo Espiratorio/efectos de los fármacos , Polvos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Formoterol's effects on the cardiovascular system are well known, but whether these effects are altered by the reformulation of inhalers to replace CFC propellants with HFA propellants is not. OBJECTIVES: To evaluate the effect of cumulative doses up to 96 microg of formoterol delivered via an HFA-134a-propelled pMDI, on cardiac safety and the QTc interval, compared the same cumulative doses delivered via a DPI, in adult patients with moderate-to-severe asthma. METHODS: This study was a multicenter, double-blind, double-dummy, placebo-controlled, three-period, crossover trial in which 22 patients with moderate-to-severe asthma received cumulative doses up to 96 microg of formoterol (12 + 12 + 24 + 48 microg) delivered via a pMDI or a dry power inhaler (DPI). Vital signs and fourteen 12-lead ECG measurements were taken at each clinic visit and at 5-10 days after the final drug administration. RESULTS: An increase from baseline in QTc interval was observed with all formoterol treatment arms in a dose-dependent manner. The maximum increases were 56.3, 62.6 and 25.0 ms for the formoterol pMDI, formoterol DPI and placebo treatments, respectively. Heart rate was increased by 10.7, 14.9 and 6.5 bpm in the pMDI, DPI and placebo groups, respectively. Both formoterol treatments were also associated with a decrease in diastolic blood pressure compared with placebo. CONCLUSIONS: With respect to cardiovascular safety parameters, the administration of formoterol via a pMDI device is comparable to its delivery via a DPI.
Asunto(s)
Propelentes de Aerosoles , Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , Etanolaminas/administración & dosificación , Hidrocarburos Fluorados , Adulto , Asma/sangre , Asma/fisiopatología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Etanolaminas/efectos adversos , Etanolaminas/uso terapéutico , Femenino , Fumarato de Formoterol , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Potasio/sangre , PolvosRESUMEN
A cross sectional survey was conducted in 2000 in coordination with the CHIESI medical representatives among 1758 French physicians caring for patients with persistent asthma (80% general practitioners, 20% specialists). This "Compli'Asthme" survey was based on a self-administered questionnaire designed to learn more about the physicians' experience with good use of inhaled drugs and to collect information on therapeutic observance, corticophobia, and use of prescribed inhalers. Poor observance was noted as an important problem by 58-85% of the participants. Most of the problems were related to inability to use the inhaler properly (children, elderly subjects) or to patients forgetting to take their medications (adults, parents). For 58% of the participating physicians, corticophobia is frequent. The patients are worried about the anabolizing effect, secondary effects, and dependence. When there is a potential problem with corticophobia, physicians generally question the patients and provide explanations to achieve good observance. Patient preference is taken into consideration by 86% of the physicians prescribing inhalation devices; 90% demonstrate use of the device at the first prescription and 68% make repeated demonstrations at subsequent consultations. For 56-87% of the physicians, poor therapeutic observance, corticophobia, and poor use of the inhaler can be detected and corrected. Patient education is an important element for 77% of the physicians for improving observance and achieving good use of the inhaler. When poor observance and poor use of the inhaler occur, the physicians responding to this questionnaire applied the currently recommended guidelines.
Asunto(s)
Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Médicos de Familia , Administración por Inhalación , Adolescente , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Adulto , Niño , Estudios Transversales , Francia , Encuestas de Atención de la Salud , Humanos , Cooperación del PacienteRESUMEN
Inhaled steroids are recommended for long-term control of asthma, but their use may be limited in young children because of difficulties in using the associated inhaler device. The use of nebulizers may help to overcome this issue, without compromising therapeutic efficacy or safety. This 14-week, multicentre, randomized, controlled, open-label, parallel-group study compared the efficacy and safety of nebulized corticosteroids in paediatric patients (aged 6 months to 6 years) with severe persistent asthma. Beclometasone dipropionate (BDP) 800 microgday(-1) suspension for nebulization and budesonide (BUD) 750 microg day(-1) given by nebulization in a twice-daily regimen, and when used in addition to the usual maintenance therapy, resulted in comparable clinical efficacy across all parameters. The primary efficacy endpoint was the number of patients who did not experience any major exacerbation, this being 40.4% and 51.7% in the BDP and BUD groups respectively in the ITT population (P = 0.28), and the mean number of global exacerbations (major plus minor) decreased respectively by -37.5% in the BDP group and -23.3% in the BUD group. Both treatments were also associated with marked reductions in the number of nights with wheezing and the number of days of oral steroid use. Moreover, the two treatment groups had a similar adverse-event incidence and profile. Only 11 adverse events were reported, and no serious adverse events were related to treatment. Urinary cortisol and the time course of height and weight were unaffected by both treatments, and BDP was confirmed to have a neutral effect on bone metabolism. In conclusion, this study demonstrates that both BDP 800 microg day(-1) suspension for nebulization and BUD 750 microgday(-1) administered by nebulization are effective, with an acceptable safety profile, for treatment of severe persistent asthma in infants and young children.
Asunto(s)
Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Beclometasona/administración & dosificación , Broncodilatadores/administración & dosificación , Budesonida/administración & dosificación , Administración por Inhalación , Antiasmáticos/efectos adversos , Beclometasona/efectos adversos , Broncodilatadores/efectos adversos , Budesonida/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Nebulizadores y Vaporizadores , Resultado del TratamientoRESUMEN
AIMS: The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatic diseases depends on their concentrations within the joint. We determined piroxicam concentrations in plasma and synovial fluid (SF) after a single oral dose of 20 mg in the form of one tablet of piroxicam-beta-cyclodextrin. METHODS: 45 patients, aged 21 to 84 years, presenting with an effusion of the knee, related to degenerative or inflammatory joint disease, were included in this study after having given their written consent. One blood and one SF sample were drawn concomitantly in each patient from 0.5 to 48 h after NSAID administration. Piroxicam assays were performed by high performance liquid chromatography. Pharmacokinetic parameters were obtained from the mean plasma and synovial concentrations measured at various sampling times. RESULTS: The peak concentration was higher in plasma (2.51+/-0.25 microg/ml) than in SF (1.31+/-0.76 microg/ml), but the elimination half-life was much longer in SF (90.7 h) than in plasma (32.5 h). The SF/plasma area under the concentration-time curve ratio (evaluating the quantity of NSAID transferred from the blood to the joint) was equal to 0.39. CONCLUSIONS: Piroxicam contained in piroxicam-beta-cyclodextrin diffused well into the SF where its pharmacokinetic profile corresponded to that of a long half-life NSAID.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Ciclodextrinas/farmacocinética , Piroxicam/farmacocinética , beta-Ciclodextrinas , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Artritis Reumatoide/tratamiento farmacológico , Ciclodextrinas/administración & dosificación , Combinación de Medicamentos , Femenino , Semivida , Humanos , Artropatías/tratamiento farmacológico , Articulación de la Rodilla/patología , Masculino , Persona de Mediana Edad , Piroxicam/administración & dosificación , Piroxicam/sangre , Líquido Sinovial/químicaRESUMEN
The objectives of this study were to assess the acceptability and efficacy of Jet (a metered dose inhaler with a 100 ml chamber giving 250 micrograms beclomethasone dipropionate per puff) in patients with mild to moderate asthma using a dose-for-dose schedule in substitution for their standard metered dose inhaler with or without an inhalation chamber. An open trial was conducted over 5 weeks in 356 asthma patients treated with inhaled corticosteroids at a mean 914 +/- 198 micrograms/24 h dose. beta 2-agonists were used by all patients, either systematically (prescription) or as needed. Prior to the study, 27% of the patients used a standard metered dose inhaler with a large-volume inhalation chamber and 73% used a standard metered dose inhaler alone. The rate of nocturnal, early morning, and diurnal symptoms and cough decreased by 31.4, 33.4, 46.9, and 37.0% respectively and the variability of peak expiratory flow rate fell from 2 +/- 0.08% to 0.9 +/- 0.02% in the group using the metered dose inhaler with the chamber and from 1.3 +/- 0.04 to 0.5 +/- 0.01% in the group using the standard metered dose inhaler. The investigators determined that treatment efficacy was good or excellent in 94.8%. These findings should be confirmed by studies comparing Jet directly with other inhalation chamber systems or with standard metered dose inhalers. For 97.5% of the patients, it was easy to learn to use Jet and 88.2% of the patients felt no discomfort when using Jet; 64.8% of the patients stated they experienced clinical improvement. At the end of the trial, 77.9% of the patients (76.3% of those who used the inhalation chamber during the study and 78.4% of those who used the metered dose inhaler alone) stated they preferred Jet over their prior system.
Asunto(s)
Antiasmáticos/administración & dosificación , Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Beclometasona/administración & dosificación , Terapia Respiratoria/instrumentación , Adolescente , Adulto , Anciano , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Peripheral blood cells collected by cytapheresis from patients with acute leukemia following induction therapy or with multiple myeloma off-therapy, were maintained in a one-stage long-term liquid culture system. The data indicate that: (1) blood-derived granulopoietic proliferation can be sustained for up to 8 weeks with generation of CFU-GM in a way similar to bone marrow cells; and (2) this normal hematopoiesis can be sustained in spite of the absence of any development of a substantial stromal adherent layer, which suggests that, unlike hematopoiesis from bone marrow, the blood-derived non-adherent cell population is a self-sustaining compartment. While autologous transplantation with peripheral progenitor cells is gaining importance as an alternative to autologous bone marrow transplantation, this study suggests that circulating progenitor cells may have a different behavior from marrow cells. This observation may be relevant to the understanding of cases of defective hematopoietic reconstitution.
Asunto(s)
Células Madre Hematopoyéticas/citología , Células Sanguíneas/citología , Adhesión Celular , Separación Celular/métodos , Células Cultivadas , Granulocitos/citología , Humanos , Mieloma Múltiple/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Factores de TiempoRESUMEN
Blood nucleated cells collected by leukapheresis and spleen cell suspension from patients with myelofibrosis with myeloid metaplasia (MMM) were studied for their haematopoietic capacity. Using committed progenitor cell assays (CFU-GM, BFU-e) and a one-stage long-term liquid stem cell system, we have shown: (1) a preferential expansion of the circulating committed progenitor cell pool above the more primitive stem cell compartment; (2) the absence of any development of a stromal adherent layer in long-term cultures of peripheral blood nucleated cells suggesting the self-sustaining capacity of the circulating primitive stem cells; (3) that the spleen is only a production site of committed progenitor cells but does not generate primitive stem cells; (4) the presence, in the spleen, of stromal progenitor cells. We conclude that the peripheral blood primitive stem cells in patients with MMM are not of splenic origin.
Asunto(s)
Hematopoyesis Extramedular , Hematopoyesis , Mielofibrosis Primaria/sangre , Bazo/fisiología , Células Cultivadas , Células Madre Hematopoyéticas/patología , Humanos , Leucaféresis , Perfusión , Mielofibrosis Primaria/patología , Bazo/patología , Factores de TiempoRESUMEN
Anaemia during malaria is not completely understood. Fourteen cases of antierythrocyte autoimmunisation with anti-I specificity were investigated in a Paris hospital during a period of 2 years. The patients lived in Gabon and had not been taking antimalarial chemoprophylaxis. All had chronic malaria (strongly positive antimalarial immunofluorescent antibody tests). All the recognised caused for anti-erythrocyte autoimmunity were excluded. One possible explanation for these observations is some sort of interaction between I antigen and Plasmodium, the result of which facilitated penetration of the erythrocyte by the malarial parasite.