摘要:

Inhaled β2-adrenoceptor agonists (β2-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective β-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of β2-agonists. However, in subsequent studies, the long-acting β2-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia.The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized β2-agonists. Nebulized and oral β2-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a β-agonist for patients with cardiovascular disease.A potential mechanism for adverse effects with regular use of β2-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting β2-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial β2-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular β2-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting β2-agonists, in contradistinction, a number of studies have shown that long-acting β2-agonists have positive anti-inflammatory effects.An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting β-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting β-agonists had significant advantages over regular use of short-acting β-agonists. More studies and data are needed on the regular use of β2-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the β-receptor, who might be more prone to adverse effects.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na+absorption, mediated by epithelial Na+channels (ENaC), and deficient Cl−transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO3−secretion. In other epithelial tissues, epithelial Na+conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl−channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl−channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways.In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y2receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na+absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca2+-dependent Cl−channel is activated that may compensate for the CFTR Cl−channel defect. Thus activation of P2Y2receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y2receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na+transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Corticosteroids are the mainstay of treatment for sarcoidosis. Although the indications for medical therapy of sarcoidosis are controversial, standard therapy for symptomatic, progressive disease consists of corticosteroids. The British Thoracic Society concluded, with respect to systemic corticosteroids for the treatment of sarcoidosis, that some patients required no treatment, some required prednisone for control of symptoms, and others, with persistent disease, appeared to benefit from long-term corticosteroid therapy. Inhaled budesonide can be an effective treatment for lung sarcoidosis, with few adverse effects, when used in combination with oral systemic corticosteroids such as deflazacort administered in a tapered regimen for 6 months. A randomized controlled trial has also demonstrated the efficacy of 3 months of treatment with oral prednisolone in a tapered regimen followed by inhaled budesonide for 15 months in patients with early stage pulmonary sarcoidosis.Alternative drugs are required in chronic resistant sarcoidosis and/or in conditions where systemic corticosteroids are contraindicated. Immunosuppressive agents (chlorambucil, cyclophosphamide, methotrexate, cyclosporine, azathioprine), anticytokine agents (thalidomide, pentoxifylline), antimalarials (chloroquine, hydroxychloroquine), melatonin and monoclonal antibody (infliximab) have been used in such situations.Chlorambucil and cyclophosphamide have been used in anecdotal cases of pulmonary sarcoidosis as corticosteroid-sparing agents. However, their toxicity and neoplastic potential recommend prudence in patient selection. A comparison between combination therapy with cyclosporine and prednisone and prednisone alone has shown an increased prevalence of serious adverse effects with combined therapy with no between-group differences in treatment efficacy. The cost and toxicity of cyclosporine limit its use to patients in whom its efficacy has been proven.In patients with chronic or refractory disease, methotrexate, usually administered once a week as a single oral dose for at least 2 years, has resulted in a significant improvement in respiratory function, chest radiographs and extrapulmonary manifestations. In most patients, this treatment enabled discontinuation of corticosteroids.Azathioprine may be effective as a corticosteroid-sparing agent in the long-term treatment of sarcoidosis. The combination of prednisolone and azathioprine over a period of 2 years has induced long-lasting remission in patients with resistant sarcoidosis. Thalidomide at low doses is effective in selected cases of sarcoidosis with cutaneous and mild pulmonary involvement. Pentoxifylline alone or combined with low doses of corticosteroids has achieved significant improvement in respiratory function in patients with pulmonary sarcoidosis. Chloroquine and hydroxychloroquine have been shown to have a specific effect in cutaneous manifestations, neurological involvement and hypercalcemia associated with sarcoidosis. Infliximab has yielded good results in patients with chronic resistant pulmonary and extrapulmonary sarcoidosis resistant to corticosteroid and cytotoxic therapy. The effectiveness of melatonin in cutaneous and pulmonary sarcoidosis has also been confirmed in a single center.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Respiratory tract infection with eventual respiratory failure is the major cause of morbidity and mortality in cystic fibrosis (CF). Infective exacerbations need to be treated promptly and effectively to minimize potentially accelerated attrition of lung function. The choice of antibiotic depends onin vitrosensitivity patterns. However, physicians treating patients with CF are increasingly faced with infection with multidrug-resistant isolates ofPseudomonas aeruginosa. In addition, innately resistant organisms such asBurkholderia cepaciacomplex,Stenotrophomonas maltophiliaandAchromobacter (Alcaligenes) xylosoxidansare becoming more prevalent. Infection with methicillin-resistantStaphylococcus aureus(MRSA) is also a problem. These changing patterns probably result from greater patient longevity and increased antibiotic use for acute exacerbations and maintenance care.Multidrug-resistantP. aeruginosainfection may be treated successfully by using two antibiotics with different mechanisms of action. In practice antibiotic choices have usually been made on a best-guess basis, but recent research suggests that more directed therapy can be achieved through the application of multiple-combination bactericidal testing (MCBT). Aerosol delivery of tobramycin for inhalation solution achieves high endobronchial concentrations that may overcome bacterial resistance as defined by standard laboratory protocols. Resistance to colistin is rare and this antibiotic should be seen as a valuable second-line drug to be reserved for multidrug-resistantP. aeruginosa. The efficacy of new antibiotic groups such as the macrolides needs to be evaluated.CF units should adopt strict segregation policies to interrupt person-to-person spread ofB. cepaciacomplex. Treatment of panresistant strains is difficult and often arbitrary. Combination antibiotic therapy is recommended, usually tobramycin and high-dose meropenem and/or ceftazidime, but the choice of treatment regimen should always be guided by the clinical response.The clinical significance ofS. maltophilia,A. xylosoxidansand MRSA infection in CF lung disease remains uncertain. If patients show clinical decline and are chronically colonized/infected with either of the former two pathogens, treatment is recommended but efficacy data are lacking. There are defined microbiological reasons for attempting eradication of MRSA but there are no proven deleterious effects of this infection on lung function in patients with CF. Various treatment protocols exist but none has been subject to a randomized, controlled trial.Multidrug-resistant microorganisms are an important and growing issue in the care of patients with CF. Each patient infected with such strains should be assessed individually and antibiotic treatment planned according toin vitrosensitivity, patient drug tolerance, and results ofin vitrostudies which may direct the physician to antibiotic combinations most likely to succeed.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Occupational rhinitis is a common heterogeneous group of inflammatory conditions in the nose, caused by exposure to airborne irritants and sensitizers in the occupational environment. The mechanism can be allergic, neurogenic or toxic.Data from several epidemiologic studies indicate that animal dander, organic dusts, latex and chemicals can cause occupational rhinitis, but because of methodological problems as well as weaknesses in the definition of occupational rhinitis, occupational exposure is probably an underestimated cause of rhinitis. The effect of rhinitis on the mental aspects of quality of life and substantial costs due to loss of productivity make it important to diagnose and treat occupational rhinitis. Diagnosis relies on a history of exposure, skin prick testing and, if possible, nasal provoacation. Avoidance of exposure, protective measures at the workplace and medical treatment, with agents such as second generation antihistamines and nasal corticosteroids, can make it possible to avoid progress of the disease from rhinitis to asthma. The efficacies of montelukast, a leukotrienne receptor antagonist, and omalizumab, an anti-immunoglobulin E monoclonal antibody in the treatment of occupational rhinitis are yet to be evaluated

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

BackgroundNoninvasive ventilatory support (NIVS) is intended to provide ventilatory assistance for a wide range of respiratory disturbances. The use of NIVS for treatment of respiratory distress may be applicable in the emergency department (ED). It may prevent endotracheal intubation and, likewise, may favorably influence the course of the patient’s hospitalization, depending on the primary disease or ventilatory disturbance.ObjectiveTo evaluate the efficacy of bilevel positive airway pressure (BiPAP) ventilation in patients with acute respiratory distress presenting in the ED.MethodsA prospective, uncontrolled, nonrandomized, nonblind study enrolled 30 patients. They were cooperative and hemodynamically stable, aged over 18 years, and presented with acute respiratory distress as defined by predetermined criteria. They were connected to a BiPAP machine through a face mask, using an initial pressure of 8/3cm H2O, which was gradually raised to 12/7cm H2O inspiratory positive airway pressure/expiratory positive airway pressure. Standard drugs, inhalation and oxygen therapies were administered as needed. The BiPAP was disconnected either upon relief of respiratory distress or on deterioration of the patient’s condition.ResultsOf the 30 patients in the study, 19 had cardiogenic pulmonary edema, four had acute asthma, three had exacerbation of COPD, three had pneumonia and one had malignant pleural effusion. BiPAP was instituted subsequent to failure of standard therapies. Twenty-six patients were classified as responders to the BiPAP ventilation and four as nonresponders (three patients were intubated after 1 hour and one patient 24 hours, post BiPAP). The total length of stay (LOS) in the ED was 3–5 hours and the mean LOS in hospital was 4.1 ± 1.5 days, versus 6.5 ± 1.2 days in LOS reports of similar patients in the same hospital during 1999, who did not undergo BiPAP ventilation. No other complications were observed.ConclusionsWe found BiPAP ventilation simple, safe, effective and well tolerated by patients in respiratory distress. The rate of endotracheal intubation after successful BiPAP ventilation was low. In carefully selected patients with respiratory distress, BiPAP ventilation may successfully replace endotracheal intubation.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

BackgroundA number of different inhaler devices are available to deliver β2-adrenoceptor agonist (β2-agonist) bronchodilators in asthma. These include hydrofluoroalkane or chlorofluorocarbon (CFC)-free propelled pressurized metered-dose inhalers (pMDIs), many dry powder inhalers and breath-actuated inhalers.ObjectiveTo determine the clinical efficacy of all available hand-held inhaler devices compared with the standard CFC-containing pMDI for the delivery of short-acting β2-agonist bronchodilators in nonacute asthma in both children and adults.MethodologyA systematic review and meta-analysis was carried out of all available randomized, controlled trials (RCTs) using the standard pMDI compared with any other hand-held inhaler device, delivering short-acting β2-agonist bronchodilators in patients with stable asthma.ResultsOne hundred and eighteen RCTs were included in this review. No clinical differences were found between the standard CFC-containing pMDI and 12 other hand-held inhaler devices for most outcome measures. We found no evidence of clinical differences between studies using either a 1 : 1 (pMDI: another inhaler) or a 2 : 1 dosing ratio.ConclusionsIn patients with stable asthma, short-acting β2-agonist bronchodilators in standard CFC-pMDIs are as effective as any other hand-held inhaler device; therefore the cheapest available device that the patient is able to use should always be considered. Pharmaceutical companies should in future submit to regulatory authorities clinical outcome data (as opposed toin vitrodata) in support of any dosing schedules greater than 1 : 1 when compared with the standard pMDI. Clinical effectiveness studies that use an intention-to-treat analysis and report more patient-centered outcomes are required.

ISSN:1175-6365    

出版商:ADIS    

年代:2003

数据来源: ADIS