American journal of respiratory medicine : drugs, devices, and other interventions最新文献

Innate host defence, involving both cellular and humoral mediators, is a prominent function of the human airways. Cellular mediators of innate immunity include dendritic cells, natural killer cells, cytotoxic T cells, macrophages and neutrophils, while humoral mediators of innate immunity consist of components of the epithelial lining fluid (ELF) covering the airways. Microbicidal substances in the ELF can selectively disrupt bacterial cell walls and membranes, sequester microbial nutrients or act as decoys for microbial attachment. Antimicrobial components of airway secretions include lysozymes, lactoferrin, secretory leukoprotease inhibitor, defensins and cathelicidins. Defensins are the most widely studied family of antimicrobial peptides present in airway fluid. Humans produce at least 10 different defensin molecules, six alpha-defensins and four beta-defensins similar in structure and function. Direct evidence that defensins have central roles in host defense has only recently become available. Some defensins and defensin-like molecules could serve as templates for the development of pulmonary pharmaceuticals. As potential therapeutics, they possess several desirable properties, including the ability to kill a broad spectrum of micro-organisms while permitting little development of microbial resistance. Many peptides can also neutralize effects of lipopolysaccharide on macrophages and other host defense cells and decrease the release of proinflammatory cytokines thereby giving protection against septic shock. Protegrin-1 is a minidefensin isolated from pig leukocytes and has proved to be an attractive template for large-scale development of antibacterials. One such protegrin analog, iseganan is in phase III clinical trials for the treatment of oral mucositis secondary to systemic chemotherapy. Other prospective uses of iseganan include control of respiratory pathogens in patients with cystic fibrosis and reduction of oral bacteria to prevent ventilator-associated pneumonia. However, in order to advance the production and clinical testing of peptide-based therapeutics, technical hurdles of synthesizing large quantities of complexly folded peptides must be first overcome. Strategies to develop potent peptide-based microbicides are promising in the struggle against increasingly resistant pathogens.

Bronchial asthma is a disease defined by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. In addition to histamine and acetylcholine, recent studies have emphasized the role of arachidonic acid metabolites (leukotrienes, prostaglandins and thromboxane A(2)) in the pathogenesis of asthma. Among these mediators, thromboxane A(2) (TXA(2)) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A(2) is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA(2) include TXA(2) receptor antagonism and thromboxane synthase inhibition. Results of double-blind, placebo-controlled clinical trials have proven the efficacies of the thromboxane receptor antagonist seratrodast and the thromboxane synthase inhibitor ozagrel in the treatment of patients with asthma. Seratrodast and ozagrel are available in Japan for the treatment of asthma. Ramatroban, another thromboxane receptor antagonist, is currently under phase III clinical evaluation in Europe and Japan for the treatment of asthma. The pharmacological profiles of the thromboxane modulators may be improved by combination with leukotriene D(4) receptor antagonists. A multi-pathway inhibitory agent such as YM 158, which is a novel orally active dual antagonist for leukotriene D(4) and thromboxane A(2 )receptors, may have potent therapeutic effects in the treatment of bronchial asthma. Large scale clinical trials are necessary to further define the role of thromboxane modulators in the treatment of patients with asthma.

Salmeterol and formoterol are both long-acting beta(2)-adrenoceptor agonists (beta(2)-agonists). They both provide excellent bronchodilating and bronchoprotective effects in patients with asthma but their are some differences between these two long-acting beta(2)-agonists in vitro and in vivo. Formoterol has a greater potency and intrinsic activity than salmeterol, which can become especially apparent at higher doses than that clinically recommended, and in contracted bronchi. Long-term use of long-acting beta(2)-agonists can induce tolerance, which can be partially reversed with corticosteroids. Long-acting beta(2)-agonists have some anti-inflammatory effects in vitro, but data in vivo are less convincing. Compared with doubling the dose of inhaled corticosteroids, the addition of inhaled long-acting beta(2)-agonists to inhaled corticosteroids improves symptom control in patients with asthma and reduces both the exacerbation rate of asthma and hospital admission rate. No enhanced airway responsiveness or loss of perception of dyspnea has been observed with the use of inhaled long-acting beta(2)-agonists. Monotherapy with long-acting beta(2)-agonists is not recommended.

Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.

An important determinant of clinical outcome of a lower respiratory tract infection may be sterilization of the infected lung, which is also dependent on sustained antibacterial concentrations achieved in the lung. For this reason, recently there has been increased interest in measuring the concentration of antimicrobial agents at different potential sites of infection in the lung. Levels of antibacterials are now measured in bronchial mucosa, epithelial lining fluid (ELF) and alveolar macrophages, as well as in sputum. Penicillins and cephalosporins reach only marginal concentrations in bronchial secretions, whereas fluoroquinolones and macrolides have been shown to achieve high concentrations. The extent of penetration of different antibacterials into the bronchial mucosa is relatively high. This is also true for beta-lactams, although their tissue concentrations never reach blood concentrations. Antibacterials penetrate less into the ELF than into the bronchial mucosa, but fluoroquinolones appear to concentrate more into alveolar lavage than into bronchial mucosa. Pulmonary pharmacokinetics is a very useful tool for describing how drugs behave in the human lung, but it does not promote an understanding of the pharmacological effects of a drug. More important, instead, is the correlation between pulmonary disposition of the drug and its minimum inhibitory concentration (MIC) values for the infectious agent. The addition of bacteriological characteristics to in vivo pharmacokinetic studies has triggered a 'pharmacodynamic approach'. Pharmacodynamic parameters integrate the microbiological activity and pharmacokinetics of an anti-infective drug by focusing on its biological effects, particularly growth inhibition and killing of pathogens. Drugs that penetrate well and remain for long periods at the pulmonary site of infection often induce therapeutic responses greater than expected on the basis of in vitro data. However, although the determination of antibacterial concentrations at the site of infection in the lung has been suggested to be important in predicting the therapeutic efficacy of antimicrobial treatment during bacterial infections of the lower respiratory tract, some studies have demonstrated that pulmonary bacterial clearance is correlated more closely to concentrations in the serum than to those in the lung homogenates, probably because they better reflect antibacterial concentration in the interstitial fluid.

Zanamivir is a potent competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza A and B viruses. Zanamivir (10 mg by inhalation via the Diskhaler twice daily, or 10 mg inhaled plus 6.4 mg intranasally 2 or 4 times daily, for 5 days) reduced the median time to alleviation of major influenza symptoms by up to 2.5 days compared with placebo. Significant reductions of 1 to 2.5 days versus placebo were observed with inhaled zanamivir in phase III trials involving otherwise healthy adults, high-risk patients or children aged 5 to 12 years. Accelerated return to normal activities, and reduced interference with sleep, consumption of relief medication and incidence of complications leading to antibacterial use were also observed with zanamivir. When used for prophylaxis, inhaled zanamivir 10 to 20 mg/day for 10 days to 4 weeks (plus 6.4 mg/day intranasally in one trial) prevented influenza A in 67% of recipients in a university community, significantly reduced the number of families with new cases of influenza compared with placebo or prevented new cases of influenza in long-term care facilities. The tolerability of inhaled or intranasal zanamivir was similar to that of placebo in otherwise healthy adults, high-risk and elderly patients, and children. Recommended dosages of zanamivir did not adversely affect pulmonary function in patients with respiratory disorders in a well-controlled trial, although there have been rare reports of bronchospasm and/or a decline in respiratory function. In conclusion, zanamivir (used within 48 hours of symptom development) reduces the duration of symptomatic illness, causes accelerated return to normal activities or reduces complications requiring antibacterial use in adults, high-risk individuals and children with influenza. Vaccination remains the intervention of choice for prophylaxis in selected populations. However, the efficacy, good tolerability profile and lack of resistance with zanamivir make it a useful option, particularly in those not covered or inadequately protected by vaccination, who are able to use the inhalation device. The use of zanamivir in patients with respiratory disorders remains unclear because of concerns regarding its potential for bronchospasm. Prospective cost-effectiveness analyses and investigations of efficacy in preventing serious complications of influenza, particularly in high-risk patients, are required. Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households.

Flunisolide is a synthetic corticosteroid approved for the treatment of persistent asthma and delivered by means of a metered-dose inhaler (MDI). A new formulation of flunisolide, using hydrofluoroalkane (HFA) as a propellant, has been developed to comply with the mandated worldwide phase-out of ozone-depleting chlorofluorocarbon (CFC) propellants. Aerosol particle size in the new flunisolide HFA solution is smaller than the flunisolide CFC suspension (1.2 vs 3.8 microm mass median aerodynamic diameter). Aerosol particle size is a key element in determining lung deposition and the regional distribution of inhaled medication within the lung. In addition, the flunisolide HFA MDI has been redesigned to include a built-in spacer. These features have improved distal lung deposition. Flunisolide HFA, at one-third the dosage (170 and 340 microg twice daily), had similar efficacy to flunisolide CFC (500 and 1000 microg twice daily) and significantly greater efficacy than placebo in a randomized, double-blind, placebo-controlled, 12-week study in patients with mild to moderate asthma. Flunisolide HFA was well tolerated in all trials. A long-term study found no suppression of adrenal function and minimal systemic effects were observed both in adults and children.