Patients with cystic fibrosis (CF) show abnormal aminoglycoside pharmacokinetics. After a conventional dose, the serum concentrations in CF patients are lower than those in nonCF patients. The lower serum concentrations in CF might be explained by increased total body clearance and/or a larger volume of distribution. The therapeutic range of aminoglycosides is narrow due to oto- and nephrotoxicity. The changed pharmacokinetics and the narrow therapeutic range make it difficult to ensure that patients with CF are adequately and safely treated with aminoglycosides. The mode of administration of aminoglycosides influences the antibacterial effect of these agents on Pseudomonas aeruginosa and the development of possible side effects. The therapeutic implications of these facts are discussed.

Bacterial infections determine life expectancy in the hereditary disease cystic fibrosis (CF). The dominant pathogens are Staphylococcus aureus and Pseudomonas aeruginosa, which persist in the patient's respiratory tract. Current explanations of the chronicity of the infections in the apparently immunocompetent host are based on defective opsonophagocytosis. This may be caused by (1) bacterial exopolysaccharide production, leading to cryptic infection types; (2) cleavage of immunoglobulin, complement, and surface receptors on immunocompetent cells by host proteases; and (3) a change from opsonic to nonopsonic antibody isotypes. Continuous antigenic stimulation of the immune system leads to local immune complex formation and a high chronic hypersensitivity reaction as well as to temporary immune unresponsiveness. Progressive tissue damage caused by lysosomal enzymes and oxygen radicals from polymorphonuclear leukocytes is thought to be ultimately responsible for respiratory failure and death in CF. Besides antibiotic treatment, anti-inflammatory therapy is therefore currently considered beneficial.

Increasing evidence from case control surveys, population studies and allergen avoidance studies suggest inhalant allergy plays an important role in the etiology of asthma. Recent studies in hospital emergency rooms have compared the prevalence of serum IgE antibodies to common allergens (mite, cat, cockroach, rye grass and ragweed pollen) in patients admitted with acute asthma attacks and in unselected age-matched control subjects. These studies, carried out in central Virginia and northern California, showed a highly increased prevalence of IgE antibodies to inhaled allergens among asthmatic patients, and suggest that the development of allergen specific IgE antibody responses is a major risk factor for emergency room admission with asthma. Presentation at the emergency room appeared to be related to patients' exposure to specific allergens: in central Virginia, in the fall, dust mite was the predominant allergy, whereas in northern California, in May-June, most asthmatic patients (greater than 90 percent) were allergic to rye grass. New immunoassay technology, based on the use of monoclonl antibodies, has been developed to measure the quantities of "indoor" allergens (mite, cat, cockroach) in asthmatic patients' houses. It is now possible to propose tentative levels of mite allergens which should be considered both as a risk for IgE antibody sensitization (2micrograms allergen/g dust) and as a risk for acute asthma attacks (10micrograms allergen/g dust). Future management of asthma will require analysis of indoor allergens and the development of efficient allergen avoidance procedures. Further research is necessary to investigate the relationship between airborne allergen levels, particle size and the precipitation of asthma attacks and also to investigate immunologic mechanisms which may cause bronchial hyperreactivity.

It is now recognized that the basic reason for airway obstruction in asthma is chronic airway inflammation. The hyperresponsiveness and "bronchospasm" are, in part at least, a consequence of the inflammation. Optimum patient care needs to focus on preventing inflammation when possible and using anti-inflammatory drugs when prevention is not possible. When chronic asthma is mild, aerosol glucocorticoids or cromolyn suffice. Acute exacerbations that do not respond fully to bronchodilator drugs usually should be treated by a course of oral glucocorticoids. A few patients with severe disease require oral glucocorticoid therapy indefinitely.

Heightened airway reactivity is a cardinal feature of asthma and correlates with many clinical features of the illness, such as the acute response to bronchodilator drugs, the magnitude of diurnal fluctuations in lung function, and the amount of therapy required to control symptoms. Data have accumulated indicating that a reduction in airway reactivity can decrease asthma morbidity, and many advocate treating asthmatic patients prophylactically to prevent acute exacerbations from developing, rather than responding to them after they have occurred. This approach is particularly effective if it is used when the airways are being exposed to stimuli to which they are sensitive. A number of drugs have been purported to reduce airway reactivity, but the most convincing evidence supports the effects of cromolyn and inhaled and oral steroids. Although each type of drug has its own advantages and disadvantages and different modes of action, the common denominator is believed to be a reduction in the state of airway inflammation.

Late inflammatory sequelae following allergen (and occupational low molecular weight sensitizing chemical) exposure, including the late asthmatic response and increased nonallergic airway responsiveness, are now felt to be more important in the pathogenesis of atopic allergic and occupational asthma than are the early bronchospastic responses. These late sequelae can be inhibited by sodium cromoglycate and by corticosteroids but not by bronchodilators. Recognition that allergic and occupational (and likely all forms of) asthma are inflammatory conditions underscores the rationale for the early use of anti-inflammatory therapeutic strategies in the management of asthma. Such "anti-inflammatory" therapeutic strategies include environmental control, sodium cromoglycate, and both inhaled and oral corticosteroids.

The availability of calcium antagonists has provided yet another therapeutic option in the management of hypertension. Calcium antagonists lower the blood pressure in hypertensive individuals while preserving the blood flow at the microcirculatory level. While all the available calcium antagonists are effective in the treatment of hypertension, they differ in their hemodynamic and pharmacologic actions. Nifedipine appears to be suitable for immediate treatment of severe hypertension and for chronic treatment of uncomplicated or refractory hypertension. In some but not all patients, co-administration of a beta-blocker is necessary to blunt reflex tachycardia. This problem is less likely with the tablet/long-acting formulation of nifedipine. Verapamil and diltiazem are useful as initial therapy for chronic mild-to-moderate hypertension. They are as effective as other first-line drugs in the treatment of uncomplicated hypertension. The heart rate with verapamil or diltiazem does not change or is slightly reduced, thus contrasting with nifedipine. Experience to date suggests that calcium antagonists do not cause adverse biochemical effects and in this respect are superior to diuretics and certain beta-blockers. Currently, verapamil is available as a sustained release preparation. In the near future, nifedipine or diltiazem may also be available in the long acting formulation to permit simplicity and to enhance patient compliance in the treatment of hypertension.

The pulmonary toxicity associated with amiodarone therapy is clinically complex and likely reflects underlying mechanisms of lung injury that result from direct toxic effects of the drug (or its metabolites) as well as indirect inflammatory and immunologic processes induced by the drug therapy (Fig 2). A role for the direct toxicity of the drug is likely because (a) toxicity in part is related to dosage and duration of therapy, (b) many patients with amiodarone pulmonary toxicity have no evidence of an inflammatory or immune response in the lung, (c) in vitro studies indicate that amiodarone can be directly toxic to cultured lung cells or perfused isolated lung tissue, and (d) recent studies suggest plausible biochemical mechanisms that may explain in part the mechanism(s) of direct toxicity of the drug. A role for indirect inflammatory or immune processes within the lung of some patients with APT is supported by: (a) variable relationship of pulmonary toxicity to amiodarone dosages and blood levels, (b) preliminary studies suggest altered immunologic markers in the blood and lungs of some patients with APT, and (c) the cellular findings of bronchoalveolar lavage indicating a CD8 lymphocytosis with or without influx of polymorphonuclear leukocytes, which is consistent with previous studies of hypersensitivity reactions. As our understanding of the biochemical and cellular mechanisms of APT improve, a number of key clinical issues may be clarified: (1) risk factor assessment for APT, (2) criteria for early diagnosis of APT, and (3) improved therapeutic approach to patients with APT.

Acquired bronchial stenosis has been associated with sleeve resection, tuberculosis, sarcoidosis, and prolonged intubation. Various modalities of therapy for the relief of such stenoses include surgery, cryotherapy, and laser photoresection. Several recent reports have described the use of angioplasty balloon catheters for dilatation of stenotic areas. In two patients with endobronchial stenosis, we found that balloon dilatation, using either angioplasty or valvuloplasty catheters, in combination with laser photoresection can be safely and effectively performed with alleviation of pulmonary symptoms.