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The levels of leukotriene C4 (LTC4), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and histamine were measured in nasal lavage fluids obtained from aspirin-sensitive, desensitized aspirin-sensitive, and aspirin-insensitive asthmatics and normal volunteers before and after ingestion of aspirin. Increased levels of LTC4 and histamine were associated with significant decreases in the FEV1 for 3 of 4 aspirin-sensitive asthmatics who had both naso-ocular and bronchospastic reactions to aspirin. In contrast, no increase in LTC4 or histamine release was detected in aspirin-sensitive asthmatics who had only bronchospastic reactions to aspirin. No significant decreases in PGE2 levels or increases in LTB4 levels were detected during these reactions to relatively low doses of aspirin regardless of the clinical symptoms, nor was any increase in mediator release apparent in lavage fluids from normal donors, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects before or after various doses of aspirin. Levels of PGE2 decreased in nasal secretions from normal volunteers, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects after ingestion of 650 mg of aspirin. These decreases were not associated with increased LTC4 or LTB4 or with histamine release, decreased FEV1, or naso-ocular symptoms. In addition, reductions of PGE2 release were similar for normal and desensitized aspirin-sensitive volunteers (63 +/- 11 versus 61 +/- 10%, respectively). The data demonstrate that LTC4 and histamine are released into nasal secretions of aspirin-sensitive asthmatics with naso-ocular and bronchospastic reactions after ingestion of low doses of aspirin without a decrease in the levels of PGE2 and suggest that LTC4 and histamine contribute to the naso-ocular and bronchospastic symptoms characteristic of reactions to aspirin.

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, Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for systemic absorption. This study examined the effects on pulmonary function, pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and nonasthmatic subjects without diabetes. RESEARCH DESIGN AND METHODS-A total of 28 healthy and 17 asthmatic (forced expiratory volume during the first second [FEV 1 ] 50 -80% of predicted value) subjects were enrolled in a two-part, open-label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part 1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects on pulmonary function.RESULTS -Inhaled insulin showed area under the curve (AUC) (0 -360 min) values that were significantly greater for healthy subjects than for asthmatic subjects (P ϭ 0.013), whereas no difference was observed for maximum concentration (C max ) in the two groups. A greater reduction of serum glucose as indicated by area over the curve (AOC) (0 -360 min) was observed in healthy subjects (P ϭ 0.007). Asthmatic subjects had greater intrasubject variations in insulin AUC (0 -360 min) and C max values than healthy subjects, but similar variations in glucose AOC (0 -360 min) . No significant changes in FEV 1 , forced vital capacity (FVC), and FEV 1 /FVC were observed from pre-to postdose times, and there were no observed safety issues.CONCLUSIONS -After inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No effects on airway reactivity were observed. Diabetic patients with asthma may need to inhale more insulin than patients with normal respiratory function in order to achieve similar glycemic control. Diabetes Care 26:764 -769, 2003I ntensive insulin therapy has been demonstrated to reduce long-term complications in patients with type 1 and type 2 diabetes (1,2). When used as a mealtime insulin in a basal/bolus regimen, short-or rapid-acting insulin significantly improved posprandial glycemic control, with less incidence of hypoglycemia (3-7). Many patients object to multiple daily injection and therefore often receive a less-than-maximal benefit of insulin therapy.The AERx insulin Diabetes Management System (AERx iDMS) was developed by Aradigm (Hayward, CA) as a pulmonary drug delivery system for liquid formulations of insulin (8,9). The AERx iDMS produces a fine droplet aerosol (mass median aerodynamic diameter of ϳ2-3 m) from disposable insulin strips, by extruding a prepackaged solution through hundreds of laser-drilled holes in a single-use nozzle (10). The rapid onset of action of inhaled insulin is very similar to rapid-acting insulin analogs (11-13). The availability of a noninvasive delivery system that achieves rapid absorption of insulin into the circulation would be beneficial for administering mealtime insulin. Such a system would allow insulin therapy to more closely mimic the endogenous in...

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