Mucolytic Agents

N-Acetylcysteine. Mucolytic agents such as N-acetylcysteine (NAC) have been used by aerosol delivery in an attempt to aid in sputum clearance. Supplied in sufficient quantity, acetylcysteine will help liquefy tenacious secretions and make their clearance easier. A review of studies on the use of NAC in CF concluded the evidence does not support its use, either via nebulizer or by mouth [93]. Intravenous NAC was tested and found not useful in acute respiratory distress syndrome [94]. In one study, patients with chronic bronchitis who took oral NAC had fewer exacerbations and better symptom improvement than did control patients [95]. In the United States, there is no use of NAC by any route for chronic bronchitis. These data need more examination and further study before any such use might be considered. A newer mucolytic agent, nacystelyn, has been developed for delivery via a dry powder inhaler. Deposition in adults and children with CF was 16% and 23%, respectively [94].

rhDNase. The efficacy of recombinant human deoxyribonuclease aerosol to help liquefy secretions has been documented [97,98] and has come into widespread use among CF patients. Since inhaled organic substances can be antigenic, assessment of rhDNase for immunogenic potential is important. Evidence suggests that antibodies develop in about 9% of subjects but are not associated with side effects [99]. From a different perspective, aerosol rhDNase therapy for 52 weeks leads to a reduction in neutrophil elastase in patients with CF [100]. This is the opposite of what might have predicted, because DNA in sputum should act to inhibit neutrophil elastase, and destruction of DNA could thus cause an increase in neutrophil elastase, an undesirable consequence.

Improvement in pulmonary function with rhDNase using a variety of delivery techniques is reported [101,102]. Decrements in function have been documented after two weeks cessation of use [103].

Not all evidence is favorable. Some evidence suggests that adding rhDNase to therapy in an acute exacerbation of does not improve recovery [104]. No improvement in cough or clearance was noted [102,105], and a retrospective study shows no reduction in hospitalizations or pulmonary function decline after institution of rhDNase [104]. Despite its widespread use, the role of rhDNase in the management of CF may not be fully established.

Tobramycin. About 7% of the inhaled dose reaches the lung using an aerosol with MMAD of 5 mm; penetration to the periphery is better with better lung function [106]. Tobramycin is widely used to treat patients with CF. Overall, evidence suggests improved lung function and probably reduced hospitalization when tobramycin is part of maintenance therapy in CF [107,108]. The delivered dose can vary widely. There was a fourfold difference in respirable mass (calculated based on size distribution) when two different nebulizers were compared using different flowrates to deliver tobramycin [34]. Nebulizer device performance is an oft-ignored subject, the assumption being that all are created equal. A study of particle size and device output performance for 14 (eight jet, six ultrasonic) devices found that only three (all jet nebulizers) had bench output characteristics suitable for tobramycin delivery [109]. These rather confusing data indicate a potential for improvement in this treatment modality.

Amiloride. Amiloride has been tested for treatment of CF because of the considered potential to reduce sputum tenacity. In pursuit of amiloride as a potentially useful agent, numerous pharmacokinetic and pharmacodynamic studies after inhalation and oral dosing were done [110-113]. Unfortunately, some more recent studies of amiloride have failed to document efficacy [114,115].

Alpha 1 Antitrypsin in CF. Alpha 1 antitrypsin (a 1-AT) can inhibit neutrophil elastase in epithelial lining fluid (ELF), restore ELF antineutrophil elastase capacity, and also reverse the inhibitory effect of CF ELF on neutrophil Pseudomonas killing [116]. Furthermore, aerosolized secretory leukoprotease inhibitor can reduce neutrophil number and also neutrophil elastase in CF subjects [117]. For these reasons some have suggested a possible role for a 1-AT in CF. This concept requires further exploration before clinical introduction. The treatment is exceedingly expensive, so use without good documentation would be inappropriate.

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