Effects of Some Preservative Agents on Rat and Guinea Pig Tracheal and Human Nasal Ciliary Beat Frequency

Abstract

Many preservatives commonly included in nasal drops and sprays are known to impair mucociliary clearance. We studied the effects of four frequently used preservatives on ciliary beat frequency (CBF) in respiratory tissue. Sodium metabisulfite and chlorbutol did not change the CBF at concentrations up to 50 mg/L in rat tracheal mucosa. Chlorocresol 25 mg/L and 50 mg/mL reversibly decreased CBF (by 33% and 68%, respectively) in 60 minutes. Benzalkonium chloride impaired CBF irreversibly already at a relatively low concentration (12.5 mg/L). To further clarify these results, we studied the effects of the most ciliotoxic (benzalkonium chloride) and nonciliotoxic (chlorbutol) preservative on guinea pig tracheal epithelium and human nasal mucosa. Although chlorbutol had no effect on the CBF, a dose-dependent decrease on CBF was seen in guinea pig and human ciliated epithelium during their immersion in benzalkonium chloride. At a concentration of 50 mg/L it stopped the ciliary activity in 40 minutes in guinea pig trachea, and in human nasal mucosa, benzalkonium chloride concentrations of 25 and 50 mg/L, decreased the CBF irreversibly (by 28% and 60%, respectively) in 60 minutes. These results suggest that chlorbutol is a safe and well tolerated preservative. Banzalkonium chloride is ciliostatic in vitro to rat, guinea pig, and human respiratory mucosa. Therefore, prolonged clinical use of benzalkonium chloride may impair mucociliary clearance, a major defense respiratory mechanism.

Nasal Toxicity of Benzalkonium Chloride

“…To our knowledge there is one investigation assessing the ciliotoxicity of pure BAC on human nasal ciliated cells. 16 In agreement with the results of this investigation, a pronounced ciliotoxicity of BAC was observed in this human ex vivo model. After application of 0.025% BAC solution, almost complete ciliary arrest was observed within 60 minutes.…”

“…In several in vitro investigations using tracheal explants of chicken embryos, guinea pigs, and rats, BAC, in concentrations ranging between 0.01 and 0.02%, revealed in part pronounced ciliotoxic effects. [13][14][15][16] Also, in human tissue specimens such as adenoids or isolated nasal epithelia, BAC proved ciliotoxic in concentrations common in commercially available nasal preparations. 16,17 In some animal experiments, alterations of the mucociliary transport system after BAC application have been found.…”

“…[13][14][15][16] Also, in human tissue specimens such as adenoids or isolated nasal epithelia, BAC proved ciliotoxic in concentrations common in commercially available nasal preparations. 16,17 In some animal experiments, alterations of the mucociliary transport system after BAC application have been found. Cessation of mucus transport after BAC application using the frog palate model was reported by Batts and coauthors.…”

Intranasal drug delivery: opportunities and toxicologic challenges during drug development

“…BKC showed in different animal models such as chicken embryo tracheas, rat and guinea pig tracheal tissue the inhibitory effect on CBF. This effect is dose and time dependent with ciliostasis and ciliotoxicity as the ultimate response [ 210 , 211 ]. In vivo histological examinations in rats showed that BKC can also provoke nasal lesions.…”

Effects of Preservatives in Nasal Formulations on the Mucosal Integrity: An Electron Microscopic Study

“…Adverse effects reported in in vitro studies were (1) a reduction in the ciliary beat frequency of chicken embryonal tracheas and human adenoids [5][6][7][8] as well as in the human nasal mucosa [9]; (2) a time-and concentration-dependent destruction of the human respiratory mucosa in tissue culture and inhibition of human neutrophil actin polymerization, degranulation, and oxidative bursts [10], and a decrease in the velocity of transport of graphite particles and an irreversible prevention of the mucociliary transport of the frog palate [11,12]. The reason for these adverse effects may be explained by the differences in the design of these studies and the subjects used (rodents or humans).…”