Ciliotoxic effect

Many papers have been published on the use and efficacy of absorption enhancers for nasal peptide and protein delivery. The enhancing effect of bile salt seemed dependent on its lipophilicity The bioavailability of gentamicin increased with increasing lipophilicity of trihydroxy bile salts (cholate > glycocholate > taur-ocholate), and the enhancement of nasal insulin bioavailability followed the rank order of deoxycholate, chenodeoxycholate, and cholate. However, most studies reported severe damage of bile salts to the mucosa. Deoxycholate had the most ciliotoxic effect, whereas taurocholate had the least ciliotoxic effect. In the case of dihydrofusidates, a dose-dependent increase in bioavailability was reported for peptides such as insulin. 

Benzalkonium chloride in vitro has a ciliotoxic effect, which develops slowly, but is irreversible. Benzalkonium chloride slows down the ciliary movement and disorganises the mucus layer. This stmcture change is supposed to be the result of an interaction of anionic substances in the mucus with the cationic benzalkonium. The ciliotoxic effect of benzalkonium chloride increases when pH is lowered from 7 to 5. Therefore nasal drops preserved with benzalkonium chloride should preferably have a pH around 7. In vivo however, long-term use of benzalkonium chloride 0.02 % did not change the rate of mucociliary clearance and the... 

In vitro exposure of chicken trachea cells to 2,3-benzofuran results in substantial inhibition of ciliary activity (Pettersson et al. 1982), which may indicate that ciliotoxicity is involved in the respiratory effects seen in mice. Certain other furan derivatives exhibit pulmonary toxicity due to metabolic activation by lung P-450 oxygenases (Boyd 1981), but 2,3-benzofuran... 

A number of ciliotoxicity studies have pointed out a low correlation between the results obtained using different in vitro and in vivo methods [121], The effects of nasal formulations on the ciliary beat frequency in vitro are usually more expressed than in vivo, since in vivo, cilia are partially protected by the mucous layer and investigated formulation is eventually cleared from the nasal cavity due to the mucociliary clearance mechanism. Also, toxic effects of the formulations on the cilia in vivo may be reversible due to the constant nasal mucosal cell turnover [121]. 

Ciliotoxic Mucociliary clearance Nasal preparation Local effect Systemic effect Preparation Formulation... 

As the mucosa is highly sensitive to irritation, nasal toxicity of active substances and excipients is an important issue in formulating nasal preparations, especially when they are intended for treatment of chronic diseases [11]. Nearly all substances used in nasal preparations have a negative influence on the ciliary beat, and are therefore ciliotoxic. The influence may vary from a temporary (reversible) effect up to an irreversible inhibition of the ciliary beat [30]. In many nasal drops and nasal sprays preservatives cause the toxic effect on cilia [31], but the active substance itself may also have a negative influence on the ciliary epithelium. Nasal drops with decongestants have been shown to exhibit relatively low cUiotoxicity (e.g. Xylometazoline nasal drops 0.025 %, 0.05 % and 0.1 % (see Table 8.4) as well as a number of licensed preparations) [32]. 

Nose drops and sprays that are not iso-osmotic have a negative influence on the ciliary epithelium. Hypo-osmotic solutions however are more ciliotoxic than hyper-osmotic ones [32]. Again the requirements should be more strict than for eye drops, because the diluting effect of the nasal liquid is much smaller than that of tears. Nasal drops are made iso-osmotic with sodium chloride, or in case of incompatibilities with glucose or mannitol. More information about osmotic pressure and tonicity, and the calculatimi of the osmotic value of solutions, is given in Sect. 18.5. 

A number of in vitro and animal experiments have demonstrated the bronchomucotropic activity of menthol (Boyd and Sheppard, 1969 Welsh et al., 1980 Chiyotani et al, 1994a), while there have been con icting reports as to whether menthol is a mucociliary stimulant (Das et al., 1970) or is ciliotoxic (Su et al., 1993). Apart from the inclusion of relatively small quantities of menthol in commercial preparations that have known bene cial mucociliary effects, there are no documented human trials to support the presence of these activities. 

---