Reversibility and clinical relevance of morphological changes after nasal application of ephedrine nasal drops 1%

Abstract

To predict the toxicity of nasal formulations, various in vitro and in vivo techniques have been used. Many of these techniques are very sensitive and it is a general problem to extrapolate the results to the clinical situation. The aim of the present study was to establish a clinically well known nasal formulation, Ephedrine Nasal Drops 1%, DAK 63 (EBE), as a relevant reference for other nasal formulations with respect to histological changes to and reversibility of the nasal mucosa after repeated short-term nasal application to rabbits. This ephedrine formulation also contains the well known local irritants, benzalkonium chloride and EDTA, which is why it is abbreviated to EBE. Seventy five μ1 was applied in one nasal cavity of rabbits ( n = 3) four times per day for 1 week, while the other cavity served as a control. Twelve rabbits were divided into four groups and were sacrificed at 4 h and 1, 7 and 21 days after last nasal application, respectively. The macro- and microscopical changes of the nasal mucosa were recorded. Except for minor greyish exudates seen at 4 h, and a slight congestion of the mucosa seen at 4 and 24 h after application, there were no gross changes of the nasal mucosa. The microscopical examination, however, showed an extended infiltration of the mucosa by eosinophils, a general inflammatory reaction and a pronounced atrophy and disorganisation of the epithelium, which was furthermore void of goblet cells and cilia. These microscopical changes were seen after 4 h and, to a minor extent, 24 h after application. After 7 days, no changes could be found, indicating that they were reversible in less than 1 week. It is concluded that EBE may be a good reference in the predictive testing of local toxicity, with respect to a cost/benefit evaluation of nasal formulations, meant for acute or short-term treatment.