REVERSIBILITY AND CLINICAL RELEVANCE OF MORPHOLOGICAL-CHANGES AFTER NASAL APPLICATION OF EPHEDRINE NASAL DROPS 1-PERCENT

To predict the toxicity of nasal formulations, various in vitro and in vivo techniques have been used. Many of these techniques are very sen sitive and it is a general problem to extrapolate the results to the c linical situation. The aim of the present study was to establish a cli nically well known nasal formulation, Ephedrine Nasal Drops 1%, DAK 63 (EBE), as a relevant reference for other nasal formulations with resp ect to histological changes to and reversibility of the nasal mucosa a fter 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 fiv e mu l was applied in one nasal cavity of rabbits (n = 3) four times p er day for 1 week, while the other cavity served asa control. Twelve r abbits 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 fo r minor greyish exudates seen at 4 h, and a slight congestion of the m ucosa seen at 4 and 24 h after application, there were no gross change s of the nasal mucosa. The microscopical examination, however, showed an extended infiltration of the mucosa by eosinophils, a general infla mmatory reaction and a pronounced atrophy and disorganisation of the e pithelium, 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, indicati ng 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 toxici ty, with respect to a cost/benefit evaluation of nasal formulations, m eant for acute or short-term treatment. (C) 1997 Elsevier Science B.V.