Effect of 5-fluorouracil in cholesteatoma development in an animal model.

This investigation was designed to evaluate the effects of the antimetabolite 5-fluorouracil (5-FU) on cholesteatoma formation in a chinchilla model. The animals received middle ear applications of propylene glycol according to a procedure previously shown to produce cholesteatomas in 60% to 70% of animals. A 5% solution of 5-FU was then applied to the lateral surface of the tympanic membrane (TM) and, after 1 month, temporal bones were taken for histologic study. No macroscopically visible cholesteatomas were present in any of the 16 temporal bones included in the study. However, microscopic invasion of epidermis to the medial side of the TM was observed in four specimens; perforations were present in three of these. Although there was considerable variability in the response to 5-FU application, the majority of specimens showed little or no proliferation of connective tissue in the lamina propria of the TM. In the four specimens in which epidermis reached the medial side of the TM, it did so either by migration through microscopic breaks in the fibrous layer or via TM perforations. Thus, 5-FU did not completely inhibit migration of epidermis into the middle ear. However, the results of this study indicate that it does tend to reduce the proliferation of TM epidermis and connective tissue, thereby reducing the likelihood of cholesteatoma formation in the experimental model.

Tympanic membrane microstructure in experimental cholesteatoma.

This study assessed changes in tympanic membrane microstructure associated with cholesteatoma development following middle ear application of 50% propylene glycol in chinchillas. Although the epidermal layer of the tympanic membrane (TM) was destroyed immediately after propylene glycol application, the epidermal basal lamina remained intact and appeared to serve as a substrate for regrowth of epidermis over the TM. During the initial phase of epidermal repair (4 to 7 days after propylene glycol administration), pseudopodial processes from the epidermal cells occasionally penetrated the basal lamina; however, no migration of epidermis into the lamina propria occurred at that time. The basal lamina remained largely intact until about 2 weeks, when it became fragmented in some areas, so that sizable gaps appeared. Hyperplastic epidermal cells then migrated through the gaps into the rapidly proliferating connective tissue of the lamina propria. At 2 to 4 weeks, degenerative changes were observed in portions of the fibrous layer, which underwent phagocytosis by foreign body giant cells. This process created defects in the fibrous layer which permitted invasion of epidermis to the medial portion of the lamina propria. The epidermis subsequently reached the medial side of the TM in areas where there was incomplete repair of the mucosal layer.

1(((5-Nitrofuranyl)methylene)amino)-4 and/or-5-substituted 2-imidazolidinones.

A series of 1-[[(5-nitrofuranyl)methylene]amino]-4- and/or -5-substituted 2-imidazolidinones was prepared utilizing three different reaction sequences. The structure of 4, the product derived from 4-methyl-2-imidazolidinone (2a), was verified by synthesis using an alternate, unequivocal route. The levo isomer l-4 was prepared by a series of reactions starting with L(+)-2-amino-1-propanol (l-10). All of the nitrofurans were examined for potential use as chemotherapeutic agents for urinary tract infections. Based on the high level of activity in the urine and the in vitro antibacterial activity (MIC) 4, l-4, and 16 are considered to be the most active as urinary tract agents.