Effects and toxicity of new fomocaine derivatives and of 2-hydroxypropyl-beta-cyclodextrin inclusion compounds in rats.

Abstract

Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with good surface anaesthesia and low toxicity, monographed in the German Extra Pharmacopoeia (DAC). In previous experiments it could be shown that both fomocaine and a couple of its derivatives need further pharmaceutical investigations. Therefore, five new C-alkylmorpholine derivatives, (OW 1, OW 3, OW 5, OW 9, and OW 11) and five 2-hydroxypropyl-beta-cyclodextrin inclusion compounds of fomocaine or OE 7000, OE 9000, OL/4, and OL/40, respectively, were compared with fomocaine and/or the respective non-cyclodextrin formulations in rats. Basing on standard methods for testing of LA effects and using two methods to characterising toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The good surface anaesthesia caused by fomocaine is not surpassed by its alkylmorpholine derivatives OW1-11. Only OW 11 seems to induce longer lasting conductance anaesthesia; the other OW substances (1-9) are in the same range like fomocaine. The toxicity is quite comparable for fomocaine and its OW derivatives. b) Substituted cyclodextrins are often a useful help if the water solubility of compounds is insufficient. The use of these cyclodextrin inclusion compounds resulted in slightly improved LA effects of complexed fomocaine, whereas there were nearly no significant differences between OE 7000 or OE 9000 and their cyclodextrin formulations. The toxicity of the complexed fomocaine was lower compared to fomocaine whereas the toxicity of both OE 7000 and OE 9000 was the same for the original compound and their cyclodextrin formulations. Obviously the paresis of N. ischiadicus is less pronounced after administration of the inclusion compounds. c) The cyclodextrin formulations of the new meta-fomocaines (OL/4 and OL/40) are, compared to the complexed fomocaine, without practically relevant LA effect. But OL/4 complexed is even more toxic than complexed fomocaine. On the basis of the experiments done with altogether five new fomocaine derivatives and five complexed fomocaines it can be summarized that neither the new derivatives nor their inclusion compounds seem to have any therapeutic advantage compared with the known mother substance fomocaine. Only the longer lasting effect of high doses of OW 11 as conductance LA could be of practical relevance.