Local anaesthetic effectivity and toxicity of fomocaine, five N-free fomocaine metabolites and two chiralic fomocaine derivatives in rats compared with procaine

Until now, no optimal local anaesthetic drug with long lasting effect and l ow toxicity has been developed. Fomocaine (CAS 17692-39-6), introduced in t he German extrapharmacopoeia (DAC) in 1979, is a local anaesthetic, which i s largely in accordance with these aspects. Now the basic ether fomocaine, its metabolites O/Se 9 (CAS 3006-96-0), O/Se 10 (CAS 31719-76-3), O/Se 11, O/Se 12 (CAS 64264-21-7) and M5 and its chiralic derivatives O/G 3 and O/G 5 were compared with procaine (CAS 59-46-1) and characterised more in detai l in rats. The metabolism of fomocaine was investigated earlier with C-14-f omocaine in rats and beagle dogs. Rac-O/G 3 and pac-GIG 5 could be separate d into the enantiomers via the diastereomeric salts. Basing on standard met hods for the testing of the local anaesthetic effects (estimation of infilt ration and conduction anaesthesia in rat tail, measurement of corneal anaes thesia) and using a couple of tests characterising the side effects and tox icity of local anaesthetic (paresis of the N. ischiadicus, tissue irritatio n, determination of the approximative i.p. LD50) it can be concluded that: a) The very good surface anaesthesia caused by fomocaine could be stated, b ut, as expected, concerning conduction anaesthesia, procaine is better qual ified for clinical use. b) Fomocaine is much more effective in conduction and surface anaesthesia t han its chiralic derivatives O/G 3 and O/G 5. c) Differences between the two enantiomers of the GIG-substances have been found, but these little discrepancies are without practical relevance. In t he case of O/G 5, agonistic effects of both enantiomers could be shown. d) Fomocaine undergoes extensive biotransformation with subsequent formatio n of 14 metabolites. Five of them (O/Se 9-O/Se 12; M5) are N-free and do no t show any pharmacological activity. e) Compared to other local anaesthetics, fomocaine is relatively non-toxic (nearly no tissue irritation, high approximative LD50), however, surprising ly the toxicity of the reference substance procaine has been found to be lo wer after i.p. administration instead of i.v. administration in comparison with fomocaine.