Local Anaesthetic Effectivity and Toxicity of Fomocaine, Five N-free Fomocaine Metabolites and Two Chiralic Fomocaine Derivatives in Rats Compared with Procaine

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Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with long lasting surface effect and low toxicity. Nevertheless, it is not optimal yet. Therefore, 7 newly synthesised derivatives, 4 diethanolamines (OE 6000, OE 7000, OE 8000, OE 9000) and 3 morpholines (OE 500, OE 1000, OE 5000) were compared with procaine-HCl (CAS 51-05-8) and tetracaine-HCl (CAS 136-47-0) in rats. Based on standard methods for the testing of LA effects and using two methods for characterising side effects and toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The very good surface anaesthesia caused by especially fomocaine and tetracaine could be stated but concerning conduction anaesthesia procaine is better qualified. b) Concerning conduction anaesthesia, diethanolamine derivatives are more potent compared to morpholine derivatives. c) Surface anaesthesia shows a different picture: the effect of fomocaine is in between. d) The paresis of the N. ischiadicus as a first sign of toxic side effects indicated that low effect is combined with short paresis. e) Compared to the LD50 of fomocaine, the toxicity of OE 500 and OE 5000 is only one half. On the basis of the experiments with fomocaine derivatives, distinct structure-activity relationships could be demonstrated for fomocaine derivatives concerning a) LA effects and b) toxicity. Altogether OE 9000 could be a promising candidate for systemic use.

Section: Morpholine Derivativesmentioning

confidence: 58%

Section: Comparison Between Fomocaine and Procaine Or Tetracaine As Rmentioning

confidence: 99%

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Local Anaesthetic Effects and Toxicity of Seven New Diethanolamine and Morpholine Derivatives of Fomocaine

Fleck

Karge

Loy

et al. 2011

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“…The therapeutic use of local anaesthetics (LA) in surgery and dentistry is increasing in the last decades [1,2]. Nowadays more than 40 LA are used in clinical routine which can be divided into three different groups: ᭹ basic ester like procaine-HCl (CAS 51-05-8), ᭹ basic anilides like lidocaine-HCl (CAS 6108-05-0) and ᭹ basic ether, existing only in a few substances like fomocaine (CAS 56583-43-8) [3].…”

Section: Introductionmentioning

confidence: 99%

Effects and Toxicity of New Fomocaine Derivatives and of 2-Hydroxypropyl-ß- cyclo dextrin Inclusion Compounds in Rats

Fleck

Wennek-Klose

Wange

et al. 2011

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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.

“…It was synthesized by Oelschläger [2], introduced into therapy in 1967 and used in dermatological practice for surface anaesthesia [4,5]. Despite fomocaine being a good surface anaesthetic, various derivatives have been synthesized [6][7][8][9][10], e.g. to improve the water solubility, the affinity to the sodium or calcium channel and also in view of possible new (systemic) applications, e.g.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and Toxicological Testing of the Enantiomers of two Chiral Fomocaine Alkylmorpholine Derivatives in Comparison to their in vitro Interactions on Drug Metabolism in Rats

Lupp

Wange

Oelschläger

et al. 2011

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Between the stereoisomers of amide-type local anaesthetics differences have been noticed with respect to pharmacokinetics and side effects, but not regarding local anaesthetic capacity. Therefore, only S-(-)-ropivacaine has been introduced into clinical practice and with bupivacaine both the racemate and the S-(-)-enantiomer (levobupivacaine) are available by now. Based on this background, the aim of the present study was to evaluate if there are also dissimilarities to be found both in the toxicity and in the effectiveness of the enantiomers of two newly synthesized chiral fomocaine alkylmorpholine derivatives, OW3 and OW13, with an additional C2-chain in 2- or an additional C3-chain in 3-position at the morpholine ring, respectively. For this purpose, in vitro the interaction capacity with cytochrome P450 (CYP)-mediated monooxygenase and oxidase functions was investigated using rat liver 9000 g supernatants or microsomes. In vivo LD50, paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus) were tested in rats. The enantiomers of both OW3 and OW13 caused a concentration dependent inhibition of all CYP-mediated model reactions investigated. With all model reactions the (-)-enantiomer of OW3 was less effective than the (+)-form, whereas the opposite was the case with OW13. Also toxicity was lower with the (-)-enantiomer of OW3 and with the (+)-form of OW13 than with the respective counterparts. With both derivatives no clear-cut dissimilarities were noticed in the local anaesthetic capacity of the enantiomers. None of the four compounds caused paresis. Thus, similar to amide-type local anaesthetics, also with the enantiomers of chiral fomocaine alkylmorpholine derivatives differences in pharmacokinetic properties and toxicity could be demonstrated.