Fleck Christian, Wennek-Klose Janett, Wange Johannes, Oelschläger Herbert
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany.
Arzneimittelforschung. 2004;54(5):265-74. doi: 10.1055/s-0031-1296969.
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.
福莫卡因（CAS 56583-43-8）是一种局部麻醉剂，具有良好的表面麻醉效果且毒性较低，被收录于《德国附加药典》（DAC）。在之前的实验中发现，福莫卡因及其几种衍生物都需要进一步的药学研究。因此，将五种新的C-烷基吗啉衍生物（OW 1、OW 3、OW 5、OW 9和OW 11）以及分别为福莫卡因或OE 7000、OE 9000、OL/4和OL/40的五种2-羟丙基-β-环糊精包合物，与福莫卡因和/或各自的非环糊精制剂在大鼠身上进行了比较。基于局部麻醉剂效果测试的标准方法，并使用两种表征局部麻醉剂毒性的方法（坐骨神经麻痹、LD50），可以得出以下结论：a）福莫卡因引起的良好表面麻醉效果未被其烷基吗啉衍生物OW1-11超越。只有OW 11似乎能诱导持续时间更长的传导麻醉；其他OW物质（1-9）与福莫卡因处于同一水平。福莫卡因及其OW衍生物的毒性相当。b）如果化合物的水溶性不足，取代环糊精通常会有所帮助。使用这些环糊精包合物使复合福莫卡因的局部麻醉效果略有改善，而OE 7000或OE 9000与其环糊精制剂之间几乎没有显著差异。复合福莫卡因的毒性低于福莫卡因，而OE 7000和OE 9000的原化合物及其环糊精制剂的毒性相同。显然，给予包合物后坐骨神经麻痹的症状不那么明显。c）新间位福莫卡因（OL/4和OL/40）的环糊精制剂与复合福莫卡因相比，几乎没有实际相关的局部麻醉效果。但OL/4复合物的毒性甚至比复合福莫卡因更大。基于对总共五种新福莫卡因衍生物和五种复合福莫卡因所做的实验，可以总结出，与已知母体物质福莫卡因相比，新衍生物及其包合物似乎都没有任何治疗优势。只有高剂量的OW 11作为传导性局部麻醉剂的较长持续效果可能具有实际意义。
