The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo

Background and objectives. Saxitoxin and its homologues are naturally occur ring compounds that block the sodium channel with high potency. They have t he potential for providing prolonged duration local anesthesia when coinjec ted with vasoconstrictors or conventional local anesthetics and are devoid of local neurotoxicity. Here, we compare sciatic nerve block with saxitoxin to those with neosaxitoxin, decarbamoyl saxitoxin, and tetrodotoxin (TTX), in a search for even safer compounds. Methods. Rats received percutaneous sciatic nerve block with toxins. The co mpounds were compared in terms of lethality, onset and duration of action f or thermal analgesia (hot-plate testing), and motor block (weight-bearing). Data were expressed as medians with 25th and 75th percentiles, and median effective concentrations were determined. Results. The median concentrations at which analgesia of 60 minutes duratio n was achieved were neosaxitoxin, 34 +/- 2 mu mol/L; saxitoxin, 58 +/- 3 mu mol/L; TTX, 92 +/- 5 mu mol/L; and decarbamoyl saxitoxin, 268 +/-; 8 mu mo l/L. Similar trends were observed for other measures of effectiveness (bloc k duration of 90 minutes, maximal block), and for lethality so thar the the rapeutic indices were similar. No toxin had a marked predominance of sensor y or motor block. The potency of TTX was intermediate between those of the saxitoxins, and its therapeutic index was slightly better. No difference wa s observed in time to onset of nerve blockade among the toxins. Conclusions. Substitutions on the saxitoxin nucleus result in large differe nces in incidence and duration of block, and toxicity. The therapeutic indi ces of the saxitoxins are similar; that of TTX is slightly better.