A Phase 1, Dose-escalation, Double-blind, Block-randomized, Controlled Trial of Safety and Efficacy of Neosaxitoxin Alone and in Combination with 0.2% Bupivacaine, with and without Epinephrine, for Cutaneous Anesthesia

作者：Lobo Kimberly; Donado Carolina; Cornelissen Laura; Kim Joseph; Ortiz Rebeca; Peake Roy W A; Kellogg Mark; Alexander Mark E; Zurakowski David; Kurgansky Katherine E; Peyton James; Bilge Aykut; Boretsky Karen; McCann Mary Ellen; Berde Charles B; Cravero Joseph^*

来源：Anesthesiology, 2015, 123(4): 873-885.

DOI：10.1097/ALN.0000000000000831

Background: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine.
Methods: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 mu g NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 mu g NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 mu g NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia.
Results: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 +/- 14, 134 +/- 63, and 164 +/- 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 mu g NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10h, P = 0.007).
Conclusion: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.

• 出版日期2015-10