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
Author:
Lobo Kimberly1, Donado Carolina1, Cornelissen Laura1, Kim Joseph1, Ortiz Rebeca1, Peake Roy W. A.1, Kellogg Mark1, Alexander Mark E.1, Zurakowski David1, Kurgansky Katherine E.1, Peyton James1, Bilge Aykut1, Boretsky Karen1, McCann Mary Ellen1, Berde Charles B.1, Cravero Joseph1
Affiliation:
1. From the Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts (K.L., C.D., L.C., J.K., R.O., D.Z., K.E.K., J.P., A.B., K.B., M.E.M., C.B.B., J.C.); Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts (R.W.A.P., M.K.); and Depa
Abstract
Abstract
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 μg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 μg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 μg 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 μg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007).
Conclusion:
NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Anesthesiology and Pain Medicine
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