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. (October 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Anesthesiology. Volume 123:Number 4(2015)
• Publication Date: 2015-10
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000831
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>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 (<italic>Bup</italic>) with and without epinephrine.</p> </sec> <sec> <title>Methods:</title> <p>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 <italic>Bup</italic>. In part 1, active sites received (1) 5 to 40 μg NeoSTX+Saline (<italic>NeoSTX-Saline</italic>), (2) 5 to 40 μg NeoSTX+Bup (<italic>NeoSTX-Bup</italic>), or (3) placebo <italic>(Saline).</italic> In part 2, active sites received 10 or 30 μg NeoSTX+Bup+Epinephrine (<italic>NeoSTX-Bup-Epi</italic>) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia.</p> </sec> <sec> <title>Results:</title> <p>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 <italic>NeoSTX-Saline</italic> and <italic>NeoSTX-Bup</italic>. All symptoms resolved without intervention. <italic>NeoSTX-Bup-Epi</italic> dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 <italic>vs.</italic> 70%, <italic>P</italic> = 0.004; numbness: 0 <italic>vs.</italic> 60%, <italic>P</italic> = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for <italic>NeoSTX-Bup-Epi</italic> was reduced at least two-fold compared with <italic>NeoSTX-Saline</italic> and <italic>NeoSTX-Bup</italic> (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; <italic>P</italic> = 0.016). <italic>NeoSTX-Bup</italic> showed prolonged cutaneous block duration compared with <italic>Bup</italic>, <italic>NeoSTX-Saline</italic>, or <italic>placebo</italic>, at all doses. Median time to near-complete recovery for 10 μg <italic>NeoSTX-Bup-Epi</italic> was almost five-fold longer compared with <italic>Bup</italic> (50 <italic>vs.</italic> 10 h, <italic>P</italic> = 0.007).</p> </sec> <sec> <title>Conclusion:</title> <p>NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.</p> </sec> </abstract>