Jay S Templin1, Matthew C Wylie, Joseph D Kim, Katherine E Kurgansky, Grzegorz Gorski, John Kheir, David Zurakowski, Gabriel Corfas, Charles Berde. 1. From the Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts (J.S.T., M.C.W., J.D.K., K.E.K., D.Z., C.B.); F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (G.G.); Department of Cardiology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts (J.K.); F.M. Kirby Neurobiology Center, and Department of Neurology and Department of Otology and Laryngology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts (G.C.). Current affiliations: Department of Psychology, University of Massachusetts, Boston, Massachusetts (J.S.T.); and Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan (G.C.).
Abstract
BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker undergoing clinical trials as a prolonged-duration local anesthetic. Rat sciatic block and intravenous infusion models were used to assess efficacy and local and systemic toxicities for NeoSTX in saline (NeoSTX-Saline), bupivacaine (Bup), and their combination (NeoSTX-Bup). Exploratory studies evaluated the effects of addition of epinephrine to NeoSTX-Bup (NeoSTX-Bup-Epi). METHODS: Rats received percutaneous sciatic blocks with escalating doses of NeoSTX-Saline or NeoSTX-Bup. Sensory-nocifensive block was assessed using modified hotplate and Von Frey filaments. Motor-proprioceptive function was assessed by extensor postural thrust. Nerves were examined histologically after 7 days and scored on the Estebe-Myers scale. Median lethal dose was estimated for NeoSTX-Saline and in combinations. Accidental intravenous overdose was simulated in isoflurane-anesthetized, spontaneously breathing rats receiving NeoSTX-Saline (n = 6), Bup (n = 7), or NeoSTX-Bup (n = 13), with respiratory, hemodynamic, and electrocardiographic endpoints. Additional groups received blocks with NeoSTX-Bup-Epi (n = 80). Investigators were blinded for behavioral and histologic studies. RESULTS: NeoSTX-Bup produced more prolonged sensory and motor block compared with NeoSTX-Saline or Bup. NeoSTX-Bup-Epi further prolonged median time to near-complete recovery for 3 μg/kg NeoSTX-Bup (hotplate: 48 vs. 6 h, P < 0.001). With sciatic injections, addition of Bup did not worsen the systemic toxicity (median lethal dose) compared with NeoSTX-Saline. Intravenous NeoSTX-Saline infusion had significantly longer times to apnea, first arrhythmia, and asystole compared with Bup (P < 0.001 for each). Histologic injury scores overall were low for all groups, with median scores of 0 (interquartile range, 0 to 0) on a 5-point scale. CONCLUSION: NeoSTX-Bup and NeoSTX-Bup-Epi hold promise for prolonged-duration local anesthesia.
BACKGROUND:Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker undergoing clinical trials as a prolonged-duration local anesthetic. Rat sciatic block and intravenous infusion models were used to assess efficacy and local and systemic toxicities for NeoSTX in saline (NeoSTX-Saline), bupivacaine (Bup), and their combination (NeoSTX-Bup). Exploratory studies evaluated the effects of addition of epinephrine to NeoSTX-Bup (NeoSTX-Bup-Epi). METHODS:Rats received percutaneous sciatic blocks with escalating doses of NeoSTX-Saline or NeoSTX-Bup. Sensory-nocifensive block was assessed using modified hotplate and Von Frey filaments. Motor-proprioceptive function was assessed by extensor postural thrust. Nerves were examined histologically after 7 days and scored on the Estebe-Myers scale. Median lethal dose was estimated for NeoSTX-Saline and in combinations. Accidental intravenous overdose was simulated in isoflurane-anesthetized, spontaneously breathing rats receiving NeoSTX-Saline (n = 6), Bup (n = 7), or NeoSTX-Bup (n = 13), with respiratory, hemodynamic, and electrocardiographic endpoints. Additional groups received blocks with NeoSTX-Bup-Epi (n = 80). Investigators were blinded for behavioral and histologic studies. RESULTS:NeoSTX-Bup produced more prolonged sensory and motor block compared with NeoSTX-Saline or Bup. NeoSTX-Bup-Epi further prolonged median time to near-complete recovery for 3 μg/kg NeoSTX-Bup (hotplate: 48 vs. 6 h, P < 0.001). With sciatic injections, addition of Bup did not worsen the systemic toxicity (median lethal dose) compared with NeoSTX-Saline. Intravenous NeoSTX-Saline infusion had significantly longer times to apnea, first arrhythmia, and asystole compared with Bup (P < 0.001 for each). Histologic injury scores overall were low for all groups, with median scores of 0 (interquartile range, 0 to 0) on a 5-point scale. CONCLUSION:NeoSTX-Bup and NeoSTX-Bup-Epi hold promise for prolonged-duration local anesthesia.
Authors: Kathleen Cullion; Claudia M Santamaria; Changyou Zhan; David Zurakowski; Tao Sun; Grant L Pemberton; Nathan J McDannold; Daniel S Kohane Journal: J Control Release Date: 2018-02-20 Impact factor: 9.776