Neosaxitoxin in Rat Sciatic Block: Improved Therapeutic Index Using Combinations with Bupivacaine, with and without Epinephrine.
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.


CONCLUSIONS
NeoSTX-Bup and NeoSTX-Bup-Epi hold promise for prolonged-duration local anesthesia.
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.).
Jay S
JS
Templin
Matthew C
MC
Wylie
Joseph D
JD
Kim
Katherine E
KE
Kurgansky
Grzegorz
G
Gorski
John
J
Kheir
David
D
Zurakowski
Gabriel
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Corfas
Charles
C
Berde
D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001340:Autonomic Nerve Block / Q000379:methods*; D002045:Bupivacaine / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D004837:Epinephrine / Q000008:administration & dosage*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012530:Saxitoxin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012584:Sciatic Nerve / Q000187:drug effects*; D016896:Treatment Outcome
D000779:Anesthetics, Local; D012530:Saxitoxin; C034902:neosaxitoxin; D002045:Bupivacaine; D004837:Epinephrine