Early Treatment with Intranasal Neostigmine Reduces Mortality in a Mouse Model ofNaja naja(Indian Cobra) Envenomation

Abstract

Objective. Most snakebite deaths occur prior to hospital arrival; yet inexpensive, effective, and easy to administer out-of-hospital treatments do not exist. Acetylcholinesterase inhibitors can be therapeutic in neurotoxic envenomations when administered intravenously, but nasally delivered drugs could facilitate prehospital therapy for these patients. We tested the feasibility of this idea in experimentally envenomed mice. Methods. Mice received intraperitoneal injections of Naja naja venom 2.5 to 10 times the estimated LD50 and then received 5 μL neostigmine (0.5 mg/mL) or 5 μL normal saline by nasal administration. Animals were observed up to 12 hours and survivors were euthanized. Results. 100% of control mice died. Untreated mice injected with 2.5× LD50 Naja naja died at average 193 minutes after injection, while 10 of 15 (67%) of treated mice survived and were behaviorally normal by 6 hours (P < 0.02). In the 5× LD50 group, survival was prolonged from 45 minutes to 196 minutes (P = 0.01) and for 10× LD50 mice, survival increased from 30 to 175 minutes (P < 0.02). Conclusion. This pilot suggests that intranasal drugs can improve survival and is the first direct demonstration that such an approach is plausible, suggesting means by which treatment could be initiated before reaching the hospital. Further investigation of this approach to neurotoxic and other types of envenomation is warranted.

The Urgent Need to Develop Novel Strategies for the Diagnosis and Treatment of Snakebites

“…This causes unnecessary administration to be inadvisable and corroboratory diagnostics to be an important first step prior to administration. Acetylcholinesterase inhibitors such as neostigmine and atropine have also come under investigation with promising results in reducing mortality from some elapid venoms [202,203,204]. Nanoparticles (particles <100 nm) are also under investigation [205], and C60 fullerine (a spheroidal carbon molecule) has shown some antivenom properties in an insect model [206] although of course this is a far cry from the mammalian system involved in human SBE.…”

Considerations for the development of a field-based medical device for the administration of adjunctive therapies for snakebite envenoming

“…Neostigmine has been used either IM or IP in mouse models to reverse the neurotoxic effects of 3FTxs found in elapid venom( Banerjee et al, 1976 ; Irshad et al, 2021 ). In addition, internasal administration of neostigmine had similar effects on a single human patient in a clinically controlled setting at very high concentration (8.4% w/v)( Lewin et al, 2013 , 2014 ). While controversial, neostigmine is commonly used in small doses as part of India's national snakebite management protocol despite potentially significant side effects( Mahadevan and Jacobsen, 2008 ; Naguib and Kopman, 2018 ; Karthika and Satapathy, 2021 ).…”

The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming

“…Interventions aimed at reducing the action of venom components, without directly interfering with the toxins, include the use of cholinesterase inhibitors, such as neostigmine, in the case of venoms whose mechanism of action is based on the blockade of the nicotinic acetylcholine receptor (nAChR) by α-neurotoxins, hence increasing the concentration of acetylcholine at the synaptic cleft [ 112 , 113 , 114 ]. Furthermore, therapeutic interventions may be directed towards improving the regenerative capacity of affected tissues and cells.…”