COMMENTARY
The Perfect Antidote “
S
cience is the great antidote to the poison of enthusiasm and superstition.”—Adam Smith, Scottish philosopher, 1723–1790
“If necessity is the mother of invention, skepticism is its abusive stepfather.”—Stephen Borron, bathtub philosopher, 1957-present Baud and colleagues1 defined an antidote as “a drug whose mechanisms of action have been determined, which is able to modify either the toxicokinetics or the toxicodynamics of the poison, and whose administration to the poisoned patient reliably induces a significant benefit.” Hall et al.2 later defined the ‘ideal’ cyanide antidote as one with “rapid onset of action, neutralizes cyanide without interfering with cellular oxygen use, tolerability and safety profiles conducive to prehospital use, safe for use with smoke-inhalation victims, not harmful when administered to non-poisoned patients, easy to administer,”—it appears that hydroxocobalamin may have many of these characteristics.2 In the same spirit, I would like to define “the perfect antidote” as a drug: 1) for which mechanisms of action have been determined; 2) which works reliably in every case where its antagonist toxicant is involved, even when multiple poisons are involved; 3) which almost never causes an adverse reaction and therefore can be given whether or not a true poisoning has occurred; 4) for which the needed dose is in microliters and administration is as simple; 5) which requires virtually no human or animal testing to establish efficacy and safety; 6) which therefore costs next to nothing in the first place; 7) which has an indefinite shelf life; and 8) for which you can get your (small) investment back if you do not use it. Is hydroxocobalamin the perfect antidote? Its mechanisms of action have been determined: it directly binds cyanide to form cyanocobalamin, an almost harmless B vitamin. It also binds nitric oxide, which provides positive benefits in hypotension, although it may transiently elevate the blood pressure in normotensive patients. Grade: A. Hydroxocobalamin does not work every time, especially when treating a complex multiple toxicant exposure like smoke inhalation. Fire smoke (a complex mixture of carbon monoxide, hydrogen cyanide,
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•
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The authors have no relevant financial information or potential conflicts of interest to disclose. A related article appears on page 1203.
1292 1292
ISSN 1069-6563 1292 PII ISSN 1069-6563583
•
carbon dioxide, volatile organic compounds, and soot) continues to kill, even when the cyanide issue is presumably addressed. Hydroxocobalamin will not raise the dead, so treatment needs to be given early, before hospital arrival. Enthusiasm for hydroxocobalamin may give way to abandonment of its use when critical smoke victims do not always respond. Skeptics say that there is no need for a cyanide antidote in life-threatening smoke inhalation at all,3,4 suggesting that it is mostly about the carbon monoxide. This is the territory of the superstitious, for whom the science,5–11 albeit imperfect, never seems to be enough. If one can look at Table 1 in the seminal study of Chou and colleagues12 and still believe that smoke inhalation and carbon monoxide are synonymous, there simply is little hope for improvement in smoke inhalation outcomes. Cyanide is not likely the determining factor in smoke inhalation toxicity in the majority of cases, but plays a predominant role in a minority of cases.11 Fire smoke aside, hydroxocobalamin has been successfully used in pure cyanide poisonings.13,14 Grade: B–. Hydroxocobalamin, not surprisingly, sometimes causes adverse effects. There is the occasional allergic reaction, but the one adverse effect that antagonizes the enthusiastic and the superstitious alike is the dark red color it imparts on everything: skin, plasma, urine . . . The burn surgeons swear that it interferes with determining the depth of burn. The emergency physician cannot trust the troponin results for the first 24 hours. And much has been made of the fact that hydroxocobalamin interferes with hemodialysis, never mind the fact that most cyanide poisoning victims never require hemodialysis. Nonetheless, serious adverse events are, so far, few and far between. Grade: B+. Hydroxocobalamin constitutes a substantial volume (500 mL) and requires an intravenous (IV) or intraosseous (IO) line for administration, making it imperfect for military use and for industrial and hazmat situations. Grade: C. Hydroxocobalamin has been tested in both animals and humans. The lofty goal of testing drugs only in vitro remains in the ether. While ethics do not allow a randomized clinical trial, multiple animal studies have demonstrated efficacy, and small human studies have demonstrated safety. Grade: C. Hydroxocobalamin does not cost next to nothing (yes, that is a bit like a double negative): by the time you mix it up and have a nurse hang it and drip it in, the “responsible party” is out $1,000. Sounds like a
© 2014 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12505
ACADEMIC EMERGENCY MEDICINE • November 2014, Vol. 21, No. 11 • www.aemj.org
• •
lot, but in the scheme of big pharma, this really is not all that much. Nonetheless, this seems to be the biggest stumbling block for many to get over in terms of its use. There is a reason that new nonsteroidal anti-inflammatory drugs and antibiotics hit the market every few months: return on investment. Drug companies make drugs for which there is a demand. Why are there so few new antidotes, which seem to emerge only about every 20 to 30 years? Because there is little economic justification for their development. If we refuse to give a fair trial to a new antidote because it is moderately costly, we are unlikely to see another. Perhaps part of the hesitation is that the victims of poisoning are often viewed as less deserving . . . After all, isn’t it the poor who suffer most house fires and the mentally ill who usually attempt suicide? (Subtext: how could they possibly deserve an expensive antidote? And why should I, the taxpayer, have to pay for it?) This is not to suggest that hydroxocobalamin should be used with reckless abandon, but that we should prospectively study its role in smoke inhalation on a larger scale (i.e., at a cost). Until such time that we adequately test hydroxocobalamin’s efficacy in smoke inhalation, we will still be “searching for guidance in the haze.”15 The alternative to new antidotes is to recycle old ones. For other poisons, like calcium channel blockers, we recycle generics, like insulin, lipids, and methylene blue. These take the place of newer antidotes that will not likely be developed. Grade: C+. Hydroxocobalamin has a shelf life of only 30 months. While the cyanide kit that it replaced had a shelf life of 36 months, the 6 months seems somehow to be the end of the world to its detractors. Grade: B–. You cannot get your money back if you do not use it. Sorry. Grade: F.
In this issue of Academic Emergency Medicine, Bebarta and colleagues16 describe the efficacious administration of hydroxocobalamin by the previously proposed17 IO route in a well-established pig model.18–21 This is only the latest in a series of realworld works of science by the authors to serve as an antidote to the poison of enthusiasm and superstition surrounding hydroxocobalamin. He and his colleagues have not been content to study hydroxocobalamin in a vacuum, but rather have compared it with old standbys18,21 and antidotes under development.20 Hydroxocobalamin appears to be equiefficacious with sodium nitrite and sodium thiosulfate in a cyanide infusion model,21 far superior to sodium thiosulfate alone in the same model,18 and essentially equally efficacious to, but less potent than, cobinamide in a similar model.20 There are new, possibly better cyanide antidotes on the horizon, including cobinamide and methanegen.20,22–26 Why? Because the demand has been created by the war on terror. Clearly, hydroxocobalamin is not the perfect antidote, so some will continue to refuse to give it a shot and, rather, wait for a better one. Perhaps Bebarta and colleagues realize that perfection is the enemy of good. Hydroxocobalamin is a solid antidote and deserves more attention by researchers and clini-
1293
cians alike. Surely, within 20 or 30 years something better will come along. But meanwhile, in the immortal words of Stephen Stills, “if you can’t be with the one you love, love the one you’re with.” Stephen W. Borron, MD ([email protected]) Texas Tech University Health Sciences Center Paul L. Foster School of Medicine Emergency Medicine El Paso, TX
Supervising Editor: Steven Bird, MD.
References 1. Baud FJ, Borron SW, Bismuth C. Modifying toxicokinetics with antidotes. Toxicol Lett 1995;82–83: 785–93. 2. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol 2009;39:541–52. 3. Barillo DJ. Diagnosis and treatment of cyanide toxicity. J Burn Care Res 2009;30:148–52. 4. Barillo DJ, Goode R, Esch V. Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature. J Burn Care Rehabil 1994;15:46–57. 5. Wetherell HR. The occurrence of cyanide in the blood of fire victims. J Forensic Sci 1966;11:167–73. 6. Silverman SH, Purdue GF, Hunt JL, Bost RO. Cyanide toxicity in burned patients. J Trauma 1988;28:171–6. 7. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761–6. 8. Borron S, Baud F, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med 2007;49:794–801. 9. Grabowska T, Skowronek R, Nowicka J, Sybirska H. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clin Toxicol 2012;50:759–63. 10. Stamyr K, Thelander G, Ernstgard L, Ahlner J, Johanson G. Swedish forensic data 1992–2009 suggest hydrogen cyanide as an important cause of death in fire victims. Inhal Toxicol 2012;24: 194–9. 11. Geldner G, Koch EM, Gottwald-Hostalek U, et al. Report on a study of fires with smoke gas development: determination of blood cyanide levels, clinical signs and laboratory values in victims. Anaesthesist 2013;62:609–16. 12. Chou KJ, Fisher JL, Silver EJ. Characteristics and outcome of children with carbon monoxide poisoning with and without smoke exposure referred for hyperbaric oxygen therapy. Pediatr Emerg Care 2000;16:151–5. 13. Baud F, Steffens W, Borron S, et al. Efficacy and Safety of Antidotes for Acute Poisoning by Cya-
1294
14.
15.
16.
17.
18.
19.
20.
nides. Brussels, Belgium: European Centre for Ecotoxicology and Toxicology of Chemicals, 2013 Technical Report No. 121. Reade MC, Davies SR, Morley PT, Dennett J. Jacobs IC; Australian Resuscitation Committee. Review article: management of cyanide poisoning. Emerg Med Australas 2012;24:225–38. Erdman AR. Is hydroxocobalamin safe and effective for smoke inhalation? Searching for guidance in the haze. Ann Emerg Med 2007;49:814–6. Bebarta VS, Pitotti RL, Boudreau S, Tannen DA. Intraosseous versus intravenous infusion of hydroxocobalamin for the treatment of acute severe cyanide toxicity in a swine model. Acad Emerg Med. 2014;1203–11. Borron SW, Arias JC, Bauer CR, Sanchez M, ndez M, Jung I. Hemodynamics after intraossFerna eous administration of hydroxocobalamin or normal saline in a goat model. Am J Emerg Med 2009;27: 1065–71. Bebarta VS, Pitotti RL, Dixon P, Lairet JR, Bush A, Tanen DA. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med 2012;59:532–9. Bebarta VS, Pitotti RL, Dixon PS, et al. Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest. Ann Emerg Med 2012;60:415–22. Bebarta VS, Tanen DA, Boudreau S, et al. Intravenous cobinamide versus hydroxocobalamin for
Borron • THE PERFECT ANTIDOTE
21.
22.
23.
24.
25.
26.
acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model. Ann Emerg Med 2014;. doi:10.1016/j.annemergmed.2014.02.009 Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier S, Bush A. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med 2010;55: 345–51. Brenner M, Benavides S, Mahon SB, et al. The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model. Clin Toxicol 2014;52:490–7. Brenner M, Kim JG, Lee J, et al. Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. Toxicol Appl Pharmacol 2010;248:269–76. Brenner M, Kim JG, Mahon SB, et al. Intramuscular cobinamide sulfite in a rabbit model of sublethal cyanide toxicity. Ann Emerg Med 2010;55:352–63. Chan A, Balasubramanian M, Blackledge W, et al. Cobinamide is superior to other treatments in a mouse model of cyanide poisoning. Clin Toxicol 2010;48:709–17. Patterson SE, Monteil AR, Cohen JF, Crankshaw DL, Vince R, Nagasawa HT. Cyanide antidotes for mass casualties: water-soluble salts of the dithiane (sulfanegen) from 3-mercaptopyruvate for intramuscular administration. J Med Chem 2013;56:1346–9.
The Perfect Antidote “
S
cience is the great antidote to the poison of enthusiasm and superstition.”—Adam Smith, Scottish philosopher, 1723–1790
“If necessity is the mother of invention, skepticism is its abusive stepfather.”—Stephen Borron, bathtub philosopher, 1957-present Baud and colleagues1 defined an antidote as “a drug whose mechanisms of action have been determined, which is able to modify either the toxicokinetics or the toxicodynamics of the poison, and whose administration to the poisoned patient reliably induces a significant benefit.” Hall et al.2 later defined the ‘ideal’ cyanide antidote as one with “rapid onset of action, neutralizes cyanide without interfering with cellular oxygen use, tolerability and safety profiles conducive to prehospital use, safe for use with smoke-inhalation victims, not harmful when administered to non-poisoned patients, easy to administer,”—it appears that hydroxocobalamin may have many of these characteristics.2 In the same spirit, I would like to define “the perfect antidote” as a drug: 1) for which mechanisms of action have been determined; 2) which works reliably in every case where its antagonist toxicant is involved, even when multiple poisons are involved; 3) which almost never causes an adverse reaction and therefore can be given whether or not a true poisoning has occurred; 4) for which the needed dose is in microliters and administration is as simple; 5) which requires virtually no human or animal testing to establish efficacy and safety; 6) which therefore costs next to nothing in the first place; 7) which has an indefinite shelf life; and 8) for which you can get your (small) investment back if you do not use it. Is hydroxocobalamin the perfect antidote? Its mechanisms of action have been determined: it directly binds cyanide to form cyanocobalamin, an almost harmless B vitamin. It also binds nitric oxide, which provides positive benefits in hypotension, although it may transiently elevate the blood pressure in normotensive patients. Grade: A. Hydroxocobalamin does not work every time, especially when treating a complex multiple toxicant exposure like smoke inhalation. Fire smoke (a complex mixture of carbon monoxide, hydrogen cyanide,
•
•
•
•
•
The authors have no relevant financial information or potential conflicts of interest to disclose. A related article appears on page 1203.
1292 1292
ISSN 1069-6563 1292 PII ISSN 1069-6563583
•
carbon dioxide, volatile organic compounds, and soot) continues to kill, even when the cyanide issue is presumably addressed. Hydroxocobalamin will not raise the dead, so treatment needs to be given early, before hospital arrival. Enthusiasm for hydroxocobalamin may give way to abandonment of its use when critical smoke victims do not always respond. Skeptics say that there is no need for a cyanide antidote in life-threatening smoke inhalation at all,3,4 suggesting that it is mostly about the carbon monoxide. This is the territory of the superstitious, for whom the science,5–11 albeit imperfect, never seems to be enough. If one can look at Table 1 in the seminal study of Chou and colleagues12 and still believe that smoke inhalation and carbon monoxide are synonymous, there simply is little hope for improvement in smoke inhalation outcomes. Cyanide is not likely the determining factor in smoke inhalation toxicity in the majority of cases, but plays a predominant role in a minority of cases.11 Fire smoke aside, hydroxocobalamin has been successfully used in pure cyanide poisonings.13,14 Grade: B–. Hydroxocobalamin, not surprisingly, sometimes causes adverse effects. There is the occasional allergic reaction, but the one adverse effect that antagonizes the enthusiastic and the superstitious alike is the dark red color it imparts on everything: skin, plasma, urine . . . The burn surgeons swear that it interferes with determining the depth of burn. The emergency physician cannot trust the troponin results for the first 24 hours. And much has been made of the fact that hydroxocobalamin interferes with hemodialysis, never mind the fact that most cyanide poisoning victims never require hemodialysis. Nonetheless, serious adverse events are, so far, few and far between. Grade: B+. Hydroxocobalamin constitutes a substantial volume (500 mL) and requires an intravenous (IV) or intraosseous (IO) line for administration, making it imperfect for military use and for industrial and hazmat situations. Grade: C. Hydroxocobalamin has been tested in both animals and humans. The lofty goal of testing drugs only in vitro remains in the ether. While ethics do not allow a randomized clinical trial, multiple animal studies have demonstrated efficacy, and small human studies have demonstrated safety. Grade: C. Hydroxocobalamin does not cost next to nothing (yes, that is a bit like a double negative): by the time you mix it up and have a nurse hang it and drip it in, the “responsible party” is out $1,000. Sounds like a
© 2014 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12505
ACADEMIC EMERGENCY MEDICINE • November 2014, Vol. 21, No. 11 • www.aemj.org
• •
lot, but in the scheme of big pharma, this really is not all that much. Nonetheless, this seems to be the biggest stumbling block for many to get over in terms of its use. There is a reason that new nonsteroidal anti-inflammatory drugs and antibiotics hit the market every few months: return on investment. Drug companies make drugs for which there is a demand. Why are there so few new antidotes, which seem to emerge only about every 20 to 30 years? Because there is little economic justification for their development. If we refuse to give a fair trial to a new antidote because it is moderately costly, we are unlikely to see another. Perhaps part of the hesitation is that the victims of poisoning are often viewed as less deserving . . . After all, isn’t it the poor who suffer most house fires and the mentally ill who usually attempt suicide? (Subtext: how could they possibly deserve an expensive antidote? And why should I, the taxpayer, have to pay for it?) This is not to suggest that hydroxocobalamin should be used with reckless abandon, but that we should prospectively study its role in smoke inhalation on a larger scale (i.e., at a cost). Until such time that we adequately test hydroxocobalamin’s efficacy in smoke inhalation, we will still be “searching for guidance in the haze.”15 The alternative to new antidotes is to recycle old ones. For other poisons, like calcium channel blockers, we recycle generics, like insulin, lipids, and methylene blue. These take the place of newer antidotes that will not likely be developed. Grade: C+. Hydroxocobalamin has a shelf life of only 30 months. While the cyanide kit that it replaced had a shelf life of 36 months, the 6 months seems somehow to be the end of the world to its detractors. Grade: B–. You cannot get your money back if you do not use it. Sorry. Grade: F.
In this issue of Academic Emergency Medicine, Bebarta and colleagues16 describe the efficacious administration of hydroxocobalamin by the previously proposed17 IO route in a well-established pig model.18–21 This is only the latest in a series of realworld works of science by the authors to serve as an antidote to the poison of enthusiasm and superstition surrounding hydroxocobalamin. He and his colleagues have not been content to study hydroxocobalamin in a vacuum, but rather have compared it with old standbys18,21 and antidotes under development.20 Hydroxocobalamin appears to be equiefficacious with sodium nitrite and sodium thiosulfate in a cyanide infusion model,21 far superior to sodium thiosulfate alone in the same model,18 and essentially equally efficacious to, but less potent than, cobinamide in a similar model.20 There are new, possibly better cyanide antidotes on the horizon, including cobinamide and methanegen.20,22–26 Why? Because the demand has been created by the war on terror. Clearly, hydroxocobalamin is not the perfect antidote, so some will continue to refuse to give it a shot and, rather, wait for a better one. Perhaps Bebarta and colleagues realize that perfection is the enemy of good. Hydroxocobalamin is a solid antidote and deserves more attention by researchers and clini-
1293
cians alike. Surely, within 20 or 30 years something better will come along. But meanwhile, in the immortal words of Stephen Stills, “if you can’t be with the one you love, love the one you’re with.” Stephen W. Borron, MD ([email protected]) Texas Tech University Health Sciences Center Paul L. Foster School of Medicine Emergency Medicine El Paso, TX
Supervising Editor: Steven Bird, MD.
References 1. Baud FJ, Borron SW, Bismuth C. Modifying toxicokinetics with antidotes. Toxicol Lett 1995;82–83: 785–93. 2. Hall AH, Saiers J, Baud F. Which cyanide antidote? Crit Rev Toxicol 2009;39:541–52. 3. Barillo DJ. Diagnosis and treatment of cyanide toxicity. J Burn Care Res 2009;30:148–52. 4. Barillo DJ, Goode R, Esch V. Cyanide poisoning in victims of fire: analysis of 364 cases and review of the literature. J Burn Care Rehabil 1994;15:46–57. 5. Wetherell HR. The occurrence of cyanide in the blood of fire victims. J Forensic Sci 1966;11:167–73. 6. Silverman SH, Purdue GF, Hunt JL, Bost RO. Cyanide toxicity in burned patients. J Trauma 1988;28:171–6. 7. Baud FJ, Barriot P, Toffis V, et al. Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761–6. 8. Borron S, Baud F, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med 2007;49:794–801. 9. Grabowska T, Skowronek R, Nowicka J, Sybirska H. Prevalence of hydrogen cyanide and carboxyhaemoglobin in victims of smoke inhalation during enclosed-space fires: a combined toxicological risk. Clin Toxicol 2012;50:759–63. 10. Stamyr K, Thelander G, Ernstgard L, Ahlner J, Johanson G. Swedish forensic data 1992–2009 suggest hydrogen cyanide as an important cause of death in fire victims. Inhal Toxicol 2012;24: 194–9. 11. Geldner G, Koch EM, Gottwald-Hostalek U, et al. Report on a study of fires with smoke gas development: determination of blood cyanide levels, clinical signs and laboratory values in victims. Anaesthesist 2013;62:609–16. 12. Chou KJ, Fisher JL, Silver EJ. Characteristics and outcome of children with carbon monoxide poisoning with and without smoke exposure referred for hyperbaric oxygen therapy. Pediatr Emerg Care 2000;16:151–5. 13. Baud F, Steffens W, Borron S, et al. Efficacy and Safety of Antidotes for Acute Poisoning by Cya-
1294
14.
15.
16.
17.
18.
19.
20.
nides. Brussels, Belgium: European Centre for Ecotoxicology and Toxicology of Chemicals, 2013 Technical Report No. 121. Reade MC, Davies SR, Morley PT, Dennett J. Jacobs IC; Australian Resuscitation Committee. Review article: management of cyanide poisoning. Emerg Med Australas 2012;24:225–38. Erdman AR. Is hydroxocobalamin safe and effective for smoke inhalation? Searching for guidance in the haze. Ann Emerg Med 2007;49:814–6. Bebarta VS, Pitotti RL, Boudreau S, Tannen DA. Intraosseous versus intravenous infusion of hydroxocobalamin for the treatment of acute severe cyanide toxicity in a swine model. Acad Emerg Med. 2014;1203–11. Borron SW, Arias JC, Bauer CR, Sanchez M, ndez M, Jung I. Hemodynamics after intraossFerna eous administration of hydroxocobalamin or normal saline in a goat model. Am J Emerg Med 2009;27: 1065–71. Bebarta VS, Pitotti RL, Dixon P, Lairet JR, Bush A, Tanen DA. Hydroxocobalamin versus sodium thiosulfate for the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med 2012;59:532–9. Bebarta VS, Pitotti RL, Dixon PS, et al. Hydroxocobalamin and epinephrine both improve survival in a swine model of cyanide-induced cardiac arrest. Ann Emerg Med 2012;60:415–22. Bebarta VS, Tanen DA, Boudreau S, et al. Intravenous cobinamide versus hydroxocobalamin for
Borron • THE PERFECT ANTIDOTE
21.
22.
23.
24.
25.
26.
acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model. Ann Emerg Med 2014;. doi:10.1016/j.annemergmed.2014.02.009 Bebarta VS, Tanen DA, Lairet J, Dixon PS, Valtier S, Bush A. Hydroxocobalamin and sodium thiosulfate versus sodium nitrite and sodium thiosulfate in the treatment of acute cyanide toxicity in a swine (Sus scrofa) model. Ann Emerg Med 2010;55: 345–51. Brenner M, Benavides S, Mahon SB, et al. The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model. Clin Toxicol 2014;52:490–7. Brenner M, Kim JG, Lee J, et al. Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity. Toxicol Appl Pharmacol 2010;248:269–76. Brenner M, Kim JG, Mahon SB, et al. Intramuscular cobinamide sulfite in a rabbit model of sublethal cyanide toxicity. Ann Emerg Med 2010;55:352–63. Chan A, Balasubramanian M, Blackledge W, et al. Cobinamide is superior to other treatments in a mouse model of cyanide poisoning. Clin Toxicol 2010;48:709–17. Patterson SE, Monteil AR, Cohen JF, Crankshaw DL, Vince R, Nagasawa HT. Cyanide antidotes for mass casualties: water-soluble salts of the dithiane (sulfanegen) from 3-mercaptopyruvate for intramuscular administration. J Med Chem 2013;56:1346–9.
