ArticlePDF AvailableLiterature Review

Hydroxocobalamin: Improved public health readiness for cyanide disasters

Authors:
  • DisasterDoc LLC

Abstract

The United States is under the constant threat of a mass casualty cyanide disaster from industrial accidents, hazardous material transportation incidents, and deliberate terrorist attacks. The current readiness for cyanide disaster by the emergency medical system in the United States is abysmal. We, as a nation, are simply not prepared for a significant cyanide-related event. The standard of care for cyanide intoxication is the cyanide antidote kit, which is based on the use of nitrites to induce methemoglobinemia. This kit is both expensive and ill suited for out-of-hospital use. It also has its own inherent toxicity that prevents rapid administration. Furthermore, our hospitals frequently fail to stock this life-saving antidote or decline to stock more than one. Hydroxocobalamin is well recognized as an efficacious, safe, and easily administered cyanide antidote. Because of its extremely low adverse effect profile, it is ideal for out-of-hospital use in suspected cyanide intoxication. To effectively prepare for a cyanide disaster, the United States must investigate, adopt, manufacture, and stockpile hydroxocobalamin to prevent needless morbidity and mortality.
... This releases cytochrome-C oxidase to resume normal cellular respiration. [21] This approach had its own toxicity; the main concerning one is the production of methemoglobin. The CAK is expensive and not suited for out-of-hospital use. ...
... In 2006, FDA approved intravenous hydroxocobalamin for the treatment of known or suspected cyanide poisoning. [22] It has been recognized as an antidote for cyanide toxicity for more than 40 years, [21,23] and is in active use in France as a cyanide antidote. ...
... 20 Sodium thiosulfate is a natural substrate of the enzyme rhodanese (Scheme 1). 4 It is often coadministered with other antidotes, e.g., as in the Cyanide Antidote Kit (CAK), or to prevent cyanide toxicity during the metabolism of sodium nitroprusside (Na 2 [Fe(CN) 5 NO]) vasodilator. 21,22 Cytotoxicity in molybdenum complexes has been reported over a large range of inhibitory concentration (IC 50 ) values. Organometallic molybdenum complexes have been reported with comparable or lower IC 50 values than the chemotherapeutic drug cisplatin in a number of cell lines. ...
... Since then, there has been several pieces of evidence in preclinical and clinical studies validating STS as an antidote to cyanide poisoning and other chemical poisoning, such as carbon monoxidecyanide toxicity in patients for whom sodium nitrite is contraindicated [48,49]. The United States, for example, has a standard cyanide antidote kit, which first uses 10mL intravenous sodium nitrite, followed immediately by 50mL intravenous STS [50]. Taken together, these results show that the mechanism of action underlying the use of STS as an antidote to cyanide poisoning is due to its ability to serve as a sulfur donor. ...
Article
Full-text available
Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H 2 S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review discusses the biochemical and molecular pathways in the generation of STS from H 2 S, its clinical usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these clinical applications and a future perspective in kidney transplantation.
... has a strong safety record in humans and has been assessed in human testing as an antidote to cyanide poisoning at intravenous doses of 5 g (39). In comparison, the mouse CoPoP dose in this study was 0.4 g, which is several orders of magnitude smaller on a milligram per kilogram basis and corresponds to a chelated cobalt dose of approximately 0.02 g. ...
Article
Full-text available
The COVID-19 pandemic has spurred interest in potent and thermostable SARS-CoV-2 vaccines. Here, we assess low-dose immunization with lyophilized nanoparticles decorated with recombinant SARS-CoV-2 antigens. The SARS-CoV-2 Spike glycoprotein or its receptor-binding domain (RBD; mouse vaccine dose, 0.1 μg) was displayed on liposomes incorporating a particle-inducing lipid, cobalt porphyrin-phospholipid (dose, 0.4 μg), along with monophosphoryl lipid A (dose, 0.16 μg) and QS-21 (dose, 0.16 μg). Following optimization of lyophilization conditions, Spike or RBD-decorated liposomes were effectively reconstituted and maintained conformational capacity for binding human angiotensin-converting enzyme 2 (hACE2) for at least a week when stored at 60°C in lyophilized but not liquid format. Prime-boost intramuscular vaccination of hACE2-transgenic mice with the reconstituted vaccine formulations induced effective antibody responses that inhibited RBD binding to hACE2 and neutralized pseudotyped and live SARS-CoV-2. Two days following viral challenge, immunized transgenic mice cleared the virus and were fully protected from lethal disease.
... Since then, there has been several pieces of evidence in preclinical and clinical studies validating STS as an antidote to cyanide poisoning and other chemical poisoning, such as carbon monoxidecyanide toxicity in patients for whom sodium nitrite is contraindicated [48,49]. The United States, for example, has a standard cyanide antidote kit, which first uses 10mL intravenous sodium nitrite, followed immediately by 50mL intravenous STS [50]. Taken together, these results show that the mechanism of action underlying the use of STS as an antidote to cyanide poisoning is due to its ability to serve as a sulfur donor. ...
Article
Full-text available
Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H2S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review discusses the biochemical and molecular pathways in the generation of STS from H2S, its clinical usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these clinical applications and a future perspective in kidney transplantation.
... However, these measurements were within the normal range for the tests and thus we do not consider the measurements to reflect any sign of toxicity, even at the elevated dosing use. The use of cobalt in CoPoP is a potential concern for a vaccine, although it is worth noting that vitamin B12, a cobalt tetrapyrrole has been shown to be safe in humans with 5 gram intravenous doses, [23] a level approximately 50 000fold higher than anticipated for CoPoP human dosing. Following mouse immunization, serum cobalt levels were not elevated relative to mice that received the RBD with alum (thus lacking any exogenous cobalt) ( Figure 6C). ...
Article
Full-text available
The receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein is a candidate vaccine antigen that binds angiotensin‐converting enzyme 2 (ACE2), leading to virus entry. Here, it is shown that rapid conversion of recombinant RBD into particulate form via admixing with liposomes containing cobalt‐porphyrin‐phospholipid (CoPoP) potently enhances the functional antibody response. Antigen binding via His‐tag insertion into the CoPoP bilayer results in a serum‐stable and conformationally intact display of the RBD on the liposome surface. Compared to other vaccine formulations, immunization using CoPoP liposomes admixed with recombinant RBD induces multiple orders of magnitude higher levels of antibody titers in mice that neutralize pseudovirus cell entry, block RBD interaction with ACE2, and inhibit live virus replication. Enhanced immunogenicity can be accounted for by greater RBD uptake into antigen‐presenting cells in particulate form and improved immune cell infiltration in draining lymph nodes. QS‐21 inclusion in the liposomes results in an enhanced antigen‐specific polyfunctional T cell response. In mice, high dose immunization results in minimal local reactogenicity, is well‐tolerated, and does not elevate serum cobalt levels. Taken together, these results confirm that particulate presentation strategies for the RBD immunogen should be considered for inducing strongly neutralizing antibody responses against SARS‐CoV‐2.
Article
Мета. Виділити групу високотоксичних хімічних речовин, які за останні десятиліття найчастіше використовуються в умисних кримінальних та суїцидальних інцидентах, диверсійних і терористичних актах, обіг, зберігання, використання та утилізацію яких потрібно особливо прискіпливо контролювати правоохоронним органам. У даній частині статті йдеться про сполуки миш’яку та ціаніди. Матеріали та методи. Аналітичний огляд наукових публікацій виконаний з використанням реферативних баз даних наукових бібліотек Pub Med, Medline і текстових баз даних наукових видавництв Elsevier, Pub Med, Central, BMJ group та інших VIP-баз даних. Використано методи системного, порівняльного та контент-аналізу. Результати та висновки. Проаналізовано наукові публікації, в яких йдеться про високотоксичні сполуки миш’яку та ціаніди, які становлять загрозу життю і здоров’ю людини. Останнім часом, зокрема понад чверть сторіччя, вони стали справжньою зброєю в руках злочинців, кримінальних елементів і терористів у всьому світі. Не можна замовчувати й суїцидальні інциденти, які також мають місце поряд з умисними кримінальними, терористичними та диверсійними актами. На основі аналізу токсичності, клінічних та морфологічних проявів інтоксикації цих хімічних речовин, враховуючи різні шляхи надходження до організму, обґрунтовано необхідність внесення їх до Переліку особливо небезпечних хімічних речовин, обіг яких, зберігання, використання та утилізація потребують більш жорсткого контролю з боку правоохоронних органів. Ключові слова: сполуки миш’яку, ціаніди, ризик для здоров’я, гострі отруєння.
Article
The Aim of the Research. To identify a group of highly toxic chemicals which over the past decades are most often used in deliberate criminal and suicidal incidents, sabotage, and terrorist act; the handling, storage, use and disposal of which must be especially carefully monitored by law enforcement agencies. In this part of the article arsenic compounds and cyanide are considered. Materials and Methods. An analytical review of scientific publications was carried out using the abstract databases of scientific libraries Pub Med, Medline and text databases of scientific publishing houses Elsevier, Pub Med, Central, BMJ group as well as other VIP databases. Methods of systemic, comparative, and content analysis were used. Results and Conclusions. Scientific publications that contain information on highly toxic arsenic compounds and cyanides, which pose a threat to human life and health, were analyzed. Recently, in particular for more than a quarter of a century, they have become a real weapon in the hands of criminals, delinquents, and terrorists all over the world. Suicidal incidents, which also take place along with intentional criminal, terrorist, and sabotage acts, should not be concealed. Based on the analysis of the toxicity, clinical and morphological expression of intoxication when exposed to these chemicals, considering various routes of entry into the body, the need to include them in the List of hazardous highly toxic chemicals, the handling, storage, use, and disposal of which require stricter control of law enforcement agencies, is justified. Key Words: arsenic compounds, cyanide, health risk, acute poisoning.
Article
Full-text available
Despite remarkable successes of immunization in protecting public health, safe and effective vaccines against a number of life‐threatening pathogens such as HIV, ebola, influenza, and SARS‐CoV‐2 remain urgently needed. Subunit vaccines can avoid potential toxicity associated with traditional whole virion‐inactivated and live‐attenuated vaccines; however, the immunogenicity of subunit vaccines is often poor. A facile method is here reported to produce lipid nanoparticle subunit vaccines that exhibit high immunogenicity and elicit protection against influenza virus. Influenza hemagglutinin (HA) immunogens are functionalized on the surface of liposomes via stable metal chelation chemistry, using a scalable advanced microfluidic mixing technology (NanoAssemblr). Immunization of mice with HA‐liposomes elicits increased serum antibody titers and superior protection against highly pathogenic virus challenge compared with free HA protein. HA‐liposomal vaccines display enhanced antigen deposition into germinal centers within the draining lymph nodes, driving increased HA‐specific B cell, and follicular helper T cell responses. This work provides mechanistic insights into highly protective HA‐liposome vaccines and informs the rational design and rapid production of next generation nanoparticle subunit vaccines. Liposomes attached with hemagglutinin (HA)—a key antigen on influenza viral surface are prepared. HA‐liposome immunization elicits higher levels of HA‐specific antibodies in mouse serum compared to soluble HA vaccination. Increased deposition of HA‐liposomes in germinal centers of draining lymph nodes leads to enhanced formation of HA‐specific germinal center B cells, which is responsible for improved humoral immune responses.
Article
Hazardous materials incidents include gas and vapor releases, spills, explosions, and fires. Incidents involving human exposure are challenging for most health care providers because of the vast number of potential chemicals involved, frequently incomplete incident information, and limited experience in exposure assessment. To facilitate improved evaluation and treatment of patients with chemical exposures, the Washington Poison Center established the Hazardous Materials Exposure Information Service in 1994. During the first 33 months of operation, this service has provided information on 70 incidents, involving a total of 1120 exposed individuals, including 501 patients treated in medical facilities. This paper reviews these incidents, the process used to collect information from the incident scene, and selected techniques for evaluating the extent of individual chemical exposure.
Article
Objective.— To describe the epidemiology of recent unintentional carbon monoxide poisoning deaths in the United States.Design.— Descriptive analysis of carbon monoxide—related deaths in the United States from 1979 through 1988, based on death certificate reports compiled by the National Center for Health Statistics.Population Studied.— All US deaths, 1979 through 1988.Results.— We reviewed data from 56 133 death certificates that contained codes implicating carbon monoxide as a contributing cause of death. Of these, 25 889 were suicides, 210 were homicides, 15 523 were associated with severe burns or house fires, and 11 547 were classified as unintentional. The number of unintentional deaths decreased steadily by about 63 deaths per year, from 1513 in 1979 to 878 in 1988. The highest death rates occurred in winter and among males, blacks, the elderly, and residents of northern states. Motor vehicle exhaust gas caused 6552 (57%) of the unintentional deaths; 5432 (83%) of these were associated with stationary automobiles.Conclusions.— The rate of unintentional death from carbon monoxide poisoning is decreasing. This may be attributable to improvements in automobile pollution control systems and improved safety of cooking and heating appliances. Prevention programs should target young drivers, males, and the elderly.(JAMA. 1991;266:659-663)
Article
Objective. —To determine whether antidotes for poisoning and overdose are available in hospitals that provide emergency department care.Design. —Written survey of hospital pharmacy directors, each of whom reported the amount currently in stock of 8 different antidotes: antivenin (Crotalidae) polyvalent, cyanide kit, deferoxamine mesylate, digoxin immune Fab, ethanol, naloxone hydrochloride, pralidoxime chloride, and pyridoxine hydrochloride.Participants. —Pharmacy directors of all hospitals with emergency departments in Colorado, Montana, and Nevada.Main Outcome Measures. —Proportions of hospitals with insufficient stocking of each antidote, defined as complete lack of the antidote or an amount inadequate to initiate treatment of 1 seriously poisoned 70-kg patient.Results. —Questionnaires were mailed to 137 hospital pharmacy directors and 108 (79%) responded. Only 1 (0.9%) of the 108 hospitals stocked all 8 antidotes in adequate amounts. The rate of insufficient stocking for individual antidotes ranged from 2% (for naloxone) to 98% (for digoxin immune Fab). In a multiple regression analysis, smaller hospital size and lack of a formal review of antidote stocking were independent predictors of the number of antidotes stocked insufficiently.Conclusions. —Insufficient stocking of antidotes is a widespread problem in Colorado, Montana, and Nevada. Although these states are served by a certified regional poison center, potentially lifesaving antidotes are frequently not available when and where they might be needed to treat a single poisoned patient.
Article
Since the publication of the first edition of this tome in 1988, it has been my major reference text of clinical toxicology, far surpassing in utility, in my opinion, any other single volume. Like many others in my field, I have anxiously awaited the second edition. Unfortunately, the new edition has now become a memorial to its primary editor and driving force, Matthew J. Ellenhorn, MD, who died before its publication. In the preface, Dr Ellenhorn relates the difficulties of writing a comprehensive toxicology text and his philosophy of doing so. Much of the clinical toxicology literature embodies anecdotal reports or uncontrolled case series, therefore much of our understanding of toxicology is derived from animal experimentation. In this edition, as with the first, Dr Ellenhorn has tried to limit his references to animal studies and is very selective in his use of anecdotal reports. As with the first edition, the
Article
SIX YEARS AGO, on December 3, 1984, a toxic gas leak at a Union Carbide pesticide plant in Bhopal, India, released methyl isocyanate (MIC) and its reaction products. The number of persons "exposed" and "injured" remains uncertain.1 Official estimates from the Indian government place the dead at around 1800.2 Others estimate mortality to have been between 2500 and 5000 and the number of injured to have been up to 200 000.3,4Until the Bhopal incident, neither deaths nor cases of toxic effects from MIC exposure had been recorded in Index Medicus.51 We have extensively surveyed the medical literature concerning effects of MIC exposure on the victims of the disaster and laboratory studies in animals. A great deal has been learned, but many questions still remain unanswered.THE BHOPAL PLANT In 1969, the Union Carbide Corporation built a formulation plant in Bhopal, India, to mix and
Article
Comment: There has been recent awareness that carbon monoxide (CO) and hydrogen cyanide are synergistic in preventing the use of oxygen by tissues. Hydrogen cyanide is the most lethal of several poisonous gases generated in fires, especially those involving foam-filled furniture such as polyurethane and polyacrylonitrile. Outside of the emergency trauma admitting room, most anesthesiologists' knowledge about cyanide poisoning stems from the use of sodium nitroprusside as a hypotensive agent where cyanide may be released. The message of this paper is "think cyanide poisoning" as well as CO toxicity when patients are rescued from fires and maintain mechanical ventilation of the lungs with oxygen. Specific cyanide antidotes may be unnecessary or should be given with great care. Serial blood samples are needed for cyanide analysis, which is a difficult assay. The efficacy of the treatment of cyanide poisoning as a result of fires needs to be rethought frequently lest the therapy prove a danger in itself. (C) Williams & Wilkins 1996. All Rights Reserved.
Article
To investigate hydroxocobalamin's role in preventing cyanide intoxication from sodium nitroprusside, we studied two groups of patients. One group received nitroprusside alone, and the other received nitroprusside and hydroxocobalamin. Red-cell and plasma cyanide levels were 83.44 +/- 23.12 and 3.51 +/- 1.01 microgram per 100 ml after nitroprusside alone and were 33.18 +/- 17.29 and 2.18 +/- 0.65 microgram per 100 ml after nitroprusside plus hydroxocobalamin. Acidosis developed in patients with red-cell cyanide levels higher than 75 microgram per 100 ml. When hydroxocobalamin infusion was stopped before sodium nitroprusside infusion was discontinued, blood cyanide levels and base deficit increased in a manner similar to that in the untreated group. The dose of nitroprusside used in each group did not differ statistically. These data show that hydroxocobalamin prevents cyanide transfer from red cells and plasma to tissue after nitroprusside metabolism, and thereby prevents cyanide toxicity from large intravenous doses of the drug.