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Alan H. Hall - One of the best experts on this subject based on the ideXlab platform.
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Which Cyanide Antidote
Critical reviews in toxicology, 2009Co-Authors: Alan H. Hall, Jane A. Saiers, Frédéric J. BaudAbstract:Cyanide has several Antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk-benefit profiles. The international medical community lacks consensus about the Antidote or Antidotes with the best risk-benefit ratio. Critical assessment of Cyanide Antidotes is needed to aid in therapeutic and administrative decisions that will improve care for victims of Cyanide poisoning (particularly poisoning from enclosed-space fire-smoke inhalation), and enhance readiness for Cyanide toxic terrorism and other mass-casualty incidents. This paper reviews preclinical and clinical data on available Cyanide Antidotes and considers the profiles of these Antidotes relative to properties of a hypothetical ideal Cyanide Antidote. Each of the Antidotes shows evidence of efficacy in animal studies and clinical experience. The data available to date do not suggest obvious differences in efficacy among Antidotes, with the exception of a slower onset of action of sodium thiosulfate (administered alone) than of the other Antidotes. The potential for serious toxicity limits or prevents the use of the Cyanide Antidote Kit, dicobalt edetate, and 4-dimethylaminophenol in prehospital empiric treatment of suspected Cyanide poisoning. Hydroxocobalamin differs from these Antidotes in that it has not been associated with clinically significant toxicity in antidotal doses. Hydroxocobalamin is an Antidote that seems to have many of the characteristics of the ideal Cyanide Antidote: 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.
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Which Cyanide Antidote
Critical Reviews in Toxicology, 2009Co-Authors: Alan H. Hall, Jane A. Saiers, Frédéric J. BaudAbstract:Cyanide has several Antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk–benefit profiles. The international medical community lacks consensus about the Antidote or Antidotes with the best risk–benefit ratio. Critical assessment of Cyanide Antidotes is needed to aid in therapeutic and administrative decisions that will improve care for victims of Cyanide poisoning (particularly poisoning from enclosed-space fire-smoke inhalation), and enhance readiness for Cyanide toxic terrorism and other mass-casualty incidents. This paper reviews preclinical and clinical data on available Cyanide Antidotes and considers the profiles of these Antidotes relative to properties of a hypothetical ideal Cyanide Antidote. Each of the Antidotes shows evidence of efficacy in animal studies and clinical experience. The data available to date do not suggest obvious differences in efficacy among Antidotes, with the exception of a slower onset of action of sodium thiosulfate (administered alo...
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Sodium thiosulfate or hydroxocobalamin for the empiric treatment of Cyanide poisoning
Annals of emergency medicine, 2006Co-Authors: Alan H. Hall, Richard C. Dart, Gregory M. BogdanAbstract:Cyanide poisoning must be seriously considered in victims of smoke inhalation from enclosed space fires; it is also a credible terrorism threat agent. The treatment of Cyanide poisoning is empiric because laboratory confirmation can take hours or days. Empiric treatment requires a safe and effective Antidote that can be rapidly administered by either out-of-hospital or emergency department personnel. Among several Cyanide Antidotes available, sodium thiosulfate and hydroxocobalamin have been proposed for use in these circumstances. The evidence available to assess either sodium thiosulfate or hydroxocobalamin is incomplete. According to recent safety and efficacy studies in animals and human safety and uncontrolled efficacy studies, hydroxocobalamin seems to be an appropriate Antidote for empiric treatment of smoke inhalation and other suspected Cyanide poisoning victims in the out-of-hospital setting. Sodium thiosulfate can also be administered in the out-of-hospital setting. The efficacy of sodium thiosulfate is based on individual case studies, and there are contradictory conclusions about efficacy in animal models. The onset of antidotal action of sodium thiosulfate may be too slow for it to be the only Cyanide Antidote for emergency use. Hydroxocobalamin is being developed for potential introduction in the United States and may represent a new option for emergency personnel in cases of suspected or confirmed Cyanide poisoning in the out-of-hospital setting.
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Pediatric Cyanide poisoning: causes, manifestations, management, and unmet needs.
Pediatrics, 2006Co-Authors: Robert J. Geller, Claudia L. Barthold, Jane A. Saiers, Alan H. HallAbstract:Confirmed cases of childhood exposure to Cyanide are rare despite multiple potential sources including inhalation of fire smoke, ingestion of toxic household and workplace substances, and ingestion of cyanogenic foods. Because of its infrequent occurrence, medical professionals may have difficulty recognizing Cyanide poisoning, confirming its presence, and treating it in pediatric patients. The sources and manifestations of acute Cyanide poisoning seem to be qualitatively similar between children and adults, but children may be more vulnerable than adults to poisoning from some sources. The only currently available Antidote in the United States (the Cyanide Antidote kit) has been used successfully in children but has particular risks associated with its use in pediatric patients. Because hemoglobin kinetics vary with age, methemoglobinemia associated with nitrite-based Antidotes may be excessive at standard adult dosing in children. A Cyanide Antidote with a better risk/benefit ratio than the current agent available in the United States is desirable. The vitamin B12 precursor hydroxocobalamin, which has been used in Europe, may prove to be an attractive alternative to the Cyanide Antidote kit for pediatric patients. In this article we review the available data on the sources, manifestations, and treatment of acute Cyanide poisoning in children and discuss unmet needs in the management of pediatric Cyanide poisoning.
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HYDROXOCOBALAMIN AS A Cyanide Antidote: SAFETY, EFFICACY AND PHARMACOKINETICS IN HEAVILY SMOKING NORMAL VOLUNTEERS
Journal of toxicology. Clinical toxicology, 1993Co-Authors: John C. Forsyth, Barry H. Rumack, Paula D. Mueller, Charles E. Becker, John D. Osterloh, Neal L. Benowitz, Alan H. HallAbstract:AbstractThe safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men who were heavy smokers. Sodium thiosulfate caused nausea, vomiting, and localized burning, muscle cramping, or twitching at the infusion site. Hydroxocobalamin was associated with a transient reddish discoloration of the skin, mucous membranes, and urine, and when administered alone produced mean elevations of 13.6% in systolic and 25.9% in diastolic blood pressure, with a concomitant 16.3% decrease in heart rate. No other clinically significant adverse effects were noted. Hydroxocobalamin alone decreased whole blood Cyanide levels by 59% and increased urinary Cyanide excretion. Pharmacokinetic parameters of hydroxocobalamin were best defined in the group who received both Antidotes: t1/2 (alpha), 0.52 h; t1/2 (beta), 2.83 h; Vd (beta), 0.24 L/kg; and mean peak serum concentration 753 mcg/mL (560 μmol/L) a...
Gary A. Rockwood - One of the best experts on this subject based on the ideXlab platform.
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Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium Cyanide poisoning.
Basic & clinical pharmacology & toxicology, 2019Co-Authors: Nathaniel C. Rice, Gary A. Rockwood, Dennean S. Lippner, Noah A. Rauscher, William L. Wilkins, Todd M. MyersAbstract:Sodium Cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make Cyanide a potential foodborne/waterborne intentional-poisoning hazard. Effective Antidotes to Cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective Cyanide Antidote that can be administered intramuscularly in pre-hospital and/or mass-casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in Cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25-200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25-100 mg/kg) increased survival after oral Cyanide poisoning, and the lower DMTS doses (6.25-25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50-200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24-72 hour. Thus, DMTS shows promise as an intramuscularly administered Cyanide Antidote useful for prompt pre-hospital or mass-casualty emergency medical treatment.
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Analysis of potential Cyanide Antidote, dimethyl trisulfide, in whole blood by dynamic headspace gas chromatography-mass spectroscopy.
Journal of chromatography. A, 2019Co-Authors: Subrata Bhadra, Gary A. Rockwood, Zhiling Zhang, Wenhui Zhou, Fredrick Ochieng, Dennean S. Lippner, Brian A. LogueAbstract:Abstract Cyanide is a rapidly acting and highly toxic chemical. It inhibits cytochrome c oxidase in the mitochondrial electron transport chain, resulting in cellular hypoxia, cytotoxic anoxia and potentially death. In order to overcome challenges associated with current Cyanide Antidotes, dimethyl trisulfide (DMTS), which converts Cyanide to less toxic thiocyanate in vivo, has gained much attention recently as a promising next-generation Cyanide Antidote. While there are three analysis methods available for DMTS, they each have significant disadvantages. Hence, in this study, a dynamic headspace (DHS) gas chromatography–mass spectroscopy method was developed for the analysis of DMTS from rabbit whole blood. The method is extremely simple, involving only acidification of a blood sample, addition of an internal standard (DMTS-d6) and DHS-GC–MS analysis. The method produced a limit of detection of 0.04 μM for DMTS with dynamic range from 0.2 to 50 μM. Inter- and intraassay accuracy (100 ± 15% and 100 ± 9%, respectively), and precision (
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Monitoring Dose Response of Cyanide Antidote Dimethyl Trisulfide in Rabbits Using Diffuse Optical Spectroscopy.
Journal of medical toxicology : official journal of the American College of Medical Toxicology, 2018Co-Authors: Jangwoen Lee, Ilona Petrikovics, Gary A. Rockwood, Brian A. Logue, Erica Manandhar, Changhoon Han, Vik Bebarta, Sari B. Mahon, Tanya Burney, Matthew BrennerAbstract:Author(s): Lee, Jangwoen; Rockwood, Gary; Logue, Brian; Manandhar, Erica; Petrikovics, Ilona; Han, Changhoon; Bebarta, Vik; Mahon, Sari B; Burney, Tanya; Brenner, Matthew | Abstract: INTRODUCTION:Cyanide (CN) poisoning is a serious chemical threat from accidental or intentional exposures. Current CN exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Dimethyl trisulfide (DMTS) is capable of reacting with CN to form the less toxic thiocyanate with high efficiency, even without the sulfurtransferase rhodanese. We investigated a soluble DMTS formulation with the potential to provide a continuous supply of substrate for CN detoxification which could be delivered via intramuscular (IM) injection in a mass casualty situation. We also used non-invasive technology, diffuse optical spectroscopy (DOS), to monitor physiologic changes associated with CN exposure and reversal. METHODS:Thirty-six New Zealand white rabbits were infused with a lethal dose of sodium Cyanide solution (20 mg/60 ml normal saline). Animals were divided into three groups and treated with saline, low dose (20 mg), or high dose (150 mg) of DMTS intramuscularly. DOS continuously assessed changes in tissue hemoglobin concentrations and cytochrome c oxidase redox state status throughout the experiment. RESULTS:IM injection of DMTS increased the survival in lethal CN poisoning. DOS demonstrated that high-dose DMTS (150 mg) reversed the effects of CN exposure on cytochrome c oxidase, while low dose (20 mg) did not fully reverse effects, even in surviving animals. CONCLUSIONS:This study demonstrated potential efficacy for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for CN detoxification via intramuscular injection in a moderate size animal model and showed that DOS was useful for optimizing the DMTS treatment.
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method development for detecting the novel Cyanide Antidote dimethyl trisulfide from blood and brain and its interaction with blood
Journal of Chromatography B, 2017Co-Authors: Loránd Kiss, Deepthika De Silva, Ching-en Chou, Secondra Holmes, Xinmei Dong, James Ross, Denise Brown, Brooke Mendenhall, Valerie Coronado, Gary A. RockwoodAbstract:Abstract The antidotal potency of dimethyl trisulfide (DMTS) against Cyanide poisoning was discovered and investigated in our previous studies. Based on our results it has better efficacy than the Cyanokit and the Nithiodote therapies that are presently used against Cyanide intoxication in the US. Because of their absence in the literature, the goal of this work was to develop analytical methods for determining DMTS from blood and brain that could be employed in future pharmacokinetic studies. An HPLC-UV method for detection of DMTS from blood, a GC–MS method for detection of DMTS from brain, and associated validation experiments are described here. These analytical methods were developed using in vitro spiking of brain and blood, and are suitable for determining the in vivo DMTS concentrations in blood and brain in future pharmacokinetic and distribution studies. An important phenomenon was observed in the process of developing these methods. Specifically, recoveries from fresh blood spiked with DMTS were found to be significantly lower than recoveries from aged blood spiked in the same manner with DMTS. This decreased DMTS recovery from fresh blood is important, both because of the role it may play in the antidotal action of DMTS in the presence of Cyanide, and because it adds the requirement of sample stabilization to the method development process. Mitigation procedures for stabilizing DMTS samples in blood are reported.
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Dimethyl trisulfide A novel Cyanide countermeasure
Toxicology and industrial health, 2016Co-Authors: Gary A. Rockwood, David E. Thompson, Ilona PetrikovicsAbstract:In the present studies, the in vitro and in vivo efficacies of a novel Cyanide countermeasure, dimethyl trisulfide (DMTS), were evaluated. DMTS is a sulfur-based molecule found in garlic, onion, broccoli, and similar plants. DMTS was studied for effectiveness as a sulfur donor-type Cyanide countermeasure. The sulfur donor reactivity of DMTS was determined by measuring the rate of the formation of the Cyanide metabolite thiocyanate. In experiments carried out in vitro in the presence of the sulfurtransferase rhodanese (Rh) and at the experimental pH of 7.4, DMTS was observed to convert Cyanide to thiocyanate with greater than 40 times higher efficacy than does thiosulfate, the sulfur donor component of the US Food and Drug Administration-approved Cyanide countermeasure Nithiodote® In the absence of Rh, DMTS was observed to be almost 80 times more efficient than sodium thiosulfate in vitro The fact that DMTS converts Cyanide to thiocyanate more efficiently than does thiosulfate both with and without Rh makes it a promising sulfur donor-type Cyanide Antidote (scavenger) with reduced enzyme dependence in vitro The therapeutic Cyanide antidotal efficacies for DMTS versus sodium thiosulfate were measured following intramuscular administration in a mouse model and expressed as antidotal potency ratios (APR = LD50 of Cyanide with Antidote/LD50 of Cyanide without Antidote). A dose of 100 mg/kg sodium thiosulfate given intramuscularly showed only slight therapeutic protection (APR = 1.1), whereas the antidotal protection from DMTS given intramuscularly at the same dose was substantial (APR = 3.3). Based on these data, DMTS will be studied further as a promising next-generation countermeasure for Cyanide intoxication.
Vikhyat S. Bebarta - One of the best experts on this subject based on the ideXlab platform.
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acquired methemoglobinemia after hydroxocobalamin administration in a patient with burns and inhalation injury
Clinical Toxicology, 2018Co-Authors: Alisha Z Jiwani, Vikhyat S. Bebarta, Leopoldo C CancioAbstract:AbstractContext: Hydroxocobalamin is an effective Cyanide Antidote. While erythema, hypertension, and chromaturia are recognized side effects, methemoglobinemia has not been reported. Methemoglobin levels are most accurately measured by co-oximetry. We describe an extensively burned patient who developed methemoglobinemia within an hour of hydroxocobalamin administration.Case details: A 47-year old man without genetic deficiencies or abnormal hemoglobin variants presented with 61% body surface area thermal burns and grade 1 inhalation injury sustained during a tugboat engine explosion. On admission, lactate was 9.24 mmol/L, methemoglobin 1%, and carboxyhemoglobin 0.2% by blood gas analysis with co-oximetry. Despite large-volume resuscitation, lactate remained elevated (7–8 mmol/L). Intravenous hydroxocobalamin (5 g) was administered at postburn hour 19 for possible Cyanide toxicity. Immediately thereafter, he became hypertensive with reflex bradycardia. Lactate decreased to 5.51 mmol/L, methemoglobin rose...
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Case Files of the University of Massachusetts Toxicology Fellowship: Does This Smoke Inhalation Victim Require Treatment with Cyanide Antidote?
Journal of Medical Toxicology, 2016Co-Authors: Eike Hamad, Kavita Babu, Vikhyat S. BebartaAbstract:Cyanide toxicity is common after significant smoke inhalation. Two cases are presented that provide framework for the discussion of epidemiology, pathogenesis, presenting signs and symptoms, and treatment options of inhalational Cyanide poisoning. An evidence-based algorithm is proposed that utilizes point-of-care testing to help physicians identify patients who benefit most from antidotal therapy.
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Patterns of Cyanide Antidote use since regulatory approval of hydroxocobalamin in the United States
American journal of therapeutics, 2014Co-Authors: Matthew J. Streitz, Vikhyat S. Bebarta, Douglas J. Borys, David L. MorganAbstract:Sodium nitrite and sodium thiosulfate are common Cyanide Antidotes. Hydroxocobalamin was approved for use in the United States in 2006. Our objective was to determine the frequency of Antidote use as reported to the US poison centers from 2005 to 2009 and describe which Antidotes were used in critically ill Cyanide toxic patients. We performed a retrospective review over 5 years (2005-2009) from 61 US poison centers. We identified all Cyanide-exposed cases that received a Cyanide Antidote. Variables collected included demographics, gastric decontamination, Antidote used, predefined serious clinical effects (hypotension, cardiac arrest, respiratory arrest, and coma), and predefined serious therapies (cardiopulmonary resuscitation, vasopressors, atropine, anticonvulsant, antidysrhythmic, and intubation/ventilation). One trained abstractor abstracted each chart to a standardized electronic form. Another investigator audited 20% of the charts. Kappa values were calculated. One hundred sixty-five exposures were identified. Mean age was 42 years (range, 3-93 years). Seventy-one percent were male. Exposures were 27% ingestion and 53% inhalation. Thirty-two percent of the ingestions were suicide attempts. Twenty percent (32 of 157) of all cases died. Over all years reported, hydroxocobalamin was administered to 29% (45 of 157) of patients, sodium nitrite to 25%, and sodium thiosulfate to 46%. Hydroxocobalamin use increased from 24% to 54% from 2007 to 2009, respectively (P = 0.024). Sodium thiosulfate use decreased from 73% to 31% (P = 0.002) and sodium nitrite use decreased from 26% to 14% (P = 0.39). The proportion of cases with serious clinical effects that received hydroxocobalamin increased each year, and the proportion that received other Antidotes decreased. Hydroxocobalamin was also administered more often in cases that required serious therapies and increased each year. Hydroxocobalamin use for Cyanide toxicity increased each year as reported to the US poison centers. Reported use of sodium thiosulfate and sodium nitrite decreased over the same years. In addition, hydroxocobalamin was used more often each year in critically ill Cyanide toxic patients than were sodium nitrite or sodium thiosulfate.
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intravenous cobinamide a novel Cyanide Antidote versus hydroxocobalamin in the treatment of acute Cyanide toxicity and apnea in a swine sus scrofa model
2013Co-Authors: Vikhyat S. Bebarta, Gerry Boss, Susan M Boudreau, Maria G Castaneda, David A TanenAbstract:Abstract : Compare time to breathing between 3 groups of swine (11/group) with Cyanide(CN) induced apnea; treated with intravenous(IV) hydroxocobalamin(HOC), IV cobinamide(COB), or IV normal saline(NS) control. Method:33 swine(45-55kg) intubated, anesthetized & instrumented (MAP and cardiac output). Isoflurane low to allow breathing; room air(0.21FiO2). CN infused until apnea. Given HOC(65mg/kg), COB(12.5mg/kg) or NS(20ml) & monitored 60min. Results:Weight, time to apnea, & CN dose similar (p0.10). At treatment, blood CN, lactate levels, & decrease in MAP similar (p0.10). 2/11 swine in NS group survived(p0.001), compared to 10/11 in HOC & 10/11 in COB group. Time to breaths post treatment similar(HOC 1:48min, COB 1:49min). Blood CN levels undetectable post HOC or COB infusion. No statistically significant differences were detected between groups for CO, MAP, RR, or min vent at 60min. Lactate, pH, and PCO2 at 60 min were similar (p0.10). Conclusion: IV COB led to similar time to breathing as IV HOC for CN induced apnea and severe toxicity. Cobinamide was 5 times as potent as hydroxocobalamin.
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Insufficient stocking of Cyanide Antidotes in US hospitals that provide emergency care.
Journal of pharmacology & pharmacotherapeutics, 2013Co-Authors: Lucas Gasco, Margaret Bonnie Rosbolt, Vikhyat S. BebartaAbstract:Objective: To identify the influence of catchment area, trauma center designation, hospital size, subspecialist employment, funding source, and other hospital characteristics on Cyanide Antidote stocking choice in US hospitals that provides emergency care. Materials and Methods: A web-based survey was sent out to pharmacy managers through two listservs; the American Society of Health-Systems Pharmacists and the American College of Clinical Pharmacy. A medical marketing company also broadcasted the survey to 2,659 individuals. We collected data on hospital characteristics (size, state, serving population, etc.,) to determine what influenced the hospital's stocking choice. Results: The survey response rate was approximately 10% ( n = 286). Thirty-eight hospitals (16%) stocked at least 4 Antidote kits. Safety profile, recommendations from a poison control center, and ease of use had the strongest influence on stocking decisions. Conclusions: Survey of 286 US hospital pharmacy managers, 38/234 (16%) hospitals had sufficient stocking of Cyanide Antidotes. Antidote preference was based on safety, ease of use, and recommendations by the local poison center, over cost.
Frédéric J. Baud - One of the best experts on this subject based on the ideXlab platform.
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Which Cyanide Antidote
Critical reviews in toxicology, 2009Co-Authors: Alan H. Hall, Jane A. Saiers, Frédéric J. BaudAbstract:Cyanide has several Antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk-benefit profiles. The international medical community lacks consensus about the Antidote or Antidotes with the best risk-benefit ratio. Critical assessment of Cyanide Antidotes is needed to aid in therapeutic and administrative decisions that will improve care for victims of Cyanide poisoning (particularly poisoning from enclosed-space fire-smoke inhalation), and enhance readiness for Cyanide toxic terrorism and other mass-casualty incidents. This paper reviews preclinical and clinical data on available Cyanide Antidotes and considers the profiles of these Antidotes relative to properties of a hypothetical ideal Cyanide Antidote. Each of the Antidotes shows evidence of efficacy in animal studies and clinical experience. The data available to date do not suggest obvious differences in efficacy among Antidotes, with the exception of a slower onset of action of sodium thiosulfate (administered alone) than of the other Antidotes. The potential for serious toxicity limits or prevents the use of the Cyanide Antidote Kit, dicobalt edetate, and 4-dimethylaminophenol in prehospital empiric treatment of suspected Cyanide poisoning. Hydroxocobalamin differs from these Antidotes in that it has not been associated with clinically significant toxicity in antidotal doses. Hydroxocobalamin is an Antidote that seems to have many of the characteristics of the ideal Cyanide Antidote: 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.
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Which Cyanide Antidote
Critical Reviews in Toxicology, 2009Co-Authors: Alan H. Hall, Jane A. Saiers, Frédéric J. BaudAbstract:Cyanide has several Antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk–benefit profiles. The international medical community lacks consensus about the Antidote or Antidotes with the best risk–benefit ratio. Critical assessment of Cyanide Antidotes is needed to aid in therapeutic and administrative decisions that will improve care for victims of Cyanide poisoning (particularly poisoning from enclosed-space fire-smoke inhalation), and enhance readiness for Cyanide toxic terrorism and other mass-casualty incidents. This paper reviews preclinical and clinical data on available Cyanide Antidotes and considers the profiles of these Antidotes relative to properties of a hypothetical ideal Cyanide Antidote. Each of the Antidotes shows evidence of efficacy in animal studies and clinical experience. The data available to date do not suggest obvious differences in efficacy among Antidotes, with the exception of a slower onset of action of sodium thiosulfate (administered alo...
David E. Thompson - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification
ACS omega, 2020Co-Authors: Indika K. Warnakula, Afshin Ebrahimpour, Márton Kiss, Ramesha D. Gaspe Ralalage, Chathuranga C. Hewa-rahinduwage, Christian T. Rios, Kyler D. Kelley, Ashley C. Whiteman, David E. ThompsonAbstract:This study reports the long-term storage stability of a formulation of the Cyanide (CN) Antidote dimethyl trisulfide (DMTS). The F3-formulated DMTS was stored in glass ampules at 4, 22, and 37 °C. ...
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from the cover in vitro and in vivo blood brain barrier penetration studies with the novel Cyanide Antidote candidate dimethyl trisulfide in mice
Toxicological Sciences, 2017Co-Authors: Loránd Kiss, James Ross, Denise Brown, Brooke Mendenhall, Valerie Coronado, Alexandra Bocsik, Fruzsina R Walter, Sarah R Crews, Jana Lowry, David E. ThompsonAbstract:Recent in vitro and in vivo studies highlight the strong potential of dimethyl trisulfide (DMTS) as an Antidote for Cyanide (CN) intoxication. Due to its high oxygen demand, the brain is one of the main target organs of CN. The blood-brain barrier (BBB) regulates the uptake of molecules into the brain. In the literature, there is no data about the ability of DMTS to penetrate the BBB. Therefore, our aim was to test the in vitro BBB penetration of DMTS and its in vivo pharmacokinetics in blood and brain. The in vitro BBB penetration of DMTS was measured by using a parallel artificial membrane permeability assay (BBB-PAMPA), and a triple BBB co-culture model. The pharmacokinetics was investigated in a mouse model by following the DMTS concentration in blood and brain at regular time intervals following intramuscular administration. DMTS showed high penetrability in both in vitro systems (apparent permeability coefficients: BBB-PAMPA 11.8 × 10-6 cm/s; cell culture 158 × 10-6 cm/s) without causing cell toxicity and leaving the cellular barrier intact. DMTS immediately absorbed into the blood after the intramuscular injection (5 min), and rapidly penetrated the brain of mice (10 min). In addition to the observed passive diffusion in the in vitro studies, the contribution of facilitated and/or active transport to the measured high permeability of DMTS in the pharmacokinetic studies can be hypothesized. Earlier investigations demonstrating the antidotal efficacy of DMTS against CN together with the present results highlight the promise of DMTS as a brain-protective CN Antidote.
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Intravascular Residence Time Determination for the Cyanide Antidote Dimethyl Trisulfide in Rat by Using Liquid-Liquid Extraction Coupled with High Performance Liquid Chromatography.
Journal of analytical methods in chemistry, 2016Co-Authors: Deepthika De Silva, David E. Thompson, Steven B. Lee, Anna Duke, Siva Krishna Angalakurthi, Ching-en Chou, Afshin Ebrahimpour, Ilona PetrikovicsAbstract:These studies represent the first report on the intravascular residence time determinations for the Cyanide Antidote dimethyl trisulfide (DMTS) in a rat model by using high performance liquid chromatography coupled with ultraviolet absorption spectroscopy (HPLC-UV). The newly developed sample preparation included liquid-liquid extraction by cyclohexanone. The calibration curves showed a linear response for DMTS concentrations between 0.010 and 0.30 mg/mL with = 0.9994. The limit of detection for DMTS via this extraction method was 0.010 mg/mL, and the limit of quantitation was 0.034 mg/mL. Thus this calibration curve provided a tool for determining DMTS in the range between 0.04 and 0.30 mg/mL. Rats were given 20 mg/kg DMTS dose (in 15% Polysorbate 80) intravenously, and blood samples were taken 15, 60, 90, 120, and 240 min after DMTS injections. The data points were plotted as DMTS concentration in RBCs versus time, and the intravascular residence time was determined graphically. The results indicated a half-life of 36 min in a rat model, suggesting that the circulation time is long enough to provide a reasonable time interval for Cyanide antagonism.
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Dimethyl trisulfide A novel Cyanide countermeasure
Toxicology and industrial health, 2016Co-Authors: Gary A. Rockwood, David E. Thompson, Ilona PetrikovicsAbstract:In the present studies, the in vitro and in vivo efficacies of a novel Cyanide countermeasure, dimethyl trisulfide (DMTS), were evaluated. DMTS is a sulfur-based molecule found in garlic, onion, broccoli, and similar plants. DMTS was studied for effectiveness as a sulfur donor-type Cyanide countermeasure. The sulfur donor reactivity of DMTS was determined by measuring the rate of the formation of the Cyanide metabolite thiocyanate. In experiments carried out in vitro in the presence of the sulfurtransferase rhodanese (Rh) and at the experimental pH of 7.4, DMTS was observed to convert Cyanide to thiocyanate with greater than 40 times higher efficacy than does thiosulfate, the sulfur donor component of the US Food and Drug Administration-approved Cyanide countermeasure Nithiodote® In the absence of Rh, DMTS was observed to be almost 80 times more efficient than sodium thiosulfate in vitro The fact that DMTS converts Cyanide to thiocyanate more efficiently than does thiosulfate both with and without Rh makes it a promising sulfur donor-type Cyanide Antidote (scavenger) with reduced enzyme dependence in vitro The therapeutic Cyanide antidotal efficacies for DMTS versus sodium thiosulfate were measured following intramuscular administration in a mouse model and expressed as antidotal potency ratios (APR = LD50 of Cyanide with Antidote/LD50 of Cyanide without Antidote). A dose of 100 mg/kg sodium thiosulfate given intramuscularly showed only slight therapeutic protection (APR = 1.1), whereas the antidotal protection from DMTS given intramuscularly at the same dose was substantial (APR = 3.3). Based on these data, DMTS will be studied further as a promising next-generation countermeasure for Cyanide intoxication.
