Cyanide, a very toxic mitochondrial poison, has a wide spread usage in various industrial activities. It is present in many synthetic materials and can be released in gaseous form during a house fire. Since CN can be easily weaponized, it is considered as a serious threat for the civilian population. The treatment of acute CN intoxication relies on (1) specific antidotes, to decrease the concentration of CN in the blood and tissues, and (2) symptomatic treatments, essential at the early stage of exposure, consisting in an aggressive ventilatory and circulatory support, akin to the treatment of any conditions associated with cardio-respiratory depression. We have recently found that the phenothiazinium chromophore methylene blue (MB), which can counteract the toxicity of various mitochondrial poisons (hydrogen sulfide and Azure B), can also oppose CN- induced acute circulatory failure. The mechanisms of action of MB as well as the limits of its efficacy, following CN intoxication, remain to be determined. The objective of our proposal is first to validate our preliminary observations and to determine the interest of the use of MB during and following CN intoxication induced coma and cardiac failure in the rat. We will determine if MB can improve the immediate and long-term outcome of CN intoxication when used alone and more importantly as an adjuvant of antidotes already approved for the treatment of CN intoxication. Second, we will explore the potential mechanisms of action of MB, using isolated contracting cardiomyocytes intoxicated with CN. These studies will be performed in collaboration with the group of Dr. Joseph Cheung, Temple University. Since MB has been used for decades for treating methemoglobinemia (1-2 mg/kg iv) in humans, our goal is to reposition methylene blue, a drug already on the WHO's list of essential medications, as a treatment of CN intoxication.
Cyanide (CN) is certainly the most emblematic and feared of all cellular/mitochondrial poisons, since it can diffuse into the blood via almost any route (transcutaneous, ingestion or inhalation), while its acute exposure can be fatal within seconds and can produce long-term neurological deficits in the survivors. CN is still an industrial hazard and a source of intoxication for subjects exposed to smoke inhalation during house fires for instance, but it also remains a potential threat for the civilian population as CN can be easily weaponized. We have recently found that intravenous administration of methylene blue (MB), an old compound which is on the WHO's list of essential medications, can restore, within seconds, the cardiac function depressed by CN; these findings have prompted us to develop this proposal, which will establish the efficacy and mode of action of MB alone or as an adjuvant to other antidotes.
| Cheung, Joseph Y; Wang, JuFang; Zhang, Xue-Qian et al. (2018) Methylene blue counteracts cyanide cardiotoxicity: cellular mechanisms. J Appl Physiol (1985) 124:1164-1176 |
| Haouzi, Philippe; Gueguinou, Maxime; Sonobe, Takashi et al. (2018) Revisiting the physiological effects of methylene blue as a treatment of cyanide intoxication. Clin Toxicol (Phila) 56:828-840 |
| Judenherc-HaouzI, Annick; Sonobe, Takashi; Bebarta, Vikhyat S et al. (2018) On the Efficacy of Cardio-Pulmonary Resuscitation and Epinephrine Following Cyanide- and H2S Intoxication-Induced Cardiac Asystole. Cardiovasc Toxicol 18:436-449 |
| Cheung, Joseph Y; Wang, JuFang; Zhang, Xue-Qian et al. (2018) Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction. Cardiovasc Toxicol 18:407-419 |
| Haouzi, Philippe; Tubbs, Nicole; Rannals, Matthew D et al. (2017) Circulatory Failure During Noninhaled Forms of Cyanide Intoxication. Shock 47:352-362 |
