Supramolecular ferric porphyrins and a cyclodextrin dimer as antidotes for cyanide poisoning

Abstract

<jats:sec><jats:title>Objectives:</jats:title><jats:p> This study aimed to evaluate the antidotal effect of a newly developed supramolecular complex, ferric porphyrins and a cyclodextrin dimer (Fe<jats:sup>III</jats:sup>PIm3CD), that possess a higher binding constant and quicker binding rate to cyanide ions than those of hydroxocobalamin (OHCbl) in the presence of serum protein. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> First, in vitro cytochrome activity and cell viability were evaluated in murine fibroblast cells cultured with various doses of Fe<jats:sup>III</jats:sup>PIm3CD and potassium cyanide (KCN). Next, BALB/c mice were pretreated with intravenous OHCbl (0.23 mmol/kg), Fe<jats:sup>III</jats:sup>PIm3CD (0.23 mmol/kg), or saline and then received KCN (lethal dose 100% (LD<jats:sub>100</jats:sub>): 0.23 mmol/kg) through a stomach tube. Finally, as a resuscitation model, KCN-induced apnea was treated with a bolus injection of an equimolar dose of antidotes followed by a slow infusion of the same reagent. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Fe<jats:sup>III</jats:sup>PIm3CD showed dose-dependent antidotal effects in vitro. Pretreatment with Fe<jats:sup>III</jats:sup> PIm3CD prevented KCN-induced apnea significantly better than OHCbl. Resuscitation with Fe<jats:sup>III</jats:sup>PIm3CD resulted in an earlier resumption of respiration than that seen with OHCbl. However, 24-h survival was similar among the treatments (Fe<jats:sup>III</jats:sup>PIm3CD, nine of nine mice; OHCbl, eight of nine mice). </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Fe<jats:sup>III</jats:sup>PIm3CD exerted significant antidotal effects on cyanide toxicity in vitro and in vivo, with a potency equal in the mortality of cyanide-poisoned mice or superior in the respiratory status during an acute phase to those of OHCbl. </jats:p></jats:sec>

Characterization of a Mouse Model of Oral Potassium Cyanide Intoxication

“…12 A number of compounds are being investigated for efficacy in treatment of CN intoxication. [13][14][15][16][17] However, little information is available on the effects of CN in young animals. Reports have indicated age differences in rhodanese activity, a key enzyme in degradation of CN.…”

Artificial Oxygen Carrier to Regulate Hypoxic Signal Transduction

“…In addition, O2 is important not only as the substrate to generate aerobic energy synthesis, but also to regulate the microenvironment in somatic and tumor cells as a regulator of hypoxic signal transduction through the HIF-1α system. Thus, O2 supply and control by AOC may shed light on the ischemia/reperfusion pathology and control of malignancies as one of the potent biological diatomic molecules, such as NO, carbon monoxide (33), or cyanide (34), all involved in the regulation of energy generation and metabolism in the intracellular microenvironment. Akira T. Kawaguchi (5) and bronchus (6), which differed at 2 days, but no longer at 4 days after surgery.…”

Artificial Oxygen Carrier as Therapeutics Rather Than Blood Substitute for Transfusion

“…These results led us to reconsider the long‐standing hypothetical mechanism “aerobic energy synthesis.” Potential theories include anti‐inflammatory action through “suppressed HIF‐1α‐mediated signal transduction” or “endogenous carbon monoxide (CO) production by induced heme oxygenase” . Thus, not only O 2 , but also nitric oxide (NO), CO , cyanide , and hydrogen molecule (H 2 ) have been reported to regulate inner respiration or cellular energy synthesis as di‐atomic molecules, which have potent influence on the microenvironment. Actually, it has been suggested that surplus O 2 beyond metabolic needs does more harm than good to tissue perfusion and the microenvironment .…”