In vitro and in vivo comparison of sulfur donors as antidotes to acute cyanide intoxication

Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur d onors (SSDs), such as thiosulfate, which increase the conversion of CN to t hiocyanate by the enzyme rhodanese, To develop pretreatments that might be useful against CN, SSDs with greater lipophilicity than thiosulfate were sy nthesized and assessed. The ability of SSDs to protect mice against 2LD(50) of sodium cyanide (NaCN) administered either 15 or 60 min following admini stration of an SSD was assessed. To study the mechanism of action of the SS D, the candidate compounds were examined in vitro for their effect on rhoda nese and 3-mercaptopyruvate sulfurtransferase (MST) activity under increasi ng SSD concentrations. Tests were conducted on nine candidate SSDs: ICD1021 (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminopropyl)]-2-aminoethyl disulfide dihydrochloride), ICD1022, (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminoprop yl)]-2-aminoethyl disulfide trihydrochloride), ICD1584 (diethyl tetrasulfid e), ICD1585 (diallyl tetrasulfide), ICD1587 (diisopropyl tetrasulfide); ICD 1738 (N-(3-aminopropyl)-2-aminoethyl 2-oxopropyl disulfide dihydrochloride) , ICD1816 (3,3' -tetrathiobis-N-acctyl-L-alanine), ICD2214 (2-aminoethyl 4- methoxyphenyl disulfide hydrochloride) and ICD2467 (bis(4-methoxyphenyl) di sulfide), These tests demonstrated that altering the chemical substituent o f the longer chain sulfide modified the ability of the candidate SSD to pro tect against CN toxicity. At least two of the SSDs at selected doses provid ed 100% protection against 2LD(50) of NaCN, normally an LD99. All compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Positive hypoactivity relationships were found with sev eral disulfides but none was found with ICD1584, a tetrasulfide, Separate s tudies suggest that the chemical reaction of potassium cyanide (KCN) and cy stine forms the toxic metabolite 2-iminothiazolidine-4-carboxylic acid. An alternative detoxification pathway, one not primarily involving the sulfur transferases. may be important in pretreatment for CN intoxication. Althoug h studies to elucidate the precise mechanisms are needed. it is clear that these newly synthesized compounds provide a new rationale for anti-CN drugs , with fewer side-effects than the methemoglobin formers, Copyright (C) 199 9 John Wiley & Sons, Ltd.