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

Abstract

Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSDs), such as thiosulfate, which increase the conversion of CN to thiocyanate by the enzyme rhodanese. To develop pretreatments that might be useful against CN, SSDs with greater lipophilicity than thiosulfate were synthesized and assessed. The ability of SSDs to protect mice against 2LD50 of sodium cyanide (NaCN) administered either 15 or 60 min following administration of an SSD was assessed. To study the mechanism of action of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3‐mercaptopyruvate sulfurtransferase (MST) activity under increasing 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‐aminopropyl)]‐2‐aminoethyl disulfide trihydrochloride), ICD1584 (diethyl tetrasulfide), ICD1585 (diallyl tetrasulfide), ICD1587 (diisopropyl tetrasulfide); ICD1738 (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) disulfide). These tests demonstrated that altering the chemical substituent of the longer chain sulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSDs at selected doses provided 100% protection against 2LD50 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 several disulfides but none was found with ICD1584, a tetrasulfide. Separate studies suggest that the chemical reaction of potassium cyanide (KCN) and cystine 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. Although 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 © 1999 John Wiley & Sons, Ltd.

The anti-inflammatory effect of dimethyl trisulfide in experimental acute pancreatitis

“…These contradictory results suggest to carefully interpret the data and nd other solutions to detect nociception in AP. In accord with our ndings, the behaviour of mice did not change in AP groups compared to the control in open eld test 38 . Interestingly, the highest dose of DMTS reduced the total moving distance during AP.…”

“…could detect allodynia and hyperalgesia with the von Frey test in AP 38 . These contradictory results suggest to carefully interpret the data and nd other solutions to detect nociception in AP.…”

The anti-inflammatory effect of dimethyl trisulfide in experimental acute pancreatitis

“…Interestingly, the highest dose of DMTS reduced the total moving distance during AP. Similar results were observed with H 2 S donor molecules, like NaHS or organic disulfides, they reduced the movement of mice 44 , 45 . The exact cause of this phenomenon is unknown, but cyanosis through converting haemoglobin to methaemoglobin 20 in response to DMTS treatment could contribute to this effect 19 .…”

Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure

“…Changes in heart rate could be detected within 15 min of exposure and remained steady for a period of almost 2 h. After 4 h, all embryos in the 200 and 400 μM treatment groups were dead. These data demonstrate changes in cardiac physiology that are consistent with mammalian responses to cyanide (1, 6, 7).…”