sodium-nitrite and cobinamide

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-β-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-β-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine β-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.

Topics: Aminooxyacetic Acid; Animals; Benserazide; Brain; Chromosomes, Human, Pair 21; Cobamides; Cystathionine beta-Synthase; Disease Models, Animal; Disease Progression; Disulfiram; Down Syndrome; Enzyme Inhibitors; Gene Dosage; Humans; Hydrogen Sulfide; Infant, Newborn; Intellectual Disability; Mice; Mitochondria; Rats; Sodium Nitrite; Species Specificity; Thiosulfates

Currently available cyanide antidotes must be given by intravenous injection over 5-10 min, making them ill-suited for treating many people in the field, as could occur in a major fire, an industrial accident, or a terrorist attack. These scenarios call for a drug that can be given quickly, e.g., by intramuscular injection. We have shown that aquohydroxocobinamide is a potent cyanide antidote in animal models of cyanide poisoning, but it is unstable in solution and poorly absorbed after intramuscular injection. Here we show that adding sodium nitrite to cobinamide yields a stable derivative (referred to as nitrocobinamide) that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection. We also show that the efficacy of nitrocobinamide is markedly enhanced by coadministering sodium thiosulfate (reducing the total injected volume), and we calculate that ∼1.4 mL each of nitrocobinamide and sodium thiosulfate should rescue a human from a lethal cyanide exposure.

Topics: Animals; Antidotes; Chlorocebus aethiops; Cobamides; COS Cells; Cyanides; Dose-Response Relationship, Drug; Injections, Intramuscular; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Rabbits; Sodium Nitrite; Structure-Activity Relationship; Thiosulfates; Time Factors