Mass Spectrometric Analysis of Purine Intermediary Metabolism Indicates Cyanide Induces Purine Catabolism in Rabbits.

Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide-a classical histotoxic hypoxia agent-we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development.

ANTIHYPOXIC ACTIVITY OF 2,6-DIMETHYLPYRIDINE-N-OXIDE.

OBJECTIVE: The aim: To study the antihypoxic activity of 2,6-dimethylpyridine-N-oxide in mice using the various experimental models of acute hypoxia under orally or intraperitoneally administration. PATIENTS AND METHODS: Materials and methods: The studies were performed on male CD-1 (SPF) mice. The antihypoxic activity of 2,6-dimethylpyridine-N-oxide was studied in three experimental models of acute hypoxia - hypercapnic hypoxia or hypoxia in a closed space, hemic hypoxia and histotoxic hypoxia at orally administration at doses 0.07; 7.1 and 71 mg/kg (respectively 1/20000, 1/200 and 1/20 of LD50) and at intraperitoneally administration at doses 7.1 and 71 mg/kg in comparison with reference drug Armadin. RESULTS: Results: It is established, that 2,6-dimethylpyridine-N-oxide shows a antihypoxic activity in the all experimental models of acute hypoxia (hypoxia in a closed space, hemic hypoxia and histotoxic hypoxia). Its antihypoxic activity in acute hemic hypoxia and in acute hypoxia in a closed space was significantly higher than of reference drug Armadin, but during acute histotoxic hypoxia did not differ from Armadin. Also at intraperitoneal administration of 2,6-dimethylpyridine-N-oxide demonstrates less pronounced antihypoxic activity than at oral administration in all experimental models of acute hypoxia, but the coefficient efficiency is higher than in the reference drug Armadin. CONCLUSION: Conclusions: 2,6-dimethylpyridine-N-oxide may be recommended for further detailed experimental studies as a perspective antihypoxant.