Therapeutic response to single intravenous bolus administration of formate dehydrogenase in methanol-intoxicated rats.

Methanol remains to be a major public and environmental health hazard. Formic acid is the toxic metabolite responsible for the metabolic acidosis observed in methanol poisoning in humans, in non-human primates and in folate-depleted rodents. Cytochrome oxidase inhibition by formate leads to lactic acid accumulation, which contributes significantly to metabolic acidosis. Toxic effects in human beings are characterized by formic acidemia, metabolic acidosis, ocular toxicity, nervous system depression, blindness, coma and death. Elimination of formate is one of the principles of management in methanol poisoning. Hemodialysis facility is not readily available in all the places, in developing countries like India. Formate dehydrogenase (EC 1.2.1.2) acts directly over formate and converts formate into CO(2) in the presence of NAD. Effect of single intravenous bolus infusion of formate dehydrogenase, obtained from Candida boidinii; in methanol-intoxicated folate deficient rat model was evaluated. Folate depletion induced by methotrexate (MTX) treatment. Carbicarb (Carb) (equimolar solution of sodium carbonate and sodium bicarbonate) was used to treat metabolic acidosis. Experimental design consists of seven groups, namely Saline control, methanol control, MTX control, Enzyme control, MTX-methanol control, MTX-methanol-Carb and MTX-methanol-Carb-Enz group. Male wistar rats treated with MTX (0.3mg/kg) for a week, were injected (i.p.) with methanol (4 gm/kg), 12h latter, Carbicarb solution was infused, following this enzyme was infused (i.v.) in bolus. Blood samples were collected every 15 min for an hour from the cannulated left jugular vein and blood methanol, formate were estimated, respectively, with HPLC and fluorimetric assay. Blood pH, blood gases pO(2), pCO(2) and bicarbonate were monitored with blood gas analyzer in order to evaluate acid base status of the animal. Results obtained show that there is significant elimination of formate within 15 min. It may be concluded that single bolus infusion of formate dehydrogenase facilitates fast removal of formate, a highly toxic metabolite in methanol poisoning.

Lower decompression sickness risk in rats by intravenous injection of foreign protein.

We have identified a novel means of reducing the risk of decompression sickness (DCS) in rats. A substantial reduction in DCS, from 55% in untreated animals to 24% in animals injected intravenously with a hydrogenase of bacterial origin, was documented for animals breathing a mixture of oxygen and hydrogen. However, this reduction was clearly not a function of metabolic elimination of H2; injections of proteins lacking hydrogenase activity also elicited a lower DCS incidence, and animals breathing hyperbaric helium had the same protective advantage as animals breathing H2. The reduction in DCS risk was shown to be caused by intravenous injection of a foreign protein. The magnitude of the effect varied: two foreign proteins tested did not induce a statistically significant response. We speculated that the foreign protein elicited an immune reaction pre-dive, which diminished the subsequent response of the immune system in DCS. Identifying the underlying mechanism may be important to understanding the pathophysiology of this malady, and may ultimately lead to a therapy applied pre-decompression for reducing DCS risk in human diving.