Acute Toxicity and Cardio-Respiratory Effects of 2-Deoxy-D-Glucose: A Promising Radio Sensitiser

Objective To evaluate the acute toxicity of 2-deoxy-D-glucose （2DG） by oral （p.o.） and intravenous （i.v.） routes, and also the cardio-respiratory effects following high doses of 2DG in animal models. Methods The LD50 of 2DG （in water） was determined in rats and mice by p.o. route and in mice by i.v. route. The effect of 2-DG （250 mg/kg, 500 mg/kg, and 1000 mg/kg, i.v.） was studied on various cardio-respiratory parameters viz., mean arterial blood pressure, heart rate and respiratory rate in anaesthetised rats. The effect of 2DG （500 mg/kg, 1000 mg/kg, and 2000 mg/kg, p.o.） was also studied on various respiratory parameters viz., respiratory rate and tidal volume in conscious rats and mice using a computer program. Results The p.o. LD50 of 2DG was found to be 〉8000 mg/kg in mice and rats, and at this dose no death was observed. The LD50 in mice by i.v. route was found to be 8000 mg/kg. At this dose 2 out of 4 mice died and the death occurred within 6 h. A significant increase in the body weight was observed after p.o. administration of 2DG in rats at 500 mg/kg, 1000 mg/kg, and 2000 mg/kg doses. There was no significant change in the body weight at 4000 mg/kg and 8000 mg/kg by the p.o. route in rats and up to 8000 mg/kg by p.o. as well as i.v. routes in mice. Intravenous administration of 2DG （250 mg/kg, 500 mg/kg, and 1000 mg/kg） in anaesthetised rats showed a time-dependent decrease in the mean arterial blood pressure. There was no change in the heart rate in any of the treatment groups. The tidal volume was not changed significantly by p.o administration in conscious rats, but a significant decrease in the respiratory frequency at 500 mg/kg and 1000 mg/kg doses was observed. In the mice also there was no change in the tidal volume after p.o, administration, but the respiratory frequency decreased significantly at 2000 mg/kg dose. Conclusion 2DG is a safe compound but can cause a fall in the blood pressure and a decrease in respiratory frequency at high doses.

Effect of Pre-treatment of α-Ketoglutarate on Cyanide-induced Toxicity and Alterations in Various Physiological Variables in Rodents

Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN） given orally （po）, intraperitoneally （ip）, subcutaneously （sc） or intravenously （iv） was determined in male mice, in the presence or absence α-KG given po, ip or iv. α-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index （PI） was calculated as the ratio of LD50 of KCN in the presence of α-KG （protected animals） and LD50 of KCN in the absence of α-KG （unprotected animals）. In a separate experiment, several physiological variables viz. mean arterial pressure （MAP）, heart rate （HR）, respiratory rate （RR）, neuromuscular transmission （NMT） and rectal temperature （RT） were measured in anesthetized female rats pre-treated （-10 rain） with po （2.0 g/kg） or iv （0.125 g/kg） α-KG and then administered sub-lethal （0.75 LD50） or lethal （2.0, 4.0 or 8.0 LD50） doses of KCN （po）. Results PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with α-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg α-KG given ip （-10 min）, respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg α-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg α-KG given po at -10, -20 or -40 rain, respectively. No appreciable protection was observed when lower doses of α-KG （ip or po） challenged KCN given by sc route. Pre-treatment of iv or po administration of α-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of α-KG （po; 2.0 g/kg）. However, no protection was observed on NMT. Protective efficacy of α-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN （po） was resolved by iv administration of α-KG Conclusions Cyanide antagonism by α-KG is best exhibited when both α-KG and KCN are given by po route. The protective effect of α-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of α-KG as an alternative cyanide antidote.

Cardiovascular Effects of an Organophosphate Toxin Isolated from Ptychodiscus brevis

:The dose-dependent hypotensive and bradycardic effects induced by an ichthyotoxic organophosphate compound isolated from the marine dinoflagellate Ptycholiscus brevis were studied. These effects were not antagonized by atropine, but potentiated by α-adrenoceptor blocker and hexamethonium. The toxin aboished the vasopressor effect elicited by phenyle phrine, indicating an α-adrenergic blocking activity. The cardiovascular depressor responses were antagonized by tetraethylammonium while blockade of cholinergic and histaminergic re ceptors or inhibition of prostaglandin synthesis failed to modify these effects. The results indi cate that the cardiovascular depressor effects of the toxin are probably mediated through α-a drenergic and ganglionic blockade accompanied by modulation of potassium channel activity