384 4. ALLOXAN 



injection is too slow, insignificant amounts of alloxan may reach the islet 

 tissue. For this reason, the site of the injection may also be important. 

 Also related to this factor is the fact that divided doses given at intervals 

 are often less effective than single doses (Meade and Klitgaard, 1960). 

 A single subcutaneous dose of 200 mg/kg to rats produces diabetes; if this 

 is divided into four 50 mg/kg doses given every 2 hr, the effect is less; if 

 divided into eight 25 mg/kg doses given every hour or every 2 hr, it is 

 ineffective. 



Some species such as chickens, ducks, carnivorous birds, and toads 

 are relatively or completely resistant to alloxan with respect to the pro- 

 duction of chronic diabetes. Among mammals there is some variation in 

 susceptibility: guinea pigs (Maske and Weinges, 1957) and monkeys (Ram- 

 fjord, 1952) can be made diabetic only with difficulty and relatively high 

 toxic doses. Perhaps /5-cell destruction can be produced in all mammals, 

 but in some the doses required are such that other tissues are damaged. 

 It is interesting that dogs can be made resistant to alloxan by administering 

 small repeated doses over several days, at which time they can receive 

 150 mg/kg intravenously, which is 3 times the diabetic dose in normal 

 animals (Loubatieres, 1948). 



The diabetogenic dose was defined by Goldner (1945) as that which will 

 produce in 80% of the animals a sustained diabetic hyperglycemia without 

 observable effects on other tissues. Although other workers have often 

 not specified comparable doses, the intravenous diabetic doses in various 

 species may be given as: rat 45-50 mg/kg (Briickmann and Wertheimer, 

 1947; Kipnis and Cori, 1957), dog 50-75 mg/kg (Goldner and Gomori, 

 1943), hamster 60 mg/kg (Harris et al, 1946), sheep 75 mg/kg (McCandless 

 et al, 1948), mouse 100 mg/kg (Tocus and Cavallo, 1961), cat 150 mg/kg 

 (Goldner, 1945), rabbit 150 mg/kg (Lisewski and Mohnike, 1959 a), pigeon 

 125-200 mg/kg (Goldner, 1945), and monkey 150-300 mg/kg (Goldner, 

 1945; Ramfjord, 1952). These doses are valid only under the experimental 

 conditions used. Subcutaneous diabetogenic doses are usually 150-250 

 mg/kg for rodents and intraperitoneal doses are 200-300 mg/kg. The lethal 

 dose bears no constant relationship to the diabetogenic dose, but is gen- 

 erally around twice that selectively eliminating /?-cells. 



Relation of Structure to Diabetogenic Activity 



There are very few derivatives of alloxan or related compounds which 

 are diabetogenic. Methyl-, ethyl-, and propylalloxan are diabetogenic, but 

 it becomes progressively harder to induce diabetes because the toxicity 

 increases with the length of the side chain (Briickmann and Wertheimer, 

 1947). Thus butyl-, phenyl-, and benzylalloxan cannot be given in doses 

 sufficient to produce diabetes, but possibly they possess the ability to de- 

 stroy /?-cells. Substitution at both N atoms, however, results in a loss of 



