ANTIBIOTICS AS CHEMOTHERAPEUTIC AGENTS 271 



cillin therapy. Among the gonococci, no naturally resistant strains have 

 been encountered (544). 



Toxicity. As to the toxicity of penicillin, it was found (5) that mice 

 were little affected by the intravenous injection of lO mg. of penicillin} 

 they became ill from the use of 20 mg. but recovered shortly. One hun- 

 dred milligrams of crude penicillin given intravenously to man caused 

 a shivering attack with a rise of temperature in about an hour. The lat- 

 ter was due to the presence of a pyrogenic substance in the preparation. 

 Certain isolated fractions of penicillin had no such pyrogenic effect. 

 Penicillin was toxic to mice when given intravenously in single doses 

 of 0.5, i.o, 1.5, and 2.0 gm. per kilogram. More highly purified prepa- 

 rations were less toxic. Higher concentrations were required for lethal 

 effect from subcutaneous administration. The toxic dose is 64 times 

 greater than the effective dose (789). 



The relative toxicity of various salts of penicillin was found (997) to 

 be, in increasing order, Na, Li, NH4, Sr, Ca, Mg, and K. Based on mil- 

 ligrams of the cation at the LD50 dose of salts of penicillin, the relative 

 toxicity was Na, Sr, NH4, Ca, K, and Mg. It was concluded that the 

 toxicity of the salts of penicillin is primarily due to the cations used in 

 their preparation. 



Penicillin is rapidly absorbed and is excreted in the urine, usually 

 within one hour (755). It does not appear to undergo any change in 

 passing through the animal body. This fact was taken advantage of, in 

 the early days when there was a shortage of penicillin, by recovering it 

 from the urine. An average yield of 30 per cent of the amount adminis- 

 tered was obtained (872). 



The degree of the antibacterial action of penicillin is proportional 

 to its concentration in the serum, maximum effects against hemolytic 

 streptococci being produced by concentrations of 0.019-0.1 56 Oxford 

 units in i ml. of serum. The LD50 for an 18-gram mouse was 32 mg. 

 of the sodium salt (437). The cardinal symptoms of toxicity were 

 choking, gasping, and rapid respiration. However, it is relatively non- 

 toxic in doses used for therapeutic purposes. 



Penicillin was thus found to combine the two most desirable quali- 

 ties of a chemotherapeutic agent, namely, a low toxicity to tissue cells 



