p-AMINOBENZOIC ACID 499 



mide against infections of Streptococcus hemolyticus in mice was also 

 antagonized by p-aminobenzoic acid. These findings were rapidly con- 

 firmed with this and other organisms for a wide variety of sulfonamides, 

 sulfones and sulfoxides as indicated in Table 6. This in vivo testing 

 allowed extensions of the interrelationship of p-aminobenzoic acid and 

 the sulfonamide drugs to pathogenic protozoa such as Toxoplasma, Plas- 

 modium lophurae and Plasmodium gallinaceum, and to such viruses as < 

 psittacosis and the virus of lymphogranuloma venereum. 



Because p-aminobenzoic acid is rapidly converted into inactive forms, 

 e.g., conjugates in animals, and is rapidly excreted in comparison to 

 sulfonamides and related compounds, the amount of the factor necessary 

 to prevent the therapeutic action of the sulfonamide drugs is often high 

 in comparison with amounts required for in vitro testing. 167, 1T4 However, 

 if the concentration of p-aminobenzoic acid at the site of the infection 

 is compared with the corresponding concentration of sulfonamide, results 

 comparable with those for in vitro testing are obtained. 174 Failure to 

 make such comparisons has resulted in conflicting reports in some cases. 



The specificity of particular sulfonamide drugs for certain organisms 

 appears to be greater in vivo than in vitro. Of a group of 33 sulfanilamide 

 derivatives, including the N 1 -heterocyclic sulfanilamides, none was found 

 to have significantly greater therapeutic activity than sulfanilamide 

 against Streptococcus hemolyticus C-203 infections in mice. However, the 

 ^-heterocyclic sulfanilamides were more effective than sulfanilamide 

 against infections of Diplococcus pneumoniae. 175 Of a group of N 1 -acyl- 

 sulfanilamides, a few were found to be effective against Streptococcus 

 hemolyticus, Diplococcus pneumoniae and Escherichia coli infections in 

 mice ; however, some of the compounds were effective only against Strep- 

 tococcus hemolyticus and Escherichia coli, while another was effective 

 only against Escherichia coli and not against the other two. 176 Conse- 

 quently, there appears to be a higher degree of specificity of chemothera- 

 peutic activity in vivo than in vitro. 



Sulfonamides, sulfones and related analogues of p-aminobenzoic acid 

 are reported to prevent the effects of endotoxins of microorganisms. 177 

 Although some attempts to verify the early work failed, 178, 179 the effects 

 of sulfonamides and related compounds on the action of endotoxins of 

 certain bacteria have been verified. 1S0 " 183 Sulfanilamide allows a signifi- 

 cant increase in the number of mice surviving injection of the endotoxins 

 of Salmonella typhimurium without affecting the process of immuniza- 

 tion. 182 - 183 The therapeutic effect of sulfanilamide was prevented by ad- 

 ministration of p-aminobenzoic acid. 183 The effect of 4-aminophenyl 

 4-nitrophenyl sulfoxide in protecting 40 to 80 per cent of the mice from 

 a lethal dose of typhoid endotoxin is antagonized by injected p-amino- 



