82 P-AMINOBENZOIC ACID 



man that did not respond to salicylate therapy (10 g. per day). On more or 

 less empiric grounds the simultaneous oral administration of PABA was 

 instituted (initial dose of 4 g. followed by 2 g. every 2 hours). Prior to the 

 use of PABA the salicylate blood level varied between 12.5 and 15 mg. per 

 100 ml. With PABA there was a steady increase in salicylate level from 

 12.5 to 34.5 mg. per 100 ml. There was a dramatic and complete clinical 

 response as the content of salicylate reached 37.5 mg. per 100 ml. of blood. 

 Separate experiments with healthy men indicated that salicylates and 

 PABA appear to have a reciprocal effect in increasing their separate con- 

 centrations in the blood when they are administered together. Increased 

 blood levels of salicylate attained by the simultaneous administration of 

 PABA are accompanied by less salicylate appearing in the urine. 



The findings of Dry et al.^^ have been confirmed by Hoaglund,^- who 

 reported that a case of rheumatic fever with refractoriness to 10 g. of 

 aspirin daily, manifested by an uninterrupted fever for 5 weeks, showed 

 dramatic improvement after the salicylate therapy was supplemented with 

 PABA in a daily dose of 24 g. 



Smith^^ has compared the combination PABA and salicylate with sali- 

 cylate alone as a treatment for a variety of rheumatic diseases exclusive of 

 acute rheumatic fever. The pain relief with the PABA-salicylate combina- 

 tion was found to be superior to that with sodium salicylate alone in 64 

 patients with rheumatoid arthritis and fibrositis. In 60 patients with osteo- 

 arthritis or with cervical osteoarthritis with radicular involvement and 

 chronic painful shoulder, the superiority was less marked. The combination 

 therapy gives longer pain relief than sodium salicylate alone. Significant 

 toxic reactions to the combinations were not observed. Sodium salicylate 

 alone, however, produced some toxic effects in 69 (55.2 %) of the 125 

 patients. 



The mechanism of action of PABA as an adjunct to salicylates has been 

 investigated by Salassa et al.,^'^ who found that PABA produces the fol- 

 lowing effects. First, it alters the detoxication of salicylate by interrupting 

 or greatly depressing the conjugation of glycine with salicylate so that only 

 very small quantities of salicyluric acid appear in the urine after ingestion 

 of salicylate. Second, it tends to lower the pH of the urine and thus de- 

 creases the renal clearance of the free salicylate fraction. Third, it causes a 

 decrease in the urinary excretion of total salicylate and a rise in the plasma 

 salicylate level as a result of the foregoing effects. In dogs, the administra- 

 tion of PABA does not alter the excretion of salicylate and does not in- 

 crease the plasma salicylate levels. 



52 R. J. Hoaglund, Am. J. Med. 9, 272 (1950). 



"R. T. Smith, J .-Lancet 70, 192 (1950). 



" R. M. Salassa, J. L. Bollmaii, and T. J. Dry, ./. Lab. Clin. Med. 33, 1393 (1948). 



