THE ACTION OF CINCHOPHEN

¹ From the Laboratory of Internal Medicine in the Boston Psychopathic Hospital and the New England Baptist Hospital, Boston, Massachusetts

1. Cinchophen does not regularly cause a great increase in the excretion of uric acid. In sixteen subjects on a purin-free diet the average output the day cinchophen was given was 525 mgm. which is within normal limits, as the accepted normal maximum of endogenous uric acid excretion is 600 mgm. The average increase in all the sixteen over the previous day was 172 mgm. or 48 per cent. The average increase in eight of these cases was only 18.4 per cent.

2. In 10 cases the output of uric acid on the cinchophen day when compared with the endogenous level was increased on the average 117 mgm. or 32 per cent.

3. In 3 cases the output of uric acid on the first cinchophen day was below the endogenous level, in one instance amounting to a fall of 42 per cent.

4. Eleven non-gouty subjects were given 3 grams of cinchophen daily for from two to six days. In nine the uric acid excretion was increased and in two decreased. The largest increase, which was 569 mgm., occurred in a two-day period.

5. Three out of five non-gouty persons given cinchophen for five or six days showed an increased output of uric acid. The maximum increase was 510 mgm.; the maximum decrease 474 mgm.

6. Fluctuations in the level of the endogenous uric acid output uninfluenced by cinchophen were tabulated in thirteen of the persons studied. The maximum variation from one day to the next ranged from 7 to 100 per cent. The average maximum fluctuation was 46 per cent. These spontaneous variations interfere seriously in attempting to measure quantitatively the effect of cinchophen on the amount of uric acid excreted.

7. The greatest increase in uric acid output occurs either on the first or second day when the administration of cinchophen is continued.

8. On discontinuing cinchophen there is usually a sudden drop below the endogenous uric acid level and this depression of the excretion may continue for three days or longer. In two out of eight observations, the uric acid output remained above the endogenous level one to two days after cinchophen was stopped.

9. Marês has stated that the urine voided in the early morning after a twelve-to fourteen-hour fast gives an hourly output of uric acid that is constant for the individual. This he regards as the true level of endogenous uric acid excretion. We have not confirmed his findings, and we do not believe there is any fixed endogenous level.

10. Cinchophen increases the uric acid concentration in the urine.

11. Failure to obtain a greatly increased excretion of uric acid from cinchophen cannot be explained as being due solely to lack of uric acid reserves as the simultaneous administration of thymus which is very rich in purin bodies and cinchophen does not always give a marked increase in the uric acid output.

12. The blood uric acid was determined one to five hours after giving cinchophen in nine subjects. In only one did a fall of the uric acid occur. Usually there was little change in the amount present in spite of an increased output in the urine. In three observations there was a definite increase in the blood uric acid after three hours.

13. A decomposition product of cinchophen gives a diazo reaction in the urine. This reaction was obtained in all of the 8 cases tested from two to twenty-one hours after the drug was given. Thus there was no evidence that our failure to obtain regularly an increased output of uric acid after cinchophen was due to faulty absorption from the gastro-intestinal tract. The protein-free blood filtrate gave a positive diazo reaction in all of 5 cases tested three hours after cinchophen was given.

14. If the action of cinchophen is solely on the kidneys increased excretion of uric acid in the urine would be followed immediately by a drop in the blood uric acid. As the blood uric acid does not regularly fall during the first three hours and may even increase, the drug must act on the tissues of the body containing uric acid reserves as well as on the kidneys.