Physicians and Surgeons in London.

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1 ON THE EXCRETION OF URIC ACID, UREA AND AM- MONIA, WITH A SCHEME OF CURVES. BY W. P. HERRINGRAM, M.D., F.R.C.P., AND E. W. GROVES, B.Sc., London. (Plate XIV.) A research carried out at the Laboratory of the Royal Colleges of Physicians and Surgeons in London. OUR object in this investigation was to discover whether the excretion of uric acid when compared with that of urea followed any definite rule, and especially whether, as has been frequently stated of late years by Dr Haig, the proportion borne by the one to the other varied inversely as the acidity of the urine. One of us had already been engaged in a similar investigation', but that experiment had left much to be desired in point both of completeness and of duration, and we desired to test the theory above referred to more fairly, and more fully. For this end we examined daily the urine of one of us (H.), who at the same time placed himself on a diet calculated to interfere as little as possible with physiological processes. The total quantity of urine passed in the twenty-four hours was measured. From specimens of this total the visible acidity, the am-monia (corresponding to what may be called the latent acidity), the urea and the uric acid were all estimated. The diet comprised Dressed butcher's meat 3 oz. Dressed fish 3 oz. Bread oz. Vegetables oz. (of which about 6 oz. were potatoes, the rest greens or fruit.) Coffee 1 pint A little milk (about 4 oz.), and water as required. 1 See p. 475 of this issue of the Joutrnal.

2 EXCREVJON OF URIC ACID. 479 No wine or other alcohol was taken except on one day as noted. This diet was chosen as being the diet natural to the person examined, and as being sufficiently alkaline to avoid all interference with excretion. The health remained good throughout '. The Processes employed were as follows: Visible acidity was tested by taking 50 c.c. of uirine, adding a few drops of phenolphthalein solution and running in a deciniormal solution of soda from a burette till the pink colour could be seeni with certainty. Ammonia or latent acidity was estimated by Schlosing and Neubauer's method, with normal sulphuric acid. Urea was estimated by the hypobroinite process corrected for variation in temperature and atmospheric pressure. Uric acid was estimated by processes described in a subsequent paper by one of us, see p. 485 of this issue of the Journal. The experiment lasted thirty days, from May 19 to June 18. The results are appended. (See Table I.) It will be seen that the average visible acidity of the urine was low, ranging usually from 25 to 40 grains of oxalic acid. This was in accordance with our wishes, for we feared lest, if Haig's theories were correct, any excess of acidity might, as he supposes, prevent excretion, and store up uric acid within the body, which on the next day of low acidity would produce a very excessive excretion. By avoiding high acidities we expected to avoid all but slight interferences, and to arrive at the physiological, rather than the pathological excretion. That this was desirable is evident, for, as far as we know, the excretion of uric acid has never been continuously compared with the excretion of urea by the help of processes which are above suspicion, anid if their relations in health are not known, it is unsafe to construct theories of disease upon their variations. To the visible acidity must be added the latent acidity as evidenced by the excretion of ammonia. It is well known that carnivora, and man in this respect behaves like them, excrete large quantities of ammonia if the acidity of the food be high or if additional acid be given to them. The excretion of ammonia can be so varied at will by the exhibition of acids and alkalies, that it appears proved that ammonia acts as a safeguard to prevent any dangerous lowering of the blood's alkalinity. Rabbits and other herbivora do not possess this power, and Haig suggests that whereas healthy people are able by producing ammonia to keep the blood's alkalinity, and therefore, 1 The weight was 10 stones.

3 480 W. P. HERRINGHAM AND E. W. GROVES. TABLE 1. (See Plate XIV.) U'ric acid Urea Nof~ Acidity - No. of e.c. equivalent - r Date of urinie to grainis Nl:3 excreted. of oxalic Graniiies in Grains Graiiis in Total Total grmis. acid. 200 c.c. Total in total total riiis (Salk.) raiiis gramnies. (Salk.) (ilaycraft) g rais v : * ' * ' a ' ' '10 38' '4 ' ' '126 : ' * '6 * 150 1' ' * '3 :0962 '094 * * a *144 1'188 18'41 31' * ' '744 11'53 21' ' ' ' ' * :1286 '127 ' * '143 ' '0 465 *1800 vi a '5 *1684 '168 1'16 17'98 28' ' '5 ' '611 9' '9 556 ' '7 078*0785 '617 9' '6 412 '1170 3_4 b '102 ' '1 435 ' '104 ' ' '8 508 ' a '8 ' ' ' '126? '1275 ' '62 28'02 33'7 522 *1860 '129~ '059 '6313 9' 'S 441 * '1O4105 ' ' '8 '122 ' ' ' ' ' ' '100 *750 11' '0 589 ' ' ' '25 42'4 657 ' ' ' '08 31' ' '094 ' ' :1486 ' :121i 121 ' '65 33'59 37' '0 ' '975 15'11 27'50 40'5 627 a Sod. salicyl. gr. 45 taken on these days. b Port wine, 3 ounces taken.

4 E,XCRETION OF URIC A ClD. 481 as he thinks, the uric acid excretion, at a normal level, the gouty man resembles rather the rabbit, in that he is less able to keep his blood alkaline, and therefore more liable to store up uric acid in his inside. In the present case the amount of ammonia is so small throughout the experiment that it may be neglected. The visible acidity represents very nearly the whole amount of acid excreted, and the state of the blood is therefore fairly indicated by the numbers in this column. We have dwelt at some length upon these points in order to shew that the conditions of the experiment would probably allow physiological processes to develop unhindered. We regret to say however that in one respect this rule was departed from. On three occasions, as shewn in the tables, salicylate of soda was exhibited. This was done in order to confirm or disprove the power of increasing the excretion of uric acid attributed to it by Haig and others. We soon saw that the physiological excretion varied so much that no law could be formed from such short intervals as we had then allowed, and we therefore left the last twelve days free from any interference by drugs. Another subject of great regret to us is that circumstances entirely beyond our control broke off the experiment on June 18. We had lhoped a longer trial Ṫo turn now to the excretion of urea and uric acid;-the total amount of urea excreted in the thirty days was grains, of uric acid, grains. The average excretion of urea, if that can be said to have an average, was 521 grains, of uric acid grains. The proportion of the totals of uric acid and urea is as 1: 39. No daily relation could be made out between the acidity and the proportion of these totals. The uric acid excretion did not as a rule rise above the average when the acidity fell, nor fall when the acidity rose. It was liable to considerable fluctuatiorns for which no reason could be discovered, and which followed no regular course. The three exhibitions of salicylate of soda apparently coincided with large exeretions of uric acid. It must however be remembered that salicylate of soda leaves the body as salicyluric acid. We are not aware that the behaviour of salicyluric acid in presence of an ammoniacal solution of silver is yet known, and it is at least possible that the apparent increase of uric acid is in reality due to some decomposition of salicyluric acid, and does not correspond to an increase in the uric acid excreted. On other days amounts of uric acid fully as large as these were excreted without any artificial acid.

5 482 W. P. HERRINGHAM AND E. W. GROVES. Nor were the effects of the excretion at all more distinct than its causes. The period of the experiment was one of usual healtb, and the life led was extremely regular. No ill effects were produced by the large excretions, nor were the days of small excretion times of remarkable content. A slight headache occurred on one day, May 28, which however was one of the lowest excretions recorded. From May 21 to May 28 a slight attack of lumbago and brachial neuralgia was experienced. The person undergoing the experiment is very subject to such attacks, which have been attributed to gout, and this period will be compared with that of another attack later. Objective symptoms were as absent as the subjective. Sphygmographic tracings are here reproduced coinciding with the most various excretions. They were taken in the forenooni, as nearly as possible at the same time on each day, so that they might represent the state of arterial tension at the time of day vhich is supposed to be that of the greatest uric acid exeretion. The tracings shew no alteration that can be referred to the excretion of uric acid. The same may be said of the exhibition of salicylate of soda. The other functions of the body were in regular and natural exercise'. It will be seen from the tables that the uric acid was estinmated by Haycraft's abbreviated method, as well as by the full process of Salkowski and Ludwig. The former was conjstantly found to give a very large excess, but the excess was so irregular that it gave nio indication as to the right amount. This method was therefore quite useless with this urine. It has been found erroneous by other experimenters also, by Salkowski himself, the originator of the silver process, and by Gossage. The error is not always of the same amount, but is always on the side of excess. Herrmann on the other hand found it to correspond accurately with the results of the gravimetric method. Haig does not appear to have compared the two2. It appears necessary, before conclusions can be founded on results obtained by Haycraft's method, that they should be compared with those of the standard process, and we are driveni to the opinioin that no results should be accepted unless such comparison has been made. 1 These were taken by Dudgeon's sphygmograph. This is liable to so many fallacies that no accurate results can be obtained with it. We leave the tracings however for what other people may think they are worth. 2 An explanation of these discrepancies is attempted in a paper on the chemical processes in this number of the Journal.

6 EXCRETION OF URIC ACID. It may be that our entire failure to corroborate Haig's observations in any one point is due to the difference of person, that what is true for his system is not true for ours. It may be on the other hand, that, having employed a very uncertain and inaccurate method, his results are themselves iinaccurate and deceptive. The conclusions which we draw from the foregoing research are that, for the person under observation, (i) The excretion of uric acid does not vary inversely with the daily acidity of the urine. (ii) Uric acid may be passed to the amount of 1 of the urea without any bad effects. The estimations of uric acid, urea, and acidity were resumed on July a and continued to July 22. The conditions were not those of health. The ineals during this time were irregular, there was rather a severe pressure of work, less than the natural amount of sleep, and some indigestion. It was however useful in that, whereas during the first period a slight attack of lumbago coincided with a rather excessive uric acid excretion, during the second a similar but severer TABLE 1. Acidity Uric acid Urea Date No. of c.c. = grains of grains grains. oxalic acid. (Salk.) vii * u e ( * a a Sod. salicyl. gr. 45 taken on this day. 48:3

7 484 W. P. HERRINGHAM AND E. W. GROVES. attack, ascribed to a chill, was accompanied by an excretion considerably below the average. This seemed therefore to shew that the excretion of uric acid was of little importance in the causation of lumbago. The daily variations during this period shewed no dependence on the visible acidity of the day. The range of visible acidity was somewhat higher, about 50 grains of oxalic acid, the urea was very much increased, probably owing to less restricted and less regular feeding, but the uric acid did not rise in proportion. The average is 12 3 grains per diem, slightly less than that of the first period. The high totals of the 18th and 19th of July with an acidity of 49 and 47 respectively shew that the uric acid can be excreted in full qntantity at this acidity level. There is nothing therefore in these numbers to shew a retention as against a diminished formation, which is the main question involved. We regret that we have done so little toward the discovery of the laws governing the excretion of uric acid. It is however in the experience of all that what is quickly found takes twice findinig, and the very inconclusiveness of our results seem to uis some evidence that they are true. MaKpa zap 1'T%Xq.

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