THE URIC ACID PROBLEM.

112 Pages·2003·5.5 MB·English

THE URIC ACID PROBLEM.
AN EXPERIMENTAL STUDY ON ANIMALS AND MAN, INCLUDING
GOUTY SUBJECTS.*
BY OTTO FOLIN, HILDING BERGLUND, AND CLIFFORD DER1CK.t
(From the Biochemical Laboratory, Harvard Medical School, and the
Medical Service, Peter Bent Brigham Hospital, Boston.)
(Received for publication, March 31, 1924.)
CONTENTS.
I. Introduction................................................... 361
II. Historical review.............................................. 362
III. Uric acid studies with dogs. Distribution of uric acid. Dis-
appearance from blood. Locality of destruction: muscle,
kidney, liver, blood. Theory of destruction. Destruction and
elimination of uric acid by Dalmatian dog.. . . . . . . . 373
IV. Uric acid studies with other animals: ducks, cats, rabbits, goats.
Theory of absorption as a feature of kidney function. Dif-
ference between herbivorous and carnivorous animals in speed
of uric acid destruction.. . . . . . . . . . 401
V. Uric acid studies with normal men. Distribution of injected uric
acid. Destruction. Elimination. Effect of diet on destruc-
tion and excretion. Interpretation of high uric acid levels in
humanblood................................................. 415
VI. Uric acid studies with gouty subjects. Destruction and excretion
of injected uric acid. Origin and consequences of high uric
acid levels in the blood of the gouty. . . 446
VII. Resume.. . . . . . . . . . 488
I.
INTRODUCTION.
To this day, gout is still recognized mainly on the basis of
visible urate deposits. The literature abounds in conficting
*This paper is No. 19 of a series of studies in metabolism from the
Harvard Medical School and allied hospitals. A part of the expenses of
this investigation has been defrayed by a grant from the Proctor Fund of
the Harvard Medical School for the Study of Chronic Diseases.
t National Research Council Fellow in Medicine.
361
This is an Open Access article under the CC BY license.
The Uric Acid Problem
guesses as to the exact nature of the underlying disorder, and
the total impression produced by this literature is one of con-
fusion rather than of progress. Various combinations of cir-
cumstances doubtless are responsible for the long period of
sterility in so unique and interesting a field of research, but
the two main causes have been, first, the apparent inapplicability
of animal experimentation, and, second, the lack of suitable ana-
lytical technique. Until all the essential facts concerning the
behavior of uric acid within the normal organism have been
ascertained, the uric acid metabolism in gout is likely to remain
a matter of mere speculation.
The investigations recorded in this paper were begun on
the basis of the conviction that we could determine uric acid
in blood with a precision certainly quite unattainable in earlier
work. We had no preformed ideas or working theories-other
than the belief that the first thing to find out should be the
behavior of administered uric acid.
The unexpected results obtained have compelled us to try
to formulate interpretations. It is impossible to do continuous
research without trying to correlate the facts. While we may
have been rather too free with new explanations, we have en-
deavored to confine ourselves to theories which can be tested
by further experimental work; and if we have omitted to protect
ourselves by reservations, we have done so because reservations
seldom serve any useful purpose and take up space-and not
because we are blind to the fact that original theories are nearly
always wrong.
II.
HISTORICAL REVIEW
Both Liebig and Wiihler knew that uric acid by oxidation can yield
allantoin,l but in their joint research2 (1838) they proved and emphasized
the fact that uric acid can be decomposed into urea and oxalic acid, and
it was this more complete decomposition, rather than the allantoin for-
mation which became dominant in the metabolism literature of their
time. In 1848 W6hler and Frerichss “proved” by intravenous injections
of uric acid into dogs, and by mouth feeding with man, that the animal
* 1 Ostwald, W., Grosse Miinner, Leipsic, 2nd edition, 1919, i.
* Wiihler, F., and Liebig, J., Ann. Chem., 1838, xxvi, 241.
3 Wijhler, F., and Frerichs, F. T., Ann. Chem., 1848, Ixv, 335.
0. Folin, H. Berglund, and C. Derick 363
organism converts the nitrogen of uric acid into urea. Their results were
later “confirmed” by Neubauerd as well as by Zabelin,s and for a long
time it was considered as settled that uric acid when introduced into the
animal organism is excreted as urea. The occurrence and possible sig-
nificance of allantoin necessarily remained unknown, since its determina-
tion or qualitative isolation from urine remained an unsolved problem.
It may be noted here that the ammoniacal silver precipitation of uric
acid was first introduced by Salkowsk? in 1871 and that it was only after
the development of this process into the classical Salkowski-Ludwig
method7 that dependable uric acid determinations in urine became pos-
sible. Up to that time Heinz’s method for uric acid, and Liebig’s titra-
tion method for urea were used. It is also to be noted that up to the
end of the last century protein metabolism, like the metabolism of fats
and carbohydrates, was looked upon as involving only oxidations, and the
excretion of uric acid signified incomplete or delayed oxidation. Thus a
great number of investigations were published intending to show an in-
creased uric acid output in man under conditions implying diminished
oxidation, such as impaired respiration, severe cyanosis, carbon monoxide
poisoning, and others (Bartelsg). The fundamental difference between
the end-products of the protein metabolism as found in birds and reptiles
on the one hand, and mammals on the other, was interpreted as reflecting
incomplete oxidations in animals which “seldom drink. “9
The first doubt as to the correctness of this deficient oxidation hypoth-
esis was raised by the results obtained by Cechl” in Salkowski’s labora-
tory (1877). These results showed that urea when fed to hens is not re-
covered as urea. Hans Meyer and JaffBu in the same year showed that
the administered urea is excreted mainly in the form of uric acid. The
theory that uric acid is the result of deficient oxidations within the body
was definitely replaced by the modern view of the synthetic origin of uric
acid in birds when Minkowski,i2 in 1886, showed that the uric acid dis-
4 Neubauer, C., Ann. Chem., 1856, xcix, 206.
5 Zabelin, Ann. Chem., 1862-63, suppl. 2, 326.
6 Salkowski, E., Virchows Arch. path. Anat., 1871, lii, 58; Arch. Physiol.,
1872, v, 210.
7 Ludwig, E. L., Anz. Akad. Wissensch. Math.-naturw. Cl., Wien, 1881,
xviii, 92. Salkowski, E., and Leube, W. 0. L., Die Lehre vom Harn,
Berlin, 1882. Ludwig, E. L., Wien. med. Jahrb., 1884, 597. Salkowski, E.,
Z. physiol. Chem., 1890, xiv, 31.
8 Bartels, K. H. C. B., Deutsch. Arch. klin. Med., 1866, 1, 13.
9 von Liebig, Justus, Animal chemistry or organic chemistry in its
application to physiology and pathology, Cambridge, 1842.
lo Cech, C. O., Ber. them. Ges., 1877, x, 1461.
11 Meyer, H., and Jaffd, M., Ber. them. Ges., 1877, x, 1930. Meyer, H.,
Beitrlge zur Kenntniss des Stoffwechsels im Organismus der Hiihner,
Dissertation, KBnigsberg, 1877.
I2 Minkowski, O., Arch. exp. Path. u. Pharmakol, 1886, xxi, 41; 1893, xxxi,
214.
The Uric Acid Problem
appeared almost completely from the urine of geese after extirpation of
the liver.
Fundamental work by Miescher and Kossel in the 70’s and early 80’s
had in the meantime furnished a chemical foundation for a more definite
interpretation of the metabolic origin of uric acid. Horbaczewski’3 first
demonstrated the formation of uric acid from nuclein materials by in
vitro experiments (with spleen pulp), but he unfortunately also side-
tracked subsequent investigations by his hypothesis of dead leucocytes
being the only precursors of the uric acid. The origin of this hypothesis
from earlier observations14 of high uric acid excretion in leukemia is ob-
vious enough, but the unconditional linking together of leucocytosis and
uric acid excretion was a .mistake.r6
Numerous investigations showing greatly increased uric acid excretion
by man after feeding thymus, pancreas, or liver were carried out in 1895
and 1896 (Weintraud, Umber, and others’e), and these proved that Hor-
baczewski’s view of leucocytosis after meals as the cause of the extra uric
acid excretion could not be correct. A clear understanding of the dif-
ferent sources of the uric acid in man was presented by Burian and Schur,lr
who introduced and successfully developed the concepts of endogenous
and exogenous uric acid (1900-06). Burian and Schur concluded from their
own experiments, as well as from data gathered from the literature, that
the endogenous uric acid output in any given individual has a constant
value, that the value is different for different individuals, and, finally,
that within wide limits the value is independent of the protein content of
the food. Siven, I* independently, obtained similar results about the same
time, and for much wider variations in the protein content of the food
(21 to 2.8 gm.).
As often happens in connection with pioneer research, so here the es-
sential conclusion was overdrawn. That the endogenous uric acid excre-
tion is influenced to a considerable, though variable, extent by the protein
content of the food was shown (1905) by Folin.19 Folin’s findings by no
means destroyed the validit,y of the endogenous uric acid concept of Burian
and Schur, but they showed that some unknown modifying factors are
I3 Horbaczewski, J., Monatsh. C&m., 1889, x, 624; 1891, xii, 221.
l4 Ranke, H., Beobachtungen und Versuche iiber die Ausscheidung
der Harnsaure beim Menschen im physiologischen Zustande und in einigen
Krankheiten, Miinchen, 1858. Jacubasch, H., Virchows Arch. path. Anat.,
1868, xliii, 196. Salkowski, E., Virchows Arch. path. Amt., 1870, 1, 174.
I5 Richter, P. F., 2. klin. Med., 1895, xxvii, 290.
16 Weintraud, W., Berl. klin. Woch., 1895, xxxii, 405. Umber, F., Z.
klin. Med., 1896, xxix, 174.
17 Burian, R., and Schur, H., Arch. Physiol., 1900, lxxx, 241; 1901, lxxxvii,
239; 1903, xciv, 273. Burian, R., Med. Klin., 1905, i, 131; 1906, ii, 479, 514,
540.
18 Siven, V. O., Skand. Arch. Physiol., 1901, xi, 123.
I9 Folin, O., Am. J. Physiol., 1905, xiii, 66.
0. Folin, H. Berglund, and C. Derick 365
involved. Mare?’ and SmetBnkaY attempted to designate these factors
on the basis of increased activity on the part of the digestive glandular
organs in response to protein food. More recently, LewiG and associates
have advanced the view that the increased uric acid which they have
obtained after feeding amino acids may be a consequence of the high
specific dynamic action of these products. Through all the more re-
cent literature on endogenous uric acid the variations in the excretions
have been interpreted on the basis of corresponding variations in the
production.
The factors governing the production and excretion of exogenous uric
acid have been subjected to much investigation. Here, as in the case of
the endogenous uric acid, the actual results obtained from metabolism
experiments have rarely been in satisfactory agreement with the under-
lying theoretical considerations. Weintraudls (1895) noticed the dis-
proportion between the amounts of purines fed in the form of calves’
thymus and the amounts of uric acid excreted. hlinkowski,23 after feed-
ing 3 gm. of hypoxanthin to a normal person recovered 49 per cent in the
form of uric acid. Burian and Schur similarly obtained only 46 per cent
recovery of urinary purines after taking 1.6 gm. of hypoxanthin. Burian
and Schur made many laborious analyses of the purine contents of
different food materials in order to learn how much was excreted. The
validity of these tissue analyseP was questioned by LoewP and again
verified by Burian and Hall.26
Burian and Schur made many feeding experiments with liver, spleen,
beef, veal, and bacon, and recorded an average purine recovery of about
50 per cent in terms of the “purine content” of the food. From their
own data, as m-e11 as those of others,27,2* representing thirteen experi-
ments with six different subjects, they concluded that, of absorbed purine
material, a large fraction disappears and about 50 per cent is normally
recovered as uric acid. Burian and Schur undoubtedly laid too much
stress on this figure, for some of their own results were quite different.
With two different individuals they recovered only about 25 per cent.
*O Mare:, F., Arch. Physiol., 1910, cxxxiv, 59.
21 Smetiinka, F., Arch. Physiol., 1911, cxxxviii, 217.
22 Lewis, H. B., and Doisy, E. A., J. Biol. Chem., 1918, xxxvi, 1. Lewis,
H. B., Dunn, M. S., and Doisy, E. A., J. Biol. Chem., 1918, xxxvi, 9. Lewis,
H. B., and Corley, R. C., J. Biol. Chem., 1923, Iv, 373.
23 Minkowski, O., Arch. exp. Path. IL. Pharmakol., 1898, xli, 375.
24 Burian, It., and Schur, H., 2. physiol. Chem., 1897, xxiii, 55.
25 Loewi, O., Arch. Physiol., 1902, lxxxviii, 296.
26 Burian, It., and Hall, J. W., Z. physiol. Chem., 1903, xxxviii, 336.
Hall, I. W., The purin bodies of food stuffs and the rBle of uric acid in
health and disease, London, 2nd edition, 1903.
27 &tiger, M., and Schmid, J., Z. physiol. Chem., 1901-02, xxxiv, 549.
28 Kaufmann, M., and Mohr, L., Deutsch. Arch. klin. Med., 1902, lxxiv,
157, 348, 586.
The Uric Acid Problem
Schittenhelm, a persistent advocate of the destruction theory, in ex-
periments with Frank,29 fed sodium nucleate (from thymus nucleic acid)
to three subjects. The recovery, in the form of urinary uric acid, was
5, 10, and 41 per cent, respectively. Dohrn,30 in a similar experiment
with thymus nucleic acid recovered 11 per cent from a normal individual.
Rother, in experiments with yeast nucleic acid in two practically nor-
mal subjects recovered 12 and 36 per cent; these figures, however, are
minimum figures, since Rother did not follow up the experiments long
enough to get the uric acid output back to the original levels.
The inevitable weak point in all feeding experiments is the uncertainty
about the extent of absorption, and the form in which absorption takes
place. This is well illustrated in these experiments. Frank and Schitten-
helm’s cases, with the low recovery, showed before the beginning of the
experiment a feces nitrogen of more than 20 per cent of the urinary ni-
trogen, indicating some intestinal disturbance. In these cases most of
the phosphorus of the nucleic acid was recovered from the feces, contrary
to what happened in their third case with the higher recovery, where
most of the phosphorus given was found in the urine. The same consider-
able increase in the phosphorus of the feces was found by Dohrn, who
concluded (as Schittenhehn might have done) that intestinal destruction
of most of the nucleic acid given, was the cause of the low urinary recovery.
SivEn,32 like Burian and Schur, registered a recovery of about 50 per
cent of the food purines, the purines having been taken as 1,000 cc. of
beef broth a day, containing a purine quantity equal to Siven’s own en-
dogenous uric acid output. Sivcn went on to prove that the loss occurred
in the intestinal canal, in other words that there was no loss in the strict
metabolic sense of the word. One of the few unanimous results obtained
by all investigators is that the feces never contain more than traces of
purine bodies. Likewise there is an agreement that the pancreatic or
intestinal juice does not break up the purine ring. Siven33 reentered a
road opened by Baginsky 34 in 1884 and now showed that Bacterium coli
in test-tube experiments in 24 to 48 hours split considerable quantities
of purines (beef broth). The degree to which this breakdown takes place
was studied by Thannhauser and Dorfmiiller,36 who showed that the
bacterial flora of the human intestines metabolizes the nitrogen of nucleo-
sides into ammonia. In 20 days’ experiments, 70 to 100 per cent were
29 Frank, F., and Schittenhelm, A., 2. physiol. Chem., 1909, lxiii, 269.
Brugsch, T., and Schittenhelm, A., Der Nukleinstoffwechsel und seine
Storungen, Jena, 1910.
30 Dohrn, M., 2. physiol. Chem., 1913, Ixxxvi, 130.
31 Rother, J., Z. physiol. Chem., 1921, cxiv, 149.
32 Siven, V. O., Arch. Physiol., 1912, cxlv, 283.
33 Siven, V. O., Arch. Physiol., 1914, clvii, 582.
34 Baginsky, A., Z. physiol. Chem., 1883-84, viii, 395.
35 Thannhauser, S. J., and Dorfmtiller, G., Z. physiol. Chem., 1918, cii,
148.
0. Folin, H. Berglund, and C. Derick 367
metabolized. Rother, in experiments with yeast nucleic acid and human
feces in test-tubes, confirmed the ammonia formation and showed that
the destruction after 49 to 48 hours in a thermostat represented about
one-half of the nucleic acid originally present.
The main conclusion to be drawn from the results reported in
these different papers is that the intermediary destruction of uric acid in
man cannot be definitely proved (or disproved) by means of feeding
experiments.36
It is interesting to note that Burian and Schur actually fortified their
theory of uric acid destruction in man by two hypodermic uric acid injec-
tions, especially since other investigators have “proved” the indestruc-
tibility of uric acid in the human organism by means of similar experiments.
Before citing the literature which has been accepted as proving that
man does not destroy uric acid, it is necessary to refer to the history of
allantoin, for the newer developments are based to a large extent on al-
lantoin findings.
In 1876, Salkowski3’Js fed solid uric acid to dogs, and showed that a
part of the uric acid was excreted in the form of allantoin. Salkowski
also found allantoin in the urine of two meat-fed dogs, but as he was un-
able to find it in the urines of seven other meat-fed dogs he failed to recog-
nize that allantoin is a normal constituent of dog’s urine. Salkowski’s
discovery remained isolated it not forgotten, until Minkowski,23 in 1898,
again discovered allantoin in the urine of dogs-after feeding the animals
with calves’ thymus. Minkowski was unable to find the allantoin when
horse meat was substituted for thymus. On feeding allantoin to man and
to dogs, he recovered in the urine about 70 per cent in the case of the dogs,
as against only about 20 per cent in man, and on the basis of these findings
Minkowski tentatively concluded that the decomposition of allantoin,
with urea formation, occurs more readily in man than in dogs. Minkow-
ski’s findings were confirmed by Cohn,39 Salkowski,40 Poduschka,” Men-
de1 42 and others. These findings necessarily raised the question whether
and to what extent allantoin occurs in urine as one of the end-products of
purine metabolism (Burian!‘). But it was only after Wiechowski had
devised a method for at least approximately dependable determinations
36 Results, supposed to indicate an intestinal destruction of endogenous
uric acid, have recently been issued by H. Steudel (Steudel, H., Z. physiol.
Chem., 1922-23, cxxiv, 267). There is no doubt that Steudel, working with
not quite fresh urines, turned over to him by Rubner, has encountered and
failed to interpret the not uncommon disappearance of uric acid in urines on
standing.
37 Salkowski, E., Ber. them. Ges., 1876, ix, 719.
38 Salkowski, E., Ber. them. Ges., 1878, xi, 500.
39 Cohn, T., 2. physiol. Chem., 1898, xxv, 507.
40 Salkowski, E., Centr. med. Wissensch., 1898, xxxvi, 929.
4I Poduschka, R., Arch. exp. Path. u. Pharmakol., 1900, xliv, 59.
42 Mendel, L. B., and Brown, E. W., Am. J. Physiol., 1899-1900, iii, 261.
The Uric Acid Problem
of small as well as of large amounts of allantoin in urine (1907) that the
researches began to yield consistent results. Wiechowski43 was able to
show that allantoin is a constant product of the endogenous metabolism
of the dog, cat, rabbit, and monkey, and that the allantoin excretion on
purine-free diets exhibits about the same degree of uniformity as Burian
and Schur had found for the endogenous excretion of uric acid in man.
In the course of his endeavors to prove that allantoin in the urines of
animals has the same origin and significance as the uric acid in man,
Wiechowski44T45 took particular pains to isolate and identify the small
amount of allantoin excreted by man on purine-free diets. The daily
allantoin excretion in man amounted to only 12 to 14 mg., and was no
greater in leukemia (one case) or in gout (two cases).
The most extensive investigations based on the concept of the identical
origin and significance of. uric acid and allantoin are those of Hunter46
and his coworkers. They have determined the total purines, the uric
acid, and the allantoin in the urines of a large series of different animals,
and have introduced the term uricolytic index to express the per cent of
uric acid nitrogen plus allantoin nitrogen represented by allantoin. This
index varies between 80 and 98 for the different animals investigated.
The fact that endogenous allantoin, at least in part, has the same meta-
bolic origin and significance as uric acid is important enough; but from
this fact it does not necessarily follow that the uric acid which is destroyed
within the animal organism is quantitatively excreted in the form of
allantoin. It would appear that Wiechowski adopted the view of such
quantitative transformation and excretion mainly because he found that
in uricolysis experiments with liver extracts the uric acid is quantitatively
converted into allantoin. This observation, coupled with the fact that
uricolysis can be obtained with tissues of animals which normally excrete
allantoin, but not with human tissues is, of course, suggestive (Wiechow-
ski,47 Jones,4s and Schittenhelm@).
But there is room for skepticism as to the true significance of such
experiments, and the interpretations drawn from them must be confirmed
by means of real metabolism experiments. The recorded metabolism
43 Wiechowski, W., Beitr. them. Physiol. u. Path., 1908, xi, 109.
*4 Wiechowski, W., Biochem. Z., 1909, xix, 368.
45 Wiechowski, W., Biochem: Z., 1910, xxv, 431.
46 Hunter, A., and Givens, M. H., J. Biol. Chem., 1912-13, xiii, 371;
1914, xvii, 37. Hunter, A., J. Biol. Chem., 1914, xviii, 107. Hunter, A.,
Givens, M. H., and Guion, C. M., J. Biol. Chem., 1914, xviii, 387. Hunter,
A., and Givens, M. H., J. Biol. Chem., 1914, xviii, 403. Hunter, A., and
Ward, F. W., Trans. Roy. Sot. Canada, 1919, xiii, sect. 4, 7.
47 Wiechowski, W., Arch. ezp. Path. u. Pharmukol., 1909, lx, 185.
48 Winternitz, M. C., and Jones, W., 2. physiol. Chem., 1909, lx, 180.
Miller, J. R., and Jones, W., 2. physiol. Chem., 1909, lxi, 395.
49 Schittenhelm, A., 2. physiol. Chem., 1909, lxiii, 248.
0. Folin, H. Berglund, and C. Derick 369
experiments bearing on the subject may be divided into three different
kinds, namely:
(n) Subcutaneous or intramuscular injections of urate solutions into
animals-which should yield approximately 100 per cent recovery in the
form of much allantoin plus a little uric acid. (Under (a) may be in-
cluded the few experiments with allantoin which are less important, but
should prove the indestructibllity of allantoin in the animal as well as
in the human organism.)
(6) Subcutaneous injections of uric acid into human subjects. These
should yield approximately 100 per cent recovery in the form of extra
uric acid. (Under (5) may be included similar experiments with definite
precursors of uric acid.)
(c) Intravenous injections of uric acid in man, which should also yield
approximately complete recovery in the form of uric acid alone.
(a) Wiechowski43 seems to have made only a couple of subcutaneous
uric acid injections in animals, probably because uric acid so administered
is distinctly toxic and this produces confusing results.
To a fasting dog he gave 600 mg. of uric acid in the form of sodium
mate. The recovery in 24 hours was 104 per cent, of which 24 per cent
was uric acid and the rest allantoin. This apparently excellent result is
somewhat impaired by the marked toxic effects accompanied by a material
increase in the total nitrogen excretion.
From a similar subcutaneous injection of urate into a rabbit, Wiechow-
ski recovered only 56 per .cent.
Hunter and Given+ have made similar experiments (with a monkey).
In their first experiment they injected subcutaneously 40 mg. per kilo
of body weight. The effects of the urate, both general and local, were
very severe. Extensive necrosis occurred at the place of the injection.
The uric acid plus allantoin recovery, if extended over a period of 8 days,
would have been 100 per cent, but the authors properly concluded that
the experiment was valueless for such purposes. In two other similar
experiments, with 20 and 30 mg. of uric acid per kilo, they recovered 40
to 50 per cent of the uric acid as such and obtained very little extra
allantoin.
These experiments taken all together constitute a rather meager con-
firmation of the view that administered uric acid must be excreted as a
mixture of uric acid and allantoin.
The excretion of allantoin in response to subcutaneous injections of
allantoin in man was studied by Wiechowski (three experiments). His
best recovery was 74 per cent. Hunter and Givens from three similar
injections of allantoin in a monkey recovered from 75 to 90 per cent. In-
jections of allantoin produced none of the toxic symptoms obtained from
uric acid.
(5) We have found the records of six hypodermic injections of uric
acid into human subjects. Two of these were made by Burian and Schur
6o Hunter, A., and Givens, M. H., J. Biol. Chem., 1914, xvii, 37.
370 The Uric Acid Problem
and have already been mentioned. They gave a recovery of about 50
per cent. Of the other four, two were made by Soetbeer and Ibrahim,sl
and two by Wiechowski.47
Soetbeer and Ibrahim dissolved the uric acid by means of piperazine.
In the first subject they injected 860 mg. of uric acid. During the day
of the injection the increase of the uric acid elimination above the previous
level corresponded to 75 per cent of the uric acid administered. The ex-
periment had to be discontinued after this 1st day, the subject refusing
further cooperation. Ibrahim then received 1,260 mg. and excreted above
the average previous output 81 per cent during the 1st day, 18 per cent
during the 2nd day, another 28 per cent extra during the 3rd day; and
during the 4th and 5th days, taken together, another 45 per cent, making
all together an extra elimination of about 170 per cent. At that time
the output was not yet back to normal, but the experiment was discon-
tinued since the condition of the subject “did not make a further con-
tinuation advisable.” At that same time the nitrogen output had risen
from a previous average of 23.1 to 26.3 gm. a day. It is quite evident that
no conclusion concerning the destruction or non-destruction of uric acid
in man can be drawn from these experiments. There is no doubt about
an extra, what we may call “toxic,” uric acid elimination playing a con-
fusing rBle in the experiment.
Wiechowski injected hypodermically into himself in two experiments
990 and 440 mg. of uric acid, respectively, both times in the form of sodium
urate. The recovery after the first injection amounted to 82 per cent,
distributed over 3 days. From the second experiment Wiechowski re-
covered 50 per cent during the 1st day, the 2nd day showed a lower out-
put than any day during the control period, and the 3rd day a slightly
elevated figure. We do not think it correct to add this to the recovery
figure from the 1st day, as Wiechowski did. His total recovery was 61
per cent.
An intramuscular injection into a gouty man of 500 mg. of uric acid
dissolved in piperasine (von Benczur, 52 in Brugsch’s Clinic) followed by fever
up to 39°C. and very marked general reaction for 2 days demonstrates
clearly the toxic effect of the injection, and the figures allow no certain
conclusion about the degree of recovery of the uric acid.
Subcutaneous or intramuscular injections of adenosine and guanosine
have proved just as unsatisfactory as the uric acid injections for demon-
strating the indestructibility of uric acid. Such injections were first used
by Thannhauser and Bommes.63 Rother,s4 at that time working with
Brugsch, presented an adequate criticism of some of the recovery cal-
culations of Thannhauser and Bommes, and, after the presentation of
new experimental material, concluded that the nucleoside injections of-
61 Soetbeer, F., and Ibrahim, J., 2. physiol. Chem., 1902, xxxv, 1.
62 von Bencsur, G., Z. ezp. Path. U. Therap., 1909-10, vii, 339.
63 Thannhauser, S. J., and Bommes, A., 2. physiol. Chem., 1914, xci, 336.
64 Rother, J., Z. physiol. Chen., 1920, cx, 245.