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Xanthine oxidase inhibitors in the management of gout.

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Xanthine Oxidase Inhibitors in the Management of Gout
By JAMESB. WYNGAARDEN,
M.D.
Duke University Medical School
The forms of therapy for gout available in the past decade have been
very successful in about two-thirds of gouty patients. Those who have not
responded satisfactorily to uricosuric therapy are by and large patients who
have some degree of renal insufficiency, or who continue to use salicylates
concurrently, or who are intolerant of the drugs.
It has been a goal in the therapy of gout to be able to regulate the production of uric acid, as well as its excretion. Experiments directed toward this
goal have been conducted with azaserine by Zuckerman, Drell and Levin,l
and with diazo-oxonorleucine by Grayzel, Seegmiller and Love.2 Both agents
are glutamine antagonists and block an early reaction of purine synthesis.
When these agents are administered to man the rate of production of uric
acid is reduced and the levels of urate in serum and urine fall. The compounds are too toxic to be therapeutically useful in gout but the experiments are of interest.
The pyrazolopyrimidines resemble the purines in structure except that
nitrogen 7 and carbon 8 of the purine ring are reversed (Fig. 118). There are
several pyrazolopyrimidine derivatives. The adenine analogue was explored
as a cancer chemotherapeutic agent some time ago, with some preliminary
success. When the studies were extended to man this compound proved to
be hepatotoxic and its use was abandoned.
4-Hydroxypyrazolo ( 3,4-d)pyrimidine is an analogue of hypoxanthine which
appeared to be biologically ineffective in tumor trials. It was shelved until
recently when interest in its use as a xanthine oxidase inhibitor developed.
Many purine analogues bind at the active site of xanthine oxidase and by
this competitive mechanism inhibit the enzyme. The pyrazolopyrimidines
were shown to be inhibitors of xanthine oxidase by Feigelson, Davidson and
Robins." This demonstration rested in the literature for some time until the
group at Burroughs Wellcome Laboratories became interested in the possible advantage of inhibiting xanthine oxidase in patients who were receiving
6-mercaptopurine as cancer chemotherapy. This latter compound is normally oxidized to 6-thiouric acid by xanthine oxidase. The question raised
was whether one could provide a smoother chemotherapeutic course by
giving a xanthine inhibitor together with 6-mercaptopurine ( 6-MP) .
Xanthine oxidase is the enzyme responsible for oxidation of hypoxanthine
to xanthine, and of xanthine to uric acid (Fig. 119). These reactions are on
the degradative side of purine nucleotide metabolism, so that inhibition of
xanthine oxidase should not have any direct effect on nucleotide production,
and nucleic acid metabolism. Figure 120 shows one of the early studies done
by Dr. Wayne Rundles4 at Duke University in which he gave 6-mercaptopurine to a patient with chronic granulocytic leukemia, and determined the
883
ARTHRITISAND RHEUMATISM,VOL. 8,
N O . 5-PART
1 (OCTOBER), 1965
884
GOUT AND PURINE METABOLISM
Adenine
4-Aminopyrazolo(3,4-d)pyr imid ine
NH2
NH2
I
I
Hypoxanthine
OH
4-Hydroxypyrazol0(3,4 -d)pyrimidine
OH
Fig. 118.--Structural
formulae of pyrazolo (3,4d)pyrimidines.
XANTHINE OXIDASE
Hypoxonthine
Fig. 119.-Action
Xonthine
Uric Acid
of xanthine oxidase on oxypurines.
amount which is excreted unchanged and the amount excreted as thiouric
acid. Later the experiment was repeated after 300 mg. of hydroxypyrazolopyrimidine (HPP) had been given. In the second instance a larger percentage
of 6-MP was excreted unchanged and the fraction converted to 6-thiouric
acid was drastically reduced.
Because of this effect on xanthine oxidase the question of what HPP
would do to uric acid levels was raised. Appropriate study disclosed that
the serum and urinary uric acid levels both fell and that there was a concomitant increase in the excretion of xanthine and hypoxanthine. The changes
in this particular subject were not great but they indicated the desirability of
extending these studies to other hyperuricemic patients, particularly those
with goutS5z6
Figure 121 shows one of the gouty patients who was treated with HPP
shortly thereafter. In this particular patient, who was asymptomatic at the
time, the serum urate level of 6 to 7 mg. per cent was reduced by HPP to
about 3 to 4 mg. per cent, and the urinary uric acid which was in the range
of 600 mg./24 hours fell to between 200 and 300 mg./24 hours in about 5
885
XANTHINE OXIDASE INHIBITORS
e
n
x
CHRONIC GRANULOCYTIC LEUKEMIA
Hgb VPRC WBC
yo
x K.L.C. F-72928
gm,/
m
o
A
URINE
SERUk
mercaptopurine.
=
A
Serum
CHRONIC NON-TOPHACEOUS
Unrestricted Diet
o
URINE
W.R.B., F45318
GOUT
Uric
Acid
mg.%
10
8
6
4
2
I
01
0=10/12/62
0: ,
0
, , ,
;-y
~,
5
12
.
!
15
,
.
,
,
20
,
.
.,?
25
I
55
i
85
115
-/
175
GOUT AND PURINE METABOLIShf
886
Uric
Acid
%
Uric
Acid
Oxy
purin
G.B.C., 874431.
ACUTE GOUTY ARTHRITIS
14, W. Nightwatchman Subsiding Second Attack Treated
With HPP Alone.
24hrs. 24hi
12 1200
I 0 - 1000-
8- 800-
6 - 600-
O =3/28/63
ig/da y
Them
I
900
Perform.Status
%,I
70
75
75 85 90
400
600
95
95
'
too
200 r--95
Fig. 122.-Effect of large dose of HPP on urate levels in gouty subjects.
days. There was an associated rise in oxypurine excretion. When the drug
was discontinued the uric acid values returned to their previous levels.
Figure 122 shows another gouty patient who was admitted for an attack of
acute gouty arthritis. HPP was given in an initial dose of 900 mg./day. At
that level his urinary uric acid fell from 1,OOO mg./24 hours to about 400
mg./24 hours and his serum uric acid from 8 or 10 mg. per cent to about 3
or 4 mg. per cent. With reduction of dosage an increase in urate levels
occurred.
Table 38 presents a summary of our first eight patient^.^ The Duke series
now comprises 40 patients with gout, but the experience shown here is
representative of the total group. In this group of patients the serum urate
level was brought to or toward normal in from 5 to 20 days. With the drop
of uricemia the urinary uric acid generally fell to an average of about half of
previous levels. The dosage used ranged from 200 to 900 mg. per day.
Oxypurine excretion increased in all patients. If xanthine oxidase inhibition were the only effect of HPP and renal function were good, the increase
in hypoxanthine and xanthine excretions would be expected to balance the
decrease in urate output. We have rarely found this. In our initial studies
we may have encountered some loss of xanthine by precipitation from certain urine samples, and incomplete recoveries. We have since found that
887
XANTHINE OXIDASE INHIBITORS
Table 38.-Eflect
of 4-Hydroxypyrazolopyrimidine (HPP)
on Purine Metabolism in Gout
Patient, No.
Age, Race, Sex
Diagnosis
HPP
Days
mg./day
Rx
Serum
Uric Acid
Urine
Uric Acid
mg./day
Urine
Oxypurine
mg./day
H. C. S., A65086
55, W, M
Acute and
Chr. Arth.
0
4U0
4
8.7
4.4
560
212
21
102
W. R. B.,F45318
41, W, M
Chronic
arthritis
0
400
5
6.5
3.2
590
364
24
108
M. N. B.,84618
58, W, M
Renal stones
acute and
Chr. Arth.
0
203
400
12
10
8.7
6.25
3.7
610
440
290
11
52
100
J. E. E..A?Z670
40. W, M
Severe Arth.
tophi
++ +
0
x00
10
x.7
5.6
455
260
7=
75
J . C. P.,F88837
59, w, M
Acute and
Chr. Arth.
nephropathy
0
300
400
6
20
11.9
6.4
3.9
280
220
180
10
35
J . L. C., E22211
60, C, M
Chr. Arth.
tophi
0
800
7
9.3
7.2
430
575
8’
32
K. E. S.,F92133
w, M
Chr. Arth.
tophi
0
300
5
8.4
5.8
480
295
16*
51
G. B. C., I374431
44, w, M
2nd acute
attack
0
900
6
11.1
4.6
890
335
14
75
75,
++++
+
2*
*Constant Protein -Constant Purine (“Nutrament” based) Diet.
the balance may occasionally be nearly perfect in patients with good renal
function immediately after HPP is given, but generally a major deficit of
oxypurines does exist. In patients with renal damage or with marked
tophaceous involvement the oxypurine increment/urate decrement ratio is
generally well below 1, perhaps below 0.5. We have also observed a number
of different kinds of response which suggest that total purine excretion may
decline as a function of time. This may sometimes be a matter of depletion
of stored urates but, curiously, the change may be in the oxypurines rather
than in the urate, so that after some months the balance may not be the
same as it was initially.
Paper and column chromatographic analyses of urine have indicated that
there are only trivial changes of other purine bases in the urine. One would
not anticipate any major change of these on the basis of the action of the
drug.
We have observed a few patients who have not responded particularly
well. In one patient, for example (Table 38, J. L. C . ) ,with chronic tophaceous
gout of severe degree and some limitation of renal function, who received
800 mg. of HPP per day, the serum urate level dropped from 9.3 mg. per
cent to 7.2 mg. per cent, but the urinary uric acid actually increased, and
there was only a modest increase in the urinary oxypurines. The atypical
responses have, by and large, been in patients with tophaceous gout with
some degree of renal involvement.
We observed a few attacks of gout early in the period after HPP was
started. In our first series of 14 subjects three had attacks in the first
888
GOUT AND PURINE METABOLISM
40 days. At that time we were giving HPP alone. It did not seem that the
rate of attacks was any greater than it had been before therapy, but in
some patients attacks of gout continued with about the established frequency. Because of this, we have subsequently added maintenance colchicine to the therapy of many subjects and the frequency of acute attacks has
been far less. The acute attacks have occurred at serum levels well within
the normal range; in fact we have observed attacks with serum levels as
low as 2 mg. per cent.
One patient was of particular interest. H e had had gout for some years,
with hypertension and renal involvement, and was not satisfactorily controlled by uricosuric therapy. H e was given HPP and almost immediately
began having staccato attacks of gout. These continued for about six weeks
in spite of regulation of the urate level at 5 mg. per cent. It was necessary
to terminate HPP therapy. On return to uricosuric therapy he has now had
only one attack of any severity in about a year and a half.
At the time we were unwilling to increase the dose of HPP to a level
which might have brought his serum urate value lower, because we were uncertain whether we might have produced hyperxanthinemia of significant degree and whether he was now having a different type of gouty attack based
on xanthine crystals rather than sodium urate crystals. We have subsequently
measured the plasma oxypurine levels in patients receiving HPP. The normal
values range from about 0.1 to 0.3 mg. per cent. During HPP therapy values
have generally been around 0.4 and 0.5 mg. per cent. Others7g8 have seen
values as high as 0.9 mg. per cent or rarely even 2 mg. per cent but xanthine
levels certainly do not rise to match the uric acid levels that existed before
therapy. The absence of a more dramatic rise of oxypurines apparently has its
basis in a very high renal clearance of hypoxanthine and xanthine.9
One of the fears has been that the increase in urinary oxypurines might
give rise to complications based on the insolubility of xanthine. The increment in oxypurines favors xanthine slightly; in our experience perhaps 55 to
60 per cent of the increase has been in xanthine. Hypoxanthine is a very
soluble compound; one would not be much concerned about even very high
levels of hypoxanthine in the urine, but xanthine is not very soluble in acid
or neutral urine. Furthermore, the pK of xanthine is 7.7 compared with a
pK of uric acid which is about 5.4. Alkalinization of the urine, therefore,
would have to be carried to impractically high levels to have any appreciable effect on xanthine solubility. The urinary levels of xanthine that may
be observed with HPP therapy approach those seen in xanthinuric subjects
who form xanthine stones. In spite of this we have not seen any xanthine
sludge or stones. We have watched for signs of toxicity very carefully, but
have seen no increase in urinary sedimentary abnormalities in any of the
patients treated. Three of some 60 patients who have received HPP for
various reasons have shown minor signs of toxicity. In one case there was a
skin rash, which did not recur when the drug was later restarted; another
patient had a drug fever which did not recur when HPP was reinstituted;
889
XANTHINE OXIDASE INHIBITORS
and one patient had a transient drop in white count which did not recur
when the drug was readministered.
In all three of these instances the patients were receiving other compounds as well as HPP, and it was not certain in our minds that HPP was
involved. Some patients had minimal gastric irritation at one time or another.
This has not been a serious problem in our minds and DY.Rundles, who
has been in the field of cancer chemotherapy for a long time and is very
alert to the problems of intolerance and toxicity, is extremely sanguine about
this compound up to this point.
Our experience now ranges up to almost two and a half years. No really
serious side effects have been observed during this time. Of course one must
temper one’s enthusiasm in recognition of the possibility of late toxic effects; for example, it is possible that this compound is incorporated into
nucleic acids, although it is converted to a ribonucleotide so sparingly, at
least in vitro, that it does not seem likely that much HPP is going to enter
the nucleic acid pool.
One might view this poor conversion to the ribonucleotide stage as unfortunate in one sense, because the ribonucleotide derivative is a very potent
pseudo-feedback inhibitor of the first step of purine biosynthesis in 0itr0.l~
This inhibition may be an explanation for what appears to be a total reduction in rate of purine synthesis in some patients, but at the present time that
is not certain. Perhaps reutilization of hypoxanthine and a resetting of the
feedback by natural purine ribonucleotides also occur.
ACKNOWLEDGMENTS
Figures 118, 120, 121, 122, and Table 38 reprinted from Rundles et a14 with permission
of the editor and publisher of the Transactions of the Association of American Physicians.
REFERENCES
1. Zuckerman, R., Drell, W., and Levin,
M. H.: Urinary Purines in Gout; Effect of Azaserine. Arth. iL7 Rheumat.
2:46, 1959.
2. Grayzel, A., Seegmiller, J. E., and
Love, E.: Suppression of Uric Acid
Synthesis in the Gouty Human by
the Use of 6-diazo-5-0x0-L-norleucine. J. Clin. Invest. 39:447, 1960.
3. Feigelson, P., Davidson, J. D., and
Robins, R. K.: Pyrazolopyrimidines
as Inhibitors and Substrates of Xanthine Oxidase. J. Biol. C h m . 226:
993, 1957.
4. Rundles, R. W., Wyngaarden, J. B.,
Hitchings, G. H., Elion, G. B., and
Silberman, H. R.: Effects of a Xanthine Oxidase Inhibitor on Thiopurine Metabolism, Hyperuricemia
and Gout. Trans. Assn. of Am. Phys.
LXXVI, 126: 1963.
5. Wyngaarden, J. B., Rundles, R. W.,
Silberman, H. R., and Hunter, S.:
Control of Hyperuricemia with Hydroxypyrazolopyrimidine, a Purine
Analogue which Inhibits Uric Acid
Synthesis. Arth. 67 Rheumat. @:306,
1963.
6. Rundles, R. W., Silberman, H. R.,
Hitchings, G. W., and Elion, G. B.:
Eftects of Xanthine Oxidase Inhibitor
on Clinical Manifestations and Purine Metabolism in Gout. Ann. Int.
Med. 60:717, 1964.
7. Klinenberg, J. R., Goldfinger, S., Miller,
J., and Seegmiller, J. E.: The Eff-ectiveness of a Xanthine Oxidase Inhibitor in the Treatment of Gout,
890
Arth. G Rheumat. 6:779, 1963.
8. Yii, T. F., and Gutman, A. B.: Effect of
Allopurinol (4-hydroxyppazolo (3,4d)-pyrimidine) on Serum and Urinary Uric Acid in Primary and Secondary Gout. Am. J . Med. 37:885,
1964.
9. Goldfinger, S., Klinenberg, J., and Seegmiller, J. E.: The Renal Excretion of
GOUT AND PURINE METABOLISM
Oxypurines. Clin. Res. 12:252, 1964.
10. McCollister, R. J., Gilbert, W. R., Jr.,
Ashton, D. M., and Wyngaarden, J.
B.: Pseudofeedback Inhibition of
Purine Synthesis of 6-Mercaptopurine
Ribonucleotide and other Purine
Analogues. J . Biol. Chem. 239:1560,
1964.
DR. SMYTH: We are all grateful to Dr. Wyngaarden for introducing for
consideration this exciting new area for research in purine metabolism.
I think it opens tremendous vistas for further exploration. One of the teams
that has been in the forefront of this exciting field of exploration has been
the group at the NIH, Dr. Klinenberg, Dr. Seegmiller and Dr. Goldfinger,
who presented some of their preliminary studies in Boston in December,
1963. We would like to ask Dr. Klinenberg to bring us up to date on their
experiences with this subject.
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