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Effect of desacetylmethylcolchicine Colcemide in acute gouty arthritis.

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Effect of Desacetylmethylcolchiicine (Colcemide) in
Acute Gouty Arthritis
By DAVID
H. NEUSTADT
Desacetylmethylcolchicine (Colcemide)
compared favorably with colchicine in
the treatment of acute gout in 17 patients. Although gastrointestinal s y m p
toms were avoided, other more serious
undesirable effects such as bone-marrow
depression a n d alopecia are cited.
Disacetylmethylcolchicina IColcemide)
esseva favorabile in comparation con
colchicina in le tractamento de gutta
acute in 17 patientes. Ben q u e symptomas gastrointestinal esseva evitate,
altere plus sene effectos adverse, per
exemplo depression del medulla ossee e
alopecia, es citate.
T
HE PURPOSE of this study is to evaluate the clinical and biochemical
effects of desacetylmethylcolchicine ( Colcemide ) in acute gouty arthritis.
An attempt is made to compare the therapeutic properties and side effects of
desacetylmethylcolchicine with those of colchicine in patients treated with
both agents.
Desacetylmethylcolchicine (hereafter referred to as Colcemide ) is a natural alkaloid which has been isolated from the plant Colchicum autumnale.’
The compound differs chemically from colchicine in that a methyl group replaces an acetyl group at the nitrogen position of the colchicine molecule.
CLINICAL MATERL4L AND
METHODS
Clinical Material
Observations are derived from a series of 22 acute attacks of gouty arthritis occurring
in 17 patients. Only patients with unequivocal acute gouty arthritis have been selected
for inclusion in this series. In three patients, two separate acute episodes were treated.
One patient afforded the opportunity of treating three distinct attacks. All other patients
were given one course of the drug for a single attack. The average known duration of
gout was 4.6 years. The age distribution of these patients ranged from 27 to 68 years.
There were 13 males and four females. Ten of these patients had previously received
colchicine for acute attacks. The majority of the patients also had received probenecid.
Method3 and Dosage
Criteria to determine clinical effects included a critical assessinent of pain and all
measurable indices of inflammatory articular involvement.
Side effects with special regard to any gastrointestinal manifestations were diligently
sought and recorded. Patients were requested to report any itching or changes in the
skin, mucous membranes or hair.
Certain laboratory information was obtained in 1.5 of the 17 patients, both before and
after therapy. These studies included: hemoglobin, total white blood cell count and
differential count, sedimentation rate, platelet count and serum iiric acid.
From the Department of Medicine, Utiiversity of Louisville School o f Medicine, Louis-
oille, Ky.
Presented in part before the International Congress of Rheumtic Diseases, Toronto,
Ontario, Canada, on June 26, 1957.
91
92
DAVID €1. NEUSTADT
Colcemide’ was supplied as an oral preparation in the form of a scored tablet containing 1 mg. of the substance. Treatment was initiated as soon as possible in every instance. The medication was started within twelve hours of the attack in the majority
and within twenty-four hours in a few. In two cases there was a delay of 48 and 72
hours, respectively.
Initially, the medication was given with instructions to take one tablet every hour
until either relief of pain or occnrrence of gastrointestinal symptoms, or a total of fifteen
tablets had been taken. Late in the study, four patients were given an initial dose of
4 mg., and then 1 mg. cvcry hour.
RFSUI~TS
Clinical Results
Striking subjective improvement occurred in 15 patients with 17 aciite attacks within 5 to 24 hours. Objective improvement took place more slowly
but was observed within 12 to 72 hours.
Table 1 lists the total dosage in mg., the therapeutic response, any side
effects, previous response to colchicine if taken and occurrence of side efiects
from colchicine. Response is graded as “Excellent,” “Good,” “Fair” or “No
effect.”An “Excellent” response indicates complete resolution of all evidence
of inflammatory articular features in 72 hours or less. “Good” is defined as
greatly improved in 73 hours with complete resolution within one week.
“Fair” described moderate improvement with partial amelioration of signs
and symptoms with full recovery within two weeks.
There was an “excellent” response in a total of 14 acute episodes in 11
patients. A “good“ response w a s obtained in 3 acute attacks in the same number of patients. There were two “fair” results, one of which occurred in a
patient who had obtained an “excellent” response in a previous attack;
the medication in the more recent instance was given 48 hours after
the onset of the attack. No effect occurred in two patients, in one of
whom two separate attacks were treated. All patients who derived excellent
results required a total dosage of 8 mg. or less, with an average of 6.5 mg.
The highest dosage given to obtain a “good“ response was 10 mg. In those
with “fair” results or “no effect,” dosage ranged from 7 to 15 mg., with
an average dosage of 10.8 mg. It is to be noted that gastrointestinal symptoms occurred only in those patients who had received the higher dosages.
Patients 13, 14, 16 and 17 (table 1 ) received 4 mg. stat doses, and all obtained excellent results with treatment. These individuals required therapy
over a very short period of time, varying from 1 to 3 hours to achieve maximum
benefit.
Table 2 is a summary of therapeutic responses and gastrointestinal side effects of Colcemide, compared with those from colchicine. A comparison of
the therapeutic responses reveals no significant superiority of either drug.
However, there is an impressive difference in the frequency of occurrence of
gastrointestinal manifestations.
No patient who attained an “excellent” response with colcemide displayed
~~
-
~.... .
“Colcenlide used in this investigation was supplied through the courtesy of Ilr. C.
Sullivan, Ciba Pharmaceutical Co., Summit, N.J.
H.
93
E F F E C T OF COLCEMlDE I N ACUTE GOUTY ARTHRITIS
TABLE1.-Results with Desacetylmethylcolchicine in 22 Attacks
Arthritis in 17 Subjects
Total
Patient Dosage
No.
(mg.)
Response
Side
Effects
Previous
Response to
Colchicine
2*
8
4. 6
Excellent
Excellent
-
Excellent
Excellent
3*
10.12
NoEffect
No Effect
I*
8. 7
ill
I . 6. 6
lhcellent
& Fair
Excellent
Mild
Diarrhea
None,
Nausea
1
,
9
EzreUent
Good
8
10
Good
9
10
11
8
7
15
Excellent
Excellent
NoEffect
12
13
14
5
51
6+
EzceUent
Excellent
Good
G
B
16
10
16
17
7
#
7t
Fair
Excellent
Excellent
Side EffecF
with Colchicine
Nausea & Diarrhea
Nausea. Vomitina
& Diarrhea
Never Given
~..
Excellent
Diarrhea
-
Not Givrn
Good
Diarrhea
Excellent
Nausea & Diarrhea
Slight
Nausea
-
Mild
Diarrhea
-
-
Nausea
-
Never Given
Never Given
Fair
Not Given
Never Given
Good to
Excellent
Good in Past
Not Given
Good
-
of
Acute Gouty
Remarks
N o advantage
Equal (without side
effecta)
Refractory t o both
Started 48 hrn. late in
2nd attack
Equal (without side
effects)
Equal (without side
effects)
Colchicine superior
-
-
Nausea. Vomiting
& Diarrhea
Recently n o effect
with Colchicine
Nausea & Cramps,
Equal (without side
effects)
Colchicine slightly
better: not taken
in two years
-
Slight Diarrhea
Nausea, Vomiting
& Diarrhea
Nausea &
Vomitina
Colcemide superior
(without side
effects)
‘ 2 attacks
t 3 attacks
# Including S t a t Dose 4 mu.
any discernible untoward reactions. One patient with a “good response developed mild nausea. Diarrhea occurred in only 3 treated attacks in two
patients, neither of whom responded to treatment. Nausea occurred in two
other patients who achieved “fair” results.
Of the 10 patients who had Colchicine in the past only one reported equivalent response without developing side effects. Some form of gastrointestinal
effect occurred in all others having an equivalent or satisfactory response.
Laboratoy Results
There were no appreciable alterations in white blood cell counts or differential counts. No significant change was found in sodium urate levels. Hemoglobulin and platelet counts also were unchanged.
Untoward Effects
There were no undesirable effects encountered in this series, other than
the occasional gastrointestinal complaints. However, a woman with chronic
tophaceous gout, not a member of this study group, was given Colcemide
for an acute exacerbation. Approximately three weeks after receiving 7 mg. of
the preparation she developed almost complete loss of scalp hair. She had also
94
DAVID H. NEUSTADT
TABLE2.-Summury of Eflects
Agents
of Desucetylmethylcolchicine Compared
with Colchicine
ISide Effects)
Vomiting
Diarrhea
Responae
No. of Attackb
Excellent
14 - 63.6'$0)
0
0
0
3 - 13.6v0
2 - 9.2%
1
0
2
0
0
-3 - 13.6%
22 100.04';
0
3
0
0
0
3
3
85 - 50r/,)
3
0
4
1
1
1
1
1
2
1
1
8
Nauaea
~
1)esacetylniethylcolchicine
(17 Patients)
Good
Fair
No Efiect
Total
Excdent
) 80%
Colchicinc
( 10 Patients)
Good
Fair
No Effect
Total
3 - 30%J
1 - 107;
1 - 10%
10 1cw;;,
6
1
3
taken large amounts of Colchicine just before the onset of depilation. Previous coiirses of Colchicine had been taken without any loss of hair. The
patient's hair gradually returned.
DISCUSSION
Any accurate appraisal of a new agent in acute gouty arthritis must be
based on its relative merits and risks as compared with drugs currently available. These special considerations include: ( 1) effectiveness in combating
acute attacks; ( 2 ) convenience of use for both doctor and patient; and (3)
undesirable side effects and potential toxicity. Colchicine, the traditional
measure, is undoubtedly the agent that must be challenged.
Although colchicine is an effective agent in the majority of acute attacks
of gouty arthritis, a high percentage of patients develop gastrointestinal
symptoms.*J In some of these, the associated nausea, vomiting and diarrhea
is of an extreme nature, which outweighs or at least markedly compromises
the benefits derived. In a few, in whom gastrointestinal intolerance is very
severe, and in some patients with gastrointestinal disease, oral colchicine
cannot be used.
Colsky and co-workers' first called attention to Colcemide as an effective
oral preparation that did not cause gastrointestinal side effects in the treatment of acute gout. Levin and others5 also reported that the oral preparation
produced favorable response without undesirable reactions in a small number of patients with acute gout.
The present preliminary study confirms these previous reports that Colcemide is an effective agent in combating the acute attack and rarely produces
gastrointestinal disturbances which frequently occur after colchicine.
Colcemide demonstrated certain definite advantages over colchicine. An
equivalent response was obtained more rapidly than with colchicine. This
reduced length of time for recovery from the acute arthritis was even more
impressive in those patients given larger initial doses. The lack of troublesome gastrointestinal disturbances also favorably influenced the length of
time for recovery. Two patients obtained prompt relief from acute attacks
EFFECT OF OLCEMIDE IN ACUTE GOUTY ARTHRITIS
9.5
with colchicine but were prevented from returning to work for a minimum
period of 7 to 10 days because of residual gastrointestinal symptoms difficult
to control. After treatment with Colcemide, they were able to return to work
in 3 and 5 days, respectively. In one patient with chronic peptic ulcer disease,
small doses of colchicine orally caused nausea and violent vomiting, and on
one occasion provoked gastrointestinal bleeding. This patient was given Colcemide with an excellent response, without any evident aggravation of his
underlying gastrointestinal disorder.
The most important of the potential disadvantages of Colcemide, as compared with colchicine, is the possible effect on the blood picture. Experimental studies in animals, as well as studies conducted with this drug in
patients with leukemia and related blood disorders, have definitely established
that this agent possesses a potent bone marrow action, if it is given in large
enough dosage."-" Although no cases have been formally reported, I have
been advised of two patients with gout who developed granulocytopenia with
anemia after receiving frequent courses of relatively high doses of Colcemide.12
However, the possibility of any bone marrow suppression from Colcemide
in ordinary clinical usage for an acute gouty attack would seem remote.
The second potentially serious side reaction worthy of comment is the
question of loss of hair. Mikkelsen and othersI3 reported a case of total
alopecia in a man following therapy with 14 mg. of Colcemide. Although
hair subsequently regrew, the experience was understandably an alarming
one. It is noteworthy that this patient also received colchicine, prednisone
and probenecid. Alopecia has not been observed, to my knowledge, after
prednisone or probenecid in clinical dosage. However, alopecia is listed in
Goodman and Gilman as a rare side reaction of c~lchicine.'~*'~
Others have observed loss of hair in patients taking Colcemide, but this
occurred in patients with leukemic disorders.6J'**1Loss of hair in leukemia is
not considered an uncommon clinical feature, when no drug can be invoked as an etiologic agent.
The manufacturers of Colceinide state that as of June 10, 1947, they have
been informed of a total of four cases of alopecia occurring after use of the
drug.12 The preparation, according to their records, has been administered to
more than 250 patients with gout. The four patients in whom alopecia developed received a dose of 10 mg. daily or more. In each instance, hair
regrew when the drug was discontinued or the dosage reduced. It is possible
that the use of smaller doses, which seem wholly effective for acute gout in
this series, would reduce the frequency of this undesirable effect. However,
in view of the patient who developed alopecia after only 7 mg. of Colcemide
and considering the usual delay in onset of loss of hair following the ingestion of the substance, I believe that this complication may represent a
form of hypersensitivity to the drug. Then, of course, the reaction would
be unrelated to the amount of the drug, and its occurrence completely unpredictable.
SUMMARY
1. Desacetylmethylcolchicine ( Colcemide ), a natural alkaloid, chemically
96
DAVID H. NEUSTADT
similar to colchicine, was administered orally to 17 patients in a series of
22 attacks of acute gouty arthritis.
2. Response to Colcemide was comparable to that with therapeutic doses
of colchicine, without the undesirable gastrointestinal symptoms, which frequently occur after colchicine.
3. Continued cautious investigation with this agent is necessary to determine the frequency of such serious reactions as bone marrow depression and
alopecia, which would markedly limit its useflilness.
REFERENCES
I. Santavy, F. and Reichstein, T.: Isolierung nener Stoffe aus dcn Samen
der Herbstzeitlose Colchicuin antumnale L. Substanzen der Herhstzeitlose
imd ihre Derivate, Helvet, Chim acta.
33:1606, 1950.
2. Gutman, A. B. and Yii, T. F.: Current
principles of inanagement in gout.
Am. J. hled. 1.3~744,1952.
3. Steinbrocker, O., Neustadt, D. H. and
Ehrlich, M.: Rutazolidin in treatment
of gout with comparison with other
agents. M. Clin. N. America ,38:611,
1954.
4. Colsky, J., Wallace, S. and Ranowitch,
M. hl.: Dcsacetylmethylcolchicine in
acutc Gouty arthritis. New England
J. Rfcd. 253~730,1955.
5. Levin, hl. H., Marcus, S., Strangt:, D.
and Sweezey, A. L.: Therapeutic
trials in acute gouty arthritis. Ann.
Rheiimat. Dis. 15233, 19.56.
0. Hock, H. E. and Gross, R.: Colchicinwirkungen u n d Granulocytopoese:
Klinesche und Experimentelle Beobachtw~genmit Substnnz Flaw Colchicum autumnale. Klin. Wchnschr.
31~816,1953.
7. Lichtman, A.: Effect of Ikmecolchin
( desmcthylcolchicine ) on peripheral
blood and bone marrow in rabbit and
cat. Thesis. Zurich, 1954.
8. .Iloe\chlin, S., Meyer, H. and Lichtman,
A.: Ein news Colchicium-Nehenidkaloid (Demecolin Ciba) als Cytostaticiim i n y e l o i s c h e r leukamen.
Schweig. med. Wchnschr. 8.3~990,
1953.
9. Leonard, B. J. and Wilkinson, J. F.:
Iksacetylmethylcolchicine in treatment of inyeloid leukemia. Brti. Med.
J. 1:874, 1955.
10. Sheehy, T. \V. and Ransone, J. W.:
D c m e c o l c i n e (Colceinid) toxicity.
Arch. Int. Med. 100~85,1957.
11. Piney, A.: Treatment of chronic myrloid lcilkaemia with a colchicum derivitive. Acta Haemat. 14~83,1955.
12. Siilliwin, C. H.: Personal conmimication.
1.7. hlikkelsen, W. M., Salin, R. W. and
I h f f , I. F.: Alopecia totalis after
tles.icetyliiiethylco1chicine therapy of
acute gout. New England J. llctl.
2.55769, 1956.
14. Goodman, L. and Gilman, A.: Thr
P1iarm:icological Basis of Therapeutics. New York, The Macmillan Co.,
195.5.
15. Brown, W. 0. and Seed, L.: Effect of
colcliicine on human tissues. Am.
J. Clin. Path. 15189, 1945.
Dcrzjitl H . Neustndt, M.D., lnstrrictor in Medicine, University
of Lorcisvillc, Louisville,
Ky.
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