1. health and fitness
2. disease

165
Treatment of Cutaneous Leishmaniasis with Allopurinol and Stibogluconate
S. Martinez, M. Gonzalez, and M. E. Vernaza
From the Department of Internal Medicine, University of Cauca,
Popayan, and the University Hospital San Jose of Popayan,
Popayan, Colombia
All forms of leishmaniasis are treated primarily with pentavalent antimonial compounds. Although these compounds have
significant toxicity and are expensive, they have remained the
mainstay of therapy because alternatives such as amphotericin
B and pentamidine have similar deficiencies. Oral agents such
as ketoconazole have not shown consistent efficacy in human
trials.
Allopurinol has been studied for the treatment of leishmaniasis because of its biochemical mechanism of action, its activity
in vitro, and growing evidence of its clinical efficacy [1]. The
investigation reported herein was undertaken by the World
Health Organization in collaboration with investigators from
the University of Cauca, Popayan, Colombia, to study the efficacy of allopurinol in the treatment of cutaneous leishmaniasis
and by investigators from the Cayetano Heredia University in
Lima, Peru, to investigate the efficacy of this agent in mucocutaneous leishmaniasis. The latter results will be reported separately.
The biochemical basis of the therapeutic activity of allopurinol, as currently understood, is the ability of leishmania to
metabolize certain purine analogs to analogs of adenosine nucleotides and incorporate these into RNA. When this occurs,
protein synthesis is halted [1-3] . Although a number of purine
analogs can inhibit the growth of leishmania, pyrazolopyrimidines have received the most attention as potential therapeutic
agents because of their lack of toxicity. Allopurinol has served
as the prototype pyrazolopyrimidine. It inhibits the growth of
leishmania in vitro and in tissue culture [4-6], and antimony
is synergistic in combination with allopurinol against leishmania in tissue culture [7].
In clinical studies, allopurinol was found to be effective for
the treatment of visceral leishmaniasis in India [8], Africa [9,
10], and Italy [11], where it has been used in combination with
pentavalent antimony in patients whose disease was resistant to
antimony. A study from Saudi Arabia [12] showed that allopurinol and ketoconazole were effective as therapy-for visceral leishmaniasis in a renal transplant recipient. A study of persons infected with HIV showed the allopurinol/antimony combination
was effective in four of five patients treated for 4 weeks and
one of six patients treated for 3 weeks [13]. In a case report of
visceral disease in a patient with AIDS, treatment with allopurinol/antimony was curative [14]. Two other patients with AIDS
were treated with allopurinol alone; one was cured, and the
other's infection was controlled by the treatment [15].
An earlier study from Colombia demonstrated that the combination of allopurinol and meglumine antimoniate was significantly more effective than antimony alone in the treatment of
cutaneous disease [16]. In a case report of cutaneous leishmaniasis [17], cure was achieved with allopurinol alone. Most recently,
a study in Iran showed allopurinol to be efficacious in 24 of 25
patients who had long-term chronic cutaneous leishmaniasis that
was resistant to all other forms of treatment [18].
Herein, we present a randomized, controlled study in which
stibogluconate alone is compared with allopurinol and stibogluconate for the treatment of cutaneous leishmaniasis; it shows
the combination to be superior to antimony alone.
Methods
Received 11 March 1996; revised 22 October 1996.
Reprints or correspondence: Dr. S. Martinez, Calle 5 2 No. 3-47, P.O. Box
1945, Popayan, Colombia.
Clinical Infectious Diseases 1997; 24:165-9
1997 by The University of Chicago. All rights reserved.
1058-4838/97/2402-0012$02.00
Trial design. We conducted this trial, which was an openlabel, randomized clinical trial, to evaluate the safety, tolerability, and efficacy of stibogluconate alone and in combination
with allopurinol in patients with cutaneous and mucocutaneous
leishmaniasis. Forty-nine patients received stibogluconate
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We conducted a randomized, controlled study in southern Colombia to determine if the addition
of allopurinol to stibogluconate was superior to stibogluconate alone in the treatment of cutaneous
leishmaniasis. Lesions that healed after a 3-month course of therapy and remained so during a
1-year period of follow-up were considered cured. The cure rate for patients treated with stibogluconate was 39%; the addition of allopurinol increased this rate to 71% (P = .005). For the treatment
of cutaneous leishmaniasis, the combination of allopurinol and stibogluconate is significantly more
effective than is stibogluconate alone. These results support those of other clinical studies in which
allopurinol and stibogluconate were shown to be superior to stibogluconate alone. The aggregate
data support the use of allopurinol as an inexpensive, orally administered agent that can be used
as an adjunct to stibogluconate or, perhaps, other oral agents in the treatment of cutaneous leishmaniasis.
166
Martinez, Gonzalez, and Vemaza
Table 1. Characteristics of patients who received allopurinol for
treatment of leishmaniasis.
No. (%) in indicated treatment group
Variable
Gender
Male
Female
Age (y)
Under 18
18 —27
28-37
38 —47
48-57
>57
Race
Black
White
Native
Occupation
Farmer
Soldier
Others
Stibogluconate
(n = 49)
Stibogluconate + allopurinol
(n = 51)
44 (90)
42 (82)
5 (10)
1 (2)
9 (18)
0
32
7
6
1
2
32
(65)
(14)
(12)
(2)
(4)
(65)
37
9
1
2
2
36
(73)
(18)
(2)
(4)
(4)
(71)
12 (25)
5 (10)
26 (53)
12 (24)
3 (6)
21 (41)
19 (39)
4 (8)
16 (31)
14 (27)
other signs of inflammation and a negative culture of the healed
lesion 3 months after the completion of treatment). Improvement was defined as a reduction in the size of a lesion 3 months
after the end of therapy, incomplete scarring, or the persistence
of parasites in a culture of a healed lesion or a healing lesion.
Failure was defined as the absence of change in a lesion and
the persistence of parasites in culture 3 months after the end
of therapy. Patients with multiple lesions were not considered
to be cured unless all lesions were healed.
Statistical analysis. A master randomization list was generated by computer at the Department of Statistics at Cauca
University. Patients were randomized to receive stibogluconate
alone or stibogluconate plus allopurinol after signing a consent
form. The x 2 test was used to detect differences between the
two treatment groups.
Results
Patient characteristics. One hundred patients were studied from May 1989 through December 1991. Eighty-six of
the patients were male, and their ages ranged from 18 years
to 57 years. All patients were from the southern Pacific coast
of Colombia. Leishmaniasis was detected by examination of
a smear, by culture, or by examination of a biopsy specimen;
only patients who had received no previous therapy were
included. Approximately one-half (47%) of the patients were
farmers, 35% were soldiers, and the remaining 18% had diverse occupations. Two-thirds were black; one-fourth were
white; and the remaining 9% were of native origin. No pa-
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alone, and 51 received the combination regimen. The protocol
was written and agreed upon by the participating investigators
and consultants at a meeting held in Lima, Peru, in April 1988.
It was subsequently approved by the Tropical Disease Research
Section of the World Health Organization and is on file in
Geneva. Herein, we report only the results of the trial for
Patients with cutaneous leishmaniasis.
Patients. Patients were excluded from the trial if they did
not give written informed consent; if they had a known or
suspected allergy to antimony or allopurinol; if they were pregnant or nursing; if they had serious concomitant diseases or
any disease other than leishmaniasis requiring treatment; or if
they had a preexisting rash or another disease of the skin. To
be enrolled, patients had to have body weights within 20% of
the ideal weights for their heights.
Drug administration. Allopurinol was given orally for 15
days in a dosage of 20 mg/(kg • d) in four divided doses. Stibogluconate (Pentostam, kindly donated by the Burroughs Wellcome Company [now Glaxo-Wellcome], Research Triangle
Park, NC) was given by injection in a dosage of 20 mg/(kg • d)
for 15 days.
Evaluation of patients. All patients received complete
physical examinations before entering the study. Since the
village in which they lived was far from major medical facilities, follow-up was conducted by a physician (S. M.) who
visited the patients monthly. Clinical evaluations were performed at intervals of 1 month, 3 months, 6 months, and 12
months after the administration of the study drug. Evaluations
included a complete history, physical examination, and electrocardiography.
Laboratory studies were performed within the start of treatment and were repeated on days 7 and 15; these studies included measurements of serum electrolytes, tests of liver and
renal function, a complete blood count, hemoglobin and hematocrit determinations, a platelet count, and urinalysis. Evaluation of the cutaneous lesions, including culture, biopsy, and
measurements of the diameter, was performed before each patient's entry into the study, on days 7 and 15, and at 1, 3, 6,
and 12 months thereafter.
Diagnostic criteria. At the time of entry into the study, a
biopsy specimen of each lesion was obtained for smear preparation, histopathologic examination, and culture. Leishmania braziliensis panamensis was identified in all but three specimens;
Leishmania braziliensis braziliensis was recovered from these
three specimens. All isolates were identified by isoenzyme
typing at the Centro Diagnostico Immunomicrobiologico in
Popayan, Colombia. The leishmanin test was performed for all
patients. For patients to be included in the study, evidence of
leishmania in a smear, a biopsy specimen, or a culture was
required.
Evaluation of efficacy. Cure was defined as a complete
clinical and parasitological response without relapse during 1
year of follow-up (i.e., complete healing and scarring of a lesion
in association with the disappearance of edema, induration, and
CID 1997;24 (February)
Allopurinol for Cutaneous Leishmaniasis
CID 1997;24 (February)
Table 2. Physical findings for patients with cutaneous leishmaniasis
who were treated with stibogluconate alone or with stibogluconate
plus allopurinol.
167
Table 4. Clinical results for patients with cutaneous leishmaniasis
who were treated with stibogluconate alone or stibogluconate plus
allopurinol.
No. (%) in indicated treatment group
binding
Stibogluconate
(n = 49)
32 (65)
9 (18)
6 (12)
0
2 (4)
32 (63)
8 (16)
6 (10)
6 (12)
0
6 (12)
28 (57)
15 (31)
2 (4)
7(14)
5 (10)
29 (57)
13 (30)
0
10 (20)
5 (10)
38 (76)
5 (10)
1 (2)
2 (4)
33 (65)
15 (29)
1 (2)
* Some patients had multiple lesions.
t Mean size of the lesions when the patients had more than one.
tients had mucocutaneous or visceral leishmaniasis. The age
ranges of the patients in each treatment group were comparable, as were the racial distributions (table 1).
Clinical manifestations of leishmaniasis. The number, location, and size of lesions did not vary significantly between
the groups (table 2). All patients had leishmania identified in
a smear, a culture, or a biopsy specimen (table 3); most had
positive leishmanin tests. Smears and biopsy yielded the best
diagnostic data. There were fewer culture-positive patients,
probably because of the high rate of bacterial contamination
of the cultures. The length of time that the lesions had been
present was similar for both groups (data not shown); most of
the patients had had the disease for months.
Clinical results. The clinical outcomes are shown in table
4. The addition of allopurinol to stibogluconate resulted in an
Stibogluconate
(n = 49)
Result
19
7
21
1
1
Cure
Relapse
Treatment failure
Patients lost to follow-up
Withdrawal from study
because of toxicity
(39)
(14)
(43)
(2)
(2)
Stibogluconate + allopurinol
(n = 51)
36
7
6
2
0
(71)
(14)
(12)
(4)
increase in the cure rate (from 39% to 71%). The relapse rate
was the same for both groups, although the failure rate was
significantly higher for the group treated with stibogluconate
alone (43%) than for the group treated with both drugs (12%).
Statistical evaluation of these outcomes showed that therapy
with the combination of stibogluconate/allopurinol was superior to that with stibogluconate alone (P = .005).
For ethical reasons, this study did not include an untreated
group of patients. However, a previous study done in this same
general geographic area [17], which included patients who refused therapy, showed that no spontaneous healing occurred
among these patients (0 of 17 patients) during the year of
follow-up.
Toxicity. Clinically important side effects were observed
only for the group of patients who received stibogluconate
alone (table 5). One patient developed severe chemical hepatitis
with neurological manifestations, and treatment was stopped
after 7 days. The cause of this adverse event is unclear, but it
was not believed to be related to antileishmanial therapy.
There was an increase in the frequency of eosinophilia and
rash in the group of patients who received allopurinol. The
Table 5. Toxicities among patients with cutaneous leishmaniasis
who were treated with stibogluconate alone or stibogluconate plus
allopurinol.
No. (%) in indicated treatment group
Table 3. Diagnostic procedures positive for leishmania among patients treated for cutaneous leishmaniasis with stibogluconate alone
or stibogluconate plus allopurinol.
No. (%) in indicated treatment group
Procedure
Smear
Culture
Biopsy
Leishmanin test
Stibogluconate
(n = 49)
38
22
39
42
(78)
(45)
(79)
(86)
Stibogluconate + allopurinol
(n = 51)
40
22
45
39
(78)
(43)
(88)
(76)
Type of toxicity
Allergic
Hepatic*
Eosinophilia
Rash
Renal
Cardiovascular
Neurological*
Total
Stibogluconate
(n = 49)
0
5
1
1
2
2
1
12
(10)
(2)
(2)
(4)
(4)
(2)
(25)
Stibogluconate + allopurinol
(n = 51)
1
3
9
14
0
0
0
27
(2)
(6)
(18)
(28)
(53)
* One patient had both severe chemical hepatitis and neurological manifestations, and it was necessary to stop treatment after 7 days.
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No. of lesions
One
Two
Three
Four
Five
Site of lesions*
Face
Arms
Legs
Chest
Other
Size of lesions (cm)t
0-2
2 —4
4-6
>6
Stibogluconate + allopurinol
(n = 51)
No (%) in indicated treatment group
168
Martinez, Gonzalez, and Vernaza rashes were generally macular or erythematous. There was no
urticaria or desquamation. These cutaneous manifestations
were mild, did not require treatment, and are consistent with the
known side effects of allopurinol. Aside from the occurrence of
eosinophilia, there were no statistically significant differences
between the two groups in terms of side effects.
Discussion
of 80%, equal to that of the allopurinol/antimony combination.
One case report from the United States described cure with
allopurinol alone [17]. A patient with a serious case of cutaneous leishmaniasis on the leg, for whom the correct diagnosis
was made just before an amputation was to be done, was completely cured with allopurinol alone (S. M., personal communication).
The data on cutaneous leishmaniasis, taken in aggregate,
suggest that allopurinol alone may be effective in certain instances; however, in general, this drug will not be efficacious
in the absence of antimony or another therapeutic agent.
Allopurinol has been used to treat gout in humans for more
than three decades. It has low toxicity, is available as a generic
compound throughout the world, and is inexpensive. The results of the present study, in addition to those previously reported [16, 18], indicate that it is possible to treat cutaneous
leishmaniasis with allopurinol at a dosage of 300 mg four times
a day for 15 days in combination with pentavalent antimony.
The cost of this amount of generic allopurinol is quite low (i.e.,
<$2 for the total dose of allopurinol). The use of allopurinol as
an adjunct to antimony or another oral agent in the treatment
of cutaneous and visceral leishmaniasis is worth further exploration.
References
1. Man JJ. Purine analogs as chemotherapeutic agents in leishmaniasis and
American trypanosomiasis. J Lab Clin Med 1991; 118:111-9.
2. Looker DL, Berens RL, Man JJ. Purine metabolism in Leishmania donovani amastigotes and promastigotes. Mol Biochem Parasitol 1983; 9:
15-28.
3. Marr JJ, Berens RL. Pyrazolopyrimidine metabolism in the pathogenic
trypanosomatidae. Mol Biochem Parasitol 1983; 7:339-56.
4. Berens RL, Man JJ, Nelson DJ, LaFon SW. Antileishmanial effect of
allopurinol and allopurinol ribonucleoside on intracellular forms of
Leishmania donovani. Biochem Pharmacol 1980; 29:2397-8.
5. Man JJ, Berens RL, Nelson DJ, et al. Antileishmanial action of 4-thiopyrazolo (3,4-d)pyrimidine and its ribonucleoside. Biological effects and
metabolism. Biochem Pharmacol 1982; 31:143-8.
6. La Fon SW, Nelson DJ, Berens RL, Man JJ. Inosine analogs: their metabolism in mouse cells and in Leishmania donovani. J Biol Chem 1985;
260:9660-5.
7. Martinez S, Looker DL, Berens RL, Marr JJ. The synergistic action of
pyrazolopyrimidines and pentavalent antimony against Leishmania
donovani and L. braziliensis. Am J Trop Med Hyg 1988;39:
250 — 5.
8. Jha TK. Evaluation of allopurinol in the treatment of kala-azar occurring
in North Bihar, India. Trans R Soc Trop Med Hyg 1983; 77:204-7.
9. Kagar PA, Rees TH, Welide BT, Hockmeyer WT, Lyerly WH. Allopurinol
in the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg
1981;75:556-9.
10. Chunge CN, Gachihi G, Muigai R, et al. Visceral leishmaniasis unresponsive to antimonial drugs. III. Successful treatment using a combination
of sodium stibogluconate plus allopurinol. Trans R Soc Trop Med Hyg
1985; 79:715-8.
11. Ragusa R, Di Cataldo A, Samperi P, Schiliro G. Treatment of visceral
leishmaniasis with meglumine and allopurinol [letter]. Am J Dis Child
1993; 147:611-2.
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
Leishmaniasis is an important disease in the developing
world and has been designated as one of the five most important
diseases worldwide by the World Health Organization. The
clinical forms of leishmaniasis are treated with parenteral pentavalent antimony. This treatment has not changed during the
past half century despite the associated toxicity, limited supply
of the drug, and the expense. Newer regimens have decreased
toxicity, but their use has not altered the unfavorable effects
of treatment with this heavy metal.
Therapy with allopurinol was evaluated because of the body
of data from in vitro and in vivo studies, which suggest that
the drug may be clinically useful when combined with antimony [1]. Since the inception of this study, two other clinical
studies have been reported that document the efficacy of allopurinol for the treatment of cutaneous leishmaniasis. The first
study, also done in Colombia, documented the efficacy of allopurinol (at the same dosage used in the present study) in combination with pentavalent antimony for treatment of this disease
[16]. The addition of allopurinol to the regimen doubled the
cure rate (74% of the patients who received the combination
regimen were cured vs. 36% who received pentavalent antimony alone). None of the untreated patients in that study were
cured, and no significant toxic effects were observed.
In the second study, allopurinol was used to treat cutaneous
disease in Iran, and 24 of 25 patients whose infections had
been resistant to chemotherapy for the preceding 10 years were
cured [18]. The present study represents a third clinical trial.
The addition of allopurinol to a preparation of antimony (in
this instance, Pentostam) clearly is beneficial. The cure rate
was substantially increased, and there was no significant toxicity due to the addition of allopurinol.
Could allopurinol be used alone for treatment of leishmaniasis? In the instance of mucocutaneous disease, the answer appears to be no. A recent study did not show improvement in
the cure rate by the addition of allopurinol (E. A. LlanosCuentas et al., unpublished data). For patients with visceral
disease [8-14], the addition of allopurinol to antimony clearly
was efficacious; in one case [16], allopurinol therapy alone
showed benefit. There is not enough evidence to suggest that
allopurinol alone can be used to successfully treat visceral
disease.
In one clinical study from Colombia [16], treatment of cutaneous disease with the combination of allopurinol plus antimony resulted in a significantly higher cure rate. This study
also showed that allopurinol therapy alone yielded a cure rate
CID 1997;24 (February)
CID 1997;24 (February)
Allopurinol for Cutaneous Leishmaniasis 12. Halim MA, Alfurayh 0, Kalin ME, Dammas S, Al-Eisa A, Damanhouri
G. Successful treatment of visceral leishmaniasis with allopurinol plus
ketoconazole in a renal transplant recipient after the occurrence of pancreatitis due to stibogluconate. Clin Infect Dis 1993;16:397-9.
13. Laguna F, LOpez-Velez R, Soriano V, Montilla P, Alvar J, GonzalezLahoz JM. Assessment of allopurinol plus meglumine antimoniate in
the treatment of visceral leishmaniasis in patients infected with HIV. J
Infect 1994;28:255-9.
14. Smith D, Gazzard B, Lindley RP, et al. Visceral leishmaniasis (kala azar)
in a patient with AIDS. AIDS 1989;3:41-3.
169
15. Dellamonica P, Bernard E, Le Fichoux Y, et al. Allopurinol for treatment
of visceral leishmaniasis in patients with AIDS. J Infect Dis 1989;160:
904 —5.
16. Martinez S, Marr JJ. Allopurinol in the treatment of American cutaneous
leishmaniasis N Engl J Med 1992; 326:741-4.
17. Baum KF, Berens RL. Successful treatment of cutaneous leishmaniasis
with allopurinol after failure of treatment with ketoconazole. Clin Infect
Dis 1994;18:813-5.
18. Momeni A-Z, Aminajavaheri M. Treatment of recurrent cutaneous leishmaniasis. Int J Dermatol 1995;34:129-33.
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