ARTICLE
Auteur(s) : Mansour Nassiri Kashani,
Alireza Firooz, Seyed Ebrahim Eskandari, Mohammad Hossein Ghoorchi,
Ali Khamesipour, Alireza Khatami, Amir Javadi, Yahya Dowlati
Medical Sciences/University of Tehran, Center for Research and
Training in Skin Diseases and Leprosy, 79 Taleqani Avenue, Tehran
14166 I.R. Iran
accepté le 27 Juin 2007
Leishmaniases are a group of diseases caused by the protozoa
Leishmania, which is transmitted by the bite of an infected female
sand fly [1].Cutaneous leishmaniasis (CL) develops after an
incubation period of 1 to 12 weeks, in a papule that enlarges and
then ulcerates [2].The prevalence of the disease is in excess of 12
million cases and 350 million people in 88 countries are at risk
[3]. Cutaneous leishmaniasis has been recognized as a major public
health problem in Iran where almost all cases are caused by either
Leishmania major or L. tropica [2].Although the adverse effects and
inconveniences of pentavalent antimony derivatives used in the
treatment of leishmaniasis for more than 7 decades are well known,
these drugs remain the mainstay of systemic treatment [4]. The
exact mechanism of its action is not known, although it inhibits
glycolysis and fatty acid oxidation in Leishmania spp [5]. The
reported efficacy of Meglumine antimoniate (MA) in the treatment of
CL varies from 2-90% depending on dosage, duration of treatment
definition of efficacy and the responsible Leishmania spp
[6].Although some information about the safety profile of the use
of pentavalent antimonies in the treatment of leishmaniasis was
available, we could not locate any clinical research in which the
primary objective had been to evaluate the adverse effects of
systemic use of MA in CL. We performed this study to evaluate the
safety of MA on liver, kidney, and pancreas functions.
Materials and methods
Study design
This study was an open-label, prospective, before and after
treatment comparison of blood urea nitrogen (BUN), creatinine,
sodium (Na), potassium (K), total (Bil T) and direct bilirubin (Bil
D), aspartate aminotransferase (AST), alanine aminotransferase
(ALT), alkaline phosphatase (Alk-Ph), amylase, lipase, gamma
glutamyl transpeptidase (γ-GT) in patients with CL treated with
standard doses of intramuscular injections of MA.
Study location
The eligible patients were recruited among patients with CL who
were referred to 2 primary care health clinics, in an area endemic
for anthroponotic CL caused by L. tropica.
Patients
Inclusion criteria were: a) parasitological confirmation (upon
study entry consisted of examination of Giemsa-stained smears of
the lesion scrapings and microscopic identification of Leishmania
amastigotes in stained smears) or isolation of the micro-organism
on Nicolle-Novy-Mac Neal (NNN) culture medium, b) age 10 to 75
years, c) normal values of the aforementioned tests before
treatment, and d) signing the informed consent form to take part in
study. For patients who were below the legal age, the informed
consent was signed by a parent or the legal guardian.
Exclusion criteria included: a) contraindication to use MA, b)
use of systemic corticosteroids, hepatotoxic, nephrotoxic, or
pancreatitis-inducing drugs during the month prior to commencement
of the study, c) acute or chronic medical conditions which might
interfere with the results of the laboratory tests, d) pregnant or
nursing women.
Drug administration
Volunteers were treated with intragluteal injections of MA
(Glucantime®; Rhone Poulenc Rorer, Paris, France) at a
dose of 20 mg Sb+5/kg/day equivalent to
60 mg/kg/day of MA for 15 days. The drug was available in
5 mL vials. The maximum administered dose was 3 vials of
Glucantime® (60 mg Sb+5/kg/day) per day.
Ethical approval
The trial was reviewed and approved by the ethical committee of the
Center for Research and Training in Skin Diseases and Leprosy,
Tehran, Iran.
Statistical analysis
Before and after treatment values of laboratory tests of study were
compared by use of paired t test and p-values < 0.05 were
considered as significant.
Results
Among the 156 screened patients, 80 patients fulfilled the study
criteria. Forty one (51.3%) patients were female and the mean
age ± SD of the patients was 30.4 ± 15.7 years, the mean duration
of disease was 3.4 ± 1.4 months and the mean weight of patients was
59.3 ± 13.0 kg. Pre-treatment and post-treatment laboratory values
are shown in table 1. There were no
significant differences in serum levels of K, amylase, lipase, and
γ-GT before and after treatment with MA 20 Sb5+
mg/kg/day for 15 days. Serum levels of BUN, creatinine, Na, Bil T
and Bil D, AST, ALT, and Alk-Ph were significantly increased (table
1). The majority of these changes were not clinically significant.
Alk-Ph levels were increased in a 68-year-old male and a
74-year-old female patient, 1.6 and 2.8 times in comparison to
baseline, respectively. AST levels increased two-fold in three men
and two women and the ALT level increased three-fold in both these
female patients. All of these abnormal values returned to normal in
2-4 weeks after completion of treatment.
Table 1 Laboratory values before and after treatment
with 20 mg Sb+5/kg/day equivalent to 60 mg/kg/day of
intramuscular injection of meglumine antimoniate
(Glucantime®) for 15 days in cutaneous leishmaniasis
|
Normal values (Range)
|
Before treatment value (mean ± SD)
|
After treatment value (mean ± SD)
|
P-value
|
Patients with abnormal value after therapy (%)
|
|
BUN (mg/dL)
|
14-50
|
24 ± 5.8
|
25.9 ± 7.0
|
0.03
|
0 (0)
|
|
Creatinin (mg/dL)
|
0.6-1.3
|
0.76 ± 0.2
|
0.81 ± 0.2
|
0.01
|
0 (0)
|
|
Na (meq/L)
|
135-148
|
142.6 ± 3.4
|
144.2 ± 3.9
|
0.01
|
3 (3.8)
|
|
K (meq/L)
|
3.5-5
|
4.3 ± 0.34
|
4.4 ± 0.3
|
0.09
|
0 (0)
|
|
Bil T (mg/dL)
|
0.1-1.2
|
0.86 ± 0.3
|
0.96 ± 0.3
|
0.02
|
4 (5)
|
|
Bil D (mg/dL)
|
0.0-0.5
|
0.4 ± 0.2
|
0.5 ± 0.2
|
0.02
|
15 (18.8)
|
|
AST (IU/L)
|
5-40
|
23.5 ± 12.1
|
36.3 ± 25.2
|
> 0.0001
|
15 (18.8)
|
|
ALT (IU/L)
|
5-40
|
20 ± 11
|
27 ± 22.9
|
0.009
|
8 (10)
|
|
Alk-Ph (IU/L)
|
180-1200
|
197.8 ± 70.6
|
279 ± 126.6
|
> 0.0001
|
11 (13.8)
|
|
Amylase (IU)/L
|
70-340
|
171.1 ± 50.1
|
157.8 ± 50.4
|
0.07
|
0 (0)
|
|
Lipase (U/mL)
|
Up to 90
|
35.1 ± 25
|
36.4 ± 23.2
|
0.65
|
0 (0)
|
|
γ-GT (IU/L)
|
|
15.9 ± 12.9
|
17.8 ± 13.1
|
0.33
|
0 (0)
|
Discussion
No universally effective method is yet available for prevention of
CL, so each year at least tens of thousands of CL cases have to be
treated with different antileishmanial drugs [1, 7-10].
Pentavalent antimonies were introduced before World War II and
became the first-line drugs for the treatment of cutaneous and
visceral leishmaniases (VL). They are considered to be of low
toxicity, depending on the cumulative doses used, and are rapidly
excreted by the kidneys [11]. Two pentavalent antimonies commonly
used for the treatment of leishmaniasis are MA
(Glucantime®) and SSG
(Pentostam®).2 Glucantime® has
been more widely used in Iran, where it is distributed by the
Ministry of Health.
Although side effects and complications are known, few studies
have been specifically designed to investigate changes in
laboratory values after treatment with pentavalent antimonies.
Wortmann et al. compared the efficacy of a 10 or 20 day course
of SSG in the treatment of CL in US military personnel, and
reported increases in amylase, lipase, AST and ALT levels and
decreases in white blood cell count, hematocrit and platelets,
which were more prominent in the group who received the drug for 20
days [12].
Lawn et al. reported both cardiac and biochemical
adverse-effects of pentavalent antiminial treatment in CL patients,
but described the treatment as well tolerated overall [13]. They
reported normal baseline liver function tests in all of their
patients. According to their findings, serum concentrations of ALT
or AST increased above the upper limit of the normal range in 85%
of patients and increased more than three times above the upper
limit of the normal range in 33% of patients. The median
transaminase concentration peaked on day 12 of treatment and
decreased thereafter, despite ongoing treatment with pentavalent
antimonial derivatives [13].
Soto et al. compared the efficacy and adverse effects of the
generic and branded pentavalent antimonies in the treatment of New
World CL in patients from Bolivia and Colombia [14]. They
administered the drug at a dose of 20 mg
Sb5+/kg/day for 20 consecutive days and reported
pancreatic enzyme abnormalities in 48-88% and liver enzyme
abnormalities in 48-87% of their patients, respectively. The lowest
frequencies of pancreatic enzyme abnormalities were observed in the
generic stibogluconate group (p < 0.01) [14]. The longer
duration of drug administration in the Soto et al. study may
explain the observed higher frequency of liver and pancreatic
enzyme increases in their study in comparison with the findings of
this study. Another explanation may be related to the different
times of the evaluation of laboratory tests in the two studies. In
this study the measurements were repeated after 15 days from the
beginning of treatment and in the Soto et al. study the
measurements were performed about 10 days after the commencement of
the treatment. They reported a regression in the values of the
means towards to the end of the treatment period [14].
Andersen et al. compared the efficacy and adverse effects of MA
to pentamidine and reported no significant difference in mean
values of creatinine among the two groups, but a significant
increase in AST mean values in MA treated patients, although it
exceeded 174 IU/L in none of the patients and the ALT level was not
statistically significantly increased [15]. In the
Glucantime-treated group, pancreatic lipase values increased to a
mean of 61 IU/L on day 4, to 73 IU/L on day 8, and were then
maintained at 71 IU/L until the end of therapy. All these values
were significantly greater than those in the pentamidine-treated
group, which had not changed from the pre-therapy values [15].
Delgado et al. reported a high frequency of adverse effects
attributed to the treatment of VL in patients who had been infected
with human immunodeficiency virus type-1 (HIV-1), and who were
treated with a standard dose of 20 Sb5+ mg/kg/d [16].
They reported hyperamylasemia, acute pancreatitis, and an increase
in serum creatinine level > 2 mg/mL in 10 (40%), 5 (20%), 3
(12%) patients out of a total of 25 patients. They reported a case
of acute renal failure as well as 3 deaths due to use of MA in the
treatment of their patients. The difference between the findings of
this study and those of Delgado et al. might be explained by the
fact of greater extent of systemic involvement in cases of HIV-1 VL
co-infection as well as possible drug interactions in at least one
of their patients [16].
In conclusion, there was no significant alteration in laboratory
values of liver, kidney, or pancreas indices before and after
treatment with MA at a dose of 20 mg/kg/day for 15 days in
patients with CL.
Acknowledgements
Financial Support: This project was funded by research grant
number: G/423/1403 from Center for Research and Training in Skin
Diseases and Leprosy, Medical Sciences/University of Tehran.
Conflict of interest: None.
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