ARTICLE
Auteur(s) :, Babak Shazad1, Babak
Abbaszadeh2, Ali
Khamesipour3,*
1Internal Medicine Department, School of Medicine,
Iran University of Medical Sciences, Tehran, Iran
2Army Medical University IRI , Etemadi Avenue, Fatemi
Street , Tehran, Iran
3Center for Research and Training in Skin Diseases and
Leprosy, Tehran University of Medical Sciences, Tehran, IranFax:
(+98-21) 8 97 06 57.
accepté le 3 Novembre 2004
Leishmaniases are among the major public health problems in many
countries of Asia.Cutaneous leishmaniasis (CL) is the most common
form of leishmaniases. Control strategies have almost all failed
especially in regard of zoonotic forms of the diseases [1].
Presently there is no vaccine available against leishmaniases [2].
There are two types of CL in Iran; zoonotic CL (ZCL) caused by L.
major and anthroponotic CL (ACL) caused by L. tropica, and many
modalities are used for the treatment of leishmaniasis [3].
Pentavalent antimonial is the current standard WHO recommended
treatment for leishmaniasis which requires multiple injections, and
has parenteral disadvantages such as local pain, toxicity and high
cost which have led to the search for alternatives. The WHO
recommendation for ZCL is no treatment except in patients with
multiple lesions, lesions close to a vital organ and large lesions
[1, 4]. Paromomycin ointment has been shown to be effective in
experimental models of murine leishmaniasis [5-7]. Local
paromomycin was considerd for use in cutaneous leishmaniasis and in
a double blind controlled cross-over trial, 20 days topical
treatment with 15% paromomycin in a soft paraffin showed a rate of
77% cure over 27% cure in the placebo group [8]. A two week course
of 15% paromomycin plus 10% urea treatment in Iran showed a
significantly higher parasitological cure in the treated group [9].
Later on a 4 week course of the same formula in Iran showed a
significantly higher cure rate than two weeks (74%) or placebo
(59%) [10].In this open study the efficacy rate of paromomycin
sulfate and intralesional injection of meglumine antimoniate in the
treatment of CL caused by L. major was compared.
Materials and methods
Study design
This study was designed as a randomized, open, comparative clinical
trial to evaluate the efficacy of paromomycin sulfate in comparsion
with intralesional injection of meglumine antimonate.
Study population
This study was performed in Mousian, Dehloran; a ZCL endemic area,
located in western Iran.
Ethical considerations
The study was approved by the Army Ethical Committee. The objective
and procedure of the trial were explained in a simple language to
potential candidates and only those volunteers who signed the
informed consent were included in the study.
Recruitment
This study was performed in a Military Base Clinic from January to
October 2001. Three hundred male CL suspected cases were refered to
the clinic. Sixty parasitologically proven cases of CL, healthy
apart from CL, lesions not in close proximity to a vital organ or
joint were included. Number of lesions 1-3, ulcer size less than 5
cm in diameter, onset of the lesion less than 3 months, no previous
standard anti-Leishmania treatment, and no history of allergy to
the paromomycin family were recruited. Each patient was interviewed
and physically examined before initiation of the treatment. A
photograph of each patient’s lesion was taken before and at week 1
after the treatment was completed.
Diagnostic criteria
Cutaneous leishmaniasis was approved by direct smear. One to three
scrapings were taken from the border of the lesion(s) of each
patient, stained with Giemsa stain [11].
Sixty male patients with proven CL were divided randomly into
two equal treatment groups. One group received 1 ml of meglumine
antimoniate intradermally every other day for 20 days. Each lesion
was injected in the upper and mid-dermis using a 30-gauge needle.
Infiltration was thorough and produced a complete blanching at the
base of the lesion [3]. In order to avoid any bias all injections
were performed by the same physician. The second group of patients
was treated with paromomycin sulfate
(0.5 mg/mm2/day) after cleaning the lesion(s) with
soap and water twice a day for 20 days and treated lesions were
left uncovered [9, 10]. The ointments were used under the
observation of medical staff.
Paromomycin sulfate
(C23H45N5O14. xH2SO4)
and meglumine antimoniate
Paromomycin ointment used in this trial contained 15% paromomycin
sulfate (MW = 615.65) and 10% urea in 30 gram of white
soft paraffin in a collapsible tube. Paromomycin ointment was
purchased from Razak Laboratories Co., Tehran, Iran.
Meglumine antimoniate (Rhone-Poulenc Rorer, Paris, France) was
kindly donated by Ministry of Health and Medical Education.
Follow up
Follow up and clinical evaluation of the patients were performed at
week 1 and week 6 after the treatment was completed. The patients
were visited once at 6 months after treatment was completed.
Parasitological evaluation was performed at week 6 only in patients
with active lesion(s).
Responses to treatment
Complete cure was defined as complete re-epithelization of all
lesions at one week after cessation of treatment. Patients with
multiple lesions were considered to be cured if all the lesions
were healed.
Partial cure (parasitological cure) was defined when clinical
cure had not occurred in any lesion in a patient but no Leishmania
amastigote was found in a direct smear of the lesion(s), 3 slides
were prepared, and stained from each active ulcer and 1,000 fields
were checked (aproximately 3 slides) [11].
Failure of treatment was defined as no clinical cure and no
parasitological cure at one week after cessation of treatment.
Relapse was defined as a reappearance of the lesion after
complete cure.
Statistical analysis
Epi-Info Version 6 was used for data entry and satistical analysis.
Student’s t-test was used to compare the means and chi-square was
used to compare the proportion. All statistical tests were two
tailed. A ρ-value of < 0.05 was considered as a significant
difference.
Results
Patient characteristics
Sixty parasitologically proven cases were selected and randomly
assigned to receive either meglumine antimoniate or paromomycin
sulfate, there was no statistical difference between the age,
weight and lesion characteristics of the two groups (table 1)(
Table 1 ).
Table 1 Initial characteristics of patients recruited
for the treatment with either paromomycin sulfate ointment or
intralesional injection of meglumine antimoniate
|
Characteristic
|
- Paromomycin sulfate
- (N = 30)
|
Meglumine antimoniate (N = 30)
|
ρ-value
|
|
Age (year)
|
20.6 ± 1.2
|
21.7 ± 2
|
0.32
|
|
Lesion size (mm)
|
21.7 ± 2.3
|
25 ± 7
|
0.21
|
|
Lesion duration (days)
|
37.8 ± 3.5
|
39 ± 5.1
|
0.24
|
|
No. of lesions per patient
|
2
|
2.4
|
0.10
|
|
No. of lesions
|
60
|
76
|
0.035
|
|
One lesion
|
11
|
3
|
|
|
Two lesions
|
8
|
8
|
|
|
Three lesions
|
11
|
19
|
|
|
Location of the lesion(s)
|
|
|
|
|
Head & neck
|
15
|
10
|
0.36
|
|
Upper extremities
|
25
|
36
|
|
|
Lower extremities
|
19
|
28
|
|
|
Trunk
|
1
|
2
|
|
|
Type of lesions
|
|
|
|
|
Papular
|
9
|
14
|
0.65
|
|
Nodular
|
5
|
9
|
|
|
Ulcerative
|
46
|
53
|
|
Treatment efficacy
Three of 30 patients in the meglumine antimoniate treatment group
and one of the patients in the paromomycin sulfate group were
withdrawn from the study because of cutaneous reactions like
erythematosis, urticaria or lymphadenitis with pain, the withdrawn
patients were put on systemic meglumine antimonate and were all
cured; 20 mg/kg for 14 days. No systemic toxic reaction
attributable to the drug was observed.
The results as shown in table 2( Table
2 ), indicates a complete cure in 18 out of 27 (67%) in the
meglumine antimoniate group and 20 out of 29 (69%) in the
paromomycin sulfate group which statistically is not significant
(p = 0.85). The partial cure rate was 7 out of 27 (26%)
in the meglumine antimoniate group and was 3 out of 29 (10%) in the
paromomycin sulfate group (not significant). The failure rate was 2
out of 27 (7%) in the meglumine antimoniate group and 6 out of 29
(21%) in the paromomycin sulfate group (not significant).
Table 2 Results of evaluation at one week after
completion of the treatment
|
Outcome
|
- Paromomycin sulfate
- No. (%)
|
- Meglumine antimoniate
- No. (%)
|
ρ-value
|
|
Cure
|
20 (69)
|
18 (67)
|
0.85
|
|
Partial cure
|
3 (10)
|
7 (26)
|
0.24
|
|
Failure
|
6 (21)
|
2 (7)
|
0.65
|
|
Total
|
29 (100)
|
27 (100)
|
|
Discussion and conclusion
Leishmaniasis caused by intracellular protozoan of the genus
Leishmania, depends upon the host immune response and the
Leishmania species, leishmaniasis presents a wide spectrum of
clinical manifestations. Based on the diversity of epidemiological
characteristics, specific to each species and its environment,
vector and reservoir control are impractical, costly and usually
require political commitment and infrastructures beyond the means
of the countries suffering most from this disease [1, 4, 12].
Antimonials are still the first line of treatment for leishmaniasis
[3]. Treatment of CL with antimonials is expensive, needs multiple
injections, is acompanied by side effects and moreover variations
in efficacy and drug resistance are reported [4, 12, 13]. In Iran
only meglumine antimoniate is available, and usually when a patient
has a limited number of lesions, intralesional injection of
meglumine antimoniate is used. Intralesional injection of meglumine
antimoniate is as effective as systemic [14] and even leads to a
faster improvement of the lesion [15], but multiple intralesional
injections around the ulcer is very painful and not all patients
tolerate it, intralesional injection also needs special medical
services which are not available in most endemic areas. In this
study intralesional injection of meglumine antimoniate was compared
with paromomycin sulfate.
Paromomycin, like all the aminoglucoside antibiotics, inhibits
protein biosynthesis in sensitive organisms [16]. Most reports have
shown successful topical treatment of CL with paromomycin
containing 12% methylbenzethonium chloride (MBCL) [5-8, 17, 18].
Regarding the fact that local pain and inflammation are frequently
reported with MBCL, in contrast to the use of paromomycin
containing 10% urea [9, 10], in this formulation, urea was replaced
for MBCL. The result of a study in Iran showed that a 4 week course
of treatment is more effective than a two week course [10].
In summary, paromomycin sulfate has been shown to be safe and as
effective as intralesional injections of meglumine antimonate in
the treatment of ZCL caused by L. major. The rate of self healing
varies from case to case and depends on various factors such as the
duration of the lesion, charecteristics of the lesion etc. Patient
memory is the only way to estimate the lesion(s) duration, there is
a report that showed paromomycin ointment is effective on ulcerated
lesions [19]. WHO recommended not to treat uncomplicated cases of
ZCL or postpone the treatment for a few weeks until enough immune
response is generated [1]. This strategy is very difficult to
implement especially in new endemic areas in which the residents
are not sure of the self healing nature of the disease. The least
beneficial use of topical paromomycin in endemic areas is to
postpone the use of antimonials for a few weeks, with increasing
antimonial resistance in leishmaniasis, the first line
anti-Leishmania drug should be reserved only for complicated cases
of CL.
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