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Abstract
Background and aim:
Cutaneous leishmaniasis (CL) has been recognized as a major public health
problem in several countries. It is highly endemic in the north and east
Mediterranean regions in the Syrian Arab Republic with more than 75.9% of
all CL cases recorded from these regions. Pentavalent antimonials have been
considered as standard treatment for leishmaniasis. Use of pentavalent antimonials
to treat leishmaniasis is associated with a range of cardiac, biochemical
and hematological adverse effects. The most serious of these is the development
of ventricular tachyarrhythmias associated with prolongation of the electrocardiographic
(EKG) rate-corrected QT interval (QTc). Whereas some studies have reported
that serious cardiac and biochemical adverse effects are common and often
require treatment interruption or discontinuation, others have reported
the drugs to be well tolerated. The aim of this study was to evaluate the
effect of Meglumine Antimoniate (MA) on EKG and some liver, kidney, and
pancreas function tests among Syrian CL patients.
Methods:
In this prospective study carried on 80 Syrian clinically suspected CL
patients referred to the Aleppo University Hospital Clinic. Fifty patients
were randomly selected and after the diagnosis of CL was made by tissue
smear and skin biopsy, EKG and blood samples were taken to evaluate liver,
kidney, and pancreas function tests before and after treatment with intramuscular
injections of MA at a dose of 20 mg Sb+5/kg/day equivalent to 60 mg/kg/day
for 21 days. Informed consent was obtained from all the cases. Data were
analyzed by use of paired t- test and p-values < 0.05 were considered as
significant.
Results:
There were 33 males and 17 females (34%) among Syrian CL patients with
a mean age and SD of 28.3 ± 11 years. The mean + SEM QTc progressively increased
from 382+2.8 msec to 402+ 2.5 msec during 21 days of treatment and the QTc
reached the threshold for potential cardiac toxicity among 6 (12%) patients
during the third week of treatment. ST depression occurred in 3% and inverted
T was observed in 4% of the patients. The mean serum levels of blood urea
nitrogen, creatinine, sodium, potassium, total and direct bilirubin, aspartate
aminotransferase, alanine aminotransferase, and alkaline phosphatase significantly
increased after treatment, although most of them were within normal ranges.
There were no significant differences in serum levels of amylase and lipase
before and after treatment, none developed clinical pancreatitis or hepatitis
and treatment modification was not required.
Conclusions:
Our results showed that one course of treatment with 20 mg Sb+5/kg/day
equivalent to 60 mg/kg/day MA for 21 days does not significantly alter the
liver, kidney and pancreas function tests. Treatment with systemic MA can
induce many ECG changes as QT prolongation and have a significant risk.
Identification of the factors before and during treatment that may increase
the risk of QTc prolongation and arrhythmias is important. Systemic MA can
be used safely in this population with adequate monitoring and the need
for treatment interruption is uncommon.
Introduction:
Leishmaniasis is prevalent in 88 countries, affecting an estimated 12
million people with approximately 2 million new cases per year, 500 000
of which are visceral leishmaniasis (VL) and l 500 000 CL (90% of them in
Afghanistan, Algeria, Brazil, the Islamic Republic of Iran, Peru, Syria,
Saudi Arabia and Sudan) [1]. Cutaneous leishmaniasis
has been endemic in Syria for hundreds of years [2].
Common local names include 'Aleppo boil' and the 'one-year boil'. The annual
number of reported CL cases is approximately 19 000. It has been documented
that Leishmania tropica subtype Mon-76 [1],
according to the Classification of Montpellier, is the causative parasite
for the anthroponotic form of the disease (ACL) in the traditional focus
of Aleppo city [3], while Phlebotomus sergenti
is the vector [4]. After 1 to 12 weeks incubation
period, the lesion appears as a red papule enlarging to a nodule or plaque
with a purple infiltrative border and central crust. Spontaneous healing
occurs after 6 to 12 months, with a remaining scar [5].
Although the adverse effects and inconveniences of pentavalent antimony
derivatives used in the treatment of leishmaniasis for more than 7 decades
are well known but these drugs remain the mainstay of systemic treatment
[6]. The mechanism of action is that this
drug inhibits the glucose uptake by promastigotes [7]
and decreases DNA, RNA and protein synthesis [8].
In addition, both aerobic and anaerobic glucose oxidation are inhibited,
resulting in a reduction in adenosine triphosphate (ATP) and guanosine triphosphate
(GTP) production in the amastigotes [9].
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 species [10].
The main aim of the present study was to evaluate the safety of systemic
use of MA on EKG, liver, kidney, and pancreas functions among Syrian CL
patients.
Materials and Methods
This study was a prospective, before and after treatment comparison of
blood urea nitrogen (BUN), creatinine, sodium (Na), potassium (K), total
bilirubin (Bil T) and direct bilirubin (Bil D), aspartate aminotransferase
(AST), alanine aminotransferase (ALT), alkaline phosphatase (Alk-Ph), amylase,
lipase and EKG carried out in the department of Dermatology and Venereology,
Aleppo University Hospital, Aleppo, Syria during the period from November
2009 to February 2010. Of 80 Syrian clinically suspected (CL) patients referred
to the Aleppo University Hospital Clinic, 50 patients were randomly selected
and after the diagnosis of (CL) was made by tissue smear and/ or skin biopsy,
EKG and blood samples were taken to evaluate liver, kidney, and pancreas
function tests before and after treatment with intramuscular injections
of MA at a dose of 20 mg Sb+5/kg/day equivalent to 60 mg/kg/day for 21 days.
Skin biopsies were taken from the active indurated margin of the lesion
under aseptic conditions. A 4 mm tissue sample was taken using a sterile
biopsy punch. Statistical before and after treatment comparison was performed
to find out the effect of Meglumine Antimoniate (MA) on some liver, kidney,
and pancreas function tests and EKG among Syrian CL patients, using of paired
t-test and p-values < 0.05 were considered as significant. Parasitological
confirmation, age 5 to 65 years, normal values of the aforementioned tests
before treatment were inclusion criteria. Informed consent was obtained
from all the cases. Contraindication to use MA, pregnant women, patients
with cardiovascular problems, those under treatment with other drugs during
the month prior to commencement of the study, acute or chronic medical conditions
which might interfere with the results of the laboratory tests were considered
as exclusion criteria. EKG was performed on the patients before starting
the treatment, during the treatment (weekly) and 1 month after stopping
the treatment. Electrocardiographic changes in P, PR, QT and QRS interval,
heart rate (HR), ST depression, ST elevation, atrial and ventricular arrhythmia
were recorded in the patient's file. Normal QT interval was defined as QT
interval less than 0.44 msec. Normal PR was defined as PR interval between
120 and 200 msec. Bradycardia was defined as heart rate less than 60 and
tachycardia was defined as heart rate more than 100 [11].
The patients were treated with intra-gluteal injections of MA (Glucantime;
Aventis, France) at a dose of 20 mg Sb+5/kg/day equivalent to 60 mg/kg/day
of MA for 21 days. The drug was available in 5 ml vials.
Results
Fifty patients were enrolled in the study. There were 33 (66%) males
and 17 (34%) females. The mean age ± SD of the patients was 28.3 ± 11 years
and the mean duration of disease was 4.0 ± 1.2 months. The mean + SEM QTc
progressively increased from 382 + 2.8 msec to 402 + 2.5 msec during 21
days of treatment and the QTc reached the threshold for potential cardiac
toxicity among 6 (12%) patients during the third week of treatment. ST depression
occurred in 3% of the patients and inverted T was observed in 4% of the
patients. No case of tachycardia was seen. Atrial arrhythmia as single premature
atrial contraction (PAC) occurred in 1 patient (2%). All of these changes
reversed after cessation of the treatment. Before and after treatment laboratory
values are shown in (table 1).
|
|
Normal values (Range) |
Before treatment |
After treatment |
P-value |
Patients with |
|
value (mean ± SD) |
value (mean ± SD) |
abnormal value |
|
|
|
after therapy (%) |
|
Na (mEq/L) |
135-148 |
141 ± 2.8 |
143.6 ± 3.1 |
0.02 |
3(6) |
|
K (mEq/L) |
3.5-5 |
4.0 ± 0.2 |
4.4 ± 0.6 |
0.03 |
0(0) |
|
AST (IU/L) |
5 - 40 |
24 + 11 |
35 + 24 |
0.002 |
10(20) |
|
ALT (IU/L) |
5 - 40 |
21 ± 10 |
25 ± 20 |
0.007 |
10(20) |
|
Alk-Ph (IU/L) |
180-1200 |
194.1 ± 61 |
280 ± 90 |
0.002 |
7(14) |
|
Bil T (mg/dL) |
0.1-1.2 |
0.80 ± 0.2 |
0.93 ± 0.2 |
0.03 |
3(6) |
|
Bil D (mg/dL) |
0.0-0.5 |
0.3 ± 0.1 |
0.5 ± 0.2 |
0.02 |
7(14) |
|
BUN (mg/dL) |
14-50 |
22 ± 4.8 |
26.2 ± 6.0 |
0.03 |
0(0) |
|
Creatinin (mg/dL) |
0.6-1.3 |
0.71 ± 0.5 |
0.87 ± 0.3 |
0.02 |
0(0) |
|
Amylase (IU/L) |
70-340 |
168.3 ± 47 |
152 ± 51 |
0.08 |
0(0) |
|
Lipase (U/mL) |
Up to 90 |
36.4 ± 21 |
38.8 ± 21.4 |
0.6 |
0(0) |
BUN = Blood urea nitrogen. Na = Serum Sodium. K = Serum potassium. Bil
T = Total bilirubin. Bil D = Direct bilirubin. AST = Aspartate aminotranferase.
ALT = Alanine aminotransferase. Alk-Ph = Alkaline phosphatase.
* significant
P-value < 0.05.
Table 1. Laboratory values before and after treatment with 60 mg/kg/day
of intramuscular injection of Meglumine Antimoniate (MA) for 21 days in
Syrian (CL) patients
There were no significant differences in serum levels of amylase and
lipase before and after treatment with MA 20 mg Sb5+/kg/day equivalent to
60 mg/kg/day for 21 days. Serum levels of BUN, creatinine, Na, K, Bil T
and Bil D, AST, ALT, and Alk-Ph were significantly increased (table 1).
The majority of these changes were not clinically significant and treatment
modification was not required. ALT levels increased two-folds in four men
and two women and the AST level increased three-folds in three male patients.
All of these abnormal values returned to normal in 2-4 weeks after completion
of treatment.
Discussion and Conclusions
Cutaneous leishmaniasis (CL) has been endemic in Syria for hundreds of
years [2]. Common local names include 'Aleppo
boil' and the 'one-year boil'. It has been documented that Leishmania tropica
is the causative parasite for the anthroponotic form of the disease (ACL)
in the traditional focus of Aleppo city [3],
while Phlebotomus sergenti is the vector [4].
The increasing incidence of ACL in this traditional focus, and the spread
to other new foci in Syria, has led the Syrian Ministry of Health to address
ACL control as a priority in the Aleppo Governorate [12].
Systemic pentavalent antimonies have been used in the treatment of leishmaniasis
since 1929 [13]. Urea Stibamate was the
first antimonial drug, later being replaced by Sodium Stibogluconate (SSG),
Pentostam. Today, SSG and Meglumine Antimonies (MA) are considered to be
standard treatments for (CL) [14]. Adverse
drug effects are unfavorable events associated in time with the use of a
medication and may have a causal relationship [15].
The safety of a drug is related to morbidity and mortality resulting from
the incidence and severity of adverse effects [16].
Pentavalent antimonies are considered to be of low toxicity, depending on
the cumulative doses used, and are rapidly excreted by the kidneys [17].
Although side effects and complications are known, few studies have been
specifically designed to investigate changes in laboratory values after
treatment with pentavalent antimonies. The adverse effects of pentavalent
antimonials and pentamidine needed to be considered jointly, irrespective
of formulation, daily dose, duration of treatment and route of administration.
Mild to moderate clinical, laboratory and electrocardiographic adverse effects
were frequent. In some cases, these effects were severe, resulting in temporary
or definitive treatment discontinuation, or even in death [18,19,20].
The study was performed in 2002 to compare 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 [21].
The investigation was carried out in 2004 to compare 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. 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) . The longer duration of drug administration in this investigation
may explain the observed higher frequency of liver and pancreatic enzyme
increases in comparison with the findings of our study [22].
The study was performed in 2005 to compare 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.
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 [23]. The investigation
was carried out in 2006 to report both cardiac and biochemical adverse effects
of pentavalent antimonial treatment in CL patients, but described the treatment
as well tolerated overall. 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. QTc interval prolongation
is a condition that, if not detected early, may cause sudden and fatal arrhythmia
and was the most frequent electrocardiographic adverse effect. This study
believed that weekly ECG monitoring should be sufficient to prevent this
condition and treatment should be discontinued if the QTc interval prolongation
exceeds 450msec [24]. The study was performed
in 2007 to report mean serum levels of blood urea nitrogen, creatinine,
sodium, total and direct bilirubin, aspartate aminotransferase, alanine
aminotransferase, and alkaline phosphatase significantly increased after
treatment, although most of them were within normal ranges. According to
their findings, there were no significant differences in serum levels of
potassium, amylase, lipase, and
γ-glutamyl transpeptidase before and after
treatment [25]. Our results was similar
to this study, but EKG changes weren,t evaluated in this study. The investigation
was performed in 2008 to evaluate EKG changes in the patients with (CL)
treated with systemic Glucantime. Their results showed that the most common
change in the Glucantime-treated patients was prolongation of QT interval
in 25 patients (19%). The second most common change was bradycardia in 14
patients (10.6%) and the third change was inverted T wave in 10 cases (7.4%).
Other changes included ST depression, ST elevation, PAC, PVC and left bundle
branch block. The electrocardiographic abnormality which was only left after
1 month was the left bundle branch block [26].
The study was performed in 1999, showed that treatment with low dose Glucantime
(15 mg/kg/day) did not induce significant EKG changes. However, prolongation
of QT interval occurred in the patients. Significant cardio toxicity caused
by low-dose, short-term therapy has not been well established and its use
has been considered relatively safe and free of significant cardiac effects.
It has been proposed that routine monitoring would not be necessary for
patients receiving 10 mgsb5+/kg/day up to 30 days or 20 mgsb5+/kg/day up
to 20 days [27]. In another study that
was carried out in 80 patients with Visceral leishmaniasis under treatment
with Sodium Stibogluconate, 40% of cases showed a flattening of T wave and
9% showed inverted T wave [28], but in
our study the problem in T wave was only inverted T in 4% of cases. The
investigation was performed in 1992, patients with mucocutaneous leshmaniasis
treated with systemic Glucantime, EKG changes occurred in (45%) that predominantly
occurred in T wave and ST segment and which reversed 2 months after stopping
the treatment [29].
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 60 mg/kg/day for 21 days in Syrian CL patients. According to
past studies and results of the current study, EKG abnormality due to antimonial
therapy in patients with normal EKG is minimal. However, we recommend the
monitoring of laboratory and electrocardiographic adverse effects at a minimum
interval of 7 days during treatment and on day 30 after the end of treatment.
Monitoring should include a complete blood count and the measurement of
BUN, creatinine, electrolytes and liver and pancreatic enzymes, in addition
to an electrocardiogram.
Acknowledgements
Financial Support: This project was funded by University of Aleppo, Aleppo,
Syria. Conflict of interest: None.
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