Kerman Leishmaniasis Research Center , journal club

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Kerman Leishmaniasis Research Center , journal
club

• Presented by Ali-Reza Fekri, MD

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Evaluation of meglumine antimonate effects on
liver pancreas function tests in patients with
cutaneous Leishmaniasis

• Authors Dr. Kashani , Dr. Firooz ,
• Journal Eur J Dermatol 2007 17 (6) 1-4

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Summery

• Cutaneous leishmaniasis has been recognized as a
  major public health problem in several countries.
• Pentavalent antimonies, meglumine antimoniate
• and sodium stibogluconate, have been
  considered as standard treatment for
  leishmaniasis.
• Side effects have been reported to be increased
• hepatic enzyme levels and electrocardiographic
  abnormalities.

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Summery

• We performed this study to evaluate the influence
  of meglumine antimoniate on some liver, kidney,
  and pancreas function tests.
• Eighty patients fulfilled the study criteria.
• Forty-one (51.3) patients were female and
• the mean age of the patients was 30.4 15.7
  years.

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Summery

• 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 Sb5/kg/day for 15 days.

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Summery

• 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 range.

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Summery

• There were no significant differences in serum
  levels of potassium, amylase, lipase, and
  c-glutamyl transpeptidase before and after
• treatment
• In conclusion it can be stated that one course of
  treatment with
• 20 mg Sb5 /kg/day MA for 15 days does not
  significantly alter the liver,
• kidney and pancreas function tests in
  patients with cutaneous Leishmaniasis.

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Introduction

• Leishmaniases are a group of diseases caused by
  the
• protozoa Leishmania, which is transmitted by
  the
• bite of an infected female sand fly .
• Cutaneous leishmaniasis (CL) develops after an
  incubation period of 1 to 12 weeks, in a papule
  that enlarges and then ulcerates .

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Introduction

• The prevalence of the disease is in excess of 12
  million
• cases and 350 million people in 88 countries
  are at risk .
• 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 .

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Introduction

• 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 .
  
• The exact mechanism of its action is not known,
  although
• inhibits glycolysis and fatty acid oxidation in
  Leishmania
• spp

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Introduction

• 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 responsible Leishmania
  spp

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Introduction

• 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.

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Materials 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 (c-
• GT) in patients with CL treated with standard
  doses of
• intramuscular injections of MA.

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Materials Methods

• 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.

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Patients inclusion criterias

• Inclusion criteria
• 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,

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Contd

• 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.

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Exclusion criteria

• 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 may
  interfere with the results of laboratory tests,
• d) pregnant or nursing women.

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Drug administration

• Volunteers were treated with intragluteal
  injections of MA
• Glucantime Rhone Poulenc Rorer, Paris,
  France) at a
• dose of 20 mg Sb5/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 Sb5/kg/day per day.

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Statistical analysis

• Before and after treatment values of laboratory
  tests of study were compared by use of paired t
  test and p-values lt 0.05 were considered as
  significant.

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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.

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Table 1
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Discussion

• Pentavalent antimonies were introduced before
  World War
• II and became the first-line drugs for the
  treatment of
• cutaneous and visceral leishmaniases .
• They are considered to be of low toxicity,
  depending on the cumulative
• doses used, and are rapidly excreted by the
  kidneys .
• Two pentavalent antimonies commonly used for the
  treatment
• of leishmaniasis are MA (Glucantime) and
  SSG
• Pentostam).

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Contd

• 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.

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Contd

• 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

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Contd

• 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 .
• 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 there
  after,
• despite ongoing treatment with pentavalent
  antimonial derivatives

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Contd

• Soto et al. compared the efficacy and adverse
  effects
• 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.
• lowest frequencies of pancreatic enzyme
  abnormalities
• were observed in the generic stibogluconate(
  p lt 0.01) .

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Contd

• 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.

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Contd

• 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
  .

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Contd

• 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 .

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Contd

• 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.

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Contd

• 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 .
• They reported hyperamylasemia, acute
  pancreatitis,
• and an increase in serum creatinine level gt 2
  mg/mL in 10 (40), 5 (20), 3 (12) patients out
  of a total of 25 patients.

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Contd

• 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

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Conclusion

• 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.