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Orally Effective Drugs for Kala-azar (Visceral
Leishmaniasis) : Focus on Miltefosine and Sitamaquine
H Sangraula*, KK Sharma**, S Rijal+, S Dwivedi++, S Koirala++
Abstract
Currently there are no effective orally administered drugs or visceral leishmaniasis or kala-azar, a parasitic
disease affecting about 0.5 million people a year, majority of whom are in India and adjacent areas of
Nepal. Symptoms of affected patients are fever, cachexia, hepatosplenomegaly and pancytopenia. The
disease is usually fatal, if left untreated.
Traditionally kala-azar is treated with four weeks of injections of sodium stibogluconate, a pentavalent
antimonial. However, this treatment has not only shown resistance in 37-64% patients of the current
Indian epidemic in Bihar (the epicentrre) but also life-threatening cardiotoxicity in 7-10% and treatmentrelated deaths in 5-10% cases, besides being unsuccessful at times. Parenteral amphotericin B is used as
a secondary agent that shows 95% effectiveness but its toxicity and high cost of even the well tolerated
liposomal complex precludes its wide use in the developing countries, where the disease is present in
epidemic proportions.
Recently, miltefosine (hexadecylphosphocholine), a compound originally developed as an antitumour
agent has been shown to be an orally effective drugs against kala-azar. All clinical trials with this drug are
conducted in India in patients of visceral leishmaniasis. A regimen of 100 mg per day or 50 mg twice
daily for 3-4 weeks was observed to produce a cure rate of 100%. Gastrointestinal side effects were
frequent (62%) but no patient discontinued the therapy. A phase III trial involving 300 HIV-negative
adults and adolescents is underway in India and the drug is hoped to be licensed in the next 2-3 years.
Few studies of phase II clinical trials mainly conducted in Kenya with another drug, sitamaquine or
kalazaquine (WR 6026), an 8-aminoquinoline has also shown promise as an orally effective agent (in a
dose of 1 mg/kg/day for two weeks) for visceral leishmaniasis.
These studies with two orally effective compounds, it appears, will open new vistas for orally effective,
affordable and acceptable drugs in the armamentarium for the treatment of kala-azar. It is expected that
in future we would have effective ways to prevent and treat all forms of leishmaniasis without discomforting
the patient.
INTRODUCTION
O
ut of the three clinical manifestations of leishmaniasiscutaneous, mucocutaneous and visceral, the latter is a
potentially fatal form of the disease and has more severe
public health consequences in several parts of the world.
Cutaneous and mucocutaneous leishmaniases are caused
respectively by Leishmania braziliensis and L. tropica (and
also by over a dozen other species in different parts of the
*Assistant Professor, **Professor, Department of Pharmacology;
+Associate Professor, ++Professor, Department of Medicine;
BP Koirala Institute of Health Sciences, Dharan, Nepal.
Received : 16.8.2001; Revised : 13.3.2002; Accepted : 13.2.2003
686
world), whereas visceral leishmaniasis is caused by L.
donovani. Visceral leishmaniasis, although has been reported
in 66 countries to affect 500,000 persons worldwide per year,
90% of these patients are in India, Nepal, Bangladesh, Brazil
and Sudan.1,2 In the Indian subcontinent, the disease is called
“kala-azar” a Hindi word for black fever or black sickness and
has been endemic for many decades. However, it has reemerged in the last three decades from near eradication and
is a major health problem in Bihar, West Bengal, Eastern Uttar
Pradesh and neighbouring areas of Nepal. The latest in the
series of epidemics of kala-azar, centered in north-eastern
India, flared up in 1970s, probably because of the
discontinuation of insecticide spraying for malaria which also
affects the ‘Phlebotomus’ sandfly that transmits the disease
JAPI • VOL. 51 • JULY 2003
in this part of the world.3 The epidemic continues to generate
as many as hundreds of thousands of cases annually. Globally,
the disability-adjusted-life-years (DALYs) lost in 1999 due to
kala-azar were estimated to be 1.20 million for men and 0.78
million for women.4 These epidemics underscore the need for
therapy that not only is highly effective and safe even in
patients who are critically ill from leishmaniasis and co-existing
diseases, e.g. tuberculosis, dysentery or AIDS (where
immunocompetence is very low) but also is easily
administered and affordable for treating a large number of
impoverished patients.
NEW HOPE FOR ORAL AGENTS
Few clinical trials, mainly conducted in the 1990s, have
opened new vistas in the oral therapy of visceral leishmaniasis,
which before 1994 was centered mainly on the drugs-sodium
stibogluconate (a pentavalent antimonial), pentamidine
isothionate and amphotericin B, all of which are highly toxic
and need to be given for prolonged periods by parenteral
route. In an attempt to improve the tolerability of IV infusion
in 1997, liposome encapsulated amphotericin B was licenced
for visceral leishmaniasis which had an added advantage of
reduced toxicity and targeted delivery of the drug to the
reticuloendothelial cells in the liver and spleen.5 In spite of
the advantages of liposomal formulation, amphotericin B
could not be successfully developed in the developing world
due to its high cost and need for parenteral administration.
On the basis of the research into the host genetics that
showed type-1 T helper (Th-1) response to be associated
with the resistance and Th-2 response to susceptibility to
leishmaniases, recombinant interferon-gamma (IFNγ) and
granulocyte-macrophage colony stimulating factor (GM-CSF)
were administered parenterally (IM) with antimonial therapy
to reduce its dose (and thus the toxicity) without
compromising the effectivity.6,7 Such a combined pharmacoimmunotherapy, although showed promising results, could
not be recommended for routine use because of cost.7 In
several studies paromomycin, an aminoglycoside,
(aminosidine) administered parenterally alone or in
combination with stibogluconate was found to give better
results than the latter alone but again a long duration of
treatment with a need for parenteral injections and variable
effects in different species of Leishmania proved to be limiting
factors in its use.7,9 Traditionally, therefore due to low cost,
pentavalent antimonial agents have been the mainstay of
treatment of visceral leishmaniasis until the end of the last
century.
With the continued efforts of the tropical disease research
(TDR) program of the World Health Organization (WHO)
which felt the need for new drugs for visceral leishmaniasis
that would be effective orally, affordable and relatively free
of severe side effects-miltefosine, a new compound has been
discovered for oral treatment of kala-azar.10 Oral treatment for
visceral leishmaniasis has been long sought, and hopes are
high that miltefosine will be the first candidate in this respect.
It is more so because decades of earlier work with azoles,
JAPI • VOL. 51 • JULY 2003
such as ketoconazole and fluconazole and other assorted
agents, like roxithromycin and allopurinol had so far failed to
discover an effective agent that could be given orally for
kala-azar and other forms of leishmaniasis.11-17
MILTEFOSINE, AN ALKYLPHOSPHONOID
(ALKYLPHOSPHOCHOLINE)
Based on the pioneering researches of Crofts et al in 1987,
where several esters of alkylphosphorylcholines which were
initially developed as antitumour agents, and shown to be
active against L. donovani promastigotes,18 a group of four
alkylphosphonoids were identified for further studies. They
were ilmofosine, edelfosine, miltefosine and SR62-834. These
compounds developed by different pharmaceutical
companies, showed remarkable activity against intracellular
amastigotes in vitro.19 Oral treatment of mice infected with L.
donovani or L. infantum with miltefosine (chemical name:
hexadecylphosphocholine, a phosphorylcholine ester of
hexadecanol) was found to be superior to sodium
stibogluconate in reducing parasite load in liver and
spleen.20,21 In these studies, among all organs the maximum
concentration of miltefosine was found to be in liver and
spleen, the two destination organs for visceral leishmaniasis
following an oral dose. Because of this reason, the drug was
observed to exert 600 times better anti-amastigote effect in
these organs than antimonial compounds.18-20
Results of Clinical trials of miltefosine in human visceral
leishmaniasis
Based on the previous preclinical work18-21 and availability
of pharmacokinetic and safety data in humans, since the drug
was already approved for clinical trials in patients of cancer,
22-24
four Phase I/II clinical trials were conducted in India
employing a total of 249 patients with miltefosine in visceral
leishmaniasis. These trials have shown the drug to be orally
effective and tolerated by majority of the leishmania-infected
population.25-28 The third investigation in this series of clinical
trials, a Phase II dose-finding study by Jha et al was conducted
at three centres in India in 1998-1999 and is the largest trial
published to date.27 The study was an open-label investigation
using a total of 120 patients, 71% of whom were males ranging
in age from 12-50 years. All had anorexia, fever and
splenomegaly with at least (2+) leishmania in a splenic aspirate.
Miltefosine in the form of 50 mg capsule was administered
orally in different dosages to sequentially enrolled four
cohorts of 30 patients each with a snack of bread and butter.
This was done to minimize the upper gastrointestinal (GI)
side effects on the basis of prior knowledge that the presence
of food does not limit GI absorption of the compound.17,18
Cohort 1 received 50 mg daily for six weeks (total dose: 2100
mg); cohort 2 received 50 mg daily for one week followed by
50 mg twice daily (100 mg/day) for three weeks (total dose:
2450 mg); cohort 3 received 100 mg daily for four weeks (total
dose: 2800 mg); and cohort 4 received 100 mg daily for one
week followed by 50 mg thrice a day (150 mg/day) for three
weeks (total dose: 3850 mg). The parasitological cure was
687
defined by the absence of parasites in a splenic aspirate
obtained after two weeks of completion of treatment. In all
120 patients there was an initial parasitological cure. Clinical
and parasitological relapses were, however observed in six
patients. The remaining 114 patients did not show any relapse
for the six months of observation period, thus registering a
cure rate of 95% (95% confidence limits (CL): 89-98%). The
final cure rate for all the cohorts was between 93 and 97%.
The cure rate for patients who had never received the therapy
with sodium stibogluconate was virtually identical to that for
patients in whom previous therapy with antimonial compound
had failed, i.e. miltefosine was as effective in those in whom
an antimonial resistance had already been observed. In this
study, miltefosine, at a dose of 100 mg daily for four weeks
showed an effectiveness of 97% (95% CL: 83-100%) in a 30
patient cohort (29 of 30 patients in cohort 3) out of total 120
patients. Because the infection was cured in five of five and
16 of 16 patients in two previous trials by the same group of
authors,25,26 the total cure rate with this dose (100 mg/d x 4
weeks) regimen was found to be 50 of 51 or 98% (95% CL: 90100).27
With this dose regimen, the adverse effects associated
with the miltefosine have usually been tolerable and reversible.
Based on the frequency of GI side effects, however the
therapeutic window of the drug appears to be narrow. GI
symptoms, such as vomiting and diarrhea although common,
were seen in 62% of patients (range 20-100%) and occurred
30 min to two hours following the drug administration. These
symptoms were observed 13% of days on which patients
received the drug, i.e. on an average of four of the 28 days of
their therapy and the symptoms were seen in patients of all
cohorts irrespective of the quantum of administered dose.
No patient, however either lost weight during or discontinued
the therapy because of GI episodes. In some patients,
hepatotoxicity and nephrotoxicity were observed but these
were reversible and treatment could be continued in most of
them. In the two patients in whom treatment had to be
discontinued, the serum activity of aspartate aminotransferase
and creatinine level rapidly returned to normal. Although the
toxicity associated with miltefosine appeared to be milder
than that seen with some parenteral therapies, GI symptoms
could be of more consequence in severely ill patients, such
as those who are malnourished or dehydrated than they were
in patients included in the clinical trials. As miltefosine has
been shown to be teratogenic in animals, it should not be
used in pregnancy.27
Because of the propensity of GI side effects which have
no bearing to the administered dose, the fourth trial was
undertaken to see whether the dose of 100 mg/day can be
given in two divided doses and the duration of therapy can
further be reduced.28 The treatment was initiated in three
groups of 18 patients each (total 54), given 50 mg twice daily
for 14 days (Group A), 21 days (Group B) and 28 days (Group
C). Cure was achieved in 89% of patients in Group A and in
100% of both Group B and Group C. Adverse effects were
primarily mild and self-limited. Authors concluded that a 21688
day, 50 mg twice daily miltefosine regimen combines high
level efficacy, convenient dosing and a relatively short
duration.28
On the basis of the overall results of four clinical trials of
miltefosine in kala-azar by the same group of workers and in
view of the observations of few relapses, effectiveness and
side effects vis-a-vis different dose regimens used, the authors
have recommended a dose of 50 mg twice daily or 100 mg per
day (approximately 2-2.5 mg/kg/day) for 3-4 weeks27-28 for the
subsequent Phase III trials and eventual regulatory
approval.29 It was suggested that the dose should be adjusted
to the patient’s weight so that a dose of 4 mg/kg/day is not
exceeded.28 The hopes from miltefosine are high and a clinical
trial involving 300 HIV-negative adult and adolescent patients
of Indian visceral leishmaniasis is already underway. 3
However, the future and ongoing clinical trials have to address
the following questions: a) Will the drug continue to be highly
effective and acceptably tolerated when more and a large
variety of patients are treated?, b) To what extent will the
miltefosine therapy be effective against syndromes caused
by 21 leishmanial species in 88 countries?, c) Will miltefosine
become one more option for treating a particular subgroup of
patients, or will it become the drug of choice for most patients
who require systemic antileishmanial therapy?, d) How will it
fare in HIV-infected patients?
Results of miltefosine in experimental cutaneous
leishmaniasis
Studies on the effectiveness of topical miltefosine in other
leishmanial syndromes, including American cutaneous
leishmaniasis, are in progress and the results of one recently
published experimental study in mice has shown the drug to
reduce the parasite burden in cutaneous leishmaniasis
induced by L. mexicana and L. major.30 The treated mice
healed their lesions much faster than the untreated infected
controls. On the basis of the encouraging results of this study,
the authors have suggested that the clinical application of
miltefosine (miltex: liquid preparation for local use) for the
treatment of cutaneous leishmaniasis may be highly efficient
because humans do not show a relapse once the cutaneous
lesions are healed.
SITAMAQUINE (KALAZAQUINE; WR6026),
AN 8-AMINOQUINOLINE
A Phase II clinical trial conducted in Kenya in 1994 showed
the effectiveness of oral sitamaquine (kalazaquin) in visceral
leishmaniasis.31,32 In this trial, one of the eight patients treated
with the drug at dose of 0.75-1 mg/kg/day for two weeks was
cured and 4 of 8 patients treated with a dose of 1 mg/kg/day
were cured. This drug is still being evaluated as an orally
effective drug for visceral leishmaniasis and to date 42
patients have been treated with various daily doses in excess
of 1 mg/kg/day. 33 However, the data on the safety and
effectiveness of different regimens have not been made
public. It is however, hoped that sitamaquine will be an
alternative drug to miltefosine to be used in those, where the
JAPI • VOL. 51 • JULY 2003
latter cannot be used due to GI intolerance or, where it does
not show a cure, or resistance develops to it. Further
experimental tests are needed to determine whether the two
drugs in combination would have a synergistic effect, since
miltefosine, being an antitumour agent acts by impairing the
integrity of cell membrances and this would increase the
availability of sitamaquine as it needs to cross the cell
membrane to reach its site of action in the chromosome.32 If a
synergy is shown, it may be possible to reduce the doses
and potential toxicity of these two orally effective
antileishmanial medications. There is also a need to study
the effect of both of these drugs in patients with AIDS.34
CONCLUSION
The study of success in achieving a cure in patients of
kala-azar by miltefosine and sitamaquine, the fruits of careful
observations of basic and clinical scientists, have not only
paved the way for the long-awaited orally administered drugs
but also have opened a path for many more to come. Phase III
clinical trials with miltefosine are already on under the aegis
of TDR programme of WHO.27 It is hoped that in the next 2-3
years, milteforsine will be a licensed antileishmanial agent
and will be affordable to those who need it most. With the
availability of more data on its safety in large and varied
population of patients and mechanism of action, the days are
not far where there will be a fundamental change in the
approach to the treatment of visceral leishmaniasis and
perhaps other leishmanial syndromes. With these
developments, one can envisage a future scenario where
parenteral therapy for kala-azar would rarely be needed.
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