Antileishmanial Agents: A Review
Parmesh Kumar Dwivedi1, Kishu
Tripathi2, Mamta Mishra3 and Suprabhat Ray1
1Amity
Institute of Pharmacy, Amity University, Uttar Pradesh, Lucknow
Campus, Lucknow
2Institute of Pharmaceutical Sciences and Research Center, Bhagwant University, Ajmer. Rajasthan
3State
Public Analytical Laboratory (FDA), Lucknow
ABSTRACT:
Leishmaniasis is a disease caused by number of protozoa in the genus leishmania,is a complex of diseases caused by 17 species of the
protozoan parasite Leishmania and transmitted by~30
species of phlebotomine sandflies. Current treatment strategies and
problems associated with it are given.
KEYWORDS: Leishmaniasis, antileishmanial
INTRODUCTION:
Leishmaniasis is a disease caused by a number of protozoa in the
genus leishmania. The protozoa may be harbored in
diseased rodents, canines and various other mammals, transmitted from the
infected mammal to man by bites from female sandflies
of the genus phlehotomus and then appear in one of
the four major clinical syndromes: visceral leishmaniasis,
cutaneous leishmaniasis, mucocutaneous leishmaniasis or
diffused cutaneous leishmaniasis.
As many as twelve million individuals, worldwide are infected by this organism.
The visceral leishmaniasis, also known as kala azar (black fever), is
caused by Leishmania donovani1. Leishmaniasis, a
vector born-disease that is caused by obligate intra-macrophage protozoa, is
endemic in large areas of the tropics, subtropics and Mediterranean basin1.
Leishmaniases are a complex of diseases caused by 17 species of the
protozoan parasite Leishmania and transmitted by~30
species of Phlebotomine sandflies.
Current
treatment strategies and problems associated with it:
Treatment of leishmaniasis
relies on specific antileishmanial drugs, and in case
of visceral leishmaniasis(VL) also an aggressive
management of concomitant bacterial or parasitic infection, anemia, hypovolemial (decreased blood volume), and malnutrition, is
needed. The drugs used for above purpose are described below:
A) Pentavalent antimonials:
Pentavalent antimonials sodium stibogluconate(60) and meglumine antimoniate
(59) have been the first line
treatment in leishmaniasis for more than 70 years.
Structure of sodium stibogluconate is still not
known. The drug gets activated within amastigote but
not in the promastigote, by conversion to the lethal
trivalent form, the mechanism of which is not known. It exerts its antileishmanial effect might be due to the action on host
macrophages2.
Antimonials
are toxic drugs with frequent sometimes life threatening (in case of VL),
adverse side effects, including cardiac arrhythmia and acute pancreatitis. Due
to its toxicity and requirement of 28 days of parenteral
administration (patients compliance) and emergence of significance resistance
has restricted its use3.
B) Pentamidine:
The
usefulness of diamidine pentamine
(61) as antileishmanial
drug has been limited by its toxicity. Nevertheless since its introduction in
1952, it has had value for cutaneous leishmaniasis (CL), VL and diffuse
CL. It is normally used as a second line drugs, when antimonials have proved ineffective.4
C) Amphotericin
B:
The
polyene antibiotics Amphotericin
B(62) has proved to be highly
effective for the treatment of antimonial resistant L. donovani VL
and cases of mucocutaneous leishmaniasis
(MCL), that have not responded to antimonials but it
is a unpleasant drug because of its toxicity and the need for slow infusion of parenteral administration over 4 hours5.
D) Miltefosine:
Miltefosine
(63), an alkyl phosphocholine
which was initially developed as an anticancer drug, is the first effective
oral drug for VL. In a recent phase IV trial, final cure rate was 82 % by
intention to treat with only 3 deaths out of 1132 patients6.
D) Miltefosine:
Miltefosine
(63), an alkyl phosphocholine
which was initially developed as an anticancer drug, is the first effective
oral drug for VL. In a recent phase IV trial, final cure rate was 82 % by
intention to treat with only 3 deaths out of 1132 patients6.
E) Paromomycin:
Paromomycin
(64), is an aminoglycoside
antibiotic with good antileishmanial activity7.
The result of phase 3 trials recently conducted in India showed excellent
efficacy and safety. No nephrotoxicity was observed,
reversible high tone ototoxicity (damage to inner
ear) was found in 2% of patients and 1.8% patients showed significant increase
(> 5 fold) in hepatic transaminases.8
Antileishmanial activity of sitamaquine (65) was first identified in 1970 at the Walter Reed Army Institute
of Research. Phase 2 study was conducted in Brazil,
Kenya and India and obtained cure rates ranging from 27-87 %, but there were
also several cases of severe renal adverse events.9
G) Combination Therapy:
It
is suggested that the way forward is to increase treatment efficacy, prevent
development of drug resistance, reduce treatment duration and decrease
treatment cost.
The
association of sodium stibogluconate and paramomycin was found to be safe and effective in early
trials conducted in India and East Africa10. The drug combination
including liposomal amphotericin B and miltefosine are currently being studied in India.
REFERENCES:
1.
Clive R.; Paul K.; Simon L C.; Shyam S., B.M.J.
2003,326, 37782.
2.
Pathak, M.K.; and Yi, T., J.Immunol. 2001, 167, 33913397.
3.
Sundar, S., Clin.
Infect. Dis. 2000, 31,
11041107.
4.
Wilson, W. D.; Nguyen, B.; Tanious, F. A.;
Mathis, A.; Hall, J. E.; Stephens,C. E.; Boykin, D.
W,. Curr. Med. Chem. Anti-Cancer Agents 2005,
5, 389-408..
5.
Roberts, C.W. , Mol. Biochem. Parasitol.
2003, 126, 129142.
6.
Berman, J. ,ExpertOpin.
Pharmacother. 2005, 6, 1381-1388.
7.
Den B.; M. & Davidson, R. N,. Expert Rev.
Anti Infect. Ther. 2006, 4, 187197.
8.
Sundar, S., N. Engl. J. Med. 2007, 356, 25712581.
9.
Jha, T. K. , Am. J. Trop. Med. Hyg. 2005, 73, 10051011.
10.
Thakur, C. P., Trans. R. Soc.
Trop. Med. Hyg. 2000, 94, 429431.
Received
on 14.12.2009
Accepted on 17.03.2010
© A&V Publication all right reserved
Research Journal of Pharmacognosy and Phytochemistry.
2(4): July-Aug. 2010, 264-266