Miltefosine: First Oral Drug for Treatment of Visceral Leishmaniasis

Agrawal, VK; Singh, Zile

doi:10.1016/s0377-1237(06)80162-0

Cited by 17 publications

(13 citation statements)

References 6 publications

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“…Furthermore, miltefosine has shown a synergistic effect with several drugs, among others, with nanotized curcumin against L. donovani (9), with amiodarone against L. mexicana (10), with allopurinol against canine VL produced by L. infantum (11), and with pentamidine against L. infantum-HIV coinfection (12). Despite its reported side effects as inducer of resistance and teratogenic action, evidence proving miltefosine antileishmanial action in vitro and in vivo led to its use as the first oral treatment for VL (13,14).…”

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confidence: 99%

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel

Pinto-Martinez

Rodríguez-Durán

Serrano-Martín

et al. 2018

Antimicrob Agents Chemother

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is the causing agent of visceral leishmaniasis, a common infection that affects millions of people from the most underdeveloped countries. Miltefosine is the only oral drug to treat infections caused by Nevertheless, its mechanism of action is not well understood. While miltefosine inhibits the synthesis of phosphatidylcholine and also affects the parasite mitochondrion, inhibiting the cytochrome oxidase, it is to be expected that this potent drug also produces its effect through other targets. In this context, it has been reported that the disruption of the intracellular Ca homeostasis represents an important object for the action of drugs in trypanosomatids. Recently, we have described a plasma membrane Ca channel in , which is similar to the L-type voltage-gated Ca channel (VGCC) present in humans. Remarkably, the parasite Ca channel is activated by sphingosine, while the L-type VGCC is not affected by this sphingolipid. In the present work we demonstrated that, similarly to sphingosine, miltefosine is able to activate the plasma membrane Ca channel from Interestingly, nifedipine, the classical antagonist of the human channel, was not able to fully block the parasite plasma membrane Ca channel, indicating that the mechanism of interaction is not identical to that of sphingosine. In this work we also show that miltefosine is able to strongly affect the acidocalcisomes from , inducing the rapid alkalinization of these important organelles. In conclusion, we demonstrate two new mechanisms of action of miltefosine in, both related to disruption of parasite Ca homeostasis.

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confidence: 99%

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel

Pinto-Martinez

Rodríguez-Durán

Serrano-Martín

et al. 2018

Antimicrob Agents Chemother

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“…Miltefosine is the first and only oral drug available for the treatment of leishmanial infection. 33 Its efficacy against VL infection makes it a standard treatment option unlike other antileishmanial therapies (antimonials, paromomycin or amphotericin B) as these include a painful regimen. Moreover, increasing cases of drug resistance against different treatments highlight the importance of other drugs, especially oral therapy against this morbid infection.…”

Section: Discussionmentioning

confidence: 99%

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Keshav

Goyal

Kaur

2021

Parasite Immunology

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Neglected tropical diseases (NTDs) affect nearly one-sixth of the world's population, and leishmaniasis is one such disease. The eukaryotic protozoan parasite of genus Leishmania with nearly 20 species is known to cause the disease leishmaniasis and is prevalent in nearly hundred countries throughout the world. 1 Female phlebotomine sand flies are transmission vectors of the disease. Parasite species and host immune response determine the disease outcome, and the three major manifestations are cutaneous, visceral and mucocutaneous leishmaniasis. 2 Visceral leishmaniasis (VL) is the deadliest of all the forms and is ranked as one of the world's leading parasitic killers with approximately 600 million people at risk across the globe and 7 th in loss of disability-adjusted life years (DALYs) (DNDi reports). In the Indian subcontinent and Africa, L. donovani is the aetiological agent of VL, while in the Mediterranean Basin, it is caused by L. infantum. 3 According to World Health Organization (WHO 2018), more than 95% of VL cases are clustered in 10 countries: India,

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“…Subsequently, it was found to be effective in vitro against the Leishmania donovani parasite [9]. Phase I-Phase III clinical trials conducted in India demonstrated that the drug was effective against VL to the extent of~95% [10][11][12]. Most of the side-effects included nausea, vomiting, abdominal pain, diarrhea and fever [11].…”

Section: Diagnosismentioning

confidence: 99%

Visceral Leishmaniasis

Bhattacharya¹,

Ghosal²,

Ganguly³

et al. 2018

Leishmaniases as Re-Emerging Diseases

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Clinically, leishmaniasis is of three types-visceral leishmaniasis (VL) or kala-azar, cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Post-kala-azar dermal leishmaniasis (PKDL) is considered as a complication of VL. VL is characterized by fever, anemia and splenomegaly in a VL-endemic area (malaria excluded). A subject with such symptoms should be subjected to an rK39 strip test. Confirmation of diagnosis is made by demonstration of the parasite (Leishmania donovani) from samples obtained by aspiration of bone marrow or iliac crest puncture. Miltefosine, stibogluconate, amphotericin B, liposomal amphotericin B and paromomycin are effective available anti-leishmaniasis drugs. Vector (Phleblotomus argentipes) control for reduction of transmission and early diagnosis and complete treatment are essential elements of case management. There is no effective vaccine against VL. This review on VL aims at providing state-art knowledge on epidemiology, diagnosis and case-management and vaccine development.

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Miltefosine: First Oral Drug for Treatment of Visceral Leishmaniasis

Cited by 17 publications

References 6 publications

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Visceral Leishmaniasis

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Miltefosine: First Oral Drug for Treatment of Visceral Leishmaniasis

Cited by 17 publications

References 6 publications

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca 2+ Channel

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca 2+ Channel

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Visceral Leishmaniasis

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Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel

Mechanism of Action of Miltefosine on Leishmania donovani Involves the Impairment of Acidocalcisome Function and the Activation of the Sphingosine-Dependent Plasma Membrane Ca ²⁺ Channel