Oral treatment of visceral leishmaniasis with miltefosine

Sundar, Shyam; Gupta, Lal B.; Makharia, M K; Singh, Manoj Kumar; Voß, Andreas; Rosenkaimer, F; Engel, Juergen; Murray, Henry W.

doi:10.1080/00034983.1999.11813462

Cited by 52 publications

(68 citation statements)

References 14 publications

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“…Efforts to improve the therapeutic arsenal against leishmaniasis have led to the application of amphotericin B in liposomes and, more recently, to the study of miltefosine activity in visceral patients in India (36). Nonetheless, the need for alternative drugs remains.…”

mentioning

confidence: 99%

Antileishmanial Activity of the Terpene Nerolidol

Arruda

D’Alexandri

Katzin

et al. 2005

Antimicrob Agents Chemother

170

104

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The activity of nerolidol, a sesquiterpene used as a food-flavoring agent and currently under testing as a skin penetration enhancer for the transdermal delivery of therapeutic drugs, was evaluated against Leishmania species. Nerolidol inhibited the growth of Leishmania amazonensis, L. braziliensis, and L. chagasi promastigotes and L. amazonensis amastigotes with in vitro 50% inhibitory concentrations of 85, 74, 75, and 67 M, respectively. The treatment of L. amazonensis-infected macrophages with 100 M nerolidol resulted in 95% reduction in infection rates. Inhibition of isoprenoid biosynthesis, as shown by reduced incorporation of [2-14 C]mevalonic acid (MVA) or [1-14 C]acetic acid precursors into dolichol, ergosterol, and ubiquinone, was observed in nerolidol-treated promastigotes. This drug effect can be attributed to the blockage of an early step in the mevalonate pathway, since incorporation of the precursor [1(n)-3 H]farnesyl pyrophosphate in polyisoprenoids is not inhibited by nerolidol. L. amazonensis-infected BALB/c mice were treated with intraperitoneal doses of 100 mg/kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. Significant reduction of lesion sizes in nerolidol treated mice was observed for both treatment routes. However, long-term follow up indicated that the disease was not cured in this highly susceptible animal model. Nonetheless, the in vitro activity of nerolidol against these parasites may prove a useful tool for the development of new drugs for the treatment of leishmaniasis. In addition, biosynthesis of dolichols with 11 and 12 isoprene units was identified in Leishmania, as described for other trypanosomatids and Apicomplexa.

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mentioning

confidence: 99%

Antileishmanial Activity of the Terpene Nerolidol

Arruda

D’Alexandri

Katzin

et al. 2005

Antimicrob Agents Chemother

170

104

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“…Recently, miltefosine (hexadecylphosphocholine [HePC]), an alkylphosphocholine originally developed as an anticancer drug and currently used for topical treatment (Miltex) of skin metastases of breast cancer (59), has been proved to be the first effective and safe oral treatment (Impavido) for Indian VL, with cure rates of about 98% (25,54). Moreover, HePC has been successfully used to treat patients with antimony-resistant VL (53,55) as well as cutaneous leishmaniasis (51).…”

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confidence: 99%

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Paris¹,

Loiseau²,

Bories³

et al. 2004

Antimicrob Agents Chemother

311

235

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Miltefosine (hexadecylphosphocholine [HePC]) has proved to be a potent oral treatment for human visceral leishmaniasis due to Leishmania donovani. The molecular mechanisms that contribute to the antileishmanial activity of HePC are still unknown. We report that in wild-type promastigotes of Leishmania donovani HePC is able to induce a cell death process with numerous cytoplasmic, nuclear, and membrane features of metazoan apoptosis, including cell shrinkage, DNA fragmentation into oligonucleosome-sized fragments, and phosphatidylserine exposure. None of these changes were detected in an HePC-resistant clone treated with the same drug concentration. Therefore, HePC does not appear to kill L. donovani promastigotes by a direct toxic mechanism but, rather, kills the promastigotes by an indirect one. Pretreatment of wild-type promastigotes with two broad caspase inhibitors, z-Val-Ala-DL-Asp(methoxy)-fluoromethylketone and Boc-Asp(methoxy)-fluoromethylketone, as well as a broad protease inhibitor, calpain inhibitor I, prior to drug exposure interfered with DNA fragmentation but did not prevent cell shrinkage or phosphatidylserine externalization. These data suggest that at least part of the apoptotic machinery operating in wild-type promastigotes involves proteases. Identification of the death-signaling pathways activated in HePC-sensitive parasites appears to be essential for a better understanding of the molecular mechanisms of action and resistance in these parasites.

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“…The effect of food on sitamaquine plasma AUC (0-τ) , AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) , and C max and on desethyl-sitamaquine AUC (0-τ) and C max , was evaluated at day 10 and day 21. After log e transformation, a linear mixed-effects model was used, fitting day and treatment (fasted or fed) as fixed effects and patient as a random effect.…”

Section: Methodsmentioning

confidence: 99%

“…Miltefosine was the first oral therapy available for VL and a significant breakthrough. [11][12][13] However, a four-week treatment schedule and a long-half life may make it vulnerable to resistance development if given as monotherapy, and teratogenicity is an issue for its use in women. 14 The recent emphasis on Leishmania elimination in India, Nepal and Bangladesh, 3,15 sustains a need for alternative, affordable, well-tolerated, and effective oral therapies.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Oral Sitamaquine Taken with or without Food and Safety and Efficacy for Treatment of Visceral Leishmaniais: A Randomized Study in Bihar, India

Sundar

Sinha²,

Dixon³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1−10 and 11−21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)(0−τ) = 6,627−8,903 ng.hr/mL, AUC(0−16) = 4,859−6,633 ng.hr/mL, maximum plasma concentration (Cmax) = 401−570 ng/mL, apparent terminal half-life (t1/2) = 18.3−22.8 hr, time to reach Cmax (tmax) = 3.5−6 hr; and desethyl-sitamaquine, AUC(0−τ) = 2,307−3,163 ng.hr/mL, Cmax = 109−154 ng/mL, t1/2 = 23.0−27.9 hr, tmax = 2−10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8–94.4%) for sitamaquine and 95% (95% confidence interval = 75.1–99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis.

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Oral treatment of visceral leishmaniasis with miltefosine

Cited by 52 publications

References 14 publications

Antileishmanial Activity of the Terpene Nerolidol

Antileishmanial Activity of the Terpene Nerolidol

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Pharmacokinetics of Oral Sitamaquine Taken with or without Food and Safety and Efficacy for Treatment of Visceral Leishmaniais: A Randomized Study in Bihar, India

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