Clinical status of agents being developed for leishmaniasis

Berman, Jonathan

doi:10.1517/13543784.14.11.1337

Cited by 50 publications

(23 citation statements)

References 48 publications

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“…The structure of HDTAB closely resembles the structure of hexadecylphosphocholine (miltefosin) (Fig. 1), the well-known drug used in chemotherapy for cancer (10) and leishmaniasis (11,30). HDTAB exhibits potent antimalarial activity in vitro and in vivo.…”

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confidence: 72%

“…Development of specific choline kinase inhibitors based on the structure of HC-3 (23, 24) and a mild inhibition of PfCK by HC-3 induced interest in studying the effects of other quaternary ammonium compounds on PfCK activity. The quaternary ammonium compound selected for the study was HDTAB because it has a quaternary ammonium group as well as its structure is very similar to the structure of hexadecylphosphocholine (miltefosin), a molecule widely used as an antiproliferative (10) and antileishmanial drug (11,30). HDTAB inhibited PfCK in a dose-dependent manner and showed 60% (P Ͻ 0.001) inhibition at 100 M (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Miltefosin inhibits the CDP-choline pathway (26) (Fig. 1) and offers antiproliferative, antileishmanial, and antimalarial drug activity (10,11,30,32). The mode of action in the latter two cases has not been well defined.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Choubey

Maity

Guha

et al. 2007

Antimicrob Agents Chemother

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Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.

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confidence: 72%

Section: Resultsmentioning

confidence: 99%

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Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Choubey

Maity

Guha

et al. 2007

Antimicrob Agents Chemother

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“…Nonetheless, there are various clinical presentations of disease due to each species (9, 21,28), and increasing numbers of reports document atypical presentations of leishmaniasis, sometimes but not always in the setting of immunocompromise (15,50). Differentiation between the Leishmania species is an issue because there are overlapping and dynamic geographic regions of risk and different susceptibilities to treatment (6,14). Thus, a method of diagnosis that is sensitive enough to detect low levels of the parasite in asymptomatic or early symptomatic infection and can distinguish between the different Leishmania species could be of tremendous utility in regions of endemicity and nonendemicity (37).…”

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confidence: 99%

Serial Quantitative PCR Assay for Detection, Species Discrimination, and Quantification of Leishmania spp. in Human Samples

et al. 2011

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The Leishmania species cause a variety of human disease syndromes. Methods for diagnosis and species differentiation are insensitive and many require invasive sampling. Although quantitative PCR (qPCR) methods are reported for leishmania detection, no systematic method to quantify parasites and determine the species in clinical specimens is established. We developed a serial qPCR strategy to identify and rapidly differentiate Leishmania species and quantify parasites in clinical or environmental specimens. SYBR green qPCR is mainly employed, with corresponding TaqMan assays for validation. The screening primers recognize kinetoplast minicircle DNA of all Leishmania species. Species identification employs further qPCR set(s) individualized for geographic regions, combining species-discriminating probes with melt curve analysis. The assay was sufficient to detect Leishmania parasites, make species determinations, and quantify Leishmania spp. in sera, cutaneous biopsy specimens, or cultured isolates from subjects from Bangladesh or Brazil with different forms of leishmaniasis. The multicopy kinetoplast DNA (kDNA) probes were the most sensitive and useful for quantification based on promastigote standard curves. To test their validity for quantification, kDNA copy numbers were compared between Leishmania species, isolates, and life stages using qPCR. Maxicircle and minicircle copy numbers differed up to 6-fold between Leishmania species, but the differences were smaller between strains of the same species. Amastigote and promastigote leishmania life stages retained similar numbers of kDNA maxi-or minicircles. Thus, serial qPCR is useful for leishmania detection and species determination and for absolute quantification when compared to a standard curve from the same Leishmania species.

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“…Since vaccines are not yet on the horizon (23), maintenance and improvement of existing treatment regimens, combined with new drug discovery initiatives, appear to be the only ways to guarantee continued control of this important tropical disease (3,11,27).…”

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In Vitro Susceptibilities of Leishmania donovani Promastigote and Amastigote Stages to Antileishmanial Reference Drugs: Practical Relevance of Stage-Specific Differences

Vermeersch¹,

Luz²,

Toté³

et al. 2009

Antimicrob Agents Chemother

210

166

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The in vitro susceptibilities of the reference strain Leishmania donovani MHOM/ET/67/L82 to sodium stibogluconate, amphotericin B, miltefosine, and the experimental compound PX-6518 were determined for extracellular log-phase promastigotes, established axenic amastigotes, fresh spleen-derived amastigotes, and intracellular amastigotes in primary mouse peritoneal macrophages. Susceptibility to amphotericin B did not differ across the various axenic models (50% inhibitory concentrations [IC 50 ], 0.6 to 0.7 M), and amphotericin B showed slightly higher potency against intracellular amastigotes (IC 50 , 0.1 to 0.4 M). A similar trend was observed for miltefosine, with comparable efficacies against the extracellular (IC 50 , 0.4 to 3.8 M) and intracellular (IC 50 , 0.9 to 4.3 M) stages. Sodium stibogluconate, used either as Pentostam or as a crystalline substance, was inactive against all axenic stages (IC 50 , >64 g Sb V /ml) but showed good efficacy against intracellular amastigotes (IC 50 , 22 to 28 g Sb V /ml); the crystalline substance was about two to three times more potent (IC 50 , 9 to 11 g Sb V /ml). The activity profile of PX-6518 was comparable to that of sodium stibogluconate, but at a much higher potency (IC 50 , 0.1 g/ml). In conclusion, the differential susceptibility determines which in vitro models are appropriate for either drug screening or resistance monitoring of clinical field isolates. Despite the more complex and labor-intensive protocol, the current results support the intracellular amastigote model as the gold standard for in vitro Leishmania drug discovery research and for evaluation of the resistance of field strains, since it also includes host cell-mediated effects. Axenic systems can be recommended only for compounds for which no cellular mechanisms are involved, for example, amphotericin B and miltefosine.Current first-line chemotherapy of leishmaniasis relies on a rather limited arsenal of drugs including sodium stibogluconate, meglumine antimoniate, amphotericin B, and miltefosine, but these entail either problems of emerging resistance, severe side effects, or high costs (5). Since vaccines are not yet on the horizon (23), maintenance and improvement of existing treatment regimens, combined with new drug discovery initiatives, appear to be the only ways to guarantee continued control of this important tropical disease (3,11,27).Both for drug screening and for determination of the susceptibility of field strains, different laboratory methods are being used that focus on the promastigote, the axenic amastigote, or the intracellular amastigote stage. However, it remains unclear how these models cross-validate each other. The differences in environmental conditions between promastigotes and amastigotes in vivo are reflected in their needs for in vitro cultivation. While promastigotes are easily cultured in suspension (8), amastigotes are more difficult to maintain in vitro, since they require macrophages as host cells to meet the highly acidic intracellular environment (15). Cultivat...

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Clinical status of agents being developed for leishmaniasis

Cited by 50 publications

References 48 publications

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Serial Quantitative PCR Assay for Detection, Species Discrimination, and Quantification of Leishmania spp. in Human Samples

In Vitro Susceptibilities of Leishmania donovani Promastigote and Amastigote Stages to Antileishmanial Reference Drugs: Practical Relevance of Stage-Specific Differences

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