Karin Seifert's research while affiliated with London School of Hygiene and Tropical Medicine and other places

Publications (38)

Article
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Background: There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was...
Article
Full-text available
Background : Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen inter...
Article
Full-text available
Background : Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen inter...
Article
Full-text available
Objectives: We examined the in vitro pharmacodynamics and cellular accumulation of the standard anti-leishmanial drugs amphotericin B and miltefosine in intracellular Leishmania donovani amastigote-macrophage drug assays. Methods: Primary mouse macrophages were infected with L. donovani amastigotes. In time-kill assays infected macrophages were...
Article
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Background: Visceral leishmaniasis (VL) is a neglected tropical disease (NTD), caused by the intracellular protozoan parasites Leishmania donovani and Leishmania infantum. Symptomatic VL is considered fatal when left untreated. At present, there is no effective vaccine licensed for human use and available chemotherapies have limitations. Understan...
Article
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Quinone-based compounds have been exploited to treat infectious diseases and cancer, with such chemicals often functioning as inhibitors of key metabolic pathways or as prodrugs. Here, we screened an aziridinyl-1,4-benzoquinone (ABQ) library against the causative agents of trypanosomiasis, and cutaneous leishmaniasis, identifying several potent str...
Article
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Visceral leishmaniasis is a neglected tropical disease, which causes significant morbidity and mortality worldwide. Characterising the pharmacokinetics and pharmacodynamics of anti-leishmanial drugs in pre-clinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of AmBisome® in L. do...
Article
This study characterised in vitro potencies of anti-leishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells and mouse peritoneal exudate macrophages (PEMs). Host cell dependent p...
Article
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The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T cell epitope enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the sa...
Article
Combination therapies for leishmaniasis, including drugs and immunomodulators, are one approach to shorten treatment courses and to improve treatment of complex manifestations of the disease. We evaluated a novel T-cell epitope enriched DNA vaccine candidate (LEISHDNAVAX) as host-directed immunotherapy in combination with a standard anti-leishmania...
Article
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Miltefosine, an effective oral treatment of visceral leishmaniasis (VL), was selected in May 2005, by the governments of India, Nepal, and Bangladesh for the elimination of VL. However, abnormally high treatment failure rates reported in patients in Bangladesh, given a miltefosine generic product ("Miltefos", Popular Pharmaceuticals Ltd.) during 20...
Article
Parasitic infections such as Leishmania induce a cascade of host physiological responses, including metabolic and immunological changes. Infection with Leishmania major protozoa causes cutaneous leishmaniasis in humans, a neglected tropical disease with suboptimal disease management. To understand the determinants of pathology, we studied L. major...
Article
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The leishmaniases are protozoal diseases that severely affect large populations in tropical and subtropical regions. There are only limited treatment options and preventative measures. Vaccines will be important for prevention, control and elimination of leishmaniasis, and could reduce the transmission and burden of disease in endemic populations....
Article
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Many of the nitroaromatic agents used in medicine function as prodrugs and must undergo activation before exerting their toxic effects. In most cases this is catalysed by FMN-dependent type I nitroreductases (NTRs), a class of enzyme absent from higher eukaryotes but expressed by bacteria and several eukaryotic microbes including trypanosomes and L...
Article
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Nitroaromatic prodrugs are used to treat a range of microbial infections with selectivity achieved by specific activation reactions. For trypanosomatid parasites, this is mediated by type I nitroreductases. Here, we demonstrate that the causative agent of leishmaniasis, Leishmania major, expresses an FMN-containing nitroreductase (LmNTR) that metab...
Article
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A noncovalent, water-soluble complex of amphotericin B (AMB) and poly(α-glutamic acid) (PGA), with AMB loadings ranging from 25 to 55% (wt/wt) using PGA with a molecular weight range of 50,000 to 70,000, was prepared as a potential new treatment for visceral leishmaniasis (VL). The AMB-PGA complex was shown to be as active as Fungizone (AMB deoxych...
Chapter
The last decade has seen significant advances in the treatment of visceral leishmaniasis. Two new drugs (miltefosine and paromomycin) have been registered for the treatment of visceral leishmaniasis since 2002. Multidrug treatments have been investigated in systematic clinical studies and are now recommended as a new treatment approach for visceral...
Conference Paper
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Evidence from in vivo Leishmania spp. infection models have demonstrated that pathology is closely associated with the host’s underlying immune response towards the protozoan parasite, including the activation state and parasiticidal ability of Leishmania’s main target cell, the macrophage. We have investigated the role of the host’s immune respons...
Article
A non-covalent complex of amphotericin B (AmB) and poly(α-glutamic acid) (PGA) was prepared to develop a safe and stable formulation for the treatment of leishmaniasis. The loading of AmB in the complex was in the range of ~20-50%. AmB was in a highly aggregated state with an aggregation ratio often above 2.0. This complex (AmB-PGA) was shown to be...
Article
Full-text available
Recent years have seen a significant improvement in available treatment options for leishmaniasis. Two new drugs, miltefosine and paromomycin, have been registered for the treatment of visceral leishmaniasis (VL) in India since 2002. Combination therapy is now explored in clinical trials as a new treatment approach for VL to reduce the length of tr...
Article
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To evaluate in vitro interactions between sitamaquine and the current antileishmanial drugs amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against intracellular Leishmania donovani amastigotes in peritoneal mouse macrophages. A second objective was to evaluate the susceptibility of antimony-resistant L. donovani iso...
Article
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There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer-drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer-drug conjugates of N-(...
Article
To evaluate the in vitro activity of anti-leishmanial drugs against intracellular Leishmania donovani amastigotes in different types of macrophages. Mouse peritoneal macrophages (PEMs), mouse bone marrow-derived macrophages (BMMPhi), human peripheral blood monocyte-derived macrophages (PBM Phi) and differentiated THP-1 cells were infected with L. d...
Article
Full-text available
Leishmaniasis is a major health problem in many parts of the world, caused by various species of Leishmania. Amastigotes are the clinically relevant form of the parasite in the human host and reside in the parasitophorous vacuole within macrophages. Polymer-drug conjugates have been used for lysosomotropic drug delivery and have already shown poten...
Article
Antileishmanial activities of 91 synthetic phospholipids against Leishmania donovani were evaluated in vitro and cytotoxicity assessed against two mammalian cell lines. Promising compounds were tested further in vivo. In vitro structure-activity relationships showed a positive contribution of head groups bearing ring systems (N-methylpiperidino and...
Article
Miltefosine (hexadecylphosphocholine) is the first oral antileishmanial drug. In this study, we addressed the question whether miltefosine-resistant Leishmania donovani promastigotes transform to miltefosine-resistant amastigotes. A promastigote line, M-mutR, showed defective internalisation of miltefosine owing to mutations in LdMT, similar to pre...
Article
Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatment...
Article
Miltefosine (hexadecylphosphocholine, MIL), registered as Impavido((R)), has become the first oral drug for the treatment of visceral and cutaneous leishmanasis. MIL is a simple molecule, very stable, relatively safe and highly efficient in clinical trials. However, MIL requires a long treatment course (28 days) and has a long half-life (around 150...
Article
Full-text available
The interaction of miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo. In vitro interactions were indifferent for miltefosine combined with amphotericin B (mean sums of fractional inhibitory concentrations [mean summation operatorFICs]...
Article
Leishmania donovani promastigote lines resistant to hexadecylphosphocholine (HePC, miltefosine) at 2.5, 5.0, 10.0, 20.0 and 40.0 microM were developed in vitro by continuous step-wise drug pressure. The 40 microM line was 15 times more resistant to HePC than the wild-type clone and showed cross-resistance to the ether lipid ET-18-OCH3 (edelfosine)...
Article
The antiprotozoal activity of phospholipid analogues, originally developed as anti-cancer drugs, has been determined in the past decade. The most susceptible parasites are Leishmania spp. and Trypanosoma cruzi with activity also shown against Trypanosoma brucei spp., Entamoeba histolytica and Acanthamoeba spp. Miltefosine, an alkylphosphocholine, w...
Article
Full-text available
Free-living amoebae of the genus Acanthamoeba are causing serious chronic conditions such as destructive keratitis in contact lens wearers or granulomatous amoebic encephalitis in individuals with compromised immune systems. Both are characterized by the lack of availability of sufficiently effective and uncomplicated, manageable treatments. Hexade...
Article
Full-text available
The protozoan parasite Entamoeba histolytica is the cause of amoebic dysentery and liver abscess. It is therefore responsible for significant morbidity and mortality in a number of countries. Infections with E. histolytica are treated with nitroimidazoles, primarily with metronidazole. At this time, there is a lack of useful alternative classes of...

Citations

... In this regard, L-AmB is the best-studied antileishmanial drug in terms of PK and PK/PD in animal models. Following IV administration of L-AmB, AmB accumulation in the liver and spleen is lower in BALB/c mice infected with L. donovani than in those of uninfected animals, indicating the impact of pathophysiology and disease-induced organ enlargement on PK (203,204). Furthermore, dose fractionation and PK/PD studies revealed the concentration-dependent in vivo activity of L-AmB in VL, suggesting higher, less frequent dosing maximizes clinical efficacy. In contrast, AmB accumulation was significantly higher in the CL skin lesions than in the uninfected control skin of mice infected with L. major. ...
... Parasite transcriptional profile during L. donovani and L. infantum infections. We examined host and parasite response at day 35 postinfection in BALB/c mice, as this time point reflects both the establishment of chronic splenic pathology and the onset of hepatic host resistance (17). We applied tissue dual RNA-seq to liver and spleen tissue isolated from uninfected mice and mice infected with either L. donovani or L. infantum amastigotes (Fig. 1A). ...
... Although experimental infection in hamsters represents a suitable model for the study of lesions associated with severe forms of VL, the analysis of pathways involved in lesion development has been limited by a lack of compatible reagents. However, recent gene expression studies have substantially contributed to our understanding of mechanisms involved in immune response to VL (25,26). ...
... 41,42 The efficacy should be determined by the drug concentration inside dermal macrophages. 43 An approach Table 4. PK parameters in non-infected mice after IV administration of a berberine-β-glycerophosphate (BER-GP) solution (7.5 mg/kg) or in blood and skin of non-infected and L. ...
... Liver pathology: Transmission electron micrographs of liver sections generated 45 days after L. donovani infection revealed increased infiltration of monocyte derived macrophages with consequent liver hyperplasia in the Wnt5A heterozygous mice as compared to the wild type controls (Figures 3A, B), which is in compliance with the correlation of monocyte/macrophage infiltration with active disease (29,30). Augmented disease in the Wnt5A heterozygous mice as compared to the wild type was furthermore indicated by the increased incidence of liver granuloma 45 days after L. donovani infection as revealed by histology ( Figures 3C, D) (26). ...
... Where appropriate, protein expression was induced by adding tetracycline (1 μg/ml). compounds (e.g., tetracycline, melarsprol, G418, and eflornithine) or DNA damaging agents (e.g., UV light, mechlorethamine, phleomycin, hydroxyurea, and methyl methanesulfonate) have been previously reported (Bot et al., 2013;Dattani & Wilkinson, 2019;Meredith et al., 2017;Wilkinson et al., 2008). ...
... In this regard, L-AmB is the best-studied antileishmanial drug in terms of PK and PK/PD in animal models. Following IV administration of L-AmB, AmB accumulation in the liver and spleen is lower in BALB/c mice infected with L. donovani than in those of uninfected animals, indicating the impact of pathophysiology and disease-induced organ enlargement on PK (203,204). Furthermore, dose fractionation and PK/PD studies revealed the concentration-dependent in vivo activity of L-AmB in VL, suggesting higher, less frequent dosing maximizes clinical efficacy. In contrast, AmB accumulation was significantly higher in the CL skin lesions than in the uninfected control skin of mice infected with L. major. ...
... In parallel, the trypanocidal potential of another nitro drug has been revisited, allowing the identification of a promising candidate, such as fexinidazole, which has been recently included as a possible candidate to treat chronic T. cruzi infection (Patterson and Fairlamb, 2019;DNDi, 2020). Despite the safety concerns regarding this pharmacological class, nitro compounds have been explored with success as a source of a potential treatment for other kinetoplastid-related diseases (Patterson and Fairlamb, 2019), such as human African trypanosomiasis (Janssens and De Muynck, 1977;Torreele et al., 2010;Eperon et al., 2014;Tarral et al., 2014;Mesu et al., 2018) and leishmaniasis (Wyllie et al., 2012;Koniordou et al., 2017). ...
... 39 The well-known pharmacokinetics suggested that proguanil rapidly absorbed with a median time to peak plasma concentration of 3 hours (range, 2-4 hours), about 75% protein bound and 40% to 60% majorly excreted by the kidneys. 40 Lipophilicity is an important parameter to state cell wall permeability, and generally, compounds with higher lipophilicity are highly penetrant across cell wall. Egan and coworkers 42 suggested that absorption models the 95% and 99% confidence limit ellipses corresponding to HIA and penetrates the BBB models in the ADMET PSA-2D and ADMET-AlogP 98 plane. ...
... Antitumor compounds have also shown activity against parasites, including palladacycle complexes that displayed trypanocidal and leishmanicidal effects (8)(9)(10)(11). Recent findings identified immunomodulators able to increase the efficacy of leishmanicidal compounds (12,13). ...