Hostname: page-component-78c5997874-g7gxr Total loading time: 0 Render date: 2024-11-20T03:28:07.821Z Has data issue: false hasContentIssue false
  • English
  • Français

Leishmania and other intracellular pathogens: selectivity, drug distribution and PK–PD

[BSP Autumn Symposium “Microbial protein targets: towards understanding and intervention”, 14th–16th September 2016, University of Durham UK]

Published online by Cambridge University Press:  06 October 2017

SIMON L. CROFT
SIMON L. CROFT*
Affiliation:
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
*
*Corresponding author: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

New drugs and treatments for diseases caused by intracellular pathogens, such as leishmaniasis and the Leishmania species, have proved to be some of the most difficult to discover and develop. The focus of discovery research has been on the identification of potent and selective compounds that inhibit target enzymes (or other essential molecules) or are active against the causative pathogen in phenotypic in vitro assays. Although these discovery paradigms remain an essential part of the early stages of the drug R & D pathway, over the past two decades additional emphasis has been given to the challenges needed to ensure that the potential anti-infective drugs distribute to infected tissues, reach the target pathogen within the host cell and exert the appropriate pharmacodynamic effect at these sites. This review will focus on how these challenges are being met in relation to Leishmania and the leishmaniases with lessons learned from drug R & D for other intracellular pathogens.

Keywords

Leishmaniapharmacodynamicspharmacokineticsdrug distribution
Type
Special Issue Review
Information
Parasitology , Volume 145 , Special Issue 2: Microbial protein targets: towards understanding and intervention , February 2018 , pp. 237 - 247
Check for updates
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Albergante, L., Timmis, J., Beattie, L. and Kaye, P. M. (2013). A Petri net model of granulomatous inflammation: implications for IL-10 mediated control of Leishmania donovani infection. PLoS Computational Biology 9, e1003334.Google Scholar
Alberts, A. (1985). Selective Toxicity. The Physicochemical Basis of Therapy, 5th Edn. Chapman & Hall, London.Google Scholar
Aljayyoussi, G., Kay, K., Ward, S. A. and Biagini, G. A. (2016). OptiMal-PK: an internet-based, user-friendly interface for the mathematical-based design of optimized anti-malarial treatment regimens. Malaria Journal 15, 344.Google Scholar
Andreu, N., Phelan, J., de Sessions, P. F., Cliff, J. M., Clark, T. G. and Hibberd, M. L. (2017). Primary macrophages and J774 cells respond differently to infection with Mycobacterium tuberculosis . Scientific Reports 7, srep42225.Google Scholar
Aronson, N., Herwaldt, B. L., Libman, M., Pearson, R., Lopez-Velez, R., Weina, P., Carvalho, E., Ephros, M., Jeronimo, S. and Magill, A. (2017). Diagnosis and treatment of Leishmaniasis: clinical practice guidelines by the infectious diseases society of America (IDSA) and the American society of tropical medicine and hygiene (ASTMH). American Journal of Tropical Medicine and Hygiene 96, 24–45.Google Scholar
Baxter, K. L., Horn, E., Gal-Ed, N., Zonno, K., O'Leary, J., Terry, P. F. and Terry, S. F. (2013). An end to the myth: there is no drug development pipeline. Science Translational Medicine 5(171), 171.Google Scholar
Ben Salah, A., Ben Messaoud, N., Guedri, E., Zaatour, A., Ben Alaya, N., Bettaieb, J., Gharbi, A., Belhadj Hamida, N., Boukthir, A., Chlif, S., Abdelhamid, K., El Ahmadi, Z., Louzir, H., Mokni, M., Morizot, G., Buffet, P., Smith, P. L., Kopydlowski, K. M., Kreishman-Deitrick, M., Smith, K. S., Nielsen, C. J., Ullman, D. R., Norwood, J. A., Thorne, G. D., McCarthy, W. F., Adams, R. C., Rice, R. M., Tang, D., Berman, J., Ransom, J., Magill, A. J. and Grogl, M. (2013). Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. The New England Journal of Medicine 368, 524–532.Google Scholar
Buates, S. and Matlashewski, G. (1999). Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: efficacy and mode of action. Journal of Infectious Diseases 179, 1485–1494.Google Scholar
Caridha, D., Parriot, S., Hudson, T. H., Lang, T., Ngundam, F., Leed, S., Sena, J., Harris, M., O'Neil, M., Sciotti, R., Read, L., Lecoeur, H., Hickman, M. and Grogl, M. (2017). Use of optical imaging technology in the validation of a new, rapid, cost-effective drug screen as part of a tiered in vivo screening paradigm for development of drugs to treat cutaneous Leishmaniasis. Antimicrobial Agents and Chemotherapy 61, e02048-16.Google Scholar
Carlier, M.-B., Scorneaux, B., Zenebergh, A., Desnottes, J.-F. and Tulkens, P. M. (1990). Cellular uptake, localization and activity of fluoroquinolones in uninfected and infected macrophages. Journal of Antimicrobial Chemotherapy 26, 27–39.Google Scholar
Castro, M. M., Gomez, M. A., Kip, A. E., Cossio, A., Ortiz, E., Navas, A., Dorlo, T. P. C. and Saravia, N. G. (2017) Pharmacokinetics of miltefosine in children and adults with cutaneous leishmaniasis. Antimicrobial Agents and Chemotherapy 61, e02198–16.Google Scholar
Claudi, B., Spröte, P., Chirkova, A., Personnic, N., Zankl, J., Schürmann, N., Schmidt, A. and Bumann, D. (2014). Phenotypic variation of Salmonella in host tissues delays eradication by antimicrobial chemotherapy. Cell 158, 722–733.Google Scholar
Coelho, A. C., Oliveira, J. C., Espada, C. R., Reimão, J. Q., Trinconi, C. T. and Uliana, S. R. B. (2016) A luciferase-expressing Leishmania braziliensis line that leads to sustained skin lesions in BALB/c mice and allows monitoring of miltefosine treatment outcome. PLoS Neglected Tropical Diseases 10(5), e0004660.Google Scholar
Costa, S., Machado, M., Cavadas, C. and do Céu Sousa, M. (2016). Antileishmanial activity of antiretroviral drugs combined with miltefosine. Parasitology Research 115, 3881–3887.Google Scholar
Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26, 1–10.Google Scholar
Croft, S. L. (1986). In vitro screens in the experimental chemotherapy of leishmaniasis and trypanosomiasis. Parasitology Today 2, 64–69.Google Scholar
Croft, S. L. and Olliaro, P. (2011). Leishmaniasis chemotherapy – challenges and opportunities. Clinical Microbiology and Infection 17, 1478–1483.Google Scholar
Croft, S. L., Neal, R. A., Pendergast, W. and Chan, J. H. (1987). The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani . Biochemical Pharmacology 36, 2633–2636.Google Scholar
Croft, S. L., Sundar, S. and Fairlamb, A. H. (2006). Drug resistance in leishmaniasis. Clinical Microbiology Reviews 19, 111–126.Google Scholar
Dancik, Y., Anissimov, Y. G., Jepps, O. G. and Roberts, M. S. (2012). Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application. British Journal of Clinical Pharmacology 73, 564–578.Google Scholar
Dartois, V. (2014). The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nature Reviews. Microbiology 12, 159–167.Google Scholar
Davidson, R. N., Scott, A., Maini, M., Bryceson, A. D. M. and Croft, S. L. (1991). Liposomal amphotericin B in drug resistant visceral leishmaniasis. The Lancet 337(8749), 1061–1062.Google Scholar
Davies, G. R. and Nuermberger, E. L. (2008). Pharmacokinetics and pharmacodynamics in the development of anti-tuberculosis drugs. Tuberculosis 88, S65–S74.Google Scholar
De Rycker, M., Hallyburton, I., Thomas, J., Campbell, L., Wyllie, S., Joshi, D., Cameron, S., Gilbert, I. H., Wyatt, P. G., Frearson, J. A., Fairlamb, A. H. and Gray, D. W. (2013) Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. Antimicrobial Agents and Chemotherapy 57, 2913–2922.Google Scholar
Dorlo, T. P. C., van Thiel, P. P. A. M., Huitema, A. D. R., Keizer, R. J., de Vries, H. J. C., Beijnen, J. H. and de Vries, P. J. (2008). Pharmacokinetics of miltefosine in old world cutaneous leishmaniasis patients. Antimicrobial Agents and Chemotherapy 52, 2855–2860.Google Scholar
Dorlo, T. P. C., Balasegaram, M., Beijnen, J. H. and de Vries, P. J. (2012). Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. Journal of Antimicrobial Chemotherapy 67, 2576–2597.Google Scholar
Duque, G. A. and Descoteaux, A. (2015). Leishmania survival in the macrophage: where the ends justify the means. Current Opinion in Microbiology 26, 32–40.Google Scholar
Edginton, A. N., Theil, F.-P., Schmitt, W. and Willmann, S. (2008). Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opinion on Drug Metabolism & Toxicology 4, 1143–1152.Google Scholar
Ehrlich, P. (1913). A lecture on chemotherapeutics. Lancet ii, 445–451.Google Scholar
El-On, J., Jacobs, G. P., Witztum, E. and Greenblatt, C. L. (1984). Development of topical treatment for cutaneous leishmaniasis caused by Leishmania major in experimental animals. Antimicrobial Agents and Chemotherapy 26, 745–751.Google Scholar
Escobar, P., Matu, S., Marques, C. and Croft, S. L. (2002). Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Tropica 81, 151–157.Google Scholar
Frézard, F., Demicheli, C. and Ribeiro, R. R. (2009). Pentavalent antimonials: new perspectives for old drugs. Molecules 14, 2317–2336.Google Scholar
Garnier, T., Mäntylä, A., Järvinen, T., Lawrence, J., Brown, M. and Croft, S. (2007 a). In vivo studies on the antileishmanial activity of buparvaquone and its prodrugs. Journal of Antimicrobial Chemotherapy 60, 802–810.Google Scholar
Garnier, T., Mäntylä, A., Järvinen, T., Lawrence, M. J., Brown, M. B. and Croft, S. L. (2007 b). Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis. Journal of Pharmacy and Pharmacology 59, 41–49.CrossRefGoogle ScholarPubMed
Gershkovich, P., Wasan, E. K., Sivak, O., Li, R., Zhu, X., Werbovetz, K. A., Tidwell, R. R., Clement, J. G., Thornton, S. J. and Wasan, K. M. (2010). Visceral leishmaniasis affects liver and spleen concentrations of amphotericin B following administration to mice. Journal of Antimicrobial Chemotherapy 65, 535–537.Google Scholar
Gilbert, I. H. (2013). Drug discovery for neglected diseases: molecular target-based and phenotypic approaches. Journal of Medicinal Chemistry 56, 7719–7726.Google Scholar
González, U., Pinart, M., Reveiz, L. and Alvar, J. (2008). Interventions for Old World cutaneous leishmaniasis. Cochrane Database of Systematic Reviews (4): CD005067.Google Scholar
González, U., Pinart, M., Rengifo-Pardo, M., Macaya, A., Alvar, J. and Tweed, J. A. (2009). Interventions for American cutaneous and mucocutaneous leishmaniasis. Cochrane Database of Systematic Reviews (2): CD004834.Google Scholar
Goodwin, L. G. (1995). Pentostam® (sodium stibogluconate); a 50-year personal reminiscence. Transactions of the Royal Society of Tropical Medicine and Hygiene 89, 339–341.Google Scholar
Gordon, S., Plüddemann, A. and Martinez Estrada, F. (2014). Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunological Reviews 262, 36–55.Google Scholar
Guler, R. and Brombacher, F. (2015). Host-directed drug therapy for tuberculosis. Nature Chemical Biology 11, 748–751.Google Scholar
Hastings, I. M., Hodel, E. M. and Kay, K. (2016). Quantifying the pharmacology of antimalarial drug combination therapy. Scientific Reports 6, srep32762.Google Scholar
Hendrickx, S., Guerin, P. J., Caljon, G., Croft, S. L. and Maes, L. (2017). Evaluating drug resistance in visceral leishmaniasis: the challenges. Parasitology online. doi: 10.1017/S0031182016002031.Google Scholar
Hirve, S., Boelaert, M., Matlashewski, G., Mondal, D., Arana, B., Kroeger, A. and Olliaro, P. (2016) Transmission dynamics of visceral Leishmaniasis in the Indian subcontinent – a systematic literature review. PLoS Neglected Tropical Diseases 10(8), e0004896.Google Scholar
Horn, D. and Duraisingh, M. T. (2014). Antiparasitic chemotherapy – from genomes to mechanisms. Annual Review of Pharmacology and Toxicology 54, 71–94.Google Scholar
Jabado, N., Jankowski, A., Dougaparsad, S., Picard, V., Grinstein, S. and Gros, P. (2000). Natural resistance to intracellular infections. Journal of Experimental Medicine 192, 1237–1248.Google Scholar
Jepps, O. G., Dancik, Y., Anissimov, Y. G. and Roberts, M. S. (2013). Modeling the human skin barrier – towards a better understanding of dermal absorption. Advanced Drug Delivery Reviews 65, 152–168.Google Scholar
Kaye, P. and Scott, P. (2011). Leishmaniasis: complexity at the host-pathogen interface. Nature Reviews. Microbiology 9, 604–615.Google Scholar
Kaye, P. M. and Beattie, L. (2016). Lessons from other diseases: granulomatous inflammation in leishmaniasis. Seminars in Immunopathology 38, 249–260.Google Scholar
Kellina, O. I., Iniakhina, A. V. and Iastrebova, R. I. (1966). Treatment of cutaneous leishmaniasis with monomycin. Med Parazitol (Mosk) 35, 283–287.Google Scholar
Khare, S., Nagle, A. S., Biggart, A., Lai, Y. H., Liang, F., Davis, L. C., Barnes, S. W., Mathison, C. J. N., Myburgh, E., Gao, M.-Y., Gillespie, J. R., Liu, X., Tan, J. L., Stinson, M., Rivera, I. C., Ballard, J., Yeh, V., Groessl, T., Federe, G., Koh, H. X. Y., Venable, J. D., Bursulaya, B., Shapiro, M., Mishra, P. K., Spraggon, G., Brock, A., Mottram, J. C., Buckner, F. S., Rao, S. P. S., Wen, B. G., et al. (2016). Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 537, 229–233.Google Scholar
Kip, A. E., Rosing, H., Hillebrand, M. J. X., Castro, M. M., Gomez, M. A., Schellens, J. H. M., Beijnen, J. H. and Dorlo, T. P. C. (2015). Quantification of miltefosine in peripheral blood mononuclear cells by high-performance liquid chromatography-tandem mass spectrometry. Journal of Chromatography. B. Analytical Technologies in the Biomedical and Life Sciences 998–999, 57–62.Google Scholar
Kloehn, J., Saunders, E. C., O'Callaghan, S., Dagley, M. J. and McConville, M. J. (2015). Characterization of metabolically quiescent Leishmania parasites in murine lesions using heavy water labeling. PLoS Pathogens 11, e1004683.Google Scholar
Koniordou, M., Patterson, S., Wyllie, S. and Seifert, K. (2017). Snapshot profiling of anti-leishmanial potency of lead compounds and drug candidates against intracellular L. donovani amastigotes with focus on human derived host cells. Antimicrobial Agents and Chemotherapy 61, e01228-16.Google Scholar
Mandell, M. A. and Beverley, S. M. (2017). Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. Proceedings of the National Academy of Sciences of the United States of America.Google Scholar
Maurin, M., Benoliel, A. M., Bongrand, P. and Raoult, D. (1992). Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm. Journal of Infectious Diseases 166, 1097–1102.Google Scholar
Miranda-Verastegui, C., Tulliano, G., Gyorkos, T. W., Calderon, W., Rahme, E., Ward, B., Cruz, M., Llanos-Cuentas, A. and Matlashewski, G. (2009). First-line therapy for human cutaneous Leishmaniasis in Peru using the TLR7 agonist imiquimod in combination with pentavalent antimony. PLoS Neglected Tropical Diseases 3, e491.Google Scholar
Moore, J. W. J., Moyo, D., Beattie, L., Andrews, P. S., Timmis, J. and Kaye, P. M. (2013). Functional complexity of the Leishmania granuloma and the potential of in silico modeling. Frontiers in Immunology 4.Google Scholar
Morgan, P., Van Der Graaf, P. H., Arrowsmith, J., Feltner, D. E., Drummond, K. S., Wegner, C. D. and Street, S. D. A. (2012). Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discovery Today 17(9–10), 419–424.Google Scholar
Mullen, A. B., Baillie, A. J. and Carter, K. C. (1998). Visceral Leishmaniasis in the BALB/c mouse: a comparison of the efficacy of a nonionic surfactant formulation of sodium stibogluconate with those of three proprietary formulations of amphotericin B. Antimicrobial Agents and Chemotherapy 42, 2722–2725.Google Scholar
Murray, H. W., Berman, J. D. and Wright, S. D. (1988). Immunotherapy for intracellular Leishmania donovani infection: gamma interferon plus pentavalent antimony. Journal of Infectious Diseases 157, 973–978.Google Scholar
Muylder, G. D., Vanhollebeke, B., Caljon, G., Wolfe, A. R., McKerrow, J. and Dujardin, J.-C. (2016). Naloxonazine, an amastigote-specific compound, affects Leishmania parasites through modulation of host-encoded functions. PLoS Neglected Tropical Diseases 10, e0005234.Google Scholar
Neal, R. A. and Croft, S. L. (1984). An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. Journal of Antimicrobial Chemotherapy 14, 463–475.Google Scholar
Nègre, E., Chance, M. L., Hanboula, S. Y., Monsigny, M., Roche, A. C., Mayer, R. M. and Hommel, M. (1992). Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lectins. Antimicrobial Agents and Chemotherapy 36, 2228–2232.Google Scholar
Nielsen, E. I. and Friberg, L. E. (2013). Pharmacokinetic-pharmacodynamic modeling of antibacterial drugs. Pharmacological Reviews 65, 1053–1090.Google Scholar
Novais, F. O., Carvalho, A. M., Clark, M. L., Carvalho, L. P., Beiting, D. P., Brodsky, I. E., Carvalho, E. M. and Scott, P. (2017). CD8+ t cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production. PLOS Pathogens 13, e1006196.Google Scholar
Orchard, S., Al-Lazikani, B., Bryant, S., Clark, D., Calder, C., Dix, I., Engkvist, O., Forster, M., Gaulton, A., Gilson, M., Glen, R., Grigorov, M., Hammond-Kosack, K., Harland, L., Hopkins, A., Larminie, C., Lynch, N., Mann, R. K., Murray-Rust, P., Lo Piparo, E., Southan, E., Steinbeck, C., Wishart, D., Henning Hermjakob, H., Overington, J. and Thornton, J. (2011) Minimum information about a bioactive entity (MIABE). Nature Reviews Drug Discovery 10, 661–669.Google Scholar
Osorio, Y., Travi, B. L., Renslo, A. R., Peniche, A. G. and Melby, P. C. (2011). Identification of small molecule lead compounds for visceral Leishmaniasis using a novel ex vivo splenic explant model system. PLoS Neglected Tropical Diseases 5, e962.Google Scholar
Parihar, S. P., Hartley, M.-A., Hurdayal, R., Guler, R. and Brombacher, F. (2016). Topical Simvastatin as host-directed therapy against severity of cutaneous Leishmaniasis in mice. Scientific Reports 6, srep33458.Google Scholar
Pasparakis, M., Haase, I. and Nestle, F. O. (2014). Mechanisms regulating skin immunity and inflammation. Nature Reviews. Immunology 14, 289–301.Google Scholar
Patel, K., Simpson, J. A., Batty, K. T., Zaloumis, S. and Kirkpatrick, C. M. (2015). Modelling the time course of antimalarial parasite killing: a tour of animal and human models, translation and challenges. British Journal of Clinical Pharmacology 79, 97–107.Google Scholar
Peña, I., Manzano, M. P., Cantizani, J., Kessler, A., Alonso-Padilla, J., Bardera, A. I., Alvarez, E., Colmenarejo, G., Cotillo, I., Roquero, I., de Dios-Anton, F., Barroso, V., Rodriguez, A., Gray, D. W., Navarro, M., Kumar, V., Sherstnev, A., Drewry, D. H., Brown, J. R., Fiandor, J. M. and Martin, J. J. (2015). New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource. Scientific Reports 5, srep08771.Google Scholar
Peniche, A. G., Renslo, A. R., Melby, P. C. and Travi, B. L. (2014) Development of an ex vivo lymph node explant model for identification of novel molecules active against Leishmania major. Antimicrobial Agents and Chemotherapy 58, 78–87.Google Scholar
Prideaux, B., Via, L. E., Zimmerman, M. D., Eum, S., Sarathy, J., O'Brien, P., Chen, C., Kaya, F., Weiner, D. M., Chen, P.-Y., Song, T., Lee, M., Shim, T. S., Cho, J. S., Kim, W., Cho, S. N., Olivier, K. N., Barry, C. E. and Dartois, V. (2015). The association between sterilizing activity and drug distribution into tuberculosis lesions. Natural Medicines 21, 1223–1227.Google Scholar
Rabinovitch, M., Zilberfarb, V. and Ramazeilles, C. (1986). Destruction of Leishmania mexicana amazonensis amastigotes within macrophages by lysosomotropic amino acid esters. Journal of Experimental Medicine 163, 520–535.Google Scholar
Rajendran, L., Knölker, H.-J. and Simons, K. (2010). Subcellular targeting strategies for drug design and delivery. Nature Reviews. Drug Discovery 9, 29–42.Google Scholar
Ravis, W. R., Llanos-Cuentas, A., Sosa, N., Kreishman-Deitrick, M., Kopydlowski, K. M., Nielsen, C., Smith, K. S., Smith, P. L., Ransom, J. H., Lin, Y.-J. and Grogl, M. (2013). Pharmacokinetics and absorption of paromomycin and gentamicin from topical creams used to treat cutaneous leishmaniasis. Antimicrobial Agents and Chemotherapy 57, 4809–4815.Google Scholar
Sampaio, S. A. P., Godoy, J. T., Paiva, L., Dillon, N. L. and de Lacaz, C. S. (1960). The treatment of American (mucocutaneous) leishmaniasis with amphotericin B. Archive of Dermatology 82, 627–635.Google Scholar
Sanz, L. M., Crespo, B., De-Cózar, C., Ding, X. C., Llergo, J. L., Burrows, J. N., García-Bustos, J. F. and Gamo, F.-J. (2012). P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS ONE 7, e30949.Google Scholar
Scott, P. and Novais, F. O. (2016). Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nature Reviews Immunology 16, 581–592.Google Scholar
Seifert, K., Escobar, P. and Croft, S. L. (2010). In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent. Journal of Antimicrobial Chemotherapy 65, 508–511.Google Scholar
Siqueira-Neto, J. L., Moon, S., Jang, J., Yang, G., Lee, C., Moon, H. K., Chatelain, E., Genovesio, A., Cechetto, J. and Freitas-Junior, L. H. (2012). An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. PLoS Neglected Tropical Diseases 6, e1671.Google Scholar
Smith, A. C., Yardley, V., Rhodes, J. and Croft, S. L. (2000). Activity of the novel immunomodulatory compound tucaresol against experimental visceral leishmaniasis. Antimicrobial Agents and Chemotherapy 44, 1494–1498.Google Scholar
Smith, D. A., Di, L. and Kerns, E. H. (2010). The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nature Reviews. Drug Discovery 9, 929–939.Google Scholar
Sundar, S., Sinha, P. K., Rai, M., Verma, D. K., Nawin, K., Alam, S., Chakravarty, J., Vaillant, M., Verma, N., Pandey, K., Kumari, P., Lal, C. S., Arora, R., Sharma, B., Ellis, S., Strub-Wourgaft, N., Balasegaram, M., Olliaro, P., Das, P. and Modabber, F. (2011). Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 377(9764), 477–486.Google Scholar
Sundar, S., Singh, A., Rai, M., Prajapati, V. K., Singh, A. K., Ostyn, B., Boelaert, M., Dujardin, J.-C. and Chakravarty, J. (2012). Efficacy of miltefosine in the treatment of visceral leishmaniasis in India after a decade of use. Clinical Infectious Diseases 55, 543–550.Google Scholar
Swietach, P., Hulikova, A., Patiar, S., Vaughan-Jones, R. D. and Harris, A. L. (2012). Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLOS ONE 7, e35949.Google Scholar
Tegazzini, D., Díaz, R., Aguilar, F., Peña, I., Presa, J. L., Yardley, V., Martin, J. J., Coteron, J. M., Croft, S. L. and Cantizani, J. (2016) A replicative in vitro assay for drug discovery against Leishmania donovani . Antimicrobial Agents and Chemotherapy 60, 3524–3532.Google Scholar
Van Bambeke, F., Barcia-Macay, M., Lemaire, S. and Tulkens, P. M. (2006). Cellular pharmacodynamics and pharmacokinetics of antibiotics: current views and perspectives. Current Opinion in Drug Discovery & Development 9(2), 218–230.Google Scholar
Van Bocxlaer, K., Yardley, V., Murdan, S. and Croft, S. L. (2016 a). Drug permeation and barrier damage in Leishmania-infected mouse skin. Journal of Antimicrobial Chemotherapy 71, 1578–1585.Google Scholar
Van Bocxlaer, K., Yardley, V., Murdan, S. and Croft, S. L. (2016 b). Topical formulations of miltefosine for cutaneous leishmaniasis in a BALB/c mouse model. Journal of Pharmacy and Pharmacology 68, 862–872.Google Scholar
Van der Greef, J. and McBurney, R. N. (2005). Innovation: rescuing drug discovery: in vivo systems pathology and systems pharmacology. Nature Reviews. Drug Discovery 4, 961–967.Google Scholar
Van Griensven, J., Diro, E., Lopez-Velez, R., Boelaert, M., Lynen, L., Zijlstra, E., Dujardin, J.-C. and Hailu, A. (2013). HIV-1 protease inhibitors for treatment of visceral leishmaniasis in HIV-co-infected individuals. The Lancet Infectious Diseases 13, 251–259.Google Scholar
Van Griensven, J., Zijlstra, E. E. and Hailu, A. (2014). Visceral Leishmaniasis and HIV coinfection: time for concerted action. PLoS Neglected Tropical Diseases 8, e3023.Google Scholar
Vinet, A. F., Jananji, S., Turco, S. J., Fukuda, M. and Descoteaux, A. (2011). Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization. Microbiology 157, 2619–2628.Google Scholar
Voak, A., Harris, A., Qaiser, Z., Croft, S. and Seifert, K. (2017). Treatment of experimental visceral leishmaniasis with single-dose liposomal amphotericin B – pharmacodynamics and biodistribution at different stages of disease. Antimicrobial Agents and Chemotherapy in press.Google Scholar
Wijnant, G. J., Van Bocxlaer, K., Yardley, V., Murdan, S. and Croft, S. L. (2017 a). Efficacy of a paromomycin plus chloroquine combination therapy in experimental cutaneous Leishmaniasis. Antimicrobial Agents and Chemotherapy in press.Google Scholar
Wijnant, G. J., Van Bocxlaer, K., Yardley, V., Harris, A., Murdan, S. and Croft, S. L. (2017 b). Accumulation of amphotericin B in lesions and healthy skin areas of L. major infected BALB/c mice after AmBisome treatment. Worldleish 6, poster C-0351. http://worldleish2017.org/documentos/Abstracts_BookWL6_final.pdf.Google Scholar
World Health Organization (2010). Control of Leishmaniasis, WHO Technical Report Series, 949.Google Scholar
Wring, S., Gaukel, E., Nare, B., Jacobs, R., Beaudet, B., Bowling, T., Mercer, L., Bacchi, C., Yarlett, N., Randolph, R., Parham, R., Rewerts, C., Platner, J. and Don, R. (2014). Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of stage 2 human African trypanosomiasis. Parasitology 141, 104–118.Google Scholar
Yurdakul, P., Dalton, J., Beattie, L., Brown, N., Erguven, S., Maroof, A. and Kaye, P. M. (2011). Compartment-specific remodeling of splenic micro-architecture during experimental visceral Leishmaniasis. American Journal of Pathology 179, 23–29.Google Scholar
Zhao, S. and Iyengar, R. (2012). Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. Annual Review of Pharmacology and Toxicology 52, 505–521.Google Scholar
Zumla, A., et al. (2015). Towards host-directed therapies for tuberculosis. Nature Reviews Drug Discovery 14, 511–512.Google Scholar