by Wijnant G-J, Croft SL, de la Flor R, Alavijeh M, Yardley V, Braillard S, Mowbray C, Van Bocxlaer K. Antimicrobial Agents and Chemotherapy 2019, 63:e00829-19.

Summary: Nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, the authors investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative Leishmania pathogen in murine models of CL. Two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of Leishmania major. A combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.

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by Caridha D, Vesely B, van Bocxlaer K, Arana B, Mowbray CE, Rafati S, Reguera R, Kreishman-Deitrick M, Buffet P, Croft SL. International Journal for Parasitology: Drugs and Drug Resistance 2019, doi: 10.1016/j.ijpddr.2019.06.003.

Summary: There have been significant advances in the treatment of visceral leishmaniasis and several novel compounds are currently in pre-clinical and clinical development. However, advances in drug research and development for cutaneous leishmaniasis have been more limited. The authors review the need for new treatments for cutaneous leishmaniasis and describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the discovery, and pre-clinical development of new drugs for cutaneous leishmaniasis.

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by Van Bocxlaer K, Caridha D, Black C, Vesely B, Leed S, Sciotti RJ, Wijnant GJ, Yardley V, Braillard S, Mowbray CE, Ioset JR, Croft SL. International Journal for Parasitology: Drugs and Drug Resistance 2019, doi: 10.1016/j.ijpddr.2019.02.002

Summary: Three chemical lead series, the nitroimidazoles, benzoxaboroles, and aminopyrazoles have been identified as innovative treatments for visceral leishmaniasis. This study evaluated the anti-leishmanial efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis (CL). DNDI-VL-0690 (nitroimidazole), DNDI-1047 (aminopyrazole), and DNDI-6148 (benzoxaborole) showed excellent antileishmanial activity across a range of species in vitro and against L. major in mice. These compounds offer novel potential drugs for the treatment of CL.

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by Bailey F, Mondragon-Shem K, Haines LR, Olabi A, Alorfi A, Ruiz-Postigo JA, Alvar J, Hotez P, Adams ER, Vélez ID, Al-Salem W, Eaton J, Acosta-Serrano A, Molyneux DH. PLOS Neglected Tropical Diseases 2019, doi: 10.1371/journal.pntd.0007092

Summary: Major depressive disorder (MDD) associated with chronic neglected tropical diseases (NTDs) has been identified as a significant and overlooked contributor to overall disease burden. The characteristic residual scarring (inactive CL) following almost all cases of active cutaneous leishmaniasis (CL) has recently been recognised as part of the CL disease spectrum due to its lasting psychosocial impact. The authors performed a systematic review of the psychosocial impact of active and inactive CL and estimated the prevalence of MDD. Upon inclusion of co-morbid MDD alone in both active and inactive CL, the DALY burden was seven times higher than the latest 2016 Global Burden of Disease study estimates, which notably omitted both psychological impact and inactive CL.

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by Cruz I, Albertini A, Barbeitas M, Arana B, Picado A, Ruiz-Postigo JA, Ndung’u JM. Parasite Epidemiology and Control 2019, e00103. doi: 10.1016/j.parepi.2019.e00103

Summary: Microscopy is the reference test for diagnosis of dermal leishmaniasis, but it has low and variable sensitivity and requires well-trained personnel. The technical complexity and cost of the more sensitive molecular techniques (e.g. PCR) limits their application in routine diagnosis in endemic areas. Point-of-care (POC) tests for early diagnosis are much needed in order to benefit both patients and communities, by reducing the risk of both sequelae and Leishmania transmission. The authors describe a Target Product Profile for a POC test for dermal leishmaniases, which was defined through several rounds of discussions and by consensus with stakeholders and experts in dermal leishmaniases.

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by López L, Vélez I, Asela C, Cruz C, Alves F, Robledo S, Arana BPLOS Neglected Tropical Diseases 2018, 2(7): e0006653. doi: 10.1371/journal.pntd.0006653.

Summary: Better therapeutic options are needed for the treatment of cutaneous leishmaniasis (CL). Anfoleish, a topical formulation based on 3% Amphotericin B and developed by HUMAX and PECET, has been shown to be safe and efficacious in animal models and in an open label study in CL patients. The authors present the results of the first controlled and randomized study assessing the safety and efficacy of Anfoleish administered topically, two or three times per day for 28 days, for the treatment of non-complicated CL in Colombia. Although Anfoleish was safe and well-tolerated, its efficacy results do not support continuing its clinical development or recommending it for the treatment of CL. Additional studies to improve its current formulation are needed.

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by Erber AC, Arana B, Bennis I, Salah AB, Boukthir A, del Mar Castro Noriega M, Cissé M, Cota GF, Handjani F, Kebede MG, Lang T, López Carvajal L, Marsh K, Martinez Medina D, Plugge E, Olliaro P. BMJ Open 2018, 8:e021372. doi: 10.1136/bmjopen-2017-021372

Summary: Outcomes affecting patients’ quality of life are hardly assessed in trials for cutaneous leishmaniasis (CL), despite potential functional and/or aesthetic impairment, which typically affects disadvantaged and vulnerable people living in rural areas. The authors describe an approach that aims to bring CL patient perspectives into designing and assessing treatments. The authors describe the set-up of this collaborative study and the protocol, which includes study design, preparation, conduct and analysis of individual interviews with approximately 80 patients in seven countries where CL is prevalent. Patient recruitment aims at covering a maximum variation of experiences. Transcripts will be analysed to identify outcomes and eligibility criteria and additional topics that are expected to emerge from the interviews.

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by Olliaro P, Boni M, Carvalho EM, Chebli H, Cisse M, Diro E, Fernandes Cota G, Erber AC, Gadisa E, Handjani F, Khamesipour A, Llanos-Cuentas A, López Carvajal L, Grout L, Lmimouni BE, Mokni M, Nahzat MS, Ben Salah A, Ozbel Y, Pascale JM, Rizzo Molina N, Rode J, Romero G, Ruiz-Postigo JA, Gore Saravia N, Soto J, Uzun S, Mashayekhi V, Vélez ID, Vogt F, Zerpa O, Arana B. PLoS Neglected Tropical Diseases 2018, 12(1): e0006141, doi: 10.1371/journal.pntd.0006141.

Summary: Cutaneous leishmaniasis (CL) includes a range of skin conditions found across several continents. While not life-threatening, CL can be invalidating and disfiguring, or become complicated. There is no safe and effective treatment for CL and there has been no investment in drug development. Despite trying many treatments, clinical researchers have made little progress, and a lack of standardized methodologies for conducting trials hampers the collation and comparison of results. This paper summarizes the principles and parameters agreed upon by researchers in two separate meetings of how to identify patients and how to measure treatment effects in a way that will make it possible to gather convincing evidence of whether a treatment works or not. Adhering to these principles will allow faster progress towards offering better care to patients with this neglected disease.

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by Mears ER, Modabber F, Don R, and Johnson GE. PLoS Neglected Tropical Diseases 9(9): e0003889. doi:10.1371/journal. pntd.0003889, 2015

Summary: The current in vivo models for the utility and discovery of new potential anti-leishmanial drugs targeting cutaneous leishmaniasis differ vastly in their immunological responses to the disease and clinical presentation of symptoms. This review assesses the efficacy and limitations of the various CL models and their potential for drug discovery and evaluation

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by González U, Pinart M, Sinclair D, Firooz A, Enk C, Vélez ID, Esterhuizen TM, Tristan M, Alvar J. Cochrane Database Syst Rev. 2015 Aug 5;8:CD008736.
doi: 10.1002/14651858.CD008736.pub2.

Summary: Leishmaniasis is caused by the Leishmania parasite, and transmitted by infected phlebotomine sandflies. Of the two distinct clinical syndromes, cutaneous leishmaniasis (CL) affects the skin and mucous membranes, and visceral leishmaniasis (VL) affects internal organs. Approaches to prevent transmission include vector control by reducing human contact with infected sandflies, and reservoir control, by reducing the number of infected animals. This review summarises trials evaluating different measures to prevent leishmaniasis, and included 14 randomized control trials up to January 2015. The review concluded that using insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing.

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