Emerging Pharmaceutical Therapeutics for Neglected Tropical Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 3924

Special Issue Editors


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Guest Editor
Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
Interests: onchocerciasis; lymphatic filariasis; neglected tropical diseases; drug dicovery; morbidity management

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Guest Editor
Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
Interests: filarial infections; drug discovery; macrofilaricide; onchocerciasis; loiasis, mansonellosis

Special Issue Information

Dear Colleagues,

In the recent past, several new candidates were identified for neglected tropical diseases (NTDs). While the first drugs were registered, e.g., fexinidazole for sleeping sickness or miltefosin and paromomycin combination for leishmaniasis in Africa, more drug candidates are in development (e.g., phase 2b/3 studies for leishmaniasis, Chagas disease or myecetoma). However, for some NTDs, the pipeline of new drug candidates is not well equipped, and only a few candidates are within phase 1 or 2 clinical trials (e.g., for onchocerciasis). In the present Special Issue, we ask authors to submit original research and review articles that relate to drug candidates for NTDs with special emphasis on their formulation, dosage form, drug delivery and pharmacokinetics, etc., as is the scope of the journal.  

Prof. Dr. Achim Hoerauf
Prof. Dr. Marc Hübner
Guest Editors

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Keywords

  • neglected tropical diseases
  • drug candidate
  • macrofilaricide
  • leishmaniasis
  • onchocerciasis
  • chagas disease
  • echinococcosis
  • foodborne trematodiases
  • African trypanosomiasis
  • lymphatic filariasis
  • schistosomiasis
  • soil-transmitted helminthiases
  • taeniasis/cysticercosis
  • formulation
  • dosage form
  • drug delivery
  • pharmacokinetics

Published Papers (3 papers)

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Research

21 pages, 12047 KiB  
Article
Repurposed Drugs That Activate Autophagy in Filarial Worms Act as Effective Macrofilaricides
by Denis Voronin, Nancy Tricoche, Ricardo Peguero, Anna Maria Kaminska, Elodie Ghedin, Judy A. Sakanari and Sara Lustigman
Pharmaceutics 2024, 16(2), 256; https://doi.org/10.3390/pharmaceutics16020256 - 9 Feb 2024
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Abstract
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human hosts. Current control strategies are based on annual or biannual mass drug administration (MDA) of the drugs Ivermectin or Ivermectin plus [...] Read more.
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human hosts. Current control strategies are based on annual or biannual mass drug administration (MDA) of the drugs Ivermectin or Ivermectin plus Albendazole, respectively. These drug regimens kill the first-stage larvae of filarial worms (i.e., microfilariae) and interrupt the transmission of infections. MDA programs for these microfilaricidal drugs must be given over the lifetime of the filarial adult worms, which can reach 15 years in the case of Onchocerca volvulus. This is problematic because of suboptimal responses to ivermectin in various endemic regions and inefficient reduction of transmission even after decades of MDA. There is an urgent need for the development of novel alternative treatments to support the 2030 elimination goals of onchocerciasis and lymphatic filariasis. One successful approach has been to target Wolbachia, obligatory endosymbiotic bacteria on which filarial worms are dependent for their survival and reproduction within the human host. A 4–6-week antibiotic therapy with doxycycline, for example, resulted in the loss of Wolbachia that subsequently led to extensive apoptosis of somatic cells, germline, embryos, and microfilariae, as well as inhibition of fourth-stage larval development. However, this long-course regimen has limited use in MDA programs. As an alternative approach to the use of bacteriostatic antibiotics, in this study, we focused on autophagy-inducing compounds, which we hypothesized could disturb various pathways involved in the interdependency between Wolbachia and filarial worms. We demonstrated that several such compounds, including Niclosamide, an FDA-approved drug, Niclosamide ethanolamine (NEN), and Rottlerin, a natural product derived from Kamala trees, significantly reduced the levels of Wolbachia in vitro. Moreover, when these compounds were used in vivo to treat Brugia pahangi-infected gerbils, Niclosamide and NEN significantly decreased adult worm survival, reduced the release of microfilariae, and decreased embryonic development depending on the regimen and dose used. All three drugs given orally significantly reduced Wolbachia loads and induced an increase in levels of lysosome-associated membrane protein in worms from treated animals, suggesting that Niclosamide, NEN, and Rottlerin were effective in causing drug-induced autophagy in these filarial worms. These repurposed drugs provide a new avenue for the clearance of adult worms in filarial infections. Full article
(This article belongs to the Special Issue Emerging Pharmaceutical Therapeutics for Neglected Tropical Diseases)
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15 pages, 7083 KiB  
Article
Onchocerciasis Drug Discovery: In Vitro Evaluation of FDA-Approved Drugs against Onchocerca gutturosa in Gambia
by Suzanne Gokool, Simon Townson, Andrew Freeman, Jadzia Siemienski-Kleyn, Jakub Zubrzycki, Senyo Tagboto, Marc P. Hübner and Ivan Scandale
Pharmaceutics 2024, 16(2), 210; https://doi.org/10.3390/pharmaceutics16020210 - 31 Jan 2024
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Abstract
Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, [...] Read more.
Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long-lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination, there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study, we have examined the anti-Onchocerca activity of a range of existing FDA-approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 × 10−5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50–99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate and rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation. Full article
(This article belongs to the Special Issue Emerging Pharmaceutical Therapeutics for Neglected Tropical Diseases)
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14 pages, 2631 KiB  
Article
Solid Lipid Nanoparticles Enhancing the Leishmanicidal Activity of Delamanid
by Javier Santamaría-Aguirre, Daniela Jacho, Miguel A. Méndez, Ana Poveda, Javier Carrión and Mónica L. Fanarraga
Pharmaceutics 2024, 16(1), 41; https://doi.org/10.3390/pharmaceutics16010041 - 27 Dec 2023
Viewed by 1662
Abstract
Leishmaniasis, a zoonotic parasitic disease transmitted by infected sandflies, impacts nearly 1 million people yearly and is endemic in many countries across Asia, Africa, the Americas, and the Mediterranean; despite this, it remains a neglected disease with limited effective treatments, particularly in impoverished [...] Read more.
Leishmaniasis, a zoonotic parasitic disease transmitted by infected sandflies, impacts nearly 1 million people yearly and is endemic in many countries across Asia, Africa, the Americas, and the Mediterranean; despite this, it remains a neglected disease with limited effective treatments, particularly in impoverished communities with limited access to healthcare. This study aims to repurpose approved drugs for an affordable leishmaniasis treatment. After the screening of potential drug candidates by reviewing databases and utilizing molecular docking analysis, delamanid was chosen to be incorporated into solid lipid nanoparticles (SLNPs). Both in cellulo and in vivo tests confirmed the successful payload release within macrophages and through the epidermis following topical application on murine skin. The evaluation of macrophages infected with L. infantum amastigotes showed that the encapsulated delamanid exhibited greater leishmanicidal activity compared with the free drug. The process of encapsulating delamanid in SLNPs, as demonstrated in this study, places a strong emphasis on employing minimal technology, ensuring energy efficiency, cost-effectiveness, and reproducibility. It enables consistent, low-cost production of nanomedicines, even on a small scale, offering a promising step toward more accessible and effective leishmaniasis treatments. Full article
(This article belongs to the Special Issue Emerging Pharmaceutical Therapeutics for Neglected Tropical Diseases)
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