{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:49:50Z","timestamp":1777416590590,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"NIH\/NIAID","doi-asserted-by":"publisher","award":["R21AI153649"],"award-info":[{"award-number":["R21AI153649"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Division of Intramural Research of the NIAID, NIH","award":["R21AI153649"],"award-info":[{"award-number":["R21AI153649"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u20136-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.<\/jats:p>","DOI":"10.3390\/pharmaceutics16020256","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T03:53:46Z","timestamp":1707450826000},"page":"256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Repurposed Drugs That Activate Autophagy in Filarial Worms Act as Effective Macrofilaricides"],"prefix":"10.3390","volume":"16","author":[{"given":"Denis","family":"Voronin","sequence":"first","affiliation":[{"name":"Systems Genomics Section, Laboratory of Parasitic Diseases, Division of Intramural Research, NIAID, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3895-7062","authenticated-orcid":false,"given":"Nancy","family":"Tricoche","sequence":"additional","affiliation":[{"name":"Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9032-6148","authenticated-orcid":false,"given":"Ricardo","family":"Peguero","sequence":"additional","affiliation":[{"name":"Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Kaminska","sequence":"additional","affiliation":[{"name":"Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elodie","family":"Ghedin","sequence":"additional","affiliation":[{"name":"Systems Genomics Section, Laboratory of Parasitic Diseases, Division of Intramural Research, NIAID, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judy A.","family":"Sakanari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2389-6113","authenticated-orcid":false,"given":"Sara","family":"Lustigman","sequence":"additional","affiliation":[{"name":"Molecular Parasitology, New York Blood Center, Lindsley F. Kimball Research Institute, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S0140-6736(10)60586-7","article-title":"Lymphatic filariasis and onchocerciasis","volume":"376","author":"Taylor","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1111\/j.1469-0691.2011.03586.x","article-title":"Filariasis in Africa-treatment challenges and prospects","volume":"17","author":"Hoerauf","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lustigman, S., Prichard, R.K., Gazzinelli, A., Grant, W.N., Boatin, B.A., McCarthy, J.S., and Basanez, M.G. (2012). A research agenda for helminth diseases of humans: The problem of helminthiases. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001582"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Prichard, R.K., Basanez, M.G., Boatin, B.A., McCarthy, J.S., Garcia, H.H., Yang, G.J., Sripa, B., and Lustigman, S. (2012). A research agenda for helminth diseases of humans: Intervention for control and elimination. PLoS Negl. Trop. Dis., 6.","DOI":"10.1371\/journal.pntd.0001549"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.pt.2003.09.004","article-title":"Mass drug treatment for lymphatic filariasis and onchocerciasis","volume":"19","author":"Molyneux","year":"2003","journal-title":"Trends Parasitol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ottesen, E.A., Hooper, P.J., Bradley, M., and Biswas, G. (2008). The global programme to eliminate lymphatic filariasis: Health impact after 8 years. PLoS Negl. Trop. Dis., 2.","DOI":"10.1371\/journal.pntd.0000317"},{"key":"ref_7","unstructured":"WHO (2010). Global programme to eliminate lymphatic filariasis. Wkly. Epidemiol. Rec., 85, 365\u2013372."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chu, B.K., Hooper, P.J., Bradley, M.H., McFarland, D.A., and Ottesen, E.A. (2010). The economic benefits resulting from the first 8 years of the Global Programme to Eliminate Lymphatic Filariasis (2000\u20132007). PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000708"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/00001432-200104000-00008","article-title":"Current status and future prospects of the Global Lymphatic Filariasis Programme","volume":"14","author":"Molyneux","year":"2001","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S1473-3099(16)30467-4","article-title":"Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: A modelling study","volume":"17","author":"Irvine","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1080\/14787210.2020.1792772","article-title":"Moxidectin: An oral treatment for human onchocerciasis","volume":"18","author":"Milton","year":"2020","journal-title":"Expert Rev. Anti. Infect. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1186\/1756-3305-7-363","article-title":"Multidimensional complexities of filariasis control in an era of large-scale mass drug administration programmes: A can of worms","volume":"7","author":"Molyneux","year":"2014","journal-title":"Parasites Vectors"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/cid\/ciu467","article-title":"Reaching the London Declaration on Neglected Tropical Diseases Goals for Onchocerciasis: An Economic Evaluation of Increasing the Frequency of Ivermectin Treatment in Africa","volume":"59","author":"Turner","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Turner, H.C., Churcher, T.S., Walker, M., Osei-Atweneboana, M.Y., Prichard, R.K., and Basanez, M.G. (2013). Uncertainty surrounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002169"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bulman, C.A., Bidlow, C.M., Lustigman, S., Cho-Ngwa, F., Williams, D., Rascon, A.A., Tricoche, N., Samje, M., Bell, A., and Suzuki, B. (2015). Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003534"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1645\/14-703.1","article-title":"Anthelmintic drug discovery: Into the future","volume":"101","author":"Geary","year":"2015","journal-title":"J. Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1017\/S0031182013001108","article-title":"Anti-Wolbachia drug discovery and development: Safe macrofilaricides for onchocerciasis and lymphatic filariasis","volume":"141","author":"Taylor","year":"2014","journal-title":"Parasitology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1098\/rspb.1998.0591","article-title":"Phylogeny of Wolbachia in filarial nematodes","volume":"265","author":"Bandi","year":"1998","journal-title":"Proc. Biol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/S0020-7519(02)00158-3","article-title":"Tetracycline treatment and sex-ratio distortion: A role for Wolbachia in the moulting of filarial nematodes?","volume":"32","author":"Casiraghi","year":"2002","journal-title":"Int. J. Parasitol."},{"key":"ref_20","first-page":"77","article-title":"The symbiotic relationship between filarial parasitic nematodes and their Wolbachia endosymbionts\u2014A resource for a new generation of control measures","volume":"46","author":"Ghedin","year":"2008","journal-title":"Symbiosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.molbiopara.2014.07.004","article-title":"Wolbachia endosymbionts and human disease control","volume":"195","author":"Slatko","year":"2014","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.pt.2021.06.004","article-title":"Anti-Wolbachia drugs for filariasis","volume":"37","author":"Johnston","year":"2021","journal-title":"Trends Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109057","DOI":"10.1016\/j.vetpar.2020.109057","article-title":"Novel anti-Wolbachia drugs, a new approach in the treatment and prevention of veterinary filariasis?","volume":"279","author":"Turner","year":"2020","journal-title":"Vet. Parasitol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0065-308X(05)60004-8","article-title":"Wolbachia bacterial endosymbionts of filarial nematodes","volume":"60","author":"Taylor","year":"2005","journal-title":"Adv. Parasitol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.molbiopara.2004.01.006","article-title":"Population dynamics of Wolbachia bacterial endosymbionts in Brugia malayi","volume":"135","author":"McGarry","year":"2004","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Landmann, F., Voronin, D., Sullivan, W., and Taylor, M.J. (2011). Anti-filarial activity of antibiotic therapy is due to extensive apoptosis after Wolbachia depletion from filarial nematodes. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002351"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E1638","DOI":"10.1073\/pnas.1203519109","article-title":"Autophagy regulates Wolbachia populations across diverse symbiotic associations","volume":"109","author":"Voronin","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/S0035-9203(00)90201-3","article-title":"Wolbachia bacteria of filarial nematodes in the pathogenesis of disease and as a target for control","volume":"94","author":"Taylor","year":"2000","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s13199-010-0067-1","article-title":"The Wolbachia endosymbiont as an anti-filarial nematode target","volume":"51","author":"Slatko","year":"2010","journal-title":"Symbiosis"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Voronin, D., Bachu, S., Shlossman, M., Unnasch, T.R., Ghedin, E., and Lustigman, S. (2016). Glucose and Glycogen Metabolism in Brugia malayi Is Associated with Wolbachia Symbiont Fitness. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153812"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1101\/gr.138420.112","article-title":"Analysis of gene expression from the Wolbachia genome of a filarial nematode supports both metabolic and defensive roles within the symbiosis","volume":"22","author":"Darby","year":"2012","journal-title":"Genome Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rances, E., Ye, Y.H., Woolfit, M., McGraw, E.A., and O\u2019Neill, S.L. (2012). The relative importance of innate immune priming in Wolbachia-mediated dengue interference. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002548"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/cmi.12084","article-title":"Wolbachia filarial interactions","volume":"15","author":"Taylor","year":"2013","journal-title":"Cell. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gunderson, E.L., Bryant, C., Bulman, C.A., Fischer, C., Luo, M., Vogel, I., Lim, K.C., Jawahar, S., Tricoche, N., and Voronin, D. (2022). Pyrvinium Pamoate and Structural Analogs Are Early Macrofilaricide Leads. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020189"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41419-017-0092-6","article-title":"Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer","volume":"9","author":"Alasadi","year":"2018","journal-title":"Cell. Death Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/nm.3699","article-title":"Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice","volume":"20","author":"Tao","year":"2014","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"762107","DOI":"10.3389\/fvets.2021.762107","article-title":"Discovering the Potent Inhibitors Against Babesia bovis in vitro and Babesia microti in vivo by Repurposing the Natural Product Compounds","volume":"8","author":"Li","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1038\/s41564-021-00968-y","article-title":"Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons","volume":"6","author":"Ojha","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Turner, J.D., Tendongfor, N., Esum, M., Johnston, K.L., Langley, R.S., Ford, L., Faragher, B., Specht, S., Mand, S., and Hoerauf, A. (2010). Macrofilaricidal activity after doxycycline only treatment of Onchocerca volvulus in an area of Loa loa co-endemicity: A randomized controlled trial. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000660"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fordjour, F.A., and Kwarteng, A. (2022). The filarial and the antibiotics: Single or combination therapy using antibiotics for filariasis. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1044412"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S0140-6736(96)11094-1","article-title":"Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection","volume":"350","author":"Gardon","year":"1997","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41598-017-00322-5","article-title":"Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis","volume":"7","author":"Aljayyoussi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","unstructured":"(2023, December 01). Available online: https:\/\/dndi.org\/research-development\/portfolio\/flubentylosin\/."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Alami, N., Carter, D.C., Kwatra, N.V., Zhao, W., Snodgrass, L., Porcalla, A.R., Klein, C.E., Cohen, D.E., Gallenberg, L., and Neenan, M. (2023). A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity. PLoS Negl. Trop. Dis., 17.","DOI":"10.1371\/journal.pntd.0011392"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Voronin, D., Schnall, E., Grote, A., Jawahar, S., Ali, W., Unnasch, T.R., Ghedin, E., and Lustigman, S. (2019). Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1008085"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"442","DOI":"10.2307\/3278769","article-title":"Chronic Brugia pahangi and Brugia malayi infections in Meriones unguiculatus","volume":"59","author":"Ash","year":"1973","journal-title":"J. Parasitol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"969","DOI":"10.2307\/3277515","article-title":"Development of subperiodic Brugia malayi in the jird, Meriones unguiculatus, with notes on infections in other rodents","volume":"56","author":"Ash","year":"1970","journal-title":"J. Parasitol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Voronin, D., and Makepeace, B.L. (2022). Symbionts on the Brain: How Wolbachia Is Strictly Corralled in Some Neotropical Drosophila spp.. mBio, 13.","DOI":"10.1128\/mbio.01182-22"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Strunov, A., Schmidt, K., Kapun, M., and Miller, W.J. (2022). Restriction of Wolbachia Bacteria in Early Embryogenesis of Neotropical Drosophila Species via Endoplasmic Reticulum-Mediated Autophagy. mBio, 13.","DOI":"10.1128\/mbio.03863-21"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Deehan, M., Lin, W., Blum, B., Emili, A., and Frydman, H. (2021). Intracellular Density of Wolbachia Is Mediated by Host Autophagy and the Bacterial Cytoplasmic Incompatibility Gene cifB in a Cell Type-Dependent Manner in Drosophila melanogaster. mBio, 12.","DOI":"10.1128\/mBio.02205-20"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.freeradbiomed.2019.04.030","article-title":"Repositioning of niclosamide ethanolamine (NEN), an anthelmintic drug, for the treatment of lipotoxicity","volume":"137","author":"Park","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_52","first-page":"3345","article-title":"Tumor suppressive role of rottlerin in cancer therapy","volume":"10","author":"Ma","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.cellsig.2017.04.001","article-title":"Niclosamide: Beyond an antihelminthic drug","volume":"41","author":"Chen","year":"2018","journal-title":"Cell. Signal."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/2\/256\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:57:44Z","timestamp":1760104664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/2\/256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,9]]},"references-count":53,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["pharmaceutics16020256"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16020256","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,9]]}}}