{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:04Z","timestamp":1778501104720,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wilhelm Doerenkamp-Foundation","award":["NATVANTAGE RESEARCH GRANT 2018"],"award-info":[{"award-number":["NATVANTAGE RESEARCH GRANT 2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 \u03bcg\/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 \u03bcg STL\/2\u00d7 day\/60 d, 72.7% at doses of 19.2 \u03bcg STL\/1\u00d7 d\/60 d and 67% at a dose of 38.4 \u03bcg STL\/2\u00d7 d\/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 \u03bcg STL\/2\u00d7 day\/60 d and 71% at a dose of 38.4 \u03bcg STL\/2\u00d7 d\/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg\/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL.<\/jats:p>","DOI":"10.3390\/ph15070776","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T23:11:19Z","timestamp":1655939479000},"page":"776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Therapeutic Efficacy of Arnica in Hamsters with Cutaneous Leishmaniasis Caused by Leishmania braziliensis and L. tropica"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-4931","authenticated-orcid":false,"given":"Sara M.","family":"Robledo","sequence":"first","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Murillo","sequence":"additional","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Arbel\u00e1ez","sequence":"additional","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Montoya","sequence":"additional","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Ospina","sequence":"additional","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-6227","authenticated-orcid":false,"given":"Franziska M.","family":"J\u00fcrgens","sequence":"additional","affiliation":[{"name":"University of M\u00fcnster, Institute of Pharmaceutical Biology and Phytochemistry, PharmaCampus, Corrensstrasse 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iv\u00e1n D.","family":"V\u00e9lez","sequence":"additional","affiliation":[{"name":"PECET-School of Medicine, University of Antioquia, Calle 70 # 52-21, Medellin 0500100, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-9705","authenticated-orcid":false,"given":"Thomas J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"University of M\u00fcnster, Institute of Pharmaceutical Biology and Phytochemistry, PharmaCampus, Corrensstrasse 48, D-48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, April 10). Leishmaniasis. Available online: http:\/\/www.who.int\/leishmaniasis\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.7241\/ourd.20171.21","article-title":"Stigmata in cutaneous leishmaniasis: Historical and new evidence-based concepts","volume":"8","year":"2017","journal-title":"Our Derm. Online"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/jcpt.13089","article-title":"Adverse reactions to meglumine antimoniate in Brazilian inpatients with visceral leishmaniases: A case series","volume":"45","author":"Serbate","year":"2020","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2174\/1381612023396258","article-title":"Chemotherapy of leishmaniasis","volume":"8","author":"Croft","year":"2002","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167","DOI":"10.4103\/0974-777X.62887","article-title":"Drug resistance in leishmaniasis","volume":"2","author":"Chakravarty","year":"2010","journal-title":"J. Global. Infect Dis."},{"key":"ref_6","unstructured":"(2022, May 03). European Medicines Agency-Community Herbal Monograph on Arnica montana L., Flos. Available online: http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Herbal_-_Community_herbal_monograph\/2014\/07\/WC500170007.pdf."},{"key":"ref_7","unstructured":"Wichtl, M. (2004). Arnicae flos. Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis, CRC Press. [3rd ed.]."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1021\/bk-1998-0691.ch010","article-title":"Arnica flowers: Pharmacology, toxicology, and analysis of the sesquiterpene lactones\u2014Their main active substances","volume":"Volume 691","author":"Lawson","year":"1998","journal-title":"Phytomedicines of Europe\u2014ACS Symposium Series 691"},{"key":"ref_9","unstructured":"European Directorate for the Quality of Medicines & HealthCare (EDQM) (2020). Arnicae tinctura. European Pharmacopoeia, Council of Europe. [10th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1111\/jphp.12724","article-title":"Arnica montana L.\u2014A plant of healing: Review","volume":"69","author":"Kriplani","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Robledo, S.M., V\u00e9lez, I.D., and Schmidt, T.J. (2018). Arnica Tincture Cures Cutaneous Leishmaniasis in Golden Hamsters. Molecules, 23.","DOI":"10.3390\/molecules23010150"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0944-7113(11)80057-7","article-title":"Decreased helenalin-induced cytotoxicity by flavonoids from Arnica as studied in a human lung carcinoma cell line","volume":"2","author":"Woerdenbag","year":"1995","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"638957","DOI":"10.3389\/fmicb.2021.638957","article-title":"Determinants of Unresponsiveness to Treatment in Cutaneous Leishmaniasis: A Focus on Anthroponotic Form Due to Leishmania tropica","volume":"12","author":"Bamorovat","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_14","first-page":"e3533","article-title":"Cutaneous leishmaniasis in the dorsal skin of hamsters: A useful model for the screening of antileishmanial drugs","volume":"62","author":"Robledo","year":"2012","journal-title":"J. Vis. Exp."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.inhe.2012.06.004","article-title":"Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence for the risk of mucosal leishmaniasis","volume":"4","author":"Blum","year":"2012","journal-title":"Int. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1086\/382135","article-title":"Persistence of Leishmania Parasites in Scars after Clinical Cure of American Cutaneous Leishmaniasis: Is There a Sterile Cure?","volume":"189","author":"Rodrigues","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0958-1669(05)80122-3","article-title":"Growth factors as wound healing agents","volume":"2","author":"Robson","year":"1991","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0039-6109(05)70569-7","article-title":"The role of growth factors in wound healing","volume":"77","author":"Steed","year":"1997","journal-title":"Surg. Clin. N. Am."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3389\/fcimb.2018.00350","article-title":"Transforming Growth Factor Beta (TGF\u03b21) and Epidermal Growth Factor (EGF) as Biomarkers of Leishmania (V) braziliensis Infection and Early Therapeutic Response in Cutaneous Leishmaniasis: Studies in Hamsters","volume":"8","author":"Montoya","year":"2018","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.2741\/2277","article-title":"Wound reepithelialization: Modulating keratinocyte migration in wound healing","volume":"12","author":"Raja","year":"2007","journal-title":"Front Biosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1677\/erc.0.0070165","article-title":"Fibroblast growth factors, their receptors and signaling","volume":"7","author":"Powers","year":"2000","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Perspective article: Growth factors and cytokines in wound healing","volume":"16","author":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"J\u00fcrgens, F.M., Herrmann, F.C., Robledo, S.M., and Schmidt, T.J. (2022). Dermal Absorption of Sesquiterpene Lactones from Arnica Tincture. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040742"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"J\u00fcrgens, F.M., Behrens, M., Humpf, H.-U., Robledo, S.M., and Schmidt, T.J. (2022). In Vitro Metabolism of Helenalin Acetate and 11\u03b1,13-Dihydrohelenalin Acetate: Natural Sesquiterpene Lactones from Arnica. Metabolites, 12.","DOI":"10.3390\/metabo12010088"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jpba.2006.06.008","article-title":"Skin penetration behaviour of sesquiterpene lactones from different Arnica preparations using a validated GC-MSD method","volume":"43","author":"Wagner","year":"2007","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.actatropica.2011.11.015","article-title":"Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of antileishmanial drugs","volume":"122","author":"Pulido","year":"2012","journal-title":"Acta Trop."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.exppara.2015.07.008","article-title":"The proliferation potential of promastigotes of the main Leishmania species of the old world in NNN culture medium prepared using blood of four different mammals","volume":"157","author":"Ladopoulos","year":"2015","journal-title":"Exp. Parasitol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1186\/s13071-016-1647-6","article-title":"Development of real-time PCR assays for evaluation of immune response and parasite load in golden hamster (Mesocricetus auratus) infected by Leishmania (Viannia) braziliensis","volume":"9","author":"Saavedra","year":"2016","journal-title":"Parasit. Vectors"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2017.02.017","article-title":"In vitro wound healing and cytotoxic activity of the gel and whole-leaf materials from selected aloe species","volume":"200","author":"Fox","year":"2017","journal-title":"J. Ethnopharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:37:36Z","timestamp":1760139456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/7\/776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ph15070776"],"URL":"https:\/\/doi.org\/10.3390\/ph15070776","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]}}}