{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:31:41Z","timestamp":1762432301134,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T00:00:00Z","timestamp":1665100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Granada","award":["B-CTS-270-UGR18","P20_00130"],"award-info":[{"award-number":["B-CTS-270-UGR18","P20_00130"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Canine leishmaniosis is a challenge in veterinary medicine and no drug to date has achieved parasite clearance in dogs. Histone deacetylase inhibitors are a drug class widely used in cancer chemotherapy. We have successfully used O-alkyl hydroxamates (vorinostat derivatives) in the treatment of a laboratory model of visceral leishmaniasis without showing toxicity. In order to test the effectiveness of a particular compound, MTC-305, a parallel-group, randomized, single-centre, exploratory study was designed in naturally infected dogs. In this clinical trial, 18 dogs were allocated into 3 groups and were treated with either meglumine antimoniate (104 mg SbV\/kg), MTC-305 (3.75 mg\/kg) or a combination of both using a lower MTC-305 dose (1.5 mg\/kg) through a subcutaneous route for 2 treatment courses of 30 days, separated by a 30-day rest period. After treatment, a follow-up time of 4 months was established. Parasite burden in bone marrow, lymph node and peripheral blood were quantified through qPCR. Antibody titres were determined through an immunofluorescence antibody test, and cytokine expression values were calculated through RT-qPCR. Treatment safety was evaluated through the assessment of haematological and biochemical parameters in blood, weight, and gastrointestinal alterations. Assessment was carried out before, between and after treatment series. Treatment with MTC-305 was effective at reducing parasite burdens and improving the animals\u2019 clinical picture. Dogs treated with this compound did not present significant toxicity signs. These results were superior to those obtained using the reference drug, meglumine antimoniate, in monotherapy. These results would support a broader clinical trial, optimised dosage, and an expanded follow-up stage to confirm the efficacy of this drug.<\/jats:p>","DOI":"10.3390\/ani12192700","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T22:47:27Z","timestamp":1665182847000},"page":"2700","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effectiveness of an O-Alkyl Hydroxamate in Dogs with Naturally Acquired Canine Leishmaniosis: An Exploratory Clinical Trial"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9152-6486","authenticated-orcid":false,"given":"Victoriano","family":"Corpas-L\u00f3pez","sequence":"first","affiliation":[{"name":"Departamento de Parasitolog\u00eda, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoriano","family":"D\u00edaz-S\u00e1ez","sequence":"additional","affiliation":[{"name":"Departamento de Parasitolog\u00eda, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Morillas-M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Departamento de Parasitolog\u00eda, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-1653","authenticated-orcid":false,"given":"Francisco","family":"Franco-Montalb\u00e1n","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Farmac\u00e9utica y Org\u00e1nica, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7868-7231","authenticated-orcid":false,"given":"M\u00f3nica","family":"D\u00edaz-Gavil\u00e1n","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Farmac\u00e9utica y Org\u00e1nica, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli\u00e1n","family":"L\u00f3pez-Viota","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia y Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"L\u00f3pez-Viota","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia y Tecnolog\u00eda Farmac\u00e9utica, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0937-698X","authenticated-orcid":false,"given":"Jos\u00e9 Antonio","family":"G\u00f3mez-Vidal","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Farmac\u00e9utica y Org\u00e1nica, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3981-9227","authenticated-orcid":false,"given":"Joaquina","family":"Mart\u00edn-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Departamento de Parasitolog\u00eda, Facultad de Farmacia, Universidad de Granada, 18011 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3201\/eid1505.080969","article-title":"Canine Leishmaniasis in Southeastern Spain","volume":"15","year":"2009","journal-title":"Emerg. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S1471-4922(02)02347-4","article-title":"Canine Leishmaniasis: Epidemiological Risk and the Experimental Model","volume":"18","author":"Moreno","year":"2002","journal-title":"Trends Parasitol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"758","DOI":"10.4269\/ajtmh.1994.50.758","article-title":"Isoenzymatic Characterization of the Etiologic Agent of Canine Leishmaniasis in the Granada Region of Southern Spain","volume":"50","year":"1994","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.tvjl.2013.07.011","article-title":"Canine Leishmaniasis: Bridging Science, Public Health and Politics","volume":"198","author":"Baneth","year":"2013","journal-title":"Vet. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.pt.2008.05.003","article-title":"Canine Leishmaniosis\u2014New Concepts and Insights on an Expanding Zoonosis: Part Two","volume":"24","author":"Cardoso","year":"2008","journal-title":"Trends Parasitol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1080\/00034983.1992.11812717","article-title":"Decreased Sensitivity to Meglumine Antimoniate (Glucantime) of Leishmania Infantum Isolated from Dogs after Several Courses of Drug Treatment","volume":"86","author":"Gramiccia","year":"1992","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1186\/s13071-015-0896-0","article-title":"Long-Term Follow-up of Dogs with Leishmaniosis Treated with Meglumine Antimoniate plus Allopurinol versus Miltefosine plus Allopurinol","volume":"8","author":"Manna","year":"2015","journal-title":"Parasites Vectors"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ijpddr.2015.05.004","article-title":"Profiling the Anti-Protozoal Activity of Anti-Cancer HDAC Inhibitors against Plasmodium and Trypanosoma Parasites","volume":"5","author":"Engel","year":"2015","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.phrs.2018.11.039","article-title":"A Nanodelivered Vorinostat Derivative Is a Promising Oral Compound for the Treatment of Visceral Leishmaniasis","volume":"139","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5734","DOI":"10.1021\/acs.jmedchem.9b02016","article-title":"O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity","volume":"63","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00436-011-2812-7","article-title":"Epidemiological Implications of the Use of Various Methods for the Diagnosis of Canine Leishmaniasis in Dogs with Different Characteristics and in Differing Prevalence Scenarios","volume":"111","year":"2012","journal-title":"Parasitol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11259-018-9714-4","article-title":"Effectiveness of the Sesquiterpene (-)-\u03b1-Bisabolol in Dogs with Naturally Acquired Canine Leishmaniosis: An Exploratory Clinical Trial","volume":"42","year":"2018","journal-title":"Vet. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.vetpar.2016.04.001","article-title":"Hair Parasite Load as a New Biomarker for Monitoring Treatment Response in Canine Leishmaniasis","volume":"223","year":"2016","journal-title":"Vet. Parasitol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/1756-3305-7-110","article-title":"Management of Canine Leishmaniosis in Endemic SW European Regions: A Questionnaire-Based Multinational Survey","volume":"7","author":"Bourdeau","year":"2014","journal-title":"Parasites Vectors"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jpsychires.2010.10.008","article-title":"The Role and Interpretation of Pilot Studies in Clinical Research","volume":"45","author":"Leon","year":"2011","journal-title":"J. Psychiatr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Thabane, L., Ma, J., Chu, R., Cheng, J., Ismaila, A., Rios, L.P., Robson, R., Thabane, M., Giangregorio, L., and Goldsmith, C.H. (2010). A Tutorial on Pilot Studies: The What, Why and How. BMC Med. Res. Methodol., 10.","DOI":"10.1186\/1471-2288-10-1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.tvjl.2008.08.009","article-title":"Study of Efficacy of Miltefosine and Allopurinol in Dogs with Leishmaniosis","volume":"182","author":"Manna","year":"2009","journal-title":"Vet. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1756-3305-4-86","article-title":"LeishVet Guidelines for the Practical Management of Canine Leishmaniosis","volume":"4","author":"Koutinas","year":"2011","journal-title":"Parasites Vectors"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1476-5381.2009.00267.x","article-title":"To Scale or Not to Scale: The Principles of Dose Extrapolation","volume":"157","author":"Sharma","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_20","first-page":"279","article-title":"Clinical Follow-up Examination after Treatment of Canine Leishmaniasis","volume":"23","author":"Moritz","year":"1999","journal-title":"Tokai J. Exp. Clin. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00436-013-3638-2","article-title":"First Study on Efficacy and Tolerability of a New Alkylphosphocholine Molecule (Oleylphosphocholine-OlPC) in the Treatment of Canine Leishmaniosis Due to Leishmania Infantum","volume":"113","author":"Montoya","year":"2014","journal-title":"Parasitol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.vetpar.2012.10.011","article-title":"Treatment of Canine Leishmaniosis with Aminosidine at an Optimized Dosage Regimen: A Pilot Open Clinical Trial","volume":"192","author":"Athanasiou","year":"2013","journal-title":"Vet. Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1756-3305-4-57","article-title":"Canine Leishmaniasis: The Key Points for QPCR Result Interpretation","volume":"4","author":"Quilez","year":"2011","journal-title":"Parasites Vectors"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.rvsc.2008.12.009","article-title":"Evidence for a Relationship between Leishmania Load and Clinical Manifestations","volume":"87","author":"Manna","year":"2009","journal-title":"Res. Vet. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"412808","DOI":"10.1155\/2014\/412808","article-title":"Relationship between Leishmania IFAT Titer and Clinicopathological Manifestations (Clinical Score) in Dogs","volume":"2014","author":"Proverbio","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1136\/vr.158.20.690","article-title":"Pathological Changes in the Bone Marrow of Dogs with Leishmaniosis","volume":"158","author":"Restucci","year":"2006","journal-title":"Vet. Rec."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"150582","DOI":"10.1155\/2014\/150582","article-title":"Morphological Changes in the Bone Marrow of the Dogs with Visceral Leishmaniasis","volume":"2014","author":"Momo","year":"2014","journal-title":"Vet. Med. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.vetimm.2006.02.001","article-title":"Isotype Patterns of Immunoglobulins: Hallmarks for Clinical Status and Tissue Parasite Density in Brazilian Dogs Naturally Infected by Leishmania (Leishmania) Chagasi","volume":"112","author":"Reis","year":"2006","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.vetpar.2012.11.007","article-title":"Detection of Leishmania Infantum Kinetoplast Minicircle DNA by Real Time PCR in Hair of Dogs with Leishmaniosis","volume":"192","author":"Iniesta","year":"2013","journal-title":"Vet. Parasitol."},{"key":"ref_30","unstructured":"WOAH\u2014World Organisation for Animal Health (2022, June 25). Terrestrial Manual Online Access. Available online: https:\/\/www.woah.org\/en\/what-we-do\/standards\/codes-and-manuals\/terrestrial-manual-online-access."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.vetimm.2007.01.014","article-title":"Anti-Leishmania Humoral and Cellular Immune Responses in Naturally Infected Symptomatic and Asymptomatic Dogs","volume":"117","author":"Cardoso","year":"2007","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.vetpar.2010.01.023","article-title":"Relationship of Leishmania-Specific IgG Levels and IgG Avidity with Parasite Density and Clinical Signs in Canine Leishmaniasis","volume":"169","author":"Neto","year":"2010","journal-title":"Vet. Parasitol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-3164.2005.00460.x","article-title":"Treatment of Canine Old World Visceral Leishmaniasis","volume":"16","author":"Noli","year":"2005","journal-title":"Vet. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00436-009-1375-3","article-title":"Comparative Study on the Short Term Efficacy and Adverse Effects of Miltefosine and Meglumine Antimoniate in Dogs with Natural Leishmaniosis","volume":"105","author":"Mateo","year":"2009","journal-title":"Parasitol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1128\/CMR.19.1.111-126.2006","article-title":"Drug Resistance in Leishmaniasis","volume":"19","author":"Croft","year":"2006","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Carri\u00f3, J., and Port\u00fas, M. (2002). In Vitro Susceptibility to Pentavalent Antimony in Leishmania Infantum Strains Is Not Modified during in Vitro or in Vivo Passages but Is Modified after Host Treatment with Meglumine Antimoniate. BMC Pharmacol., 2.","DOI":"10.1186\/1471-2210-2-11"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.rvsc.2006.10.008","article-title":"Evaluation of Renal and Hepatic Functions in Dogs Naturally Infected by Visceral Leishmaniasis Submitted to Treatment with Meglumine Antimoniate","volume":"83","author":"Lopes","year":"2007","journal-title":"Res. Vet. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1590\/0074-0276108052013014","article-title":"Biodistribution of Meglumine Antimoniate in Healthy and Leishmania (Leishmania) Infantum Chagasi-Infected BALB\/c Mice","volume":"108","author":"Borborema","year":"2013","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/jsap.12150","article-title":"Biomarkers in the Assessment of Acute and Chronic Kidney Diseases in the Dog and Cat","volume":"54","author":"Cobrin","year":"2013","journal-title":"J. Small Anim. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/j.1939-165X.2005.tb00041.x","article-title":"Selection and Interpretation of Clinical Pathology Indicators of Hepatic Injury in Preclinical Studies","volume":"34","author":"Boone","year":"2005","journal-title":"Vet. Clin. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s11259-005-0059-4","article-title":"Pancreatitis Associated with N-Methyl-Glucamine Therapy in a Dog with Leishmaniasis","volume":"29","author":"Aste","year":"2005","journal-title":"Vet. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1053\/j.tcam.2012.04.003","article-title":"Acute Pancreatitis in Dogs: Advances in Understanding, Diagnostics, and Treatment","volume":"27","author":"Mansfield","year":"2012","journal-title":"Top. Companion Anim. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/1091581809352111","article-title":"A Nonclinical Safety Assessment of the Histone Deacetylase Inhibitor Vorinostat","volume":"29","author":"Kerr","year":"2015","journal-title":"Int. J. Toxicol."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/12\/19\/2700\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:47:56Z","timestamp":1760143676000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/12\/19\/2700"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,7]]},"references-count":43,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ani12192700"],"URL":"https:\/\/doi.org\/10.3390\/ani12192700","relation":{},"ISSN":["2076-2615"],"issn-type":[{"type":"electronic","value":"2076-2615"}],"subject":[],"published":{"date-parts":[[2022,10,7]]}}}