Effectiveness of the sesquiterpene (-)-α-bisabolol in dogs with naturally acquired canine leishmaniosis: an exploratory clinical trial
The use of natural products is a promising approach for treating visceral leishmaniosis. (-)-α-Bisabolol is a sesquiterpene that have been proved active in vivo on Leishmania infantum-infected mice without showing toxicity. A single-centre, parallel-group, randomized, exploratory study was designed to assess its efficacy in a canine leishmaniosis model involving naturally infected dogs. In this clinical trial, 12 dogs were allocated into two groups and were treated with either meglumine antimoniate (100 mg/kg) through subcutaneous route or (-)-α-bisabolol (30 mg/kg) through oral route for two treatment series of 30 days, separated by a 30-day interval. A 4-month follow-up period was established as well. Parasite loads in bone marrow, lymph node and blood were estimated through quantitative PCR. Antibody titres were determined through immunofluorescence antibody test and cytokine expression values were estimated through real-time reverse transcription-PCR. Treatment safety was assessed through the evaluation of weight, gastrointestinal alterations and hematological and biochemical parameters in blood. Analyses were performed before and after treatment, and after a 4-months follow-up period. Treatment with the sesquiterpene was effective at decreasing parasite loads and increasing gamma-interferon expression level. Dogs treated with (-)-α-bisabolol did not show any toxicity sign. These results were better than those obtained using the reference drug, meglumine antimoniate. The natural compound seemed to induce a Th1 immune response that led to parasitological and clinical improvement without showing any safety issue, suggesting a high potential for the treatment of canine and human visceral leishmaniosis.
Keywords(-)-α-bisabolol Canine leishmaniosis Treatment Sesquiterpene Oral route
The authors wish to thank the animal shelter Sociedad Protectora de Animales y Plantas (Fuente Vaqueros, Spain), registered as an animal husbandry centre (register number ES190790000096), which provided the use of its facilities for the experiment. This work was supported by the University of Granada CEI-Biotic project 2013/1/4 and a University of Granada Research Results Transfer Grant Program, Pilot Prototypes and Experiences PR/12/011.
Compliance with ethical standards
The experiment, including owners’ informed consent, housing, treatment and sampling, was approved by the Ethics Committee of Animal Experimentation (CEEA) of the University of Granada, the Andalusia Committee of Animal Experimentation and the Ministry of Agriculture of the Andalusia Government, in accordance with the EU Directive 2010/63/EU.
Conflict of interest
All authors have no conflict of interest to disclose.
- Bhattacharyya T, Ayandeh A, Falconar AK, Sundar S, El-Safi S, Gripenberg Ma, Bowes DE, Thunissen C, Singh OP, Kumar R, Ahmed O, Eisa O, Saad A, Pereira S, Boelaert S, Mertens M, Miles P, M. a (2014) IgG1 as a Potential Biomarker of Post-chemotherapeutic relapse in visceral leishmaniasis, and adaptation to a rapid diagnostic test. PLoS Negl Trop Dis 8:e3273. https://doi.org/10.1371/journal.pntd.0003273
- Colares AV, Almeida-Souza F, Taniwaki NN, Souza CDSF., Costa D, Calabrese JGM, Abreu-Silva KDS, A.L., 2013. In vitro antileishmanial activity of essential oil of Vanillosmopsis arborea (Asteraceae) baker. Evidence-based Complement. Altern Med 2013:1–7. https://doi.org/10.1155/2013/727042
- Corpas-López V, Merino-Espinosa G, Acedo-Sánchez C, Díaz-Sáez V, Morillas-Márquez F, Martín-Sánchez J (2016a) Hair parasite load as a new biomarker for monitoring treatment response in canine leishmaniasis. Vet Parasitol 223:20–25. https://doi.org/10.1016/j.vetpar.2016.04.001 CrossRefPubMedGoogle Scholar
- Corpas-López V, Merino-Espinosa G, Díaz-Sáez V, Morillas-Márquez F, Navarro-Moll MC, Martín-Sánchez J (2016b) The sesquiterpene (-)-a-bisabolol is active against the causative agents of old world cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis. Apoptosis 21:1071–1081. https://doi.org/10.1007/s10495-016-1282-x CrossRefPubMedGoogle Scholar
- Corpas-López V, Merino-Espinosa G, López-Viota M, Gijón-Robles P, Morillas-Mancilla MJ, López-Viota J, Díaz-Sáez V, Morillas-Márquez F, Navarro-Moll MC, Martín-Sánchez J (2016c) Topical treatment of leishmania tropica infection using (–)-a-bisabolol ointment in a hamster model: effectiveness and safety assessment. J Nat Prod. https://doi.org/10.1021/acs.jnatprod.6b00740
- Fernández-Cotrina J, Iniesta V, Belinchón-Lorenzo S, Muñoz-Madrid R, Serrano F, Parejo JC, Gómez-Gordo L, Soto M, Alonso C, Gómez-Nieto LC (2013) Experimental model for reproduction of canine visceral leishmaniosis by Leishmania infantum. Vet Parasitol 192:118–128. https://doi.org/10.1016/j.vetpar.2012.10.002 CrossRefPubMedGoogle Scholar
- Ferreira FM, Castro RAO, Batista MA, Rossi FMO, Silveira-Lemos D, Frézard F, Moura SAL, Rezende SA (2014) Association of water extract of green propolis and liposomal meglumine antimoniate in the treatment of experimental visceral leishmaniasis. Parasitol Res 113:533–543. https://doi.org/10.1007/s00436-013-3685-8 CrossRefPubMedGoogle Scholar
- Gómez Pérez V, García-Hernandez R, Corpas-López V, Tomás AM, Martín-Sanchez J, Castanys S, Gamarro F (2016) Decreased antimony uptake and overexpression of genes of thiol metabolism are associated with drug resistance in a canine isolate of Leishmania infantum. Int J Parasitol Drugs Drug Resist 6:133–139. https://doi.org/10.1016/j.ijpddr.2016.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
- Manna L, Reale S, Picillo E, Vitale F, Gravino AE (2008) Interferon-gamma (INF-??), IL4 expression levels and Leishmania DNA load as prognostic markers for monitoring response to treatment of leishmaniotic dogs with miltefosine and allopurinol. Cytokine 44:288–292. https://doi.org/10.1016/j.cyto.2008.08.017 CrossRefPubMedGoogle Scholar
- Manna L, Corso R, Galiero G, Cerrone A, Muzj P, Gravino AE (2015) Long-term follow-up of dogs with leishmaniosis treated with meglumine antimoniate plus allopurinol versus miltefosine plus allopurinol. Parasit Vectors 8:289. https://doi.org/10.1186/s13071-015-0896-0 CrossRefPubMedPubMedCentralGoogle Scholar
- Morales-Yuste M, Morillas-Márquez F, Díaz-Sáez V, Barón-López S, Acedo-Sánchez C, Martín-Sánchez J (2012) Epidemiological implications of the use of various methods for the diagnosis of canine leishmaniasis in dogs with different characteristics and in differing prevalence scenarios. Parasitol Res 111:155–164. https://doi.org/10.1007/s00436-011-2812-7 CrossRefPubMedGoogle Scholar
- Noli C, Auxilia ST (2005) Treatment of canine old World visceral leishmaniasis: vet. Dermatol 16:213–232Google Scholar
- Proverbio D, Spada E, De Giorgi B, Perego G, Valena R, E., 2014. Relationship between Leishmania IFAT titer and clinicopathological manifestations (clinical score) in dogs. Biomed Res Int. 2014, 412808. https://doi.org/10.1155/2014/412808
- Schmidt TJ, Khalid SA, Romanha AJ, Alves TM, Biavatti MW, Brun R, Da Costa FB, de Castro SL, Ferreira VF, de Lacerda MVG, Lago JHG, Leon LL, Lopes NP, das Neves Amorim RC, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, de NC Soeiro, Steindel M, Tempone M, A.G (2012) The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I. Curr Med Chem 19:2128–2175Google Scholar
- Solano-Gallego L, Riera C, Roura X, Iniesta L, Gallego M, Valladares JE, Fisa R, Castillejo S, Alberola J, Ferrer L, Arboix M, Portús M (2001) Leishmania infantum-specific IgG, IgG1 and IgG2 antibody responses in healthy and ill dogs from endemic areas. Evolution in the course of infection and after treatment. Vet Parasitol 96:265–276CrossRefPubMedGoogle Scholar