Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baneth G (2013) Canine leishmaniasis: Bridging science, public health and politics. Vet J 198:9–10. https://doi.org/10.1016/j.tvjl.2013.07.011
Bhatia SP, McGinty D, Letizia CS, Api AM (2008) Fragrance material review on alpha-bisabolol. Food Chem Toxicol 46(1):S72-6. https://doi.org/10.1016/j.fct.2008.06.025
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
Carrillo E, Moreno J (2009) Cytokine profiles in canine visceral leishmaniasis. Vet Immunol Immunopathol 128:67–70. https://doi.org/10.1016/j.vetimm.2008.10.310
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, Morillas-Márquez F, Navarro-Moll MC, Merino-Espinosa G, Díaz-Sáez V, Martín-Sánchez J (2015) (–)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis. J Nat Prod 78:1202–1207. https://doi.org/10.1021/np5008697
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
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
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
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
Forrer M, Kulik EM, Filippi A, Waltimo T (2013) The antimicrobial activity of alpha-bisabolol and tea tree oil against solobacterium moorei, a gram-positive bacterium associated with halitosis. Arch Oral Biol 58:10–16. https://doi.org/10.1016/j.archoralbio.2012.08.001
Ganzera M, Schneider P, Stuppner H (2006) Inhibitory effects of the essential oil of chamomile (Matricaria recutita L.) and its major constituents on human cytochrome P450 enzymes. Life Sci 78:856–861. https://doi.org/10.1016/j.lfs.2005.05.095
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
Gramiccia M, Gradoni L, Orsini S (1992) Decreased sensitivity to meglumine antimoniate (Glucantime) of Leishmania infantum isolated from dogs after several courses of drug treatment. Ann Trop Med Parasitol 86:613–620
Iniesta L, Gállego M, Portús M (2005) Immunoglobulin G and E responses in various stages of canine leishmaniosis. Vet Immunol Immunopathol 103:77–81. https://doi.org/10.1016/j.vetimm.2004.08.011
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
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
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
Martin Sanchez J, Morillas Marquez F, Sanchiz Marin MC, Acedo Sanchez C (1994) Isoenzymatic characterization of the etiologic agent of canine leishmaniasis in the Granada region of southern Spain. Am J Trop Med Hyg 50:758–762
Martín-Sánchez J, Morales-Yuste M, Acedo-Sánchez C, Barón S, Díaz V, Morillas-Márquez F (2009) Canine leishmaniasis in southeastern Spain. Emerg Infect Dis 15:795–798. https://doi.org/10.3201/eid1505.080969
Mary C, Faraut F, Deniau M, Dereure J, Aoun K, Ranque S, Piarroux R (2010) Frequency of drug resistance gene amplification in clinical leishmania strains. Int J Microbiol. https://doi.org/10.1155/2010/819060
Mateo M, Maynard L, Vischer C, Bianciardi P, Miró G (2009) Comparative study on the short term efficacy and adverse effects of miltefosine and meglumine antimoniate in dogs with natural leishmaniosis. Parasitol Res 105:155–162. https://doi.org/10.1007/s00436-009-1375-3
Maurya AK, Singh M, Dubey V, Srivastava S, Luqman S, Bawankule DU (2014) α-(-)-bisabolol reduces pro-inflammatory cytokine production and ameliorates skin inflammation. Curr Pharm Biotechnol 15:173–181. https://doi.org/10.2174/1389201015666140528152946
Miró G, Cardoso L, Pennisi MG, Oliva G, Baneth G (2008) Canine leishmaniosis - new concepts and insights on an expanding zoonosis: part two. Trends Parasitol 24:371–377. https://doi.org/10.1016/j.pt.2008.05.003
Monge-Maillo B, López-Vélez R (2013) Therapeutic options for visceral leishmaniasis. Drugs 73:1863–1888. https://doi.org/10.1007/s40265-013-0133-0
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
Moreno J, Alvar J (2002) Canine leishmaniasis: Epidemiological risk and the experimental model. Trends Parasitol 18:399–405. https://doi.org/10.1016/S1471-4922(02)02347-4
Noli C, Auxilia ST (2005) Treatment of canine old World visceral leishmaniasis: vet. Dermatol 16:213–232
Noli C, Saridomichelakis MN (2014) An update on the diagnosis and treatment of canine leishmaniosis caused by Leishmania infantum (syn. L. chagasi). Vet J 202:425–435. https://doi.org/10.1016/j.tvjl.2014.09.002
Orav A, Raal A, Arak E (2010) Content and composition of the essential oil of Chamomilla recutita (L.) Rauschert from some European countries. Nat Prod Res 24:48–55. https://doi.org/10.1080/14786410802560690
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
Quinnell RJ, Courtenay O, Shaw M-A, Day MJ, Garcez LM, Dye C, Kaye PM (2001) Tissue Cytokine Responses in Canine Visceral Leishmaniasis. J Infect Dis 183:1421–1424
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 19:2128–2175
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 96:265–276
Sundar S, Singh A, Rai M, Chakravarty J (2015) Single-dose indigenous liposomal amphotericin B in the treatment of Indian visceral leishmaniasis: a phase 2 study. Am J Trop Med Hyg 92:513–517. https://doi.org/10.4269/ajtmh.14-0259
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Corpas-López, V., Merino-Espinosa, G., Acedo-Sánchez, C. et al. Effectiveness of the sesquiterpene (-)-α-bisabolol in dogs with naturally acquired canine leishmaniosis: an exploratory clinical trial. Vet Res Commun 42, 121–130 (2018). https://doi.org/10.1007/s11259-018-9714-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11259-018-9714-4