Abstract
Given the need to develop new drugs for the treatment of cutaneous leishmaniasis, not only effective and safe, but also more widely accepted by patients, easily administered in rural settings and cheaper, in the present study the in vitro and in vivo therapeutic potential and cytotoxicity profile of an ethanolic and a glycolic extracts obtained from the branches of Caesalpinia spinosa (Molina) Kuntze and their respective formulations (lotion and emulsion) were evaluated. Finally, the usefulness of the two formulations as topical treatment was validated in 10 patients with uncomplicated CL. Both extracts were active against L. braziliensis at concentrations <22 μg / mL, with low toxicity in U-937 and HL60 cells when administered pure and for Hep G2 and Detroit 551 cells when administered at concentrations <20%. either the extracts nor the formulations were irritating or did not cause any corrosive or any other sign of dermal toxicity. The exposure of fibroblasts to he glycolic extract and to the formulations favored the migration of fibroblasts and repair of the monolayer after 16 h of contact, allowing the closing of the gap between 33.9% and 70.9%. Both the extracts and the formulations favored the complete cure of the hamsters with cutaneous leishmaniasis in percentages greater than 80%. After being applied to the skin, lotion and emulsion are absorbed, penetrate, and although they can be detected in plasma up to 24 hours (the lotion) or 6 hours (the emulsion) after application, most of the products it is retained in the skin. Lastly, the treatment of 10 patients with the lotion and the emulsion showed the complete healing of the lesions with the repair of he damaged skin and without adverse effects. In conclusion, the results demonstrate leishmanicidal and healing properties for C. spinosa that give it the potential to become a safe alternative for the local treatment of cutaneous leishmaniasis. It is necessary to validate these results in controlled clinical trials and determine the efficacy and safety of treatment with C. spinosa phytotherapeutic products.
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References
Alvar, J., Yactayo, S., Bern, C. (2006). Leishmaniasis and poverty. Trends in Parasitol. 22: 552-556.
Alvar, J., Vélez., I.D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., den Boer, M., WHO Leishmaniasis Control Team. (2012). Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 7: 35671
Ben-Salah, A., Ben-Messaoud, N., Guedri, E., Zaatour, A., Ben-Alaya., N, Bettaieb, J., Gharbi, A., Belhadj-Hamida, N., Boukthir, A., Chlif, S., Abdelhamid K., El Ahmadi, Z., Louzir, H., Mokni, M., Morizot, G., Buffet, P., Smith, P.L., Kopydlowski, K.M., Kreishman Deitrick, M., Smith, K.S., Nielsen, C.J., Ullman, D.R., Norwood, J.A., Thorne, G.D., McCarthy, W.F., Adams, R.C., Rice, R.M., Tang, D., Berman, J., Ransom, J., Magill, A.J., Grogl, M. (2013). Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med. 368: 524-32. doi: 10.1056/NEJMoa1202657.
Bennis, I., Thys, S., Filali, H., De Brouwere, V., Sahibi, H., Boelaert, M. (2017). Psychosocial impact of scars due to cutaneous leishmaniasis on high school students in Errachidia province, Morocco. Infect Dis Poverty. 6: 146. Doi: 10.1186/s40249-017-0267-5
Cardona-Arias, J.A., Patiño-Martínez, D.A., López-Carvajal, L. (2017a). Evaluaciones económicas en leishmaniasis cutánea: revisión sistemática de literatura 1980-2015. Revista de Economía del Caribe. 20: 52-70.
Cardona-Arias, J.A., López-Carvajal, L., Tamayo Plata, M.P., Vélez I.D. (2017b). Costeffectiveness analysis of thermotherapy versus pentavalent antimonials for the treatment of cutaneous leishmaniasis. J Evid Based Med. 10: 81-90. Doi: 10.1111/jebm.12245.
Cardona-Arias, J.A., López-Carvajal, L., Tamayo-Plata, M.P., Vélez, I.D. (2018). Comprehensive economic evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Colombia. BMC Public Health. 18: 185. Doi: 10.1186/s12889-018-5060-2
Castañeda DM, Pombo LM, Urueña CP, Hernández JF, Fiorentino S. (2012). A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line. BMC Complement Altern Med. 12: 38. Doi: 10.1186/1472-6882-12-38
De la Cruz-Lapa, P. (2004). Aprovechamiento integral y racional de la tara. Revista del Instituto de Investigación FIGMMG. 7: 64-73.
De la Cruz, H., Vilcapoma, G., Zevallos P.A. (2007). Ethnobotanical study of medicinal plants used by the Andean people of Canta, Lima, Perú. J Ethnopharmacol. 111: 284-94.
Hotez, P. (2013). Forgotten People, Forgotten Diseases: The Neglected Tropical Diseases and Their Impact on Global Health and Development, 2nd ed.; ASM Press: Washington, DC, USA.
Kloucek, P., Polesny, Z., Svobodova, B., Vlkova, E., Kokoska, L. (2005). Antibacterial screening of some Peruvian medicinal plants used in Callería District. J Ethnopharmacol. 99: 309-312. Doi: 10.1016/j.jep.2005.01.062
Kondo, K., Takaishi, Y., Shibata, H., Higuti, T. (2006). ILSMRs (intensifier of beta-lactamsusceptibility in methicillin-resistant Staphylococcus aureus) from Tara [Caesalpinia spinosa (Molina) Kuntze]. Phytomed. 13: 209-212. Doi: 10.1016/j.phymed.2004.08.001
Ladopoulos, T., Ntais, P., Tsirigotakis, N., Dokianakis, E., Antoniou, M. (2015). 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. Exp Parasitol. 157: 124‐127. Doi:10.1016/j.exppara.2015.07.008
López, L., Vélez, I., Asela, C., Cruz, C., Alves, F., Robledo, S., Arana, B. (2018). A phase II study to evaluate the safety and efficacy of topical 3% amphotericin B cream (Anfoleish) for the treatment of uncomplicated cutaneous leishmaniasis in Colombia. PLoS Negl Trop Dis. 12:e0006653. Doi: 10.1371/journal.pntd.0006653.
Montalvo, A.M., Fraga, J., Montano, I., Monzote, L., Van der Auwera, G., Marín, M., Muskus, C. (2016). Molecular identification of Leishmania spp. clinical isolates from Colombia based on hsp70 gene. Biomédica. 36: 37-44. Doi: 10.7705/biomedica.v36i2.2688.
Montoya, A., Daza, A., Muñoz, D., Ríos, K., Taylor, V., Cedeño, D., Vélez, I.D., Echeverri, F., Robledo, S.M. (2015). Development
f a novel formulation with hypericin to treat cutaneous leishmaniasis based on photodynamic therapy in in vitro and in vivo studies. Antimicrob Agents Chemother. 59: 5804-5813. Doi: 10.1128/AAC.00545-15
Narváez, A., Calvo, A., Troya, A.M. (2009). Las poblaciones naturales de la tara (Caesalpinia spinosa) en el Ecuador: una aproximación al conocimiento de la diversidad genética y el contenido de taninos a través de estudios moleculares y bioquímicos. Serie Investigación y Sistematización No. 7. Programa Regional Ecobona-Intercooperation, Laboratorio de Biotecnología Vegetal Escuela de Ciencias Biológicas Pontificia Universidad Católica del Ecuador PUCE. Quito. 39 pp.
OECD. (2004), Test No. 427: Skin Absorption: In Vivo Method, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264071063-en
OECD. (2017), Test No. 402: Acute Dermal Toxicity, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264070585-en
OECD. (2019a). Test No. 431: In vitro skin corrosion: Reconstructed human epidermis (RHE) test method, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264264618-en
OECD. (2019b). Test No. 439: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. https://doi.org/10.1787/9789264242845-en
Oryan, A. (2015). Plant-derived compounds in treatment of leishmaniasis. Iran J Vet Res. 16: 1-19.
Parvizi, M. M., Handjani, F., Moein, M., Hatam, G., Nimrouzi, M., Hassanzadeh, J., Hamidizadeh, N., Khorrami, H. R., Zarshenas, M. M. (2017). Efficacy of cryotherapy plus topical Juniperus excelsa M. Bieb cream versus cryotherapy plus placebo in the treatment of Old World cutaneous leishmaniasis: A triple-blind randomized controlled clinical trial. PLoS Negl Trop Dis. 11:e0005957. https://doi.org/10.1371/journal.pntd.0005957
Pulido, S.A., Muñoz, D.L., Restrepo, A.M., Mesa, C.V, Alzate, J.F., Vélez, I.D., Robledo, S.M. (2012). Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of antileishmanial drugs. Acta Trop. 122: 36-45. Doi: 10.1016/j.actatropica.2011.11.015
Rangel-Ch., J.O. (2015). La biodiversidad de Colombia: significado y distribución regional. Rev. Acad. Colomb. Cienc. Ex. Fis. Nat. 39: 176-200. Doi: http://dx.doi.org/10.18257/raccefyn.136
Rigano, L., Deola, M., Zaccariotto, F., Colleoni, T., Lionetti, N. (2019). A New Gelling Agent and Rheology Modifier in Cosmetics: Caesalpinia spinosa Gum. Cosmetics. 6: 34.
Robledo S.M., Carrillo, L.M., Daza, A., Restrepo, A.M., Muñoz, D.L., Tobón, J., Murillo, J.D., López, A., Ríos, C., Mesa, C.V., Upegui, Y.A., Valencia-T., A., Mondragón-Sh, K., Rodríguez, B., Vélez, I.D. (2012). Cutaneous leishmaniasis in the dorsal skin of hamsters: A useful model for the screening of antileishmanial drugs. J Vis Exp. pii: 3533. Doi: 10.3791/3533
Robledo, M.B, Robledo, S.M., Ceballos, A.L., Vélez, I.D., Gómez, N., Zuluaga, J.J. (2018). Formulación del producto crema aceite en agua útil para aplicación tópica en mucosas y piel contra enfermedades producidas por parásitos, hongos y bacterias. Resolución No. 32414 de mayo 11 de 2018.
Santander, S. P., Aoki, M., Hernández, J. F., Pombo, M., Moins-Teisserenc, H., Mooney, N., Fiorentino, S. (2011). Galactomannan from Caesalpinia spinosa induces phenotypic and functional maturation of human dendritic cells. Int Immunopharmacol. 11: 652-660. Doi: 10.1016/j.intimp.2011.01.006
Sen, R., Chatterjee, M. (2011). Plant derived therapeutics for the treatment of leishmaniasis. Phytomed. 18: 1056-69. Doi: 10.1016/j.phymed.2011.03.004
Sosa, N., Capitán, Z., Nieto, J., Nieto, M., Calzada, J., Paz, H., Spadafora, C., Kreishman- Deitrick, M., Kopydlowski, K., Ullman, D., McCarthy, W.F., Ransom, J., Berman, J., Scott, C., Grogl, M. (2013). Randomized, double-blinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for cutaneous leishmaniasis in Panama. Am J Trop Med Hyg. 89: 557-563. Doi: 10.4269/ajtmh.12-0736
Sosa, N., Pascale, J.M., Jiménez, A.I., Norwood, J.A., Kreishman-Detrick, M., Weina, P.J., Lawrence, K., McCarthy, W.F., Adams, R.C., Scott, C., Ransom, J., Tang, D., Grogl, M. (2019). Topical paromomycin for New World cutaneous leishmaniasis. PLoS Negl Trop Dis. 13 (5): e0007253. Doi: 10.1371/journal.pntd.0007253
Soto, J., Soto, P., Ajata, A., Luque, C., Tintaya, C., Paz D, Rivero D., Berman, J. (2019). Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial. Clin Infect Dis. 68: 844-849. Doi: 10.1093/cid/ciy619
Skowyra, M. Falguera, V., Gallego, G., Peiró, S., Almajano, M. del P. (2014). Antioxidant properties of aqueous and ethanolic extracts of tara (Caesalpinia spinosa) pods in vitro and in model food emulsions. J Sci Food Agric. 94: 911-918.
Trouiller, P., Olliaro, P., Torreele, E., Orbinski, J., Laing, R., Ford, N. (2002). Drug development for neglected diseases: A deficient market and a publicontrol negativohealth policy failure. Lancet. 359: 2188-2194.
Upegui, Y., Ríos, K., Quiñones, W., Echeverri, F., Archbold, R., Murillo, J.D., Torres, F., Escobar, G., Vélez, I.D., Robledo, S.M. (2019). Chroman-4-one hydrazones derivatives: Synthesis, characterization, and in vitro and in vivo antileishmanial effects. Med Chem Res. 28: 2184-2199 (2019). Doi: 10.1007/s00044-019-02446-x
Urueña, C., Mancipe, J., Hernández, J., Castañeda, D., Pombo, L., Gómez, A., Asea, A., Fiorentino, S. (2013). Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model. BMC Complement Altern Med. 13: 74. Doi.org/10.1186/1472-6882-13-74
The United States Pharmacopeia; the national formulary. (2016). 39a. rev. (USP39) 34a. ed. (NF34). Rockville, Md.: United States Pharmacopeial Convention, c2016.
Vélez, I.D., Robledo, S.M., Robledo, M.B., Ceballos, A.L., Giraldo, N.A., Gómez, A., Zuluaga, J.J. (2017). Cream formulation with amphotericin B and oil in water useful for topical application to mucous tissue and skin against diseases produced by leishmaniasis. US9801895B1.
World Health Organization. (2010). Control of the leishmaniasis: Report of a meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22-26 March 2010.WHO Technical Report Series 949.
Zerehsaz, F., Beheshti, S., Reza Rezaian, G., Joubeh, S. (2003). Erysipeloid cutaneous leishmaniasis: Treatment with a new, topical, pure herbal extract. Eur J Dermatol. 13: 145-148.
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