La Sulfamida: primer antibiótico sintético que aún permanece Un vistazo al ayer y hoy de las Sulfamidas
Palabras clave:
Sulfamidas, Antibiotico sintético, Infecciones humanas, Infecciones animalesResumen
Con las sulfamidas se inició la elaboración de antibióticos sintéticos, en su momento fue de gran ayuda para el dolor y el alivio de muchas enfermedades que permitieron salvar muchas vidas humanas, además, fueron la base para la generación de nuevos antibióticos para infecciones humanas y de animales. Las sulfamidas han tenido un papel clave para la recuperación de la salud. Sin embargo, el uso desmedido de estos antibióticos junto con su abuso en diferentes actividades productivas como: la crianza de animales, han provocado su aparición en diferentes compartimentos ambientales y denominados contaminantes emergentes. La presencia y permanencia de estos contaminantes representa un riesgo a la salud ambiental y la población, porque son ecotóxicos y teratogénicos, además favorecen la adquisición de resistencia a antibióticos tanto en bacterias patógenas como en bacterias autóctonas.
Citas
Accinelli, C., Koskinen, W. C., Becker, J. M., & Sadowsky, M. J. (2007). Environmental fate of two sulfonamide antimicrobial agents in soil. Journal of Agricultural and Food Chemistry, 55(7), 2677–2682. https://doi.org/10.1021/jf063709j
Baran, W., Adamek, E., Ziemiańska, J., & Sobczak, A. (2011). Effects of the presence of sulfonamides in the environment and their influence on human health. Journal of Hazardous Materials, 196, 1–15. https://doi.org/10.1016/j.jhazmat.2011.08.082
Bentley, R. (2009). Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams). Journal of Industrial Microbiology and Biotechnology, 36(6), 775–786. https://doi.org/10.1007/s10295-009-0553-8
Białk-Bielińska, A., Stolte, S., Arning, J., Uebers, U., Böschen, A., Stepnowski, P., & Matzke, M. (2011). Ecotoxicity evaluation of selected sulfonamides. Chemosphere, 85(6), 928–933. https://doi.org/10.1016/j.chemosphere.2011.06.058
Bielen, A., Šimatović, A., Kosić-Vukšić, J., Senta, I., Ahel, M., Babić, S., Jurina, T., González Plaza, J. J., Milaković, M., & Udiković-Kolić, N. (2017). Negative environmental impacts of antibiotic-contaminated effluents from pharmaceutical industries. Water Research, 126, 79–87. https://doi.org/10.1016/j.watres.2017.09.019
Boxall, A. B. A. (2010). Veterinary medicines and the environment. Handbook of Experimental Pharmacology, 199, 291–314. https://doi.org/10.1007/978-3-642-10324-7_12
Calvo, J., & Martínez-Martínez, L. (2009). Mecanismos de acción de los antimicrobianos. Enfermedades Infecciosas y Microbiología Clínica, 27(1), 44–52. https://doi.org/10.1016/j.eimc.2008.11.001
Chen, J., & Xie, S. (2018). Overview of sulfonamide biodegradation and the relevant pathways and microorganisms. Science of The Total Environment, 640–641, 1465–1477. https://doi.org/https://doi.org/10.1016/j.scitotenv.2018.06.016
Cheong, M. S., Seo, K. H., Chohra, H., Yoon, Y. E., Choe, H., Kantharaj, V., & Lee, Y. B. (2020). Influence of sulfonamide contamination derived from veterinary antibiotics on plant growth and development. Antibiotics, 9(8), 1–18. https://doi.org/10.3390/antibiotics9080456
Christensen, S. B. (2021). Drugs that changed society: History and current status of the early antibiotics: Salvarsan, sulfonamides, and β-lactams. In Molecules (Vol. 26, Issue 19). https://doi.org/10.3390/molecules26196057
Dibbern, D. A., & Montanaro, A. (2008). Allergies to sulfonamide antibiotics and sulfur-containing drugs. Annals of Allergy, Asthma and Immunology, 100(2), 91–101. https://doi.org/10.1016/s1081-1206(10)60415-2
Donoso, A., & Santis, D. (2020). A propósito de la epidemia meningocóccica chilena (1941-1942): El niño con shock séptico hace 80 años desde la perspectiva médica y social. Revista Chilena de Pediatría, 91, 440. https://doi.org/10.32641/rchped.v91i3.1714
Eliopoulos, G. M., & Huovinen, P. (2001). Resistance to Trimethoprim-Sulfamethoxazole. Clinical Infectious Diseases, 32(11), 1608–1614. https://doi.org/10.1086/320532
Grenni, P. (2022). Antimicrobial Resistance in Rivers: A Review of the Genes Detected and New Challenges. Environmental Toxicology and Chemistry, 41(3), 687–714. https://doi.org/10.1002/etc.5289
Hutchings, M. I., Truman, A. W., & Wilkinson, B. (2019). Antibiotics: past, present and future. Current Opinion in Microbiology, 51, 72–80
. https://doi.org/https://doi.org/10.1016/j.mib.2019.10.008
Iyer, H. V. (2008). History Revisited—Prontosil Red. The Journal of Emergency Medicine, 35(2), 209–210. https://doi.org/https://doi.org/10.1016/j.jemermed.2007.07.064
Jia, A., Hu, J., Wu, X., Peng, H., Wu, S., & Dong, Z. (2011). Occurrence and source apportionment of sulfonamides and their metabolites in Liaodong Bay and the adjacent Liao River basin, North China. Environmental Toxicology and Chemistry, 30(6), 1252–1260. https://doi.org/10.1002/etc.508
Jiang, H., Cheng, H., Liang, Y., Yu, S., Yu, T., Fang, J., & Zhu, C. (2019). Diverse Mobile Genetic Elements and Conjugal Transferability of Sulfonamide Resistance Genes (sul1, sul2, and sul3) in Escherichia coli Isolates From Penaeus vannamei and Pork From Large Markets in Zhejiang, China. Frontiers in Microbiology, 10(August). https://doi.org/10.3389/fmicb.2019.01787
Jin, C., Wei, S., Sun, R., Zou, W., Zhang, X., Zhou, Q., Liu, R., & Huang, L. (2020). The Forms, Distribution, and Risk Assessment of Sulfonamide Antibiotics in the Manure–Soil–Vegetable System of Feedlot Livestock. Bulletin of Environmental Contamination and Toxicology, 105(5), 790–797. https://doi.org/10.1007/s00128-020-03010-9
Kergoat, L., Besse-Hoggan, P., Leremboure, M., Beguet, J., Devers, M., Martin-Laurent, F., Masson, M., Morin, S., Roinat, A., Pesce, S., & Bonnineau, C. (2021). Environmental Concentrations of Sulfonamides Can Alter Bacterial Structure and Induce Diatom Deformities in Freshwater Biofilm Communities. Frontiers in Microbiology, 12(May). https://doi.org/10.3389/fmicb.2021.643719
Khan, D. A., Knowles, S. R., & Shear, N. H. (2019). Sulfonamide Hypersensitivity: Fact and Fiction. Journal of Allergy and Clinical Immunology: In Practice, 7(7), 2116–2123. https://doi.org/10.1016/j.jaip.2019.05.034
Lees, P., Pelligand, L., Giraud, E., & Toutain, P. L. (2021). A history of antimicrobial drugs in animals: Evolution and revolution. Journal of Veterinary Pharmacology and Therapeutics, 44(2), 137–171. https://doi.org/10.1111/jvp.12895
Lekshmi, M., Ammini, P., Kumar, S., & Varela, M. F. (2017). The food production environment and the development of antimicrobial resistance in human pathogens of animal origin. Microorganisms, 5(1). https://doi.org/10.3390/microorganisms5010011
Matsuura, R., Kanehara, R., Kadoya, A., & Suzuki, S. (2021). Adsorption of sulfonamides to marine diatoms and arthropods. Environmental Toxicology and Pharmacology, 82(June 2020), 103557. https://doi.org/10.1016/j.etap.2020.103557
Parra Ruiz, J., Pea Monje, A., Martnez Prez, M. ., & Hernndez Quero, J. (2006). Quinolonas. Sulfamidas. Trimetoprima. Cotrimoxazol. Medicine - Programa de Formaci?N M?Dica Continuada Acreditado, 9(54), 3538–3543. https://doi.org/10.1016/s0211-3449(06)74213-8
Prescott, J. F. (2017). History and Current Use of Antimicrobial Drugs in Veterinary Medicine. Microbiology Spectrum, 5(6). https://doi.org/10.1128/microbiolspec.arba-0002-2017
Proia, L., Von Schiller, D., Sànchez-Melsió, A., Sabater, S., Borrego, C. M., Rodríguez-Mozaz, S., & Balcázar, J. L. (2016). Occurrence and persistence of antibiotic resistance genes in river biofilms after wastewater inputs in small rivers. Environmental Pollution, 210, 121–128. https://doi.org/10.1016/j.envpol.2015.11.035
Ramirez-Cando, L. J., Chicaiza Ramírez, S. E., Ramos López, A. D., & Álvarez, C. I. (2019). Detección de antibióticos betalactámicos, tetraciclinas y sulfamidas como contaminantes emergentes en los ríos San Pedro y Pita del cantón Rumiñahui. La Granja, 30(2), 88–102. https://doi.org/10.17163/lgr.n30.2019.08
Schwartz, R. S. (2004). Paul Ehrlich’s Magic Bullets. New England Journal of Medicine, 350(11), 1079–1080. https://doi.org/10.1056/NEJMp048021
Solberg, C. O. (2013). Medisinsk historie - Historien om antibiotika. Tidskriftet Norsk Legeforening, 133(23–24), 2502–2507
.
Straub, J. O. (2016). Aquatic environmental risk assessment for human use of the old antibiotic sulfamethoxazole in Europe. Environmental Toxicology and Chemistry, 35(4), 767–779. https://doi.org/10.1002/etc.2945
Supuran, C. T. (2017). Special issue: Sulfonamides. Molecules, 22(10). https://doi.org/10.3390/molecules22101642
Then, R. L. (1989). Resistance to Sulfonamides. 1, 291–312. https://doi.org/10.1007/978-3-642-74095-4_12
Viana, P., Meisel, L., Lopes, A., De Jesus, R., Sarmento, G., Duarte, S., Sepodes, B., Fernandes, A., Dos Santos, M. M. C., Almeida, A., & Oliveira, M. C. (2021). Identification of antibiotics in surface-groundwater. A tool towards the ecopharmacovigilance approach: A portuguese case-study. Antibiotics, 10(8). https://doi.org/10.3390/antibiotics10080888
Vicente, D., & Pérez-Trallero, E. (2010). Tetraciclinas, sulfamidas y metronidazol. Enfermedades Infecciosas y Microbiologia Clinica, 28(2), 122–130. https://doi.org/10.1016/j.eimc.2009.10.002
Wu, S., Dalsgaard, A., Hammerum, A. M., Porsbo, L. J., & Jensen, L. B. (2010). Prevalence and characterization of plasmids carrying sulfonamide resistance genes among Escherichia coli from pigs, pig carcasses and human. Acta Veterinaria Scandinavica, 52(1), 1–7. https://doi.org/10.1186/1751-0147-52-47
Ye, C., Shi, J., Zhang, X., Qin, L., Jiang, Z., Wang, J., Li, Y., & Liu, B. (2021). Occurrence and bioaccumulation of sulfonamide antibiotics in different fish species from Hangbu-Fengle River, Southeast China. Environmental Science and Pollution Research, 28(32), 44111–44123. https://doi.org/10.1007/s11356-021-13850-5
Yousef, F., Mansour, O., Herbali, J., & Author, C. (n.d.). IN-VITRO IN-VIVO IN-SILICO JOURNAL ISSN NO: COMING SOON Review Sulfonamides : Historical Discovery Development (Structure-Activity Relationship Notes). 1. www.openaccesspub.org
Yu, L., Song, C., Zhang, C., Fan, L., Qiu, L., Wu, W., Meng, S., Hu, G., & Chen, J. (2018). Occurrence of sulfonamides in fish in the lower reaches of Yangtze River, China and estimated daily intake for understanding human dietary exposure. Aquaculture, 495(December 2016), 538–544. https://doi.org/10.1016/j.aquaculture.2018.06.033
Zaffiri, L., Gardner, J., & Toledo-Pereyra, L. H. (2012). History of antibiotics. from salvarsan to cephalosporins. Journal of Investigative Surgery, 25(2), 67–77. https://doi.org/10.3109/08941939.2012.664099
Zhou, J., Yun, X., Wang, J., Li, Q., & Wang, Y. (2022). A review on the ecotoxicological effect of sulphonamides on aquatic organisms. Toxicology Reports, 9(November 2021), 534–540. https://doi.org/10.1016/j.toxrep.2022.03.034
Baran, W., Adamek, E., Ziemiańska, J., & Sobczak, A. (2011). Effects of the presence of sulfonamides in the environment and their influence on human health. Journal of Hazardous Materials, 196, 1–15. https://doi.org/10.1016/j.jhazmat.2011.08.082
Bentley, R. (2009). Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence β-lactams). Journal of Industrial Microbiology and Biotechnology, 36(6), 775–786. https://doi.org/10.1007/s10295-009-0553-8
Białk-Bielińska, A., Stolte, S., Arning, J., Uebers, U., Böschen, A., Stepnowski, P., & Matzke, M. (2011). Ecotoxicity evaluation of selected sulfonamides. Chemosphere, 85(6), 928–933. https://doi.org/10.1016/j.chemosphere.2011.06.058
Bielen, A., Šimatović, A., Kosić-Vukšić, J., Senta, I., Ahel, M., Babić, S., Jurina, T., González Plaza, J. J., Milaković, M., & Udiković-Kolić, N. (2017). Negative environmental impacts of antibiotic-contaminated effluents from pharmaceutical industries. Water Research, 126, 79–87. https://doi.org/10.1016/j.watres.2017.09.019
Boxall, A. B. A. (2010). Veterinary medicines and the environment. Handbook of Experimental Pharmacology, 199, 291–314. https://doi.org/10.1007/978-3-642-10324-7_12
Calvo, J., & Martínez-Martínez, L. (2009). Mecanismos de acción de los antimicrobianos. Enfermedades Infecciosas y Microbiología Clínica, 27(1), 44–52. https://doi.org/10.1016/j.eimc.2008.11.001
Chen, J., & Xie, S. (2018). Overview of sulfonamide biodegradation and the relevant pathways and microorganisms. Science of The Total Environment, 640–641, 1465–1477. https://doi.org/https://doi.org/10.1016/j.scitotenv.2018.06.016
Cheong, M. S., Seo, K. H., Chohra, H., Yoon, Y. E., Choe, H., Kantharaj, V., & Lee, Y. B. (2020). Influence of sulfonamide contamination derived from veterinary antibiotics on plant growth and development. Antibiotics, 9(8), 1–18. https://doi.org/10.3390/antibiotics9080456
Christensen, S. B. (2021). Drugs that changed society: History and current status of the early antibiotics: Salvarsan, sulfonamides, and β-lactams. In Molecules (Vol. 26, Issue 19). https://doi.org/10.3390/molecules26196057
Dibbern, D. A., & Montanaro, A. (2008). Allergies to sulfonamide antibiotics and sulfur-containing drugs. Annals of Allergy, Asthma and Immunology, 100(2), 91–101. https://doi.org/10.1016/s1081-1206(10)60415-2
Donoso, A., & Santis, D. (2020). A propósito de la epidemia meningocóccica chilena (1941-1942): El niño con shock séptico hace 80 años desde la perspectiva médica y social. Revista Chilena de Pediatría, 91, 440. https://doi.org/10.32641/rchped.v91i3.1714
Eliopoulos, G. M., & Huovinen, P. (2001). Resistance to Trimethoprim-Sulfamethoxazole. Clinical Infectious Diseases, 32(11), 1608–1614. https://doi.org/10.1086/320532
Grenni, P. (2022). Antimicrobial Resistance in Rivers: A Review of the Genes Detected and New Challenges. Environmental Toxicology and Chemistry, 41(3), 687–714. https://doi.org/10.1002/etc.5289
Hutchings, M. I., Truman, A. W., & Wilkinson, B. (2019). Antibiotics: past, present and future. Current Opinion in Microbiology, 51, 72–80
. https://doi.org/https://doi.org/10.1016/j.mib.2019.10.008
Iyer, H. V. (2008). History Revisited—Prontosil Red. The Journal of Emergency Medicine, 35(2), 209–210. https://doi.org/https://doi.org/10.1016/j.jemermed.2007.07.064
Jia, A., Hu, J., Wu, X., Peng, H., Wu, S., & Dong, Z. (2011). Occurrence and source apportionment of sulfonamides and their metabolites in Liaodong Bay and the adjacent Liao River basin, North China. Environmental Toxicology and Chemistry, 30(6), 1252–1260. https://doi.org/10.1002/etc.508
Jiang, H., Cheng, H., Liang, Y., Yu, S., Yu, T., Fang, J., & Zhu, C. (2019). Diverse Mobile Genetic Elements and Conjugal Transferability of Sulfonamide Resistance Genes (sul1, sul2, and sul3) in Escherichia coli Isolates From Penaeus vannamei and Pork From Large Markets in Zhejiang, China. Frontiers in Microbiology, 10(August). https://doi.org/10.3389/fmicb.2019.01787
Jin, C., Wei, S., Sun, R., Zou, W., Zhang, X., Zhou, Q., Liu, R., & Huang, L. (2020). The Forms, Distribution, and Risk Assessment of Sulfonamide Antibiotics in the Manure–Soil–Vegetable System of Feedlot Livestock. Bulletin of Environmental Contamination and Toxicology, 105(5), 790–797. https://doi.org/10.1007/s00128-020-03010-9
Kergoat, L., Besse-Hoggan, P., Leremboure, M., Beguet, J., Devers, M., Martin-Laurent, F., Masson, M., Morin, S., Roinat, A., Pesce, S., & Bonnineau, C. (2021). Environmental Concentrations of Sulfonamides Can Alter Bacterial Structure and Induce Diatom Deformities in Freshwater Biofilm Communities. Frontiers in Microbiology, 12(May). https://doi.org/10.3389/fmicb.2021.643719
Khan, D. A., Knowles, S. R., & Shear, N. H. (2019). Sulfonamide Hypersensitivity: Fact and Fiction. Journal of Allergy and Clinical Immunology: In Practice, 7(7), 2116–2123. https://doi.org/10.1016/j.jaip.2019.05.034
Lees, P., Pelligand, L., Giraud, E., & Toutain, P. L. (2021). A history of antimicrobial drugs in animals: Evolution and revolution. Journal of Veterinary Pharmacology and Therapeutics, 44(2), 137–171. https://doi.org/10.1111/jvp.12895
Lekshmi, M., Ammini, P., Kumar, S., & Varela, M. F. (2017). The food production environment and the development of antimicrobial resistance in human pathogens of animal origin. Microorganisms, 5(1). https://doi.org/10.3390/microorganisms5010011
Matsuura, R., Kanehara, R., Kadoya, A., & Suzuki, S. (2021). Adsorption of sulfonamides to marine diatoms and arthropods. Environmental Toxicology and Pharmacology, 82(June 2020), 103557. https://doi.org/10.1016/j.etap.2020.103557
Parra Ruiz, J., Pea Monje, A., Martnez Prez, M. ., & Hernndez Quero, J. (2006). Quinolonas. Sulfamidas. Trimetoprima. Cotrimoxazol. Medicine - Programa de Formaci?N M?Dica Continuada Acreditado, 9(54), 3538–3543. https://doi.org/10.1016/s0211-3449(06)74213-8
Prescott, J. F. (2017). History and Current Use of Antimicrobial Drugs in Veterinary Medicine. Microbiology Spectrum, 5(6). https://doi.org/10.1128/microbiolspec.arba-0002-2017
Proia, L., Von Schiller, D., Sànchez-Melsió, A., Sabater, S., Borrego, C. M., Rodríguez-Mozaz, S., & Balcázar, J. L. (2016). Occurrence and persistence of antibiotic resistance genes in river biofilms after wastewater inputs in small rivers. Environmental Pollution, 210, 121–128. https://doi.org/10.1016/j.envpol.2015.11.035
Ramirez-Cando, L. J., Chicaiza Ramírez, S. E., Ramos López, A. D., & Álvarez, C. I. (2019). Detección de antibióticos betalactámicos, tetraciclinas y sulfamidas como contaminantes emergentes en los ríos San Pedro y Pita del cantón Rumiñahui. La Granja, 30(2), 88–102. https://doi.org/10.17163/lgr.n30.2019.08
Schwartz, R. S. (2004). Paul Ehrlich’s Magic Bullets. New England Journal of Medicine, 350(11), 1079–1080. https://doi.org/10.1056/NEJMp048021
Solberg, C. O. (2013). Medisinsk historie - Historien om antibiotika. Tidskriftet Norsk Legeforening, 133(23–24), 2502–2507
.
Straub, J. O. (2016). Aquatic environmental risk assessment for human use of the old antibiotic sulfamethoxazole in Europe. Environmental Toxicology and Chemistry, 35(4), 767–779. https://doi.org/10.1002/etc.2945
Supuran, C. T. (2017). Special issue: Sulfonamides. Molecules, 22(10). https://doi.org/10.3390/molecules22101642
Then, R. L. (1989). Resistance to Sulfonamides. 1, 291–312. https://doi.org/10.1007/978-3-642-74095-4_12
Viana, P., Meisel, L., Lopes, A., De Jesus, R., Sarmento, G., Duarte, S., Sepodes, B., Fernandes, A., Dos Santos, M. M. C., Almeida, A., & Oliveira, M. C. (2021). Identification of antibiotics in surface-groundwater. A tool towards the ecopharmacovigilance approach: A portuguese case-study. Antibiotics, 10(8). https://doi.org/10.3390/antibiotics10080888
Vicente, D., & Pérez-Trallero, E. (2010). Tetraciclinas, sulfamidas y metronidazol. Enfermedades Infecciosas y Microbiologia Clinica, 28(2), 122–130. https://doi.org/10.1016/j.eimc.2009.10.002
Wu, S., Dalsgaard, A., Hammerum, A. M., Porsbo, L. J., & Jensen, L. B. (2010). Prevalence and characterization of plasmids carrying sulfonamide resistance genes among Escherichia coli from pigs, pig carcasses and human. Acta Veterinaria Scandinavica, 52(1), 1–7. https://doi.org/10.1186/1751-0147-52-47
Ye, C., Shi, J., Zhang, X., Qin, L., Jiang, Z., Wang, J., Li, Y., & Liu, B. (2021). Occurrence and bioaccumulation of sulfonamide antibiotics in different fish species from Hangbu-Fengle River, Southeast China. Environmental Science and Pollution Research, 28(32), 44111–44123. https://doi.org/10.1007/s11356-021-13850-5
Yousef, F., Mansour, O., Herbali, J., & Author, C. (n.d.). IN-VITRO IN-VIVO IN-SILICO JOURNAL ISSN NO: COMING SOON Review Sulfonamides : Historical Discovery Development (Structure-Activity Relationship Notes). 1. www.openaccesspub.org
Yu, L., Song, C., Zhang, C., Fan, L., Qiu, L., Wu, W., Meng, S., Hu, G., & Chen, J. (2018). Occurrence of sulfonamides in fish in the lower reaches of Yangtze River, China and estimated daily intake for understanding human dietary exposure. Aquaculture, 495(December 2016), 538–544. https://doi.org/10.1016/j.aquaculture.2018.06.033
Zaffiri, L., Gardner, J., & Toledo-Pereyra, L. H. (2012). History of antibiotics. from salvarsan to cephalosporins. Journal of Investigative Surgery, 25(2), 67–77. https://doi.org/10.3109/08941939.2012.664099
Zhou, J., Yun, X., Wang, J., Li, Q., & Wang, Y. (2022). A review on the ecotoxicological effect of sulphonamides on aquatic organisms. Toxicology Reports, 9(November 2021), 534–540. https://doi.org/10.1016/j.toxrep.2022.03.034
Descargas
Publicado
2022-11-15
Cómo citar
Bairán Pérez, G. . ., Torres Ramirez, E., & Chávez Bravo , E. . (2022). La Sulfamida: primer antibiótico sintético que aún permanece Un vistazo al ayer y hoy de las Sulfamidas. RD-ICUAP, 8(24), 98–111. Recuperado a partir de http://rd.buap.mx/ojs-rdicuap/index.php/rdicuap/article/view/990
Número
Sección
Artículos
Licencia
Definir aviso de derechos.
Los datos de este artículo, así como los detalles técnicos para la realización del experimento, se pueden compartir a solicitud directa con el autor de correspondencia.
Los datos personales facilitados por los autores a RD-ICUAP se usarán exclusivamente para los fines declarados por la misma, no estando disponibles para ningún otro propósito ni proporcionados a terceros.
