The use of Hydroxychloroquine during the COVID-19 pandemic: a literature review study
DOI:
https://doi.org/10.33448/rsd-v10i10.19118Keywords:
COVID-19; SARS-CoV-2; Hydroxychloroquine.Abstract
COVID-19 is an infectious disease caused by SARS-CoV-2, has a high transmission rate and has resulted in thousands of registered deaths worldwide. Currently, there are no clinical studies proving the effectiveness of specific drugs against SARS-Cov-2. However, previous experiences with similar viruses indicated potential effectiveness for certain drugs, including the use of Hydroxychloroquine (HCQ). At the beginning of the COVID-19 pandemic, the World Health Organization and the Ministry of Health of Brazil guided the use of HCQ as a therapeutic option. However, its role in viral infection by SARS-CoV-2, in addition to its real benefits in vivo, was unknown. Therefore, the aim of this study was to conduct a literature review on the use of HCQ in cases of COVID-19, and to discuss the results found in studies that performed in vitro and in vivo tests, in order to investigate its therapeutic efficacy. The review was carried out using descriptors in a computerized database. The antiviral efficacy of HCQ against SARS-CoV-2 in vitro has been described by several authors, inhibiting virus replication and mediating cytokine storm through its immunomodulatory effects. However, in vivo analyzes in complex organisms showed no effect on reducing viral load, as well as no clinical benefit to the patient. Thus, although preliminary in vitro results have shown to be positive and promising, evidence from randomized clinical trials indicated that HCQ did not cause the same effects in vivo against COVID-19.
References
Abella, B. S., Jolkovsky, E. L., Biney, B. T., Uspal, J. E., Hyman, M. C., Frank, I., Hensley, S. E., Gill, S., Vogl, D. T., Maillard, I., Babushok, D. V., Huang, A. C., Nasta, S. D., Walsh, J. C., Wiletyo, E. P., Gimotty, P. A., Milone, M. C., & Amaravadi, R. K. (2021). Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers. JAMA Internal Medicine, 181(2), 195. https://doi.org/10.1001/jamainternmed.2020.6319
Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., Baric, R. S., & Denison, M. R. (2018). Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio, 9(2). https://doi.org/10.1128/mBio.00221-18
Andrade, K. R. C. de, Carvalho, V. K. da S., Farinasso, C. M., Lima, A. A. de, Silva, R. B., Wachira, V. K., Capucho, H. C., Souza, P. M. de, Vanni, T., Sachetti, C. G., & Rêgo, D. F. (2020). Terapia medicamentosa para infecções por coronavírus em humanos: revisão sistemática rápida. Ciência & Saúde Coletiva, 25(9), 3517–3554. https://doi.org/10.1590/1413-81232020259.14242020
Ben-Zvi, I., Kivity, S., Langevitz, P., & Shoenfeld, Y. (2012). Hydroxychloroquine: From Malaria to Autoimmunity. Clinical Reviews in Allergy & Immunology, 42(2), 145–153. https://doi.org/10.1007/s12016-010-8243-x
Bortoli, R., & Santiago, M. (2007). Chloroquine ototoxicity. Clinical Rheumatology, 26(11), 1809–1810. https://doi.org/10.1007/s10067-007-0662-6
Boulware, D. R., Pullen, M. F., Bangdiwala, A. S., Pastick, K. A., Lofgren, S. M., Okafor, E. C., Skipper, C. P., Nascene, A. A., Nicol, M. R., Abassi, M., Engen, N. W., Cheng, M. P., LaBar, D., Lother, S. A., MacKenzie, L. J., Drobot, G., Marten, N., Zarychanski, R., Kelly, L. E., … Hullsiek, K. H. (2020). A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. New England Journal of Medicine, 383(6), 517–525. https://doi.org/10.1056/NEJMoa2016638
Brunton, L. L., Hidal-Dandan, R., & Knollmann, B. C. (2019). As bases farmacológicas da terapêutica de Goodman & Gilman. In Artmed (13a).
Caly, L., Druce, J. D., Catton, M. G., Jans, D. A., & Wagstaff, K. M. (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research, 178, 104787. https://doi.org/10.1016/j.antiviral.2020.104787
Chen, C., Zhang, Y., Huang, J., Yin, P., Cheng, Z., Wu, J., Chen, S., Zhang, Y., Chen, B., Lu, M., Luo, Y., Ju, L., Zhang, J., & Wang, X. (2020). Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. MedRxiv, 2020.03.17.20037432. https://doi.org/10.1101/2020.03.17.20037432
Cortegiani, A., Ingoglia, G., Ippolito, M., Giarratano, A., & Einav, S. (2020). A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Journal of Critical Care, 57, 279–283. https://doi.org/10.1016/j.jcrc.2020.03.005
Estrela, C. (2018). Metodologia Científica: Ciência, Ensino, Pesquisa (Artes Médicas (Ed.); 3a.).
Fiocruz. (2021). Boletim observatório COVID-19 - Semanas epidemiológicas 10 e 11. Observatório Covid-19/Fiocruz, 7-20/3/21.
Furtado, R. H. M., Berwanger, O., Fonseca, H. A., Corrêa, T. D., Ferraz, L. R., Lapa, M. G., Zampieri, F. G., Veiga, V. C., Azevedo, L. C. P., Rosa, R. G., Lopes, R. D., Avezum, A., Manoel, A. L. O., Piza, F. M. T., Martins, P. A., Lisboa, T. C., Pereira, A. J., Olivato, G. B., Dantas, V. C. S., … Cavalcanti, A. B. (2020). Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. The Lancet, 396(10256), 959–967. https://doi.org/10.1016/S0140-6736(20)31862-6
Furuta, Y., Komeno, T., & Nakamura, T. (2017). Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proceedings of the Japan Academy, Series B, 93(7), 449–463. https://doi.org/10.2183/pjab.93.027
Gautret, P., Lagier, J.-C., Parola, P., Hoang, V. T., Meddeb, L., Mailhe, M., Doudier, B., Courjon, J., Giordanengo, V., Vieira, V. E., Tissot Dupont, H., Honoré, S., Colson, P., Chabrière, E., La Scola, B., Rolain, J.-M., Brouqui, P., & Raoult, D. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents, 56(1), 105949. https://doi.org/10.1016/j.ijantimicag.2020.105949
Goldman, F. D., Gilman, A. L., Hollenback, C., Kato, R. M., Premack, B. A., & Rawlings, D. J. (2000). Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood, 95(11), 3460–3466. http://www.ncbi.nlm.nih.gov/pubmed/10828029
Iser, B. P. M., Sliva, I., Raymundo, V. T., Poleto, M. B., Schuelter-Trevisol, F., & Bobinski, F. (2020). Suspected COVID-19 case definition: a narrative review of the most frequent signs and symptoms among confirmed cases. Epidemiologia e Serviços de Saúde, 29(3). https://doi.org/10.5123/S1679-49742020000300018
Jia, H. P., Look, D. C., Shi, L., Hickey, M., Pewe, L., Netland, J., Farzan, M., Wohlford-Lenane, C., Perlman, S., & McCray, P. B. (2005). ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia. Journal of Virology, 79(23), 14614–14621. https://doi.org/10.1128/JVI.79.23.14614-14621.2005
Jose, R. J., & Manuel, A. (2020). COVID-19 cytokine storm: the interplay between inflammation and coagulation. The Lancet Respiratory Medicine, 8(6), e46–e47. https://doi.org/10.1016/S2213-2600(20)30216-2
Kawai, T., & Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology, 11(5), 373–384. https://doi.org/10.1038/ni.1863
Keyaerts, E., Vijgen, L., Maes, P., Neyts, J., & Ranst, M. Van. (2004). In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochemical and Biophysical Research Communications, 323(1), 264–268. https://doi.org/10.1016/j.bbrc.2004.08.085
Ko, J. Y., Danielson, M. L., Town, M., Derado, G., Greenlund, K. J., Kirley, P. D., Alden, N. B., Yousey-Hindes, K., Anderson, E. J., Ryan, P. A., Kim, S., Lynfield, R., Torres, S. M., Barney, G. R., Bennett, N. M., Sutton, M., Talbot, H. K., Hill, M., Hall, A. J., … George, A. (2020). Risk Factors for Coronavirus Disease 2019 (COVID-19)–Associated Hospitalization: COVID-19–Associated Hospitalization Surveillance Network and Behavioral Risk Factor Surveillance System. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaa1419
Kumar, M., Taki, K., Gahlot, R., Sharma, A., & Dhangar, K. (2020). A chronicle of SARS-CoV-2: Part-I - Epidemiology, diagnosis, prognosis, transmission and treatment. Science of The Total Environment, 734, 139278. https://doi.org/10.1016/j.scitotenv.2020.139278
Lagneaux, L., Delforge, A., Carlier, S., Massy, M., Bernier, M., & Bron, D. (2001). Early induction of apoptosis in B-chronic lymphocytic leukaemia cells by hydroxychloroquine: activation of caspase-3 and no protection by survival factors. British Journal of Haematology, 112(2), 344–352. https://doi.org/10.1046/j.1365-2141.2001.02553.x
Lee, T. C., MacKenzie, L. J., McDonald, E. G., & Tong, S. Y. C. (2020). An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (Can’t Get No) Satisfaction. International Journal of Infectious Diseases, 98, 216–217. https://doi.org/10.1016/j.ijid.2020.06.095
Lima, C. M. A. de O. (2020). Information about the new coronavirus disease (COVID-19). Radiologia Brasileira, 53(2), V–VI. https://doi.org/10.1590/0100-3984.2020.53.2e1
Liu, J., Cao, R., Xu, M., Wang, X., Zhang, H., Hu, H., Li, Y., Hu, Z., Zhong, W., & Wang, M. (2020). Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery, 6(1), 6–9. https://doi.org/10.1038/s41421-020-0156-0
Maisonnasse, P., Guedj, J., Contreras, V., Behillil, S., Solas, C., Marlin, R., Naninck, T., Pizzorno, A., Lemaitre, J., Gonçalves, A., Kahlaoui, N., Terrier, O., Fang, R. H. T., Enouf, V., Dereuddre-Bosquet, N., Brisebarre, A., Touret, F., Chapon, C., Hoen, B., … Le Grand, R. (2020). Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature. https://doi.org/10.1038/s41586-020-2558-4
Manohar, S., Tripathi, M., & Rawat, D. (2014). 4-Aminoquinoline Based Molecular Hybrids as Antimalarials: An Overview. Current Topics in Medicinal Chemistry, 14(14), 1706–1733. https://doi.org/10.2174/1568026614666140808125728
Mansilla, E., Marin, G. H., Nuñez, L., Drago, H., Sturla, F., Mertz, C., Rivera, L., Ichim, T., Riordan, N., & Raimondi, C. (2010). The Lysosomotropic Agent, Hydroxychloroquine, Delivered in a Biodegradable Nanoparticle System, Overcomes Drug Resistance of B-Chronic Lymphocytic Leukemia Cells In Vitro. Cancer Biotherapy and Radiopharmaceuticals, 25(1), 97–103. https://doi.org/10.1089/cbr.2009.0655
Martinez, M. A. (2020). Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. Antimicrobial Agents and Chemotherapy, 64(5). https://doi.org/10.1128/AAC.00399-20
Mates, M., Nesher, G., & Zevin, S. (2007). Quinines--past and present. Harefuah, 146(7), 560–562, 572. http://www.ncbi.nlm.nih.gov/pubmed/17803173
Mauthe, M., Orhon, I., Rocchi, C., Zhou, X., Luhr, M., Hijlkema, K.-J., Coppes, R. P., Engedal, N., Mari, M., & Reggiori, F. (2018). Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy, 14(8), 1435–1455. https://doi.org/10.1080/15548627.2018.1474314
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet, 395(10229), 1033–1034. https://doi.org/10.1016/S0140-6736(20)30628-0
Ministerio da Saúde. (2021). Painel Coronavirus. https://covid.saude.gov.br/
Ministério da Saúde. (2020). Ministério da Saúde amplia orientações para uso de Cloroquina. https://www.gov.br/saude/pt-br/assuntos/noticias/ministerio-da-saude-amplia-orientacoes-para-uso-da-cloroquina-2
Mitjà, O., & Clotet, B. (2020). Use of antiviral drugs to reduce COVID-19 transmission. The Lancet Global Health, 8(5), e639–e640. https://doi.org/10.1016/S2214-109X(20)30114-5
Nosál, R., Jančinová, V., & Petríková, M. (1995). Chloroquine inhibits stimulated platelets at the arachidonic acid pathway. Thrombosis Research, 77(6), 531–542. https://doi.org/10.1016/0049-3848(95)00028-3
Oliveira, W. K. de, Duarte, E., França, G. V. A. de, & Garcia, L. P. (2020). Como o Brasil pode deter a COVID-19. Epidemiologia e Serviços de Saúde, 29. https://doi.org/10.5123/S1679-49742020000200023
Organização Pan-Americana da Saúde. (2020). FOLHA INFORMATIVA COVID-19 - ESCRITÓRIO DA OPAS E DA OMS NO BRASIL. https://www.paho.org/pt/COVID19
Page, F. (1951). TREATMENT OF LUPUS ERYTHEMATOSUS WITH MEPACRINE. The Lancet, 258(6687), 755–758. https://doi.org/10.1016/S0140-6736(51)91643-1
Pereira, A. S., Shitsuka, D. M., Parreira, F. J., & Shitsuka, R. (2018). Metodologia da pesquisa científica (N. UFSM (Ed.); 1a).
Rainsford, K. D., Parke, A. L., Clifford-Rashotte, M., & Kean, W. F. (2015). Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology, 23(5), 231–269. https://doi.org/10.1007/s10787-015-0239-y
Rempenault, C., Combe, B., Barnetche, T., Gaujoux-Viala, C., Lukas, C., Morel, J., & Hua, C. (2018). Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Annals of the Rheumatic Diseases, 77(1), 98–103. https://doi.org/10.1136/annrheumdis-2017-211836
Retallack, H., Di Lullo, E., Arias, C., Knopp, K. A., Laurie, M. T., Sandoval-Espinosa, C., Mancia Leon, W. R., Krencik, R., Ullian, E. M., Spatazza, J., Pollen, A. A., Mandel-Brehm, C., Nowakowski, T. J., Kriegstein, A. R., & DeRisi, J. L. (2016). Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proceedings of the National Academy of Sciences, 113(50), 14408–14413. https://doi.org/10.1073/pnas.1618029113
Rolain, J.-M., Colson, P., & Raoult, D. (2007). Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. International Journal of Antimicrobial Agents, 30(4), 297–308. https://doi.org/10.1016/j.ijantimicag.2007.05.015
Rynes, R. I., & Bernstein, H. N. (1993). Ophthalmologic safety profile of antimalarial drugs. Lupus, 2 Suppl 1, S17-9. http://www.ncbi.nlm.nih.gov/pubmed/8485566
Schrezenmeier, E., & Dörner, T. (2020). Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology, 16(3), 155–166. https://doi.org/10.1038/s41584-020-0372-x
Sheahan, T. P., Sims, A. C., Leist, S. R., Schäfer, A., Won, J., Brown, A. J., Montgomery, S. A., Hogg, A., Babusis, D., Clarke, M. O., Spahn, J. E., Bauer, L., Sellers, S., Porter, D., Feng, J. Y., Cihlar, T., Jordan, R., Denison, M. R., & Baric, R. S. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications, 11(1), 222. https://doi.org/10.1038/s41467-019-13940-6
Skipper, C. P., Pastick, K. A., Engen, N. W., Bangdiwala, A. S., Abassi, M., Lofgren, S. M., Williams, D. A., Okafor, E. C., Pullen, M. F., Nicol, M. R., Nascene, A. A., Hullsiek, K. H., Cheng, M. P., Luke, D., Lother, S. A., MacKenzie, L. J., Drobot, G., Kelly, L. E., Schwartz, I. S., … Boulware, D. R. (2020).
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. Annals of Internal Medicine, 173(8), 623–631. https://doi.org/10.7326/M20-4207
Tang, W., Cao, Z., Han, M., Wang, Z., Chen, J., Sun, W., Wu, Y., Xiao, W., Liu, S., Chen, E., Chen, W., Wang, X., Yang, J., Lin, J., Zhao, Q., Yan, Y., Xie, Z., Li, D., Yang, Y., … Xie, Q. (2020).
Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ, m1849. https://doi.org/10.1136/bmj.m1849
Tett, S., Cutler, D., Day, R., & Brown, K. (1989). Bioavailability of hydroxychloroquine tablets in healthy volunteers. British Journal of Clinical Pharmacology, 27(6), 771–779.
https://doi.org/10.1111/j.1365-2125.1989.tb03439.x
The RECOVERY Collaborative Group. (2020). Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine, 383(21), 2030–2040. https://doi.org/10.1056/NEJMoa2022926
Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30(3), 269–271. https://doi.org/10.1038/s41422-020-0282-0
WHO Solidarity trial consortium. (2021). Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. New England Journal of Medicine, 384(6), 497–511. https://doi.org/https://doi.org/10.1101/2020.10.15.20209817
Winkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., Fox, J. M., Chen, R. E., Earnest, J. T., Keeler, S. P., Ritter, J. H., Kang, L.-I., Dort, S., Robichaud, A., Head, R., Holtzman, M. J., & Diamond, M. S. (2020). SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nature Immunology, 21(11), 1327–1335. https://doi.org/10.1038/s41590-020-0778-2
Wolfe, F., & Marmor, M. F. (2010). Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care & Research, 62(6), 775–784. https://doi.org/10.1002/acr.20133
World Health Organization. (2021). WHO CORONAVIRUS DISEASE (COVID-19) DASHBOARD.
Xavier, A. R., Silva, J. S., Almeida, J. P. C. L., Conceição, J. F. F., Lacerda, G. S., & Kanaan, S. (2020). COVID-19: clinical and laboratory manifestations in novel coronavirus infection. Jornal Brasileiro de Patologia e Medicina Laboratorial, 56. https://doi.org/10.5935/1676-2444.20200049
Xia, S., Zhu, Y., Liu, M., Lan, Q., Xu, W., Wu, Y., Ying, T., Liu, S., Shi, Z., Jiang, S., & Lu, L. (2020). Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cellular & Molecular Immunology, 17(7), 765–767. https://doi.org/10.1038/s41423-020-0374-2
Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., Liu, X., Zhao, L., Dong, E., Song, C., Zhan, S., Lu, R., Li, H., Tan, W., & Liu, D. (2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases, 71(15), 732–739. https://doi.org/10.1093/cid/ciaa237
Zhang, X., Wu, J., Du, F., Xu, H., Sun, L., Chen, Z., Brautigam, C. A., Zhang, X., & Chen, Z. J. (2014). The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop. Cell Reports, 6(3), 421–430. https://doi.org/10.1016/j.celrep.2014.01.003
Zhou, Q., McCracken, M. A., & Strobl, J. S. (2002). Control of Mammary Tumor Cell Growth in Vitro by Novel Cell Differentiation and Apoptosis Agents. Breast Cancer Research and Treatment, 75(2), 107–117. https://doi.org/10.1023/A:1019698807564
Zimmermann, P., Ziesenitz, V. C., Curtis, N., & Ritz, N. (2018). The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms. Frontiers in Immunology, 9. https://doi.org/10.3389/fimmu.2018.00302
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2021 Amanda Brito Silva; Beatriz Bonfadini de Sá Galbraith; Camila Lopes Rieke Borges; Daniel Pereira de Rezende Sarmento Costa; Danilo Bines; Gabriela Carreiro Kubitschek Lopes; Hannah Barboza Vianna Bekierman; Helena Ferreira Bruzzi Porto; Júlia Moraes de Andrade Seabra; Julia Vieira Santos; Michel Vladimir de Sousa Cabral ; Pedro Henrique Saugo; Victor Gonçalves de Andrade ; Pedro Leite Azevedo
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.