Evaluating the Clinical Failure of Oral Hydroxychloroquine in SARS-CoV-2 Treatment: A Systematic Literature Review Justifying the Potential for Inhaled Delivery
DOI:
https://doi.org/10.24191/cos.v13i1.10098Keywords:
hydroxychloroquine, SARS-CoV-2, COVID-19, oral, inhaleAbstract
A systematic review was conducted to summarize the evidence regarding the administration of hydroxychloroquine (HCQ) through oral and inhalation for treating SARS-CoV-2 infection during pandemic. We limit inclusion for studies evaluating the administration of oral or inhalation of HCQ monotherapy on infected person only. Most of the treatments were given via oral delivery and no evidence on HCQ inhalation for SARS-CoV-2 infected patients. Aside from 400 mg per day is the most common HCQ treatment dosage, majority of the studies highlighted that HCQ does not significantly contribute to reduction of new incident, severity, viral shedding time and mortality when compared with control group. Further study of inhaled HCQ is needed as this route of administration could offer a promising alternative to the current oral dosing regimens, potentially improving the therapeutic outcomes and reducing the risk of toxicity for patients.
References
Abd-Elaziz, K., Oude Elberink, H., & Diamant, Z. (2020). Improved bioavailability of cromolyn sodium using inhaled PA101 delivered via eFlow® nebulizer. European Clinical Respiratory Journal, 7(1). https://doi.org/10.1080/20018525.2020.1809083
Ader, F., Peiffer-Smadja, N., Poissy, J., Bouscambert-Duchamp, M., Belhadi, D., Diallo, A., Delmas, C., Saillard, J., Dechanet, A., Mercier, N., Dupont, A., Alfaiate, T., Lescure, F. X., Raffi, F., Goehringer, F., Kimmoun, A., Jaureguiberry, S., Reignier, J., Nseir, S., … Mentré, F. (2021). An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clinical Microbiology and Infection, 27(12), 1826–1837. https://doi.org/10.1016/j.cmi.2021.05.020
Agusti, A., Guillen, E., Ayora, A., Anton, A., Aguilera, C., Vidal, X., Andres, C., Alonso, M., Espuga, M., Esperalba, J., Gorgas, Q., Almirante, B., & Ribera, E. (2022). Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial. Enferm Infecc Microbiol Clin, 40(6), 289–295. https://doi.org/10.1016/j.eimc.2020.10.023
Alavi, M., Asare-Addo, K., & Nokhodchi, A. (2020). Lectin Protein as a Promising Component to Functionalize Micelles, Liposomes and Lipid NPs against Coronavirus. Biomedicines, 8(12), 580. https://doi.org/10.3390/biomedicines8120580
Aromataris, E., Fernandez, R., Godfrey, C., Holly, C., Kahlil, H., & Tungpunkom, P. (2015). Summarizing systematic reviews: methodological development, conduct and reporting of an Umbrella review approach. Int J Evid Based Healthc, 13(3), 132–140.
Arshad, S., Kilgore, P., Chaudhry, Z. S., Jacobsen, G., Dee, D., Huitsing, K., Brar, I., Alangaden, G. J., Ramesh, M. S., Mckinnon, J. E., Neill, W. O., Zervos, M., & Task, H. F. C.-. (2020). Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. International Journal of Infectious Diseases, 97(January), 396–403.
Avezum, A., F Oliveira, G. B., Oliveira, H., Lucchetta, R. C., eria A Pereira, V. F., Dabarian, A. L., Vieira, R. DO, Silva, D. V, M Kormann, A. P., Tognon, A. P., De Gasperi, R., Hernandes, M. E., M Feitosa, A. D., Piscopo, A., Souza, A. S., Miguel, C. H., Nogueira, V. O., esar Minelli, C., Magalh, C. C., … Mota, M. (2022). Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE − Coalition V): A double-blind, multicentre, randomised, controlled trial. Lancet Reg Health Am, 11, 100243. https://doi.org/10.1016/j.lana.2022.100268
Azman, M., Sabri, A. H., Anjani, Q. K., Mustaffa, M. F., & Hamid, K. A. (2022). Intestinal Absorption Study: Challenges and Absorption Enhancement Strategies in Improving Oral Drug Delivery. Pharmaceuticals, 15(8), 1–24. https://doi.org/10.3390/ph15080975
Bansal, P., Goyal, A., Cusick, A., Lahan, S., Dhaliwal, H. S., Bhyan, P., Bhattad, P. B., Aslam, F., Ranka, S., Dalia, T., Chhabra, L., Sanghavi, D., Sonani, B., & Davis, J. M. (2021). Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019. Annals of Medicine, 53(1), 117–134. https://doi.org/10.1080/07853890.2020.1839959
Barnabas, R. V., Brown, E. R., Bershteyn, A., Karita, H. C. S., Johnston, C., Thorpe, L. E., Kottkamp, A., Neuzil, K. M., Laufer, M. K., Deming, M., Paasche-Orlow, M. K., Kissinger, P. J., Luk, A., Paolino, K., Landovitz, R. J., Hoffman, R., Schaafsma, T. T., Krows, M. L., Thomas, K. K., … Baeten, J. M. (2021). Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Randomized Trial. Annals of Internal Medicine, 174(3), 344–352. https://doi.org/10.7326/M20-6519
Barratt-Due, A., Olsen, I. C., Nezvalova-Henriksen, K., Kåsine, T., Lund-Johansen, F., Hoel, H., Holten, A. R., Tveita, A., Mathiessen, A., Haugli, M., Eiken, R., Kildal, A. B., Berg, Å., Johannessen, A., Heggelund, L., Dahl, T. B., Skåra, K. H., Mielnik, P., Le, L. A. K., … Aukrust, P. (2021). Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial. Annals of Internal Medicine, 174(9), 1261–1269. https://doi.org/10.7326/M21-0653
Bentur, O., Hutt, R., Brassil, D., Bäckman, P., Gonda, I., Boushey, H., Cahrous, B., Coller, B., & MacArthur, R. (2021). Phase 1 Randomized Placebo-Controlled Study in Healthy Adult Volunteers to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Inhaled Aerosolized Hydroxychloroquine Sulfate – A Potential Treatment for COVID-19. The Journal of Allergy and Clinical Immunology, 147(2), AB237. https://doi.org/10.1016/J.JACI.2020.12.011
Bentur, O. S., Hutt, R., Brassil, D., Kriegegr, A. C., Bäckman, P., Charous, B. L., Boushey, H., Gonda, I., Coller, B. S., & MacArthur, R. B. (2023). Preclinical and Human Phase 1 Studies of Aerosolized Hydroxychloroquine: Implications for Antiviral COVID-19 Therapy. MedRxiv, 2023.06.22.23291702. https://doi.org/10.1101/2023.06.22.23291702
Bitaraf, E., Ahmadi, S. A. Y., Gandomi-Mohammadabadi, A., Noorani Mejareh, Z., Abdollahi, B., Balasi, J., Moodi, F., Hemmati, N., & Kabir, A. (2021). Effects of Immune System-Related Medications on COVID-19 Outcome in a Cohort of Iranian Patients: Preliminary Report of a Data Mining Study. Journal of Immunology Research, 2021. https://doi.org/10.1155/2021/9934134
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
Catteau, L., Dauby, N., Montourcy, M., Bottieau, E., Hautekiet, J., Goetghebeur, E., Van Ierssel, S., Duysburgh, E., Van Oyen, H., Wyndham-Thomas, C., Van Beckhoven, D., Collaborative, B., On Covid-19, G., Surveillance, H., Bafort, K., Belkhir, L., Bossuyt, N., Caprasse, P., Colombie, V.-C., … Mokrane, S. (2020). Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants. International Journal of Antimicrobial Agents, 56, 106144. https://doi.org/10.1016/j.ijantimicag.2020.106144
Cavalcanti, A. B., Zampieri, F. G., Rosa, R. G., Azevedo, L. C. P., Veiga, V. C., Avezum, A., Damiani, L. P., Marcadenti, A., Kawano-Dourado, L., Lisboa, T., Junqueira, D. L. M., de Barros e Silva, P. G. M., Tramujas, L., Abreu-Silva, E. O., Laranjeira, L. N., Soares, A. T., Echenique, L. S., Pereira, A. J., Freitas, F. G. R., … Berwanger, O. (2020). Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. New England Journal of Medicine, 383(21), 2041–2052. https://doi.org/10.1056/nejmoa2019014
Chen, C.-P., Lin, Y.-C., Chen, T.-C., Tseng, T.-Y., Wong, H.-L., Kuo, C.-Y., Lin, W.-P., Huang, S.-R., Wang, W.-Y., Liao, J.-H., Liao, C.-S., Hung, Y.-P., Lin, T.-H., Chang, T.-Y., Hsiao, C.-F., Huang, Y.-W. I., Chung, W.-S., Cheng, C.-Y., & Cheng, S.-H. I. (2020). A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). PLoS ONE, 15(12), e0242763. https://doi.org/10.1371/journal.pone.0242763
Chen, X., & Geiger, J. D. (2020). Janus sword actions of chloroquine and hydroxychloroquine against COVID-19. Cellular Signalling, 73, 109706. https://doi.org/10.1016/J.CELLSIG.2020.109706
Choi, M. J., Kang, M., Shin, S. Y., Noh, J. Y., Cheong, H. J., Kim, W. J., Jung, J., & Song, J. Y. (2021). Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study. International Journal of Infectious Diseases, 102, 275–281. https://doi.org/10.1016/j.ijid.2020.10.062
Costedoat-Chalumeau, N., Dunogué, B., Leroux, G., Morel, N., Jallouli, M., Le Guern, V., Piette, J. C., Brézin, A. P., Melles, R. B., & Marmor, M. F. (2015). A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye. Clinical Reviews in Allergy and Immunology, 49(3), 317–326. https://doi.org/10.1007/s12016-015-8469-8
de Reus, Y. A., Hagedoorn, P., Sturkenboom, M. G. G., Grasmeijer, F., Bolhuis, M. S., Sibum, I., Kerstjens, H. A. M., Frijlink, H. W., & Akkerman, O. W. (2022). Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers. PLoS ONE, 17(8 August), 1–12. https://doi.org/10.1371/journal.pone.0272034
Derendorf, H. (2020). Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin. International Journal of Antimicrobial Agents, 55(6), 106007. https://doi.org/10.1016/J.IJANTIMICAG.2020.106007
Dhanani, J., Taniguchi, L. U., & Ranzani, O. T. (2022). Optimising aerosolized therapies in critically ill patients. Intensive Care Medicine, 48(10), 1418–1421. https://doi.org/10.1007/s00134-022-06800-3
Eedara, B. B., Alabsi, W., Encinas-Basurto, D., Polt, R., Ledford, J. G., & Mansour, H. M. (2021). Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection. Pharmaceutics, 13(7). https://doi.org/10.3390/PHARMACEUTICS13071077
Estenssoro, E., Loudet, C. I., & Dubin, A. (2022). Clinical characteristics , respiratory management , and determinants of oxygenation in COVID-19 ARDS : A prospective cohort study. Journal of Critical Care, 71(15401).
Fabbri, L. M., Piattella, M., Caramori, G., & Ciaccia, A. (1996). Oral vs inhaled asthma therapy. Pros, cons and combinations. Drugs, 52(SUPPL. 6), 20–28. https://doi.org/10.2165/00003495-199600526-00005
Fan, H. wei, Ma, Z. xiang, Chen, J., Yang, X. ye, Cheng, J. lin, & Li, Y. bin. (2015). Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC–MS/MS. Rheumatology and Therapy, 2(2), 183–195. https://doi.org/10.1007/s40744-015-0012-0
Fassihi, S. C., Nabar, N. R., & Fassihi, R. (2020). Novel approach for low-dose pulmonary delivery of hydroxychloroquine in COVID-19. British Journal of Pharmacology, 177(21), 4997–4998. https://doi.org/10.1111/BPH.15167
Fernandez-Ruiz, R., Bornkamp, N., Kim, M. Y., Askanase, A., Zezon, A., Tseng, C. E., Belmont, H. M., Saxena, A., Salmon, J. E., Lockshin, M., Buyon, J. P., & Izmirly, P. M. (2020). Discontinuation of hydroxychloroquine in older patients with systemic lupus erythematosus: A multicenter retrospective study. Arthritis Research and Therapy, 22(1), 1–9. https://doi.org/10.1186/s13075-020-02282-0
Furst, D. E. (1996). Pharmacokinetics of hydroxychloroquine and chloroquine during. Lupus, 5(Suppl.1), 11–15.
Gao, Y., Wang, W., Yue, X., Wang, G., Zhang, K., Wu, C., Zhao, Z., Huang, Z., & Zhang, X. (2025). Inhalable nanoparticle-based delivery systems for the treatment of pulmonary infections: Status quo and barrier-overcoming strategies. Drug Delivery, 32(1), 2544683. https://doi.org/10.1080/10717544.2025.2544683
Giridhar Reddy, S. (2021). Controlled release studies of hydroxychloroquine sulphate (Hcq) drug-using biodegradable polymeric sodium alginate and lignosulphonic acid blends. Rasayan Journal of Chemistry, 14(4), 2209–2215. https://doi.org/10.31788/RJC.2021.1446508
Govender, M., & Choonara, Y. E. (2025). Drug Delivery Systems for Respiratory Diseases: Insights into the Therapeutic Innovations for Pulmonary Administration. Pharmaceutics 2025, Vol. 17, 17(5). https://doi.org/10.3390/PHARMACEUTICS17050539
Hasöksüz, M., Kiliç, S., & Saraç, F. (2020). Coronaviruses and sars-cov-2. In Turkish Journal of Medical Sciences (Vol. 50, Number SI-1, pp. 549–556). Turkiye Klinikleri. https://doi.org/10.3906/sag-2004-127
Hawari, F., Dodin, Y., Tayyem, R., Najjar, S., Kakish, H., Fara, M. A., Zou’bi, A. Al, & Idkaidek, N. (2023). Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 36(2), 76–81. https://doi.org/10.1089/JAMP.2022.0062
He, S., Gui, J., Xiong, K., Chen, M., Gao, H., & Fu, Y. (2022). A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. Journal of Nanobiotechnology, 20(1), 1–22. https://doi.org/10.1186/S12951-022-01307-X/TABLES/1
Hernandez-Cardenas, C., Thirion-Romero, I., Rodríguez-Llamazares, S., Rivera-Martinez, N. E., Meza-Meneses, P., Remigio-Luna, A., Perez-Padilla, R., Jurado-Camacho, L. F., Aguirre-Pérez, T., Vásquez-Pérez, J. A., Ramirez-Venegas, A., Tapia-Pastrana, G., & Cruz-Ruiz, N. G. (2021). Hydroxychloroquine for the treatment of severe respiratory infection by COVID-19: A randomized controlled trial. PLoS ONE, 16(9 September), 1–15. https://doi.org/10.1371/journal.pone.0257238
Homayun, B., Lin, X., & Choi, H. J. (2019). Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics, 11(3). https://doi.org/10.3390/pharmaceutics11030129
Hooks, M., Bart, B., Vardeny, O., Westanmo, A., & Adabag, S. (2020). Effects of hydroxychloroquine treatment on QT interval. Heart Rhythm, 17(11), 1930. https://doi.org/10.1016/J.HRTHM.2020.06.029
Hu, G., & Christman, J. W. (2019). Editorial: Alveolar macrophages in lung inflammation and resolution. Frontiers in Immunology, 10(SEP), 493829. https://doi.org/10.3389/FIMMU.2019.02275/TEXT
Hua, S. (2020). Advances in Oral Drug Delivery for Regional Targeting in the Gastrointestinal Tract - Influence of Physiological, Pathophysiological and Pharmaceutical Factors. Frontiers in Pharmacology, 11(April), 1–22. https://doi.org/10.3389/fphar.2020.00524
Idkaidek, N., Hawari, F., Dodin, Y., & Obeidat, N. (2021). Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients. Drug Research, 71(5), 250–256. https://doi.org/10.31083/J.RCM.2020.04.264
Johnston, C., Brown, E. R., Stewart, J., Stankiewicz Karita, H. C., Kissinger, P. J., Dwyer, J., Hosek, S., Oyedele, T., Paasche-Orlow, M. K., Paolino, K., Heller, K. B., Leingang, H., Haugen, H. S., Dong, T. Q., Bershteyn, A., Sridhar, A. R., Poole, J., Noseworthy, P. A., Ackerman, M. J., … Stroger, J. H. (2021). Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial. EClinicalMedicine, 33, 100773. https://doi.org/10.1016/j.eclinm.2021.100773
Jorge, A. M., Melles, R. B., Zhang, Y., Lu, N., Rai, S. K., Young, L. H., Costenbader, K. H., Ramsey-Goldman, R., Lim, S. S., Esdaile, J. M., Clarke, A. E., Urowitz, M. B., Askanase, A., Aranow, C., Petri, M., & Choi, H. (2018). Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. Arthritis Research and Therapy, 20(1), 4–11. https://doi.org/10.1186/s13075-018-1634-8
Kavanagh, O., Marie Healy, A., Dayton, F., Robinson, S., O’Reilly, N. J., Mahoney, B., Arthur, A., Walker, G., & Farragher, J. P. (2020). Inhaled hydroxychloroquine to improve efficacy and reduce harm in the treatment of COVID-19. Medical Hypotheses, 143, 110110. https://doi.org/10.1016/J.MEHY.2020.110110
Khamis, F., Al Naabi, H., Al Lawati, A., Ambusaidi, Z., Al Sharji, M., Al Barwani, U., Pandak, N., Al Balushi, Z., Al Bahrani, M., Al Salmi, I., & Al-Zakwani, I. (2020). Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia. International Journal of Infectious Diseases, 102, 275–281. https://doi.org/10.1016/j.ijid.2020.11.008
Klimke, A., Hefner, G., Will, B., & Voss, U. (2020). Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection. Medical Hypotheses, 142, 109783. https://doi.org/10.1016/j.mehy.2020.109783
Kolli, A. R., Calvino-Martin, F., & Hoeng, J. (2022). Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections. Pharmaceutical Research, 39(1), 57–73. https://doi.org/10.1007/s11095-021-03152-3
Kolli, A. R., Semren, T. Z., Bovard, D., Majeed, S., Van Der Toorn, M., Scheuner, S., Guy, P. A., Kuczaj, A., Mazurov, A., Frentzel, S., Calvino-Martin, F., Ivanov, N. V, O’mullane, J., Peitsch, M. C., & Hoeng, J. (2022). Pulmonary Delivery of Aerosolized Chloroquine and Hydroxychloroquine to Treat COVID-19: In Vitro Experimentation to Human Dosing Predictions. The AAPS Journal, 24(1). https://doi.org/10.1208/s12248-021-00666-x
Liu, C., Liu, Y., Xi, L., He, Y., Liang, Y., Mak, J. C. W., Mao, S., Wang, Z., & Zheng, Y. (2023). Interactions of Inhaled Liposome with Macrophages and Neutrophils Determine Particle Biofate and Anti-Inflammatory Effect in Acute Lung Inflammation. ACS Applied Materials & Interfaces, 15(1), 479–493. https://doi.org/10.1021/ACSAMI.2C17660
Maheshwari, R., Kuche, K., Mane, A., Chourasiya, Y., Tekade, M., & Tekade, R. K. (2018). Manipulation of Physiological Processes for Pharmaceutical Product Development. In Dosage Form Design Considerations: Volume I (pp. 701–729). Elsevier. https://doi.org/10.1016/B978-0-12-814423-7.00020-4
McDonnell, M., Suleem, I., Rutherford, R., O’Regan, A., & Gilmartin, J. J. (2011). Experience of hydroxychloroquine in the treatment of pulmonary sarcoidosis in the west of Ireland: An insight into clinical practice. European Respiratory Journal, 38(Suppl 55).
Merad, M., & Martin, J. C. (2020). Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nature Reviews Immunology, 20(6), 355–362. https://doi.org/10.1038/s41577-020-0331-4
Minutello, K., & Gupta, V. (2022, January 12). Cromolyn Sodium. StatPearls Publishing. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557473/
Mitjà, O., Corbacho-Monné, M., Ubals, M., Alemany, A., Suñer, C., Tebé, C., Tobias, A., Peñafiel, J., Ballana, E., Pérez, C. A., Admella, P., Riera-Martí, N., Laporte, P., Mitjà, J., Clua, M., Bertran, L., Sarquella, M., Gavilán, S., Ara, J., … Clotet, B. (2021). A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. The New England Journal of Medicine, 384(5), 417–427. https://doi.org/10.1056/NEJMOA2021801
Mitjà, O., Corbacho-Monné, M., Ubals, M., Tebé, C., Peñafiel, J., Tobias, A., Ballana, E., Alemany, A., Riera-Martí, N., Pérez, C. A., Suñer, C., Laporte, P., Admella, P., Mitjà, J., Clua, M., Bertran, L., Sarquella, M., Gavilán, S., Ara, J., … Vall-Mayans, M. (2020). Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized- Controlled Trial. Clin Infect Dis, 54(650), 1–54.
Mubagwa, K. (2020). Cardiac effects and toxicity of chloroquine: a short update. International Journal of Antimicrobial Agents, 56(2). https://doi.org/10.1016/j.ijantimicag.2020.106057
Nagaraja, B. S., Ramesh, K. N., Dhar, D., Mondal, M. S., Dey, T., Saha, S., Khan, M. A., Rutul, S. D., Pratik, K., Manjula, J., Sangeeth, T. A., & Singh, V. (2020). HyPE study: hydroxychloroquine prophylaxis-related adverse events’ analysis among healthcare workers during COVID-19 pandemic: a rising public health concern. Journal of Public Health (Oxford, England), 42(3), 493–503. https://doi.org/10.1093/PUBMED/FDAA074
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Journal of Clinical Epidemiology, 134, 178–189. https://doi.org/10.1016/j.jclinepi.2021.03.001
Pastick, K. A., Okafor, E. C., Wang, F., Lofgren, S. M., Skipper, C. P., Nicol, M. R., Pullen, M. F., Rajasingham, R., McDonald, E. G., Lee, T. C., Schwartz, I. S., Kelly, L. E., Lother, S. A., Mitjà, O., Letang, E., Abassi, M., & Boulware, D. R. (2020). Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infectious Diseases, 7(4), 1–9. https://doi.org/10.1093/ofid/ofaa130
Patel, M. R., Patel, R. B., & Thakore, S. D. (2018). Nanoemulsion in drug delivery. Applications of Nanocomposite Materials in Drug Delivery, 667–700. https://doi.org/10.1016/B978-0-12-813741-3.00030-3
Perinel, S., Launay, M., Botelho-Nevers, É., Diconne, É., Louf-Durier, A., Lachand, R., Murgier, M., Page, D., Vermesch, R., Thierry, G., & Delavenne, X. (2020). Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients. Clinical Infectious Diseases, 71(16), 2227–2229. https://doi.org/10.1093/CID/CIAA394
Prasad Dhibar, D., Arora, N., Chaudhary, D., Prakash, A., Medhi, B., Singla, N., Mohindra, R., Suri, V., Bhalla, A., Sharma, N., Singh, M. P., Lakshmi, P. V. M., Goyal, K., & Ghosh, A. (123 C.E.). The “myth of Hydroxychloroquine (HCQ) as post-exposure prophylaxis (PEP) for the prevention of COVID-19” is far from reality. Scientific Reports, 13, 378. https://doi.org/10.1038/s41598-022-26053-w
Reis, G., Moreira Silva, E. A. D. S., Medeiros Silva, D. C., Thabane, L., Singh, G., Park, J. J. H., Forrest, J. I., Harari, O., Quirino Dos Santos, C. V., Guimarães De Almeida, A. P. F., Figueiredo Neto, A. D. De, Savassi, L. C. M., Milagres, A. C., Teixeira, M. M., Simplicio, M. I. C., Ribeiro, L. B., Oliveira, R., & Mills, E. J. (2021). Effect of Early Treatment with Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization among Patients with COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Network Open, 4(4), 1–14. https://doi.org/10.1001/jamanetworkopen.2021.6468
Sagoschen, I., Keller, K., Wild, J., Münzel, T., & Hobohm, L. (2022). Case Fatality of Hospitalized Patients with COVID-19 Infection Suffering from Acute Respiratory Distress Syndrome in Germany. Viruses, 14(11), 2515. https://doi.org/10.3390/v14112515
Schwartz, I., Boesen, M. E., Cerchiaro, G., Doram, C., Edwards, B. D., Ganesh, A., Greenfield, J., Jamieson, S., Karnik, V., Kenney, C., Lim, R., Menon, B. K., Mponponsuo, K., Rathwell, S., Ryckborst, K. J., Stewart, B., Yaskina, M., Metz, L., Richer, L., … Collaborators, A. H. C.-19. (2021). Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial. CMAJ Open, 9(2), E693–E702. https://doi.org/10.9778/cmajo.20210069
Self, W. H., Semler, M. W., Leither, L. M., Casey, J. D., Angus, D. C., Brower, R. G., Chang, S. Y., Collins, S. P., Eppensteiner, J. C., Filbin, M. R., Files, D. C., Gibbs, K. W., Ginde, A. A., Gong, M. N., Harrell, F. E., Hayden, D. L., Hough, C. L., Johnson, N. J., Khan, A., … Brown, S. M. (2020). Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients with COVID-19: A Randomized Clinical Trial. JAMA - Journal of the American Medical Association, 324(21), 2165–2176. https://doi.org/10.1001/jama.2020.22240
Shaaban, W., Hammoud, M., Abdulraheem, A., Elsayed, Y. Y., & Alkazemi, N. (2021). Hydroxychloroquine, a successful treatment for lung disease in ABCA3 deficiency gene mutation: a case report. Journal of Medical Case Reports, 15(1). https://doi.org/10.1186/S13256-020-02604-5
Singh, T. U., Parida, S., Lingaraju, M. C., Kesavan, M., Kumar, D., & Singh, R. K. (2020). Drug repurposing approach to fight COVID-19. Pharmacological Reports, 72(6), 1479–1508. https://doi.org/10.1007/s43440-020-00155-6
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: A randomized trial. Annals of Internal Medicine, 173(8), 623–631. https://doi.org/10.7326/M20-4207
Taher, M., Shaari, S. S., & Susanti, D. (2021). Potential Nanospray Inhalation of Remdesivir and Hydroxychloroquine using Poly (lactic-co-glycolic) Acid as Fast Delivery for Covid-19 Treatment. Journal of Pharmacy , 1(1), 34–44. https://doi.org/10.31436/JOP.V1I1.50
Tai, T. T., Wu, T. J., Wu, H. D., Tsai, Y. C., Wang, H. T., Wang, A. M., Shih, S. F., & Chen, Y. C. (2021). A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study. Clinical and Translational Science, 14(1), 132–136. https://doi.org/10.1111/cts.12923
Tai, W., Chow, M. Y. T., Chang, R. Y. K., Tang, P., Gonda, I., Macarthur, R. B., Chan, H. K., & Kwok, P. C. L. (2021). Nebulised isotonic hydroxychloroquine aerosols for potential treatment of covid-19. Pharmaceutics, 13(8). https://doi.org/10.3390/pharmaceutics13081260
Tai, W., He, L., Zhang, X., Pu, J., Voronin, D., Jiang, S., Zhou, Y., & Du, L. (2020). ARTICLE Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cellular & Molecular Immunology, 17, 613–620. https://doi.org/10.1038/s41423-020-0400-4
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, 369. https://doi.org/10.1136/BMJ.M1849
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
Ucan, A., Cerci, P., Efe, S., Akgun, H., Ozmen, A., Yagmuroglu, A., Bilgin, M., & Avci, D. (2020). Benefits of treatment with favipiravir ıin hospitalized patients for COVID-19: a retrospective observational case-control study. Virol J, 18, 102. https://doi.org/10.1186/s12985-021-01577-1
Villa Zapata, L., Boyce, R. D., Chou, E., Hansten, P. D., Horn, J. R., Gephart, S. M., Subbian, V., Romero, A., & Malone, D. C. (2022). QTc Prolongation with the Use of Hydroxychloroquine and Concomitant Arrhythmogenic Medications: A Retrospective Study Using Electronic Health Records Data. Drugs - Real World Outcomes, 9(3), 415–423. https://doi.org/10.1007/s40801-022-00307-5
Wang, B., Wang, L., Yang, Q., Zhang, Y., Qinglai, T., Yang, X., Xiao, Z., Lei, L., & Li, S. (2024). Pulmonary inhalation for disease treatment: Basic research and clinical translations. Materials Today Bio, 25, 100966. https://doi.org/10.1016/J.MTBIO.2024.100966
Xu, X., Chen, P., Wang, J., Feng, J., Zhou, H., Li, X., Zhong, W., & Hao, P. (2020). Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. 63(3), 457–460. https://doi.org/10.1007/s11427-020-1637-5
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
Yavuz, S., Alsamhouri, R., & Francis, N. (2021). Childhood Interstitial Lung Disease Masquerading as Post COVID-19 Respiratory Distress. Cureus, 13(11). https://doi.org/10.7759/CUREUS.20061
Yetkin, E., Yalta, K., & Waltenberger, J. (2020). An antiarrhythmic approach to hydroxychloroquine-induced QT prolongation. Netherlands Heart Journal, 28(7–8), 437–438. https://doi.org/10.1007/s12471-020-01464-4
Zhou, L., Ayeh, S. K., Chidambaram, V., & Karakousis, P. C. (2021). Modes of transmission of SARS-CoV-2 and evidence for preventive behavioral interventions. BMC Infectious Diseases, 21(1), 1–9. https://doi.org/10.1186/s12879-021-06222-4
Zhou, P., Yang, X. Lou, Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., Chen, H. D., Chen, J., Luo, Y., Guo, H., Jiang, R. Di, Liu, M. Q., Chen, Y., Shen, X. R., Wang, X., … Shi, Z. L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273. https://doi.org/10.1038/s41586-020-2012-7
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Compendium of Oral Science

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Materials contained in the journal may be reproduced for educational purposes provided that both the author(s) and the journal are appropriately recognised; otherwise duplication is not permitted. No articles, reports, or portions there of may be translated into other languages, published in books, journals, magazines, or any other print form without written permission from the authors and from the journal.
Disclaimer: The statements, opinions and data expressed in the articles and reports herein are those of the author(s) and not of the publisher and the editor(s). The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any schemes, methods, instructions or ideas referred to in the content.









