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Pharmacology of Chloroquine and Hydroxychloroquine

Browning, D., Pharmacology of Chloroquine and Hydroxychloroquine, 2014, 35-63, doi:10.1007/978-1-4939-0597-3_2

Apr 2014

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020

^*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

4,500+ studies for 81 treatments. c19hcq.org

Review of the pharmacology of CQ and HCQ. Some notable points:

- HCQ and CQ are equipotent but CQ is more toxic, the therapeutic ratio is higher for HCQ.
- Concentrations in different tissues can vary >10x, in particular the concentration in the lung is much higher in animal experiments.
- Tissue uptake as a function of dosage is nonlinear.

36 preclinical studies support the efficacy of HCQ for COVID-19:

10 In Silico studies1-10

23 In Vitro studies1,11-32

3 In Vivo animal studies15,24,33

Important missing comments or errors? Let us know.

1. González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.acs.org, doi.org.

2. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

3. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

4. Navya et al., A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714.sciencedirect.com, doi.org.

5. Yadav et al., Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study, Research Square, doi:10.21203/rs.3.rs-628277/v1.researchsquare.com, doi.org.

6. Hussein et al., Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979.sciencedirect.com, doi.org.

7. Baildya et al., Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891.sciencedirect.com, doi.org.

8. Noureddine et al., Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations, Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334.sciencedirect.com, doi.org.

9. Tarek et al., Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention, European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6.springer.com, doi.org.

10. Rowland Yeo et al., Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1955.wiley.com, doi.org.

11. Hitti et al., Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization, Immunology, doi:10.1111/imm.13835.wiley.com, doi.org.

12. Yan et al., Super-resolution imaging reveals the mechanism of endosomal acidification inhibitors against SARS-CoV-2 infection, ChemBioChem, doi:10.1002/cbic.202400404.wiley.com, doi.org.

13. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

14. Alsmadi et al., The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel, AAPS PharmSciTech, doi:10.1208/s12249-023-02627-3.springer.com, doi.org.

15. Wen et al., Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells, Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjad048.oup.com, doi.org.

16. Kamga Kapchoup et al., In vitro effect of hydroxychloroquine on pluripotent stem cells and their cardiomyocytes derivatives, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1128382.frontiersin.org, doi.org.

17. Milan Bonotto et al., Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection, Antiviral Research, doi:10.1016/j.antiviral.2023.105655.sciencedirect.com, doi.org.

18. Miao et al., SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells, Cell Chemical Biology, doi:10.1016/j.chembiol.2023.02.001.sciencedirect.com, doi.org.

19. Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8.nature.com, doi.org.

20. Faísca et al., Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, Pharmaceutics, doi:10.3390/pharmaceutics14040877.mdpi.com, doi.org.

21. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

22. Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.plos.org, doi.org.

23. Dang et al., Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, bioRxiv, doi:10.1101/2021.03.16.435741.biorxiv.org, doi.org.

24. Shang et al., Inhibitors of endosomal acidification suppress SARS-CoV-2 replication and relieve viral pneumonia in hACE2 transgenic mice, Virology Journal, doi:10.1186/s12985-021-01515-1.biomedcentral.com, doi.org.

25. Wang et al., Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, Phytomedicine, doi:10.1016/j.phymed.2020.153333.nih.gov, doi.org.

26. Sheaff, R., A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, bioRxiv, doi:10.1101/2020.08.02.232892.biorxiv.org, doi.org.

27. Ou et al., Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLOS Pathogens, doi:10.1371/journal.ppat.1009212.plos.org, doi.org.

28. Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:10.1016/j.micpath.2020.104228.sciencedirect.com, doi.org.

29. Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704.frontiersin.org, doi.org.

30. Liu et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0.nature.com, doi.org.

31. Yao et al., 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), Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237.oup.com, doi.org.

32. Wang (B) et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res. 30, 269–271, doi:10.1038/s41422-020-0282-0.nature.com, doi.org.

33. Shu-Han Lin et al., Inhalable Chitosan-Based Hydrogel as a Mucosal Adjuvant for Hydroxychloroquine in the Treatment for SARS-CoV-2 Infection in a Hamster Model, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2023.08.001.sciencedirect.com, doi.org.

Browning et al., 4 Apr 2014, peer-reviewed, 1 author.

This Paper HCQ All

Abstract: 2 Pharmacology of Chloroquine and Hydroxychloroquine Abbreviations 4AQR 4AQs ABW APC BCVA C CpG ODN CV CYP DFE DNA ERK FP GVF HC HIV HMG-CoA IBW IFN IL LD50 LDL M mRNA NG RA RNA RPE 4-Aminoquinoline retinopathy 4-Aminoquinolines (chloroquine and hydroxychloroquine) Actual body weight Antigen presenting cell Best corrected visual acuity Chloroquine CpG oligodeoxynucleotide Color vision Cytochrome P450 enzymes Dilated fundus examination Deoxyribonucleic acid Extracellular signal-regulated kinases Ferriprotoporphyrin IX Goldmann visual fields Hydroxychloroquine Human immunodeficiency virus 3-Hydroxy-3-methylglutarylcoenzyme A reductase Ideal body weight Interferon Interleukin Lethal dose 50 Low-density lipoprotein Mole Mitochondrial ribonucleic acid Not given Rheumatoid arthritis Ribonucleic acid Retinal pigment epithelium SARS SLE TLR TNF TNF-α V Severe acute respiratory syndrome Systemic lupus erythematosus Toll-like receptor Tumor necrosis factor Tumor necrosis factor α Volume of distribution This chapter covers the pharmacology of chloroquine and hydroxychloroquine, which is similar for both drugs [1], but the details are different. For example, both drugs are partially excreted in feces, but the proportions differ slightly—8–10 % for chloroquine and 15–24 % for hydroxychloroquine. Generally, whatever is said in this chapter about one drug can be assumed to apply to the other unless otherwise specified [1, 2]. Because both drugs are derivatives of a 4-aminoquinoline (4AQ) nucleus, they are referred to as 4AQs, and the retinopathy that they can cause is termed 4-aminoquinoline retinopathy (4AQR) [3]. Commonly used abbreviations in this chapter are collected in “Abbreviations” for reference. Each term will be first used in its full form, along with its abbreviation. 2.1 History In the 1600s, the Jesuits who proselytized Chile discovered from the Incas that the bark of the cinchona tree can cure malaria [4, 5]. Additional medicinal qualities of cinchona bark were described in the 1700s, and the British and Dutch transplanted these trees to Javan plantations in the early 1900s D.J. Browning, Hydroxychloroquine and Chloroquine Retinopathy, DOI 10.1007/978-1-4939-0597-3_2, © Springer Science+Business Media New York 2014 35 2 Pharmacology of Chloroquine and Hydroxychloroquine for the production of quinine. In 1894, Payne described the use of quinine to treat systemic lupus erythematosus (SLE) [6]. Other alkaloids contained in cinchona bark, such as pamaquine, were also successfully used to treat SLE [5]. When the Japanese army occupied Java in World War II, the natural supply of quinine was lost, and synthesis of antimalarials was pursued in the United States [7]. Quinacrine, a 9-aminoacridine compound, was first used, but had the unpleasant side effect of staining the skin and sclera yellow in a manner indistinguishable from icterus [8–10]. The 4AQs, chloroquine and hydroxychloroquine, were found to be effective as antimalarials and did not discolor the skin. Chloroquine was first synthesized in 1934 by Andersag of I.G. Farbenindustrie in a German effort to find drugs better than quinine [11]. The Germans lost interest in the drug when they judged it to be too toxic for use in man, but the Americans restudied the drug and found it to be effective against malaria and sufficiently safe [3, 7, 12]. Hydroxychloroquine was synthesized in 1946 and proposed as a safer alternative to chloroquine in 1955 [13]. Resistance to..

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J Pharmacol Exp Ther. 1962;137:156–61.', 'journal-title': 'J Pharmacol Exp Ther'}, { 'key': '2_CR92', 'doi-asserted-by': 'crossref', 'first-page': '447', 'DOI': '10.1016/0002-9343(87)90444-X', 'volume': '82', 'author': 'ML Estes', 'year': '1987', 'unstructured': 'Estes ML, Ewing-Wilson D, Chou SM, Mitsumoto H, Hanson M, Shirey E, ' 'Ratliff NM. Chloroquine neuromyotoxicity. Clinical and pathological ' 'perspective. Am J Med. 1987;82:447–55.', 'journal-title': 'Am J Med'}, { 'key': '2_CR93', 'doi-asserted-by': 'crossref', 'first-page': '631', 'DOI': '10.1007/BF02976712', 'volume': '26', 'author': 'KA Kim', 'year': '2003', 'unstructured': 'Kim KA, Park JY, Lee SJ, Lim S. Cytochrome P450 2C8 and CYP3A4/5 are ' 'involved in chloroquine metabolism in human liver microsomes. Arch Pharm ' 'Res. 2003;26:631–7.', 'journal-title': 'Arch Pharm Res'}, { 'key': '2_CR94', 'doi-asserted-by': 'crossref', 'first-page': '332', 'DOI': '10.1007/s00296-004-0442-4', 'volume': '25', 'author': 'E Ben-Chetrit', 'year': '2005', 'unstructured': 'Ben-Chetrit E, Tischel R, Hinz B, Levy M. The effects of colchicine and ' 'hydroxychloroquine on the cyclo-oxygenases COX-1 and COX-2. Rheumatol ' 'Int. 2005;25:332–5.', 'journal-title': 'Rheumatol Int'}, { 'key': '2_CR95', 'doi-asserted-by': 'crossref', 'first-page': '813', 'DOI': '10.1002/j.1552-4604.1987.tb03002.x', 'volume': '27', 'author': 'E Ette', 'year': '1987', 'unstructured': 'Ette E, Brown-Awala EA, Essien EE. Chloroquine elimination in humans: ' 'effect of low-dose cimetidine. J Clin Pharmacol. 1987;27:813–6.', 'journal-title': 'J Clin Pharmacol'}, { 'key': '2_CR96', 'first-page': '292', 'volume': '23', 'author': 'HN Bernstein', 'year': '1991', 'unstructured': 'Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol. ' '1991;23:292–6.', 'journal-title': 'Ann Ophthalmol'}, { 'key': '2_CR97', 'doi-asserted-by': 'crossref', 'first-page': '52', 'DOI': '10.1016/0002-9343(83)91271-8', 'volume': '75', 'author': 'LA Runge', 'year': '1983', 'unstructured': 'Runge LA. Risk/benefit analysis of hydroxychloroquine sulfate treatment ' 'in rheumatoid arthritis. Am J Med. 1983;75:52–6.', 'journal-title': 'Am J Med'}, { 'key': '2_CR98', 'doi-asserted-by': 'crossref', 'first-page': '1327', 'DOI': '10.1097/00007611-198810000-00033', 'volume': '81', 'author': 'WL Terrell III', 'year': '1988', 'unstructured': 'Terrell III WL, Haik KG, Haik Jr GM. Hydroxychloroquine sulfate and ' 'retinopathy. South Med J. 1988;81:1327–8.', 'journal-title': 'South Med J'}, { 'key': '2_CR99', 'doi-asserted-by': 'crossref', 'first-page': '685', 'DOI': '10.1002/art.1780200208', 'volume': '20', 'author': 'IL Dwosh', 'year': '1977', 'unstructured': 'Dwosh IL, Stein HB, Urowitz MB, Smythe HA, Hunter T, Ogryzlo MA. ' 'Azathioprine in early rheumatoid arthritis. Comparison with gold and ' 'chloroquine. Arthritis Rheum. 1977;20:685–92.', 'journal-title': 'Arthritis Rheum'}, { 'key': '2_CR100', 'doi-asserted-by': 'crossref', 'first-page': '280', 'DOI': '10.1002/art.1780130310', 'volume': '13', 'author': 'AH Mackenzie', 'year': '1970', 'unstructured': 'Mackenzie AH. An appraisal of chloroquine. Arthritis Rheum. ' '1970;13:280–91.', 'journal-title': 'Arthritis Rheum'}, { 'key': '2_CR101', 'doi-asserted-by': 'crossref', 'first-page': '81', 'DOI': '10.1001/archopht.1982.01030030083006', 'volume': '100', 'author': 'DR Tobin', 'year': '1982', 'unstructured': 'Tobin DR, Krohel G, Rynes RI. Hydroxychloroquine-seven-year experience. ' 'Arch Ophthalmol. 1982;100:81–3.', 'journal-title': 'Arch Ophthalmol'}, { 'key': '2_CR223', 'doi-asserted-by': 'crossref', 'unstructured': 'Henkind P, Rothfield NF. Ocular abnormalities in patients treated with ' 'synthetic antimalarial drugs. New Engl J Med. 1963;269:434–9.', 'DOI': '10.1056/NEJM196308292690901'}, { 'key': '2_CR102', 'doi-asserted-by': 'crossref', 'first-page': '356', 'DOI': '10.1191/0961203302lu203ra', 'volume': '11', 'author': 'Y Molad', 'year': '2002', 'unstructured': 'Molad Y, Gorshtein A, Wysenbeek AJ, Guedj D, Weinberger A, Amit-Vazina ' 'M. Protective effect of hydroxychloroquine in systemic lupus ' 'erythematosus. Prospective long-term study of an Israeli cohort. Lupus. ' '2002;11:356–61.', 'journal-title': 'Lupus'}, { 'key': '2_CR103', 'doi-asserted-by': 'crossref', 'first-page': '831', 'DOI': '10.3899/jrheum.120572', 'volume': '40', 'author': 'PS Akhavan', 'year': '2013', 'unstructured': 'Akhavan PS, Su J, Lou W, Gladman DD, Urowitz MB, Fortin PR. The early ' 'protective effect of hydroxychloroquine on the risk of cumulative damage ' 'in patients with systemic lupus erythematosus. J Rheumatol. ' '2013;40:831–41.', 'journal-title': 'J Rheumatol'}, { 'key': '2_CR104', 'doi-asserted-by': 'crossref', 'first-page': '30', 'DOI': '10.1002/art.1780050105', 'volume': '5', 'author': 'E Scull', 'year': '1962', 'unstructured': 'Scull E. Chloroquine and hydroxychloroquine therapy in rheumatoid ' 'arthritis. Arthritis Rheum. 1962;5:30–6.', 'journal-title': 'Arthritis Rheum'}, { 'key': '2_CR105', 'first-page': '182', 'volume': '77', 'author': 'AW Bagnall', 'year': '1957', 'unstructured': 'Bagnall AW. The value of chloroquine in rheumatoid disease. A four year ' 'study of continuous therapy. Can Med Assoc J. 1957;77:182–94.', 'journal-title': 'Can Med Assoc J'}, { 'key': '2_CR106', 'doi-asserted-by': 'crossref', 'first-page': '321', 'DOI': '10.1016/0002-9343(83)91211-1', 'volume': '75', 'author': 'EM Adams', 'year': '1983', 'unstructured': 'Adams EM, Yocum DE, Bell CL. Hydroxychloroquine in the treatment of ' 'rheumatoid arthritis. Am J Med. 1983;75:321–6.', 'journal-title': 'Am J Med'}, { 'key': '2_CR107', 'doi-asserted-by': 'crossref', 'first-page': '71', 'DOI': '10.1097/00000441-195322510-00012', 'volume': '225', 'author': 'GG Haydu', 'year': '1953', 'unstructured': 'Haydu GG. Rheumatoid arthritis therapy: a rationale and the use of ' 'chloroquine diphosphate. Am J Med Sci. 1953;225:71–5.', 'journal-title': 'Am J Med Sci'}, { 'key': '2_CR108', 'doi-asserted-by': 'crossref', 'first-page': '80', 'DOI': '10.1191/096120398678919778', 'volume': '7', 'author': 'E Tsakonas', 'year': '1998', 'unstructured': 'The Canadian Hydroxychloroquine Study Group, Tsakonas E, Joseph L, ' 'Esdaile JM, Choquette D, et al. A long-term study of hydroxychloroquine ' 'withdrawal on exacerbations in systemic lupus erythematosus. Lupus. 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' 'Discontinuation of antimalarial drugs in systemic lupus erythematosus. J ' 'Rheumatol. 1999;26:808–15.', 'journal-title': 'J Rheumatol'}, { 'key': '2_CR115', 'doi-asserted-by': 'crossref', 'first-page': '26', 'DOI': '10.1136/ard.41.Suppl_1.26', 'volume': '41', 'author': 'HE Paulus', 'year': '1982', 'unstructured': 'Paulus HE. An overview of benefit/risk of disease modifying treatment of ' 'rheumatoid arthritis as of today. Ann Rheum Dis. 1982;41:26–9.', 'journal-title': 'Ann Rheum Dis'}, { 'key': '2_CR116', 'doi-asserted-by': 'crossref', 'first-page': '1168', 'DOI': '10.1136/ard.2006.068676', 'volume': '66', 'author': 'GS Alarcon', 'year': '2007', 'unstructured': 'Alarcon GS, McGwin G, Bertoli AM, Fessler BJ, Calvo-Alen J, Bastian HM, ' 'Vila LM, Reveille JD. Effect of hydroxychloroquine on the survival of ' 'patients with systemic lupus erythematosus: data from LUMINA, ' 'multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66:1168–72.', 'journal-title': 'Ann Rheum Dis'}, { 'key': '2_CR117', 'doi-asserted-by': 'crossref', 'first-page': 'S4', 'DOI': '10.1177/0961203396005001031', 'volume': '5', 'author': 'R Fox', 'year': '1996', 'unstructured': 'Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune ' 'disease and prospects for drug development. Lupus. 1996;5:S4–10.', 'journal-title': 'Lupus'}, { 'key': '2_CR118', 'doi-asserted-by': 'crossref', 'first-page': '705', 'DOI': '10.1517/14740338.2011.566555', 'volume': '10', 'author': 'C Abarientos', 'year': '2011', 'unstructured': 'Abarientos C, Sperber K, Shapiro DL, Aronow WS, Chao CP, Ash JY. ' 'Hydroxychloroquine in systemic lupus erythematosus and rheumatoid ' 'arthritis and its safety in pregnancy. Expert Opin Drug Saf. ' '2011;10:705–14.', 'journal-title': 'Expert Opin Drug Saf'}, { 'key': '2_CR119', 'doi-asserted-by': 'crossref', 'first-page': '713', 'DOI': '10.1002/art.1780390502', 'volume': '39', 'author': 'American College of Rheumatology Ad Hoc Committee on Clinical Guidelines', 'year': '1996', 'unstructured': 'American College of Rheumatology Ad Hoc Committee on Clinical ' 'Guidelines. Guidelines for the management of rheumatoid arthritis. ' 'Arthritis Rheum. 1996;39:713–22.', 'journal-title': 'Arthritis Rheum'}, { 'key': '2_CR120', 'doi-asserted-by': 'crossref', 'first-page': '357', 'DOI': '10.1002/1529-0131(199902)42:2<357::AID-ANR19>3.0.CO;2-J', 'volume': '42', 'author': 'DE Furst', 'year': '1999', 'unstructured': 'Furst DE, Lindsley H, Baethge B, Botstein GR, Caldwell J, Dietz F, ' 'Ettlinger R, Golden HE, McLaughlin GE, Moreland LW, et al. Dose-loading ' 'with hydroxychloroquine improves the rate of response in early, active ' 'rheumatoid arthritis. Arthritis Rheum. 1999;42:357–65.', 'journal-title': 'Arthritis Rheum'}, { 'key': '2_CR121', 'doi-asserted-by': 'crossref', 'first-page': '729', 'DOI': '10.1002/jps.20792', 'volume': '96', 'author': 'AM Kaufmann', 'year': '2007', 'unstructured': 'Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing ' 'drugs: analysis and therapeutic implications. J Pharm Sci. ' '2007;96:729–46.', 'journal-title': 'J Pharm Sci.'}, { 'key': '2_CR122', 'doi-asserted-by': 'crossref', 'first-page': '161', 'DOI': '10.3109/03009747609165456', 'volume': '5', 'author': 'A Elman', 'year': '1976', 'unstructured': 'Elman A, Gullberg R, Nillson E, Rendahl I, Wachtmeister L. Choroquine ' 'retinopathy in patients with rheumatoid arthritis. Scand J Rheumatol. 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Impact of the revised American Academy of Ophthalmology ' 'guidelines regarding hydroxychloroquine screening on actual practice. Am ' 'J Ophthalmol. 2013;155:418–28.', 'journal-title': 'Am J Ophthalmol'}, { 'key': '2_CR126', 'doi-asserted-by': 'crossref', 'first-page': '410', 'DOI': '10.1016/j.ajo.2013.04.011', 'volume': '156', 'author': 'DJ Browning', 'year': '2013', 'unstructured': 'Browning DJ. Reply to impact of the revised American Academy of ' 'Ophthalmology guidelines regarding hydroxychloroquine screening on ' 'actual practice. Am J Ophthalmol. 2013;156:410–1.', 'journal-title': 'Am J Ophthalmol'}, { 'key': '2_CR127', 'doi-asserted-by': 'crossref', 'first-page': '1318', 'DOI': '10.1136/ard.51.12.1318', 'volume': '51', 'author': 'EF Morand', 'year': '1992', 'unstructured': 'Morand EF, McCloud PI, Littlejohn GO. Continuation of long term ' 'treatment with hydroxychloroquine in systemic lupus erythematosus and ' 'rheumatoid arthritis. 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' 'Can Med Assoc J. 1962;86:176–8.', 'journal-title': 'Can Med Assoc J.'}, { 'key': '2_CR131', 'doi-asserted-by': 'crossref', 'first-page': '132', 'DOI': '10.1097/IEB.0b013e318220f383', 'volume': '12', 'author': 'M Easterbrook', 'year': '2011', 'unstructured': 'Easterbrook M. Clinical characteristics of hydroxychloroquine ' 'retinopathy. Evid Based ophthalmol. 2011;12:132–3.', 'journal-title': 'Evid Based ophthalmol.'}, { 'key': '2_CR132', 'doi-asserted-by': 'crossref', 'first-page': '1321', 'DOI': '10.1016/S0161-6420(03)00409-3', 'volume': '110', 'author': 'I Mavrikakis', 'year': '2003', 'unstructured': 'Mavrikakis I, Sfikakis PP, Mavrikakis E, Rougas K, Nikolaou A, ' 'Kostopoulos C, Mavrikakis M. The incidence of irreversible retinal ' 'toxicity in patients treated with hydroxychloroquine—a reappraisal. 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Reflection React. 2006;6:67–8.', 'journal-title': 'Reflection React'}, { 'key': '2_CR136', 'doi-asserted-by': 'crossref', 'first-page': '738', 'DOI': '10.1016/0002-9394(68)91300-7', 'volume': '66', 'author': 'RE Carr', 'year': '1968', 'unstructured': 'Carr RE, Henkind P, Rothfield N, Siegel IM. Ocular toxicity of ' 'antimalarial drugs-long-term follow-up. Am J Ophthalmol. 1968;66:738–44.', 'journal-title': 'Am J Ophthalmol'}, { 'key': '2_CR137', 'doi-asserted-by': 'crossref', 'first-page': '579', 'DOI': '10.1136/bmj.3.5618.579', 'volume': '3', 'author': 'SPB Percival', 'year': '1968', 'unstructured': 'Percival SPB, Meanock I. Chloroquine: ophthalmological safety and ' 'clinical assessment in rheumatoid arthritis. 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J ' 'Rheumatol. 1993;20:1874–9.', 'journal-title': 'J Rheumatol'}, { 'key': '2_CR143', 'doi-asserted-by': 'crossref', 'first-page': '171', 'DOI': '10.3109/03009747809095649', 'volume': '7', 'author': 'FA Wollheim', 'year': '1978', 'unstructured': 'Wollheim FA, Hanson A, Laurell CB. Chloroquine treatment in rheumatoid ' 'arthritis. Scand J Rheumatol. 1978;7:171–6.', 'journal-title': 'Scand J Rheumatol'}, { 'key': '2_CR144', 'doi-asserted-by': 'crossref', 'first-page': '3284', 'DOI': '10.1002/art.22156', 'volume': '65', 'author': 'N Costedoat-Chalumeau', 'year': '2006', 'unstructured': 'Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hummoud HA, Aymard G, Cacoub ' 'P, Frances C, Wechsler B, et al. Low blood concentration of ' 'hydroxychloroquine is a marker for and predictor of disease ' 'exacerbations in patients with systemic lupus erythematosus. 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