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Toxicology of Hydroxychloroquine and Chloroquine and the Pathology of the Retinopathy They Cause

  • David J. Browning
Chapter

Abstract

The 4-aminoquinolines are predictably toxic at high enough concentrations. Toxicity in all tissues derives from derangement of lysosomal function and is dose dependent. Chloroquine is more toxic than hydroxychloroquine. The sensitivity of different cell types varies, but all cells exhibiting toxic effects accumulate myelin bodies.

Keywords

Ganglion Cell Retinal Pigment Epithelium Retinal Pigment Epithelium Cell Ideal Body Weight Autophagic Vacuole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ABW

Actual body weight

4AQs

4-Aminoquinolines (chloroquine and hydroxychloroquine)

4AQR

4-Aminoquinoline retinopathy

A2E

N-retinylidene-N-retinylethanolamine

C

Chloroquine

C-tubes

Curvilinear tubules

d

Day

ED50

Effective dose 50

EOG

Electrooculogram

ERG

Electroretinogram

GCL

Ganglion cell layer

g

Gram

HC

Hydroxychloroquine

IBW

Ideal body weight

IM

Intramuscular

INL

Inner nuclear layer

IP

Intraperitoneal

IPL

Inner plexiform layer

IV

Intravenous

kg

Kilogram

L

Liter

LD50

Lethal dose 50

M

Mole

MCB

Membranous cytoplasmic body

mfERG

Multifocal electroretinography

mg

Milligram

μM

Micromoles/L

nm

Nanometer

NSAID

Nonsteroidal anti-inflammatory drug

PR

Photoreceptor

RA

Rheumatoid arthritis

RPE

Retinal pigment epithelium

TD50

Toxic dose 50

References

  1. 1.
    Carr RE, Henkind P, Rothfield N, Siegel IM. Ocular toxicity of antimalarial drugs-long-term follow-up. Am J Ophthalmol. 1968;66:738–44.PubMedGoogle Scholar
  2. 2.
    Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: Is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease? Am J Ophthalmol. 2001;131:761–6.PubMedGoogle Scholar
  3. 3.
    Jones SK. Ocular toxicity and hydroxychloroquine: guidelines for screening. Br J Dermatol. 1999;140:3–7.PubMedGoogle Scholar
  4. 4.
    Bacon P, Spalton DJ, Smith SE. Blindness from quinine toxicity. Br J Ophthalmol. 1988;72:219–24.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Canning CR, Hague S. Ocular quinine toxicity. Br J Ophthalmol. 1988;72:23–6.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Thompson PE, Webel LM. 4-Aminoquinolines. Antimalarial agents. 1972;150–196.Google Scholar
  7. 7.
    Banks CN. Melanin: blackguard or red herring? Another look at chloroquine retinopathy. Aust N Z J Ophthalmol. 1987;15:365–70.PubMedGoogle Scholar
  8. 8.
    Shearer RV, Dubois EL. Ocular changes induced by long-term hydroxychloroquine (Plaquenil) therapy. Am J Ophthalmol. 1967;64:245–52.PubMedGoogle Scholar
  9. 9.
    Browning DJ. Bull's-eye maculopathy associated with quinacrine therapy for malaria. Am J Ophthalmol. 2004;137:577–9.PubMedGoogle Scholar
  10. 10.
    Rothfield N. Efficacy of antimalarials in systemic lupus erythematosus. Am J Med. 1988;85:53–6.PubMedGoogle Scholar
  11. 11.
    Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol. 2012;8:522–33.PubMedGoogle Scholar
  12. 12.
    Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells. Invest Ophthalmol Vis Sci. 2010;51:6030–7.PubMedGoogle Scholar
  13. 13.
    McChesney EQ, Fitch CD. 4-Aminoquinolines. In: Peters W, Richards WHG, editors. Antimalarial drugs II. Current antimalarials and new drug developments. Berlin: Springer; 1984. p. 3–60.Google Scholar
  14. 14.
    Mackenzie AH. An appraisal of chloroquine. Arthritis Rheum. 1970;13:280–91.PubMedGoogle Scholar
  15. 15.
    Tett S, Cutler D, Day R. Antimalarials in rheumatic diseases. Baillieres Clin Rheumatol. 1990;4:467–89.PubMedGoogle Scholar
  16. 16.
    Cann HM, Verhulst HL. Fatal acute chloroquine poisoning in children. Pediatrics. 1961;27:95–102.PubMedGoogle Scholar
  17. 17.
    Titus EO. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit. 1989;11:369–79.PubMedGoogle Scholar
  18. 18.
    Frisk-Holmberg M, Bergkvist Y, Domeij-Nyberg B, Hellstrom L, Jansson R. Chloroquine serum concentration and side effects: evidence for dose dependent kinetics. Clin Pharmacol Ther. 1979;25:345–50.PubMedGoogle Scholar
  19. 19.
    Munster T, Gibbs JP, Shen D, Baethge BA, Botstein GR, Caldwell J, Dietz F, Ettlinger R, Golden HE, Lindsley H, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46:1460–9.PubMedGoogle Scholar
  20. 20.
    Laaksonen AL, Koskiahde V, Juva K. Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. A clinical study with determination of serum concentrations of chloroquine and hydroxychloroquine. Scand J Rheumatol. 1974;3:103–8.PubMedGoogle Scholar
  21. 21.
    Frisk-Holmberg M, Bergqvist Y. Chloroquine disposition in man. Br J Clin Pharmacol. 1982;14:624P–6.Google Scholar
  22. 22.
    Abraham R, Hendy RJ. Irreversible lysosomal damage induced by chloroquine in the retinae of pigmented and albino rats. Exp Mol Pathol. 1970;12:185–200.PubMedGoogle Scholar
  23. 23.
    Bruce-Chwatt LJ. Chloroquine blindness? Lancet. 1968;2:1039.PubMedGoogle Scholar
  24. 24.
    Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2002;109:1377–82.PubMedGoogle Scholar
  25. 25.
    Marmor MF. New American Academy of Ophthalmology recommendations on screening for hydroxychloroquine retinopathy. Arthritis Rheum. 2003;48:1764–70.PubMedGoogle Scholar
  26. 26.
    Schwartz SG, Mieler WF. Retinal and choroidal manifestations of systemic medications. In: Arevalo JF, editor. Retinal and choroidal manifestations of selected systemic diseases. New York: Springer; 2013. p. 479–92.Google Scholar
  27. 27.
    Missner S, Kellner U. Comparison of different screening methods for chloroquine/ hydroxychloroquine retinopathy: multifocal electroretinography, color vision, perimetry, ophthalmoscopy, and fluorescein angiography. Graefes Arch Clin Exp Ophthalmol. 2012;250:319–25.PubMedGoogle Scholar
  28. 28.
    Fung AE, Samy CN, Rosenfeld PJ. Optical coherence tomography findings in hydroxychloroquine and chloroquine-associated maculopathy. Retinal Cases Brief Rep. 2007;1:128–30.Google Scholar
  29. 29.
    Labriola LT, Jeng D, Fawzi AA. Retinal toxicity of systemic medications. Int Ophthalmol Clin. 2012;52:149–66.PubMedGoogle Scholar
  30. 30.
    Ehrenfeld M, Nesher R, Merin S. Delayed-onset chloroquine retinopathy. Br J Ophthalmol. 1986;70:281–3.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Mackenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983;75:40–5.PubMedGoogle Scholar
  32. 32.
    Fleck BW, Bell AL, Mitchell JD, Thomson BJ, Hurst NP, Nuki G. Screening for antimalarial maculopathy in rheumatology clinics. Br Med J. 1985;291:782–5.Google Scholar
  33. 33.
    Cox NH, Paterson WD. Ocular toxicity of antimalarials in dermatology: a survey of current practice. Br J Dermatol. 1994;131:878–82.PubMedGoogle Scholar
  34. 34.
    Elman A, Gullberg R, Nillson E, Rendahl I, Wachtmeister L. Chloroquine retinopathy in patients with rheumatoid arthritis. Scand J Rheumatol. 1975;5:161–6.Google Scholar
  35. 35.
    Easterbrook M. Ocular effects and safety of antimalarial agents. Am J Med. 1988;85:23–9.PubMedGoogle Scholar
  36. 36.
    Scherbel AL. Use of synthetic antimalarial drugs and other agents for rheumatoid arthritis: historic and therapeutic perspectives. Am J Med. 1983;75:1–4.PubMedGoogle Scholar
  37. 37.
    Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS. 2002;110:481–9.PubMedGoogle Scholar
  38. 38.
    Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011;129:30–9.PubMedGoogle Scholar
  39. 39.
    Browning DJ. Hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity. Am J Ophthalmol. 2002;133:649–56.PubMedGoogle Scholar
  40. 40.
    Levy GD, Munz SJ, Paschal J, Cohen HB, Prince KJ, Peterson T. Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. 1997;40:1482–6.PubMedGoogle Scholar
  41. 41.
    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. Ophthalmology. 2003;110:1321–6.PubMedGoogle Scholar
  42. 42.
    Lai TYY, Chan WM, Li H, Lai RYK, Lam DSC. Multifocal electroretinographic changes in patients receiving hydroxychloroquine therapy. Am J Ophthalmol. 2005;140:794–807.PubMedGoogle Scholar
  43. 43.
    Albert DA, Debois LKL, Lu KF. Antimalarial ocular toxicity, a critical appraisal. J Clin Rheumatol. 1998;4:57–62.PubMedGoogle Scholar
  44. 44.
    Mackenzie AH. Antimalarial drugs for rheumatoid arthritis. Am J Med. 1983;75:48–58.PubMedGoogle Scholar
  45. 45.
    Maksymowych W, Russell AS. Antimalarials in rheumatology: efficacy and safety. Semin Arthritis Rheum. 1987;16:206–21.PubMedGoogle Scholar
  46. 46.
    Leblanc B, Jezequei S, Davies T, Hanton G, Taradach C. Binding of drugs to eye melanin is not predictive of ocular toxicity. Regul Toxicol Pharmacol. 1998;28:124–32.PubMedGoogle Scholar
  47. 47.
    Duncker G, Bredehorn T. Chloroquine-induced lipidosis in the rat retina: functional and morphological changes after withdrawal of the drug. Graefes Arch Clin Exp Ophthalmol. 1996;234:378–81.PubMedGoogle Scholar
  48. 48.
    Rosenthal AR, Kolb H, Bergsma D, Huxsoll D, Hopkins JL. Chloroquine retinopathy in the rhesus monkey. Invest Ophthalmol Vis Sci. 1978;17:1158–75.PubMedGoogle Scholar
  49. 49.
    Ivanina TA, Zueva MV, Lebedeva MN, Bogoslovsky AI, Bunin AJ. Ultrastructural alterations in rat and cat retina and pigment epithelium induced by chloroquine. Graefes Arch Clin Exp Ophthalmol. 1983;220:32–8.PubMedGoogle Scholar
  50. 50.
    Mcchesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med. 1983;75:11–8.PubMedGoogle Scholar
  51. 51.
    Sparrow JR. Lipofuscin of the retinal pigment epithelium. In: Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC, editors. Atlas of fundus autofluorescence imaging. Berlin: Springer; 2007. p. 3–16.Google Scholar
  52. 52.
    Dillon J, Wang Z, Avalle LB, Gaillard ER. The photochemical oxidation of A2E results in the formation of a 5, 8, 6', 8'-bis-furanoid oxide. Exp Eye Res. 2004;79:537–42.PubMedGoogle Scholar
  53. 53.
    Jang CH, Choi JH, Byun MS, Jue DM. Chloroquine inhibits production of TNF-alpha, IL-1 beta, and IL-6 from lipopolysaccharide-stimulated human monocytes/ macrophages by different modes. Rheumatology. 2006;45:703–10.PubMedGoogle Scholar
  54. 54.
    Eldred GE, Lasky MR. Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature. 1993;361:724–6.PubMedGoogle Scholar
  55. 55.
    Mititelu M, Wong BJ, Brenner M, Bryar PJ, Jampol LM, Fawzi AA. Progression of hydroxychloroquine toxic effects after drug therapy cessation. New evidence from multimodal imaging. Arch Ophthalmol. 2013;131:1187–97.Google Scholar
  56. 56.
    Zeller RW, Deering D. Corneal complication of chloroquine (Aralen) Phosphate therapy. JAMA. 1958;168:2263–4.Google Scholar
  57. 57.
    Calkins LL. Corneal epithelial changes occurring during chloroquine (Aralen) therapy. AMA Arch Ophthalmol. 1958;60:981–8.PubMedGoogle Scholar
  58. 58.
    Hobbs HE, Calnan CD. Visual disturbances with antimalarial drugs, with particular reference to chloroquine keratopathy. AMA Arch Dermatol. 1959;80:557–63.Google Scholar
  59. 59.
    Mason CG. Ocular accumulation and toxicity of certain systemically administered drugs. J Toxicol Environ Health. 1977;2:977–95.PubMedGoogle Scholar
  60. 60.
    Henkind P, Rothfield NF. Ocular abnormalities in patients treated with synthetic antimalarial drugs. New Engl J Med. 1963;269:434–9.Google Scholar
  61. 61.
    Hobbs HE, Calnan CD. The ocular complications of chloroquine therapy. Lancet. 1958;1:1207–9.PubMedGoogle Scholar
  62. 62.
    Graniewski-Wijnands HS, Van Lith GHM, Vijfvinkel-Bruinenga S. Ophthalmological examination of patients taking chloroquine. Doc Ophthalmol. 1979;48:231–4.Google Scholar
  63. 63.
    Grierson DJ. Hydroxychloroquine and visual screening in a rheumatology outpatient clinic. Ann Rheum Dis. 1997;56:188–90.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Yam JCS, Kwok AKH. Ocular toxicity of hydroxychloroquine. Hong Kong Med J. 2006;12:294–304.PubMedGoogle Scholar
  65. 65.
    Hobbs HE, Eadie SP, Somerville F. Ocular lesions after treatment with chloroquine. Br J Ophthalmol. 1961;45:284–97.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Smith JL. Ocular complications of rheumatic fever and rheumatoid arthritis. Am J Ophthalmol. 1957;43:575–82.PubMedGoogle Scholar
  67. 67.
    Easterbrook M. Is corneal deposition of antimalarial any indication of retinal toxicity? Can J Ophthalmol. 1990;25:249–51.PubMedGoogle Scholar
  68. 68.
    Easterbrook M. The ocular safety of hydroxychloroquine. Semin Arthritis Rheum. 1993;23:62–7.PubMedGoogle Scholar
  69. 69.
    Weise EE, Yannuzzi LA. Ring maculopathies mimicking chloroquine retinopathy. Am J Ophthalmol. 1974;78:204–10.PubMedGoogle Scholar
  70. 70.
    Reed H, Campbell AA. Central scotomata following chloroquine therapy. Can Med Assoc J. 1962;86:176–8.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Scherbel AL, Mackenzie AH, Nousek JE, Atdjian M. Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy—a study of 741 patients treated with and without chloroquine drugs. New Engl J Med. 1965;273:360–6.PubMedGoogle Scholar
  72. 72.
    Easterbrook M. Screening for antimalarial toxicity. Can J Ophthalmol. 1993;28:51–2.PubMedGoogle Scholar
  73. 73.
    Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet. 1959;2:478.PubMedGoogle Scholar
  74. 74.
    Percival SPB, Behrman J. Ophthalmological safety of chloroquine. Br J Ophthalmol. 1969;53:101–9.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Araiza-Casillas R, Cardenas F, Morales Y, Cardiel MH. Factors associated with chloroquine-induced retinopathy in rheumatic diseases. Lupus. 2004;13:119–24.PubMedGoogle Scholar
  76. 76.
    Marks JS, Power BJ. Is chloroquine obsolete in treatment of rheumatic disease? Lancet. 1979;1:371–3.PubMedGoogle Scholar
  77. 77.
    Mantyjarvi M. Hydroxychloroquine treatment and the eye. Scand J Rheumatol. 1985;14:171–4.PubMedGoogle Scholar
  78. 78.
    Elder M, Rahman AMA. Early paracentral visual field loss in patients taking hydroxychloroquine. Arch Ophthalmol. 2006;124:1729–33.PubMedGoogle Scholar
  79. 79.
    Teoh SC-B, Lim J, Koh A, Lim T, Fu E. Abnormalities on the multifocal electroretinogram may precede clinical signs of hydroxychloroquine retinotoxicity. Eye (Lond). 2006;20:129–32.Google Scholar
  80. 80.
    Bunch TW, O'Duffy JD. Disease modifying drugs for progressive rheumatoid arthritis. Mayo Clin Proc. 1980;55:161–79.PubMedGoogle Scholar
  81. 81.
    Bernstein HN. Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am J Med. 1983;75:25–34.PubMedGoogle Scholar
  82. 82.
    Lozier JR, Friedlander MH. Complications of antimalarial therapy. Int Ophthalmol Clin. 1989;29:172–8.PubMedGoogle Scholar
  83. 83.
    Dubois EL. Antimalarials in the management of discoid and systemic lupus erythematosus. Semin Arthritis Rheum. 1978;8:33–51.PubMedGoogle Scholar
  84. 84.
    Fuld H. Retinopathy following chloroquine therapy. Lancet. 1959;2:617–8.Google Scholar
  85. 85.
    Mcchesney EW, Banks Jr WF, Sullivan DJ. Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats. Toxicol Appl Pharm. 1965;7:627–36.Google Scholar
  86. 86.
    Easterbrook M. An ophthalmological view on the efficacy and safety of chloroquine versus hydroxychloroquine. J Rheumatol. 1999;26:1866–7.PubMedGoogle Scholar
  87. 87.
    Block JA. Hydroxychloroquine and retinal safety. Lancet. 1998;351:771.PubMedGoogle Scholar
  88. 88.
    Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. 1997;36:799–805.PubMedGoogle Scholar
  89. 89.
    Rynes R. Ophthalmologic considerations in using antimalarials in the United States. Lupus. 1996;5:S73–4.PubMedGoogle Scholar
  90. 90.
    Spalton DJ. Retinopathy and antimalarial drugs-the British experience. Lupus. 1996;5:S70–2.PubMedGoogle Scholar
  91. 91.
    Finbloom DS, Silver K, Newsome DA, Gunkel R. Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity. J Rheumatol. 1985;12:692–4.PubMedGoogle Scholar
  92. 92.
    Goldman L, Preston RH. Reactions to chloroquine observed during the treatment of various dermatologic disorders. Am J Trop Med Hyg. 1957;6:654–7.PubMedGoogle Scholar
  93. 93.
    Bothwell B, Furst DE. Hydroxychloroquine. In: Day RO, Furst DE, editors. Antirheumatic therapy: actions and outcomes. Basel: Piet L.C.M. van Riel and Barry Bresnihan; 2005. p. 81–92.Google Scholar
  94. 94.
    Raines MF, Bhargava SK, Rosen ES. The blood-retinal barrier in chloroquine retinopathy. Invest Ophthalmol Vis Sci. 1989;30:1726–31.PubMedGoogle Scholar
  95. 95.
    Blomquist PH. Screening for hydroxychloroquine toxicity. Comp Ophthalmol Update. 2000;1:245–50.Google Scholar
  96. 96.
    Arden GB, Kolb H. Antimalarial therapy and early retinal changes in patients with rheumatoid arthritis. Br Med J. 1966;1:270–3.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Tzekov R. Ocular toxicity due to chloroquine and hydroxychloroquine: electrophysiological and visual function correlates. Doc Ophthalmol. 2005;110:111–20.PubMedGoogle Scholar
  98. 98.
    Schultz KR, Gilman AL. The lysosomotropic amines, chloroquine and hydroxychloroquine: a potentially novel therapy for graft-versus-host disease. Leuk Lymphoma. 1997;24:201–10.PubMedGoogle Scholar
  99. 99.
    Tanenbaum L, Tuffanelli DL. Antimalarial agents: chloroquine, hydroxychloroquine, and quinacrine. Arch Dermatol. 1980;116:587–91.PubMedGoogle Scholar
  100. 100.
    Rynes RI. Ophthalmologic safety of long-term hydroxychloroquine sulfate treatment. Am J Med. 1983;75:35–9.PubMedGoogle Scholar
  101. 101.
    el-Sayed NK, Abdel-Khalek LR, Gaafar KM, Hanafy LK. Profiles of serum proteins and free amino acids associated with chloroquine retinopathy. Acta Ophthalmol Scand. 1998;76:422–30.PubMedGoogle Scholar
  102. 102.
    Wang C, Fortin PR, Li Y, Panaritis T, Gans M, Esdaile JM. Discontinuation of antimalarial drugs in systemic lupus erythematosus. J Rheumatol. 1999;26:808–15.PubMedGoogle Scholar
  103. 103.
    Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus. 1996;5:S16–22.PubMedGoogle Scholar
  104. 104.
    van Jaarsveld CHM, Jahangier ZN, Jacobs JWG, Blaauw AAM, van Albada-Kuipers GA, ter Borg EJ, Brus HLM, Schenk Y, van der Veen MJ, Bijlsma JWJ, Rheumatic Research Foundation. Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis. Rheumatology. 2000;39:1374–82.PubMedGoogle Scholar
  105. 105.
    Freedman A, Steinberg VL. Chloroquine in rheumatoid arthritis. A double blindfold trial of treatment for one year. Ann Rheum Dis. 1960;19:243–50.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Runge LA. Risk/benefit analysis of hydroxychloroquine sulfate treatment in rheumatoid arthritis. Am J Med. 1983;75:52–6.PubMedGoogle Scholar
  107. 107.
    Scull E. Chloroquine and hydroxychloroquine therapy in rheumatoid arthritis. Arthritis Rheum. 1962;5:30–6.PubMedGoogle Scholar
  108. 108.
    Morand EF, McCloud PI, Littlejohn GO. Continuation of long term treatment with hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis. 1992;51:1318–21.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Wilson W. Retinopathy following chloroquine therapy. Br J Ophthalmol. 1961;45:756–8.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Percival SPB, Meanock I. Chloroquine: ophthalmological safety and clinical assessment in rheumatoid arthritis. Br Med J. 1968;3:579–84.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Hughes JT, Esiri M, Oxbury JM, Whitty CWM. Chloroquine myopathy. Q J Med. 1971;40:85–93.PubMedGoogle Scholar
  112. 112.
    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.PubMedGoogle Scholar
  113. 113.
    Seckin U, Ozoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatol Int. 2000;19:203–4.PubMedGoogle Scholar
  114. 114.
    Ben-Zvi I, Kivity S, Langevitz P. Hydroxy-chloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012;42:145–53.Google Scholar
  115. 115.
    Rollo IM. Drugs used in the chemotherapy of malaria. In: Goodman LS, Gilman A, editors. The pharmacological basis of therapeutics. New York: Macmillan; 1975. p. 1045–68.Google Scholar
  116. 116.
    Aguayo AJ, Hudgson P. Observations on the short-term effects of chloroquine on skeletal muscle; an experimental study in the rabbit. J Neurol Sci. 1970;11:301–25.PubMedGoogle Scholar
  117. 117.
    Eadie MJ, Ferrier TM. Chloroquine myopathy. J Neurol Neurosurg Psychiatry. 1966;29:331–7.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Neville HE, Maundry-Sewry CA, McDougall J, Sewell JR, Dubowitz V. Chloroquine-induced cytosomes with curvilinear profiles in muscle. Muscle Nerve. 1979;2:376–81.PubMedGoogle Scholar
  119. 119.
    Macdonald RD, Engel AG. Experimental chloroquine myopathy. J Neuropathol Exp Neurol. 1970;29:479–99.PubMedGoogle Scholar
  120. 120.
    Mastaglia FL, Papadimitriou JM, Dawkins RL, Beveridge B. Vacuolar myopathy associated with chloroquine, lupus erythematosus and thymoma; report of a case with unusual mitochondrial changes and lipid accumulation in muscle. J Neurol Sci. 1977;34:315–28.PubMedGoogle Scholar
  121. 121.
    Rewcastle NB, Humphrey JG. Vacuolar myopathy; clinical, histochemical, and microscopic study. Arch Neurol. 1965;12:570–82.PubMedGoogle Scholar
  122. 122.
    Begg TB, Simpson JA. Chloroquine neuromyopathy. Br Med J. 1964;1:770.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Fedorko ME, Hirsch JG, Cohn ZA. Autophagic vacuoles produced in vitro; I. Studies on cultured macrophages exposed to chloroquine. J Cell Biol. 1968;38:377–91.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol. 1964;80:407–12.PubMedGoogle Scholar
  125. 125.
    Smith B, O'Grady F. Experimental chloroquine myopathy. J Neurol Neurosurg Psychiat. 1966;29:255–8.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Yoshida T, Fukatsu R, Tsuzuki K, Aizawa Y, Hayashi Y, Sasaki N, Takamuru Y, Fujii N, Takahata N. Amyloid precursor protein, A beta and amyloid-associated proteins involved in chloroquine retinopathy in rats—immunopathological studies. Brain Res. 1997;764:283–8.PubMedGoogle Scholar
  127. 127.
    Drenckhahn D, Lullmann-Rauch R. Drug-induced lipidosis: differential susceptibilities of pigment epithelium and neuroretina toward several amphiphilic cationic drugs. Exp Mol Pathol. 1978;28:360–71.PubMedGoogle Scholar
  128. 128.
    Gaafar KM, Abdel-Khalek LR, el-Sayed NK, Ramadan GA. Lipidemic effect as a manifestation of chloroquine retinotoxicity. Arzneimittelforschung. 1995;45:1231–5.PubMedGoogle Scholar
  129. 129.
    Mahon GJ, Anderson HR, Gardiner TA, McFarlane S, Archer DB, Stitt AW. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res. 2004;28:277–84.PubMedGoogle Scholar
  130. 130.
    Gaynes BI, Torczynski E, Varro Z, Grostern R, Perlman J. Retinal toxicity of chloroquine hydrochloride administered by intraperitoneal injection. J Appl Toxicol. 2008;28:895–900.PubMedGoogle Scholar
  131. 131.
    Hallberg A, Naeser P, Andersson A. Effects of long-term chloroquine exposure on the phospholipid metabolism of the retina and pigment epithelium of the mouse. Acta Ophthalmol Scand. 1990;68:125–30.Google Scholar
  132. 132.
    Gregory MH, Rutty DA, Wood RD. Differences in the retinotoxic action of chloroquine and phenothiazine derivatives. J Pathol. 1970;102:139–50.PubMedGoogle Scholar
  133. 133.
    Smith RS, Berson EL. Acute toxic effects of chloroquine on the cat retina: ultrastructural changes. Invest Ophthalmol Vis Sci. 1971;10:237–46.Google Scholar
  134. 134.
    Meier-Ruge W. Experimental investigation of the morphogenesis of chloroquine retinopathy. Arch Ophthalmol. 1965;73:540–4.PubMedGoogle Scholar
  135. 135.
    Bonanomi MT, Dantas NC, Medeiros FA. Retinal nerve fiber layer thickness measurements in patients using chloroquine. Clin Experiment Ophthalmol. 2006;34:130–6.Google Scholar
  136. 136.
    Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond). 2010;24:756–63.Google Scholar
  137. 137.
    Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye (Lond). 2009;24:340–6.Google Scholar
  138. 138.
    Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. 2010;62:775–84.Google Scholar
  139. 139.
    Davies NP, Morland AB. Macular pigments: their characteristics and putative role. Prog Retin Eye Res. 2004;23:533–59.PubMedGoogle Scholar
  140. 140.
    Demirkaya N, van Dijk HW, van Schuppen SM, Abramoff MD, Garvin MK, Sonka M, Schlingemann RO, Verbraak FD. Effect of age on individual retinal layer thickness in normal eyes as measured with spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54:4934–40.PubMedGoogle Scholar
  141. 141.
    Ramsey MS, Fine BS. Chloroquine toxicity in the human eye-histopathologic observations by electron microscopy. Am J Ophthalmol. 1972;73:229–35.PubMedGoogle Scholar
  142. 142.
    Lloyd LA, Hiltz JW. Ocular complications of chloroquine therapy. Can Med Assoc J. 1965;92:508–13.PubMedCentralPubMedGoogle Scholar
  143. 143.
    Bernstein HN, Ginsberg J. The pathology of chloroquine retinopathy. Arch Ophthalmol. 1964;71:238–45.PubMedGoogle Scholar
  144. 144.
    Wetterholm DH, Winter FC. Histopathology of chloroquine retinal toxicity. Arch Ophthalmol. 1964;71:82–7.PubMedGoogle Scholar
  145. 145.
    Bernstein H, Zvaifler N, Rubin M, Mansour AM. The ocular deposition of chloroquine. Invest Ophthalmol Vis Sci. 1963;2:384–92.Google Scholar
  146. 146.
    Bailey LA, Hiltz JW. Ocular complications of chloroquine therapy. Can Med Assoc J. 1965;6:508–13.Google Scholar
  147. 147.
    Ratliff NB, Estes ML, Myles JL, Shirey EK, McMahon JT. Medial intelligence-diagnosis of chloroquine cardiomyopathy by endomyocardial biopsy. New Engl J Med. 1987;316:191–3.PubMedGoogle Scholar
  148. 148.
    Stauber WT, Hedge AM, Trout JJ, Schottelius BA. Inhibition of lysosomal function in red and white skeletal muscles by chloroquine. Exp Neurol. 1981;71:295–306.PubMedGoogle Scholar
  149. 149.
    Schmalbruch H. The early changes in experimental myopathy induced by chloroquine and chlorphentermine. J Neuropathol Exp Neurol. 1980;39:65–81.PubMedGoogle Scholar
  150. 150.
    Trout JJ, Stauber WT, Schottelius BA. Increased autophagy in chloroquine treated tonic and phasic muscles: an alternative view. Tissue Cell. 1982;13:393–401.Google Scholar
  151. 151.
    Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47:3531–8.PubMedGoogle Scholar
  152. 152.
    Fischer VW. Evolution of a chloroquine-induced cardiomyopathy in the chicken. Exp Mol Pathol. 1976;25:242–52.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • David J. Browning
    • 1
  1. 1.Charlotte Eye Ear Nose & Throat AssociatesCharlotteUSA

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