Preclinical Foundations: Relevant Anatomy and Physiology

  • David J. Browning


Reviewing the preclinical science relevant to the mechanisms and risk factors for chloroquine and hydroxychloroquine retinopathy can solidify clinical understanding of that condition. This chapter gathers the scattered and often difficult-to-access pertinent facts and concepts.


Systemic Lupus Erythematosus Retinal Pigment Epithelium Outer Segment Ganglion Cell Layer Internal Limit Membrane 
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.



4-Aminoquinolines (chloroquine and hydroxychloroquine)


Antigen presenting cell


4-Aminoquinoline retinopathy


Bruch’s membrane


Blood–retina barrier




CpG oligodeoxynucleotide


CD number


Cluster of differentiation T3 cell co-receptor

CD74 gene

Cluster of differentiation 74 gene


Daily dose in mg/kg

DN cells

Double negative cells

DP cells

Double positive cells


Effective concentration 50 %


External limiting membrane


Foveal avascular zone


Ganglion cell layer


Human leukocyte antigen


Interferon alpha


Invariant chain

IκκK complex

Inhibitor of kappa B kinase complex




Internal limiting membrane


Inner nuclear layer


Inner plexiform layer


Interleukin-1 receptor-associated kinase


Inner segment/outer segment


Rate constant for elimination




Major histocompatibility complex






Nuclear factor-κβ essential modifier regulatory subunit


Nuclear factor-κβ


Nerve fiber layer


Nucleotide-binding and oligomerizing domain-like receptors


Optical coherence tomography


Outer plexiform layer


Outer nuclear layer


Pathogen-associated molecular pattern


Rheumatoid arthritis


Royal College of Surgeons


Radial peripapillary capillary


Retinal pigment epithelium


Spectral domain optical coherence tomography


Systemic lupus erythematosus

SP cells

Single positive cells


T cell receptor


T cell receptor–cluster of differentiation 3T cell co-receptor complex


Time domain optical coherence tomography

Th cells

Helper T cells

Treg cells

Regulatory T cells


Volume of distribution


Vascular endothelial growth factor


  1. 1.
    Hogan MJ, Alvarado JA, Weddell JE. Retina. Histology of the human eye: an atlas and textbook. Philadelphia: WB Saunders; 1971. p. 393–522.Google Scholar
  2. 2.
    Curcio CA, Allen KA. Topography of ganglion cells in the human retina. J Comp Neurol. 1990;300:5–25.PubMedGoogle Scholar
  3. 3.
    Gass JDM. Stereoscopic atlas of macular diseases diagnosis and treatment. St Louis: Mosby-Year Book; 1997. p. 1–599.Google Scholar
  4. 4.
    Jonas JB, Nguyen NX, Naumann GO. The retinal nerve fiber layer in normal eyes [Abstract]. Ophthalmology. 1989;96:627–32.PubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    Boulton M. Ageing of the retinal pigment epithelium. Prog Retin Eye Res. 1991;11:125–51.Google Scholar
  7. 7.
    Davies NP, Morland AB. Macular pigments: their characteristics and putative role. Prog Retin Eye Res. 2004;23:533–59.PubMedGoogle Scholar
  8. 8.
    Snodderly DM, Brown PK, Delori FC, Auran JD. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. Invest Ophthalmol Vis Sci. 1984;25:660–74.PubMedGoogle Scholar
  9. 9.
    Snodderly DM, Auran JD, Delori FC. The macular pigment. II. Spatial distribution in primate retinas. Invest Ophthalmol Vis Sci. 1984;25:685.Google Scholar
  10. 10.
    Anderson C, Blaha GR, Marx JL. Humphrey visual field findings in hydroxychloroquine toxicity. Eye (Lond). 2011;25:1535–45.Google Scholar
  11. 11.
    Marmor MF, Chien FY, Johnson MW. Value of red targets and pattern deviation pots in visual field screening for hydroxychloroquine retinopathy. JAMA Ophthalmol. 2013;131:476–80.PubMedGoogle Scholar
  12. 12.
    Jonas JB, Schneider U, Naumann GOH. Count and density of human retinal photoreceptors. Graefes Arch Clin Exp Ophthalmol. 1992;230:505–10.PubMedGoogle Scholar
  13. 13.
    Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye (Lond). 2009;24:340–6.Google Scholar
  14. 14.
    William M, Hart J, editors. Adler’s physiology of the eye. St. Louis: Mosby; 2003. p. 309–10.Google Scholar
  15. 15.
    Grover S, Murthy RK, Brar VS, Chalam KV. Comparison of retinal thickness in normal eyes using stratus and spectralis optical coherence tomography. Invest Ophthalmol Vis Sci. 2010;51:2644–7.PubMedGoogle Scholar
  16. 16.
    Bentaleb-Machkour Z, Jouffroy E, Rabilloud M, Grange JD, Kodjikian L. Comparison of central macular thickness measured by three OCT models and study of interoperator variability. Scientific World Journal. 2012;2012:1–6.Google Scholar
  17. 17.
    Giani A, Cigada M, Esmaili DD, Salvetti P, Luccarelli S, Marziani E, Luiselli C, Sabella P, Cereda M, Eandi C, Staurenghi G. Artifacts in automatic retinal segmentation using different optical coherence tomography instruments. Retina. 2010;30:607–16.PubMedGoogle Scholar
  18. 18.
    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
  19. 19.
    Wagner-Schuman M, Dubis AM, Nordgren RN, Lei Y, Odelll D, Chiao H, Weh E, Fischer W, Sulai Y, Dubra A, Carroll J. Race- and sex-related differences in retinal thickness and foveal pit morphology. Invest Ophthalmol Vis Sci. 2011;52:625–34.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Besharse JC, Defoe DM. Role of the retinal pigment epithelium in photoreceptor membrane turnover. In: Marmor MF, Wolfensberger TJ, editors. The retinal pigment epithelium. New York: Oxford University Press; 1998. p. 152–72.Google Scholar
  21. 21.
    Bosch E, Horwitz J, Bok D. Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction. J Histochem Cytochem. 1993;41:253–63.PubMedGoogle Scholar
  22. 22.
    Feeney L. Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci. 1978;17:583–600.PubMedGoogle Scholar
  23. 23.
    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
  24. 24.
    Bok D. Retinal photoreceptor-pigment epithelium interactions. Invest Ophthalmol Vis Sci. 1985;26:1659–94.PubMedGoogle Scholar
  25. 25.
    Holz FG, Schutt F, Kopitz J, Eldred GE, Kruse FE, Volcker HE, Cantz M. Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 1999;40:737–43.PubMedGoogle Scholar
  26. 26.
    Young RW. Visual cells and the concept of renewal. Invest Ophthalmol Vis Sci. 1976;15:725.Google Scholar
  27. 27.
    Katz ML, Drea CM, Eldred GE, Hess HH, Robison WGJR. Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res. 1986;43:561–73.PubMedGoogle Scholar
  28. 28.
    Feeney-Burns L, Hilderbrand ES, Eldridge S. Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci. 1984;25:195–200.PubMedGoogle Scholar
  29. 29.
    Cuervo AM, Dice JF. When lysosomes get old. Exp Gerontol. 2000;35:119–31.PubMedGoogle Scholar
  30. 30.
    Radu RA, Han Y, Bui TV, Nusinowitz S, Bok D, Lichter J, Widder K, Travis GH, Mata NL. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci. 2005;46:4393–401.PubMedGoogle Scholar
  31. 31.
    Eldred GE, Lasky MR. Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature. 1993;361:724–6.PubMedGoogle Scholar
  32. 32.
    Sparrow JR, Parish CA, Hashimoto M, Nakanishi K. A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture. Invest Ophthalmol Vis Sci. 1999;40:2988–95.PubMedGoogle Scholar
  33. 33.
    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
  34. 34.
    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
  35. 35.
    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
  36. 36.
    Ben-Shabat S, Parish CA, Vollmer HR, Itagaki Y, Fishkin N, Nakanishi K, Sparrow JR. Biosynthetic studies of A2E, a major fluorophore of retinal pigment epithelial lipofuscin. J Biol Chem. 2002;277:7183–90.PubMedGoogle Scholar
  37. 37.
    Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell. 1999;98:13–23.PubMedGoogle Scholar
  38. 38.
    De S, Sakmar TP. Interaction of A2E with model membranes. Implications to the pathogenesis of age-related macular degeneration. J Gen Physiol. 2002;120:147–57.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME. Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 2000;41:2303–8.PubMedGoogle Scholar
  40. 40.
    Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res. 2005;80:595–606.PubMedGoogle Scholar
  41. 41.
    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
  42. 42.
    Bruinink A, Zimmermann G, Riesen F. Neurotoxic effects of chloroquine in vitro. Arch Toxicol. 1991;65:480–4.PubMedGoogle Scholar
  43. 43.
    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
  44. 44.
    Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model. Retina. 2011;31:1609–19.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Stepien KE, Han DP, Schell J, Godara P, Rha J, Carroll J. Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss. Trans Am Ophthalmol Soc. 2009;107:28–34.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Chen E, Brown DM, Benz MS, Fish RH, Wong TP, Kim RY, Major JC. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the "flying saucer" sign). Clin Ophthalmol. 2010;4:1151–8.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Osterberg G. Topography of the layer of rods and cones in the human retina. Acta Ophthalmol. 1935;13:6–97.Google Scholar
  48. 48.
    Spitznas M. The fine structure of the so-called outer limiting membrane in the human retina. Graefes Arch Clin Exp Ophthalmol. 1970;180:44–56.Google Scholar
  49. 49.
    Wong IY, Iu LP, Koizumi H, Lai WW. The inner segment/outer segment junction: what have we learnt so far? Curr Opin Ophthalmol. 2012;23:2010–8.Google Scholar
  50. 50.
    Rodriguez-Padilla JA, Hedges III TR, Monson B, Srinivasan V, Wojtkowski M, Reichel E, Duker JS, Schuman JS, Fujimoto JG. High-speed ultra-high-resolution optical coherence tomography findings in hydroxychloroquine retinopathy. Arch Ophthalmol. 2007;125:775–80.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Labriola LT, Jeng D, Fawzi AA. Retinal toxicity of systemic medications. Int Ophthalmol Clin. 2012;52:149–66.PubMedGoogle Scholar
  52. 52.
    Tao Y, Li XX, Jiang YR, Bai XB, Wu BD, Dong JQ. Diffusion of macromolecule through retina after experimental branch retinal vein occlusion and estimate of intraretinal barrier [abstract]. Curr Drug Metab. 2007;8:151–6.PubMedGoogle Scholar
  53. 53.
    Sato S, Hirooka K, Baba T, Tenkumo K, Nitta E, Shiraga F. Correlation between the ganglion cell-inner plexiform layer thickness measured with Cirrus HD-OCT and macular visual field sensitivity measured with microperimetry. Invest Ophthalmol Vis Sci. 2013;54:3046–51.PubMedGoogle Scholar
  54. 54.
    Gomez ML, Mojana F, Bartsch DU, Freeman WR. Imaging of long-term retinal damage after resolved cotton wool spots. Ophthalmology. 2009;116:2407–14.PubMedGoogle Scholar
  55. 55.
    Mcleod D. Why cotton wool spots should not be regarded as retinal nerve fiber layer infarcts. Br J Ophthalmol. 2005;89:229–37.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Raines MF, Bhargava SK, Rosen ES. The blood-retinal barrier in chloroquine retinopathy. Invest Ophthalmol Vis Sci. 1989;30:726–1731.Google Scholar
  57. 57.
    Penfold PL, Wen L, Madigan MC, Gillies MC, King NJC, Provis JM. Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM-1) expression of the ECV304 cell line: implications for macular degeneration. Clin Exp Immunol. 2000;121:458–65.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Singh S, Dass R. The central artery of the retina I. Origin and course. Br J Ophthalmol. 1960;44:193–212.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Henkind P. Radial peripapillary capillaries of the retina. I. Anatomy: human and comparative. Br J Ophthalmol. 1967;51:115–23.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Iwasaki M, Inomata H. Relation between superficial capillaries and foveal structures in the human retina. Invest Ophthalmol Vis Sci. 1986;27:1698–705.PubMedGoogle Scholar
  61. 61.
    Stone J, Itin A, Alon T, Pe’er J, Gnessin H, Chan-Ling T, Keshet E. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci. 1995;15:4738–47.PubMedGoogle Scholar
  62. 62.
    Gariano RF, Kalina RE, Hendrickson AE. Normal and pathological mechanisms in retinal vascular development. Surv Ophthalmol. 1996;40:481–90.PubMedGoogle Scholar
  63. 63.
    Gariano RF, Iruela-Arispe ML, Hendrickson AE. Vascular development in primate retina: comparison of laminar plexus formation in monkey and human. Invest Ophthalmol Vis Sci. 1994;35:3442–55.PubMedGoogle Scholar
  64. 64.
    Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt’s essential immunology. Oxford: Wiley-Blackwell; 2011.Google Scholar
  65. 65.
    Hennessy EJ, Parker AE, O’Neill LAJ. Targeting toll-like receptors: emerging therapeutics. Rev Drug Discov. 2010;9:293–307.Google Scholar
  66. 66.
    Kyburz D, Brentano F, Gay S. Mode of action of hydroxychloroquine in RA—evidence of an inhibitory effect on toll-like receptor signaling. Nat Clin Pract Rheumatol. 2006;2:458–9.PubMedGoogle Scholar
  67. 67.
    Katz SJ, Russell AS. Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action. Curr Eye Res. 2011;23:278–81.Google Scholar
  68. 68.
    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
  69. 69.
    Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, Chang B, Duramad O, Coffman RL. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med. 2005;202:1131–9.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Schlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416:603–7.PubMedGoogle Scholar
  71. 71.
    Kalia S, Dutz JP. New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther. 2007;20:160–74.PubMedGoogle Scholar
  72. 72.
    Goldman FD, Gilman AL, Hollenback C, Kato RM, Premack BA, Rawlings DJ. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. Blood. 2000;95:3460–8.PubMedGoogle Scholar
  73. 73.
    Fox R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus. 1996;5:S4–S10.PubMedGoogle Scholar
  74. 74.
    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
  75. 75.
    Cruz da Silva J, Mariz HA, da Rocha Jr LF, de Oliveira PSS, Dantas AT, Duarte ALBP, Pitta IDR, Galdino SL, Pitta MGDR. Hydroxychloroquine decreases TH17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics. 2013;68:766–71.Google Scholar
  76. 76.
    Maddur MS, Miossec P, Kaveri SV, Bayry J. Th 17 cells. Biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J. Pathology. 2012;181:8–18.Google Scholar
  77. 77.
    Ferreira da Rocha Jr L, Duarte ALBP, Dantas AT, Mariz HA, Pitta IDR, Galdino SL, Pitta MGDR. Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity. J Rheumatol. 2012;39:1320–5.Google Scholar
  78. 78.
    Shah K, Lee WW, Lee SH, Kim SH, Kang SW, Craft J, Kang I. Dysregulated balance of TH17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther. 2010;12:R53–63.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Weber SM, Levitz SM. Chloroquine Interferes with lipopolysaccharide-induced TNF-α gene expression by a nonlysosomotropic mechanism. J Immunol. 2000;165:1534–40.PubMedGoogle Scholar
  80. 80.
    Wozniacka A, Lesiak A, Narbutt J, McCauliffe DP, Sysa-Jedrzejowska A. Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus. 2006;15:268–75.PubMedGoogle Scholar
  81. 81.
    Karres I, Kremer JP, Dietl I, Steckholzer U, Jochum M, Ertel W. Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am J Physiol. 1998;274:R1058–64.PubMedGoogle Scholar
  82. 82.
    Sant AJ, Miller J. MHC class II antigen processing: biology of invariant chain. Curr Opin Immunol. 1994;6:57–63.PubMedGoogle Scholar
  83. 83.
    Zarbin MA. Recombinant T-cell receptor ligands in the treatment of uveitis. Arch Ophthalmol. 2013;131:399–400.Google Scholar
  84. 84.
    Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu Rev Immunol. 1997;15:821–50.PubMedGoogle Scholar
  85. 85.
    Nowell J, Quaranta V. Chloroquine affects biosynthesis of Ia Molecules by inhibiting dissociation of invariant chains from α − β dimers in B cells. J Exp Med. 1985;162:1371–6.PubMedGoogle Scholar
  86. 86.
    Loss Jr GE, Sant AJ. Invariant chain retains MHC class II molecules in the endocytic pathway. J Immunol. 1993;150:3187–97.PubMedGoogle Scholar
  87. 87.
    Ziegler HK, Unanue ER. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982;79:175–8.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Moorthy RS, Rao PK, Read RW, Van Gelder RN, Vitale AT, Bodaghi B, Parrish CM. Intraocular inflammation and uveitis. San Francisco: American Academy of Ophthalmology; 2012. p. 38–9.Google Scholar
  89. 89.
    Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, et al. Chloroquine enhances human CD8 T cell responses against soluble antigens in vivo. J Exp Med. 2005;202:817–28.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Kleijmeer MJ, Ossevoort MS, van Veen CJH, van Hellemond JJ, Neefjes JJ, Kast WM, Melief CJM, Geuze HJ. MHC class II compartments and the kinetics of antigen presentation in activated mouse spleen dendritic cells. J Immunol. 1995;154:5715–24.PubMedGoogle Scholar
  91. 91.
    Maric MA, Taylor MD, Blum JS. Endosomal aspartic proteinases are required for invariant-chain processing. Proc Natl Acad Sci U S A. 1994;91:2171–5.PubMedCentralPubMedGoogle Scholar
  92. 92.
    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
  93. 93.
    Koch N, Moldenhauer G, Hofmann WJ, Moller P. Rapid intracellular pathway gives rise to cell surface expression of the MHC class II-associated invariant chain (CD74). J Immunol. 1991;147:2643–51.PubMedGoogle Scholar
  94. 94.
    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.PubMedGoogle Scholar
  95. 95.
    Yu Z, Kastenmuller G, He Y, Belcredi P, Moller G, Prehn C, Mendes J, et al. Differences between human plasma and serum metabolite profiles. PLoS One. 2011;6:e21230. doi: 10.1371/journal.pone.0021230.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci. 2007;96:729–46.PubMedGoogle Scholar
  97. 97.
    Oda K, Koriyama Y, Yamada E, Ikehara Y. Effects of weakly basic amines on proteolytic processing and terminal glycosylation of secretory proteins in cultured rat hepatocytes. J Biol Chem. 1986;240:739–45.Google Scholar
  98. 98.
    de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F. Lysosomotropic agents. Biochem Pharmacol. 1974;23:2495–531.PubMedGoogle Scholar
  99. 99.
    Goldstein A, Aronow L, Kalman SM. Principles of drug action: the basis of pharmacology. New York: John Wiley and Sons; 2013.Google Scholar
  100. 100.
    Chloroquine. DrugBank: open data drug & drug target database. 2005. Accessed 22 Aug 2013.
  101. 101.
    Hydroxychloroquine. DrugBank: open data drug & drug target database. 2007. Accessed 22 Aug 2013.
  102. 102.
    Ward PA. The chemosuppression of chemotaxis. J Exp Med. 1966;124:209–26.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Klaassen CD, Watkins III JB. Casarett and Doull’s essentials of toxicology. New York: McGraw Hill; 2010.Google Scholar
  104. 104.
    McChesney EQ, Fitch CD. 4-Aminoquinolines. In: Richards WHG, Peters W, editors. Antimalarial drugs II. Current antimalarials and new drug developments. Berlin: Springer; 1984. p. 3–60.Google Scholar
  105. 105.
    Mackenzie AH. Antimalarial drugs for rheumatoid arthritis. Am J Med. 1983;75:48–58.PubMedGoogle Scholar
  106. 106.
    Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and pharmacokinetics. New York: McGraw Hill Medical; 2012. p. 153–75.Google Scholar
  107. 107.
    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
  108. 108.
    Miller DR, Fiechtner JJ, Carpenter JR, Brown RR, Stroshane RM, Stecher VJ. Plasma hydroxychloroquine concentrations and efficacy in rheumatoid arthritis. Arthritis Rheum. 1987;30:567–71.PubMedGoogle Scholar
  109. 109.
    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
  110. 110.
    Rowland M, Tozer TN. Clinical pharmacokinetics and pharmacodynamics. Concepts and applications. Philadelphia: Wolters Kluwer; 2011. p. 579.Google Scholar
  111. 111.
    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.PubMedGoogle Scholar
  112. 112.
    Tett S, Cutler D, Day R. Antimalarials in rheumatic diseases. Baillieres Clin Rheumatol. 1990;4:467–89.PubMedGoogle Scholar

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© 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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