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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 known with p < 0.00000000001 from 421 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
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.
Browning et al., 4 Apr 2014, peer-reviewed, 1 author.
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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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