From methylene blue to chloroquine: A brief review of the development of an antimalarial therapy

Department of Pathology, University of Minnesota School of Medicine, Duluth, MN, USA.
Parasitology Research (Impact Factor: 2.1). 03/2012; 111(1):1-6. DOI: 10.1007/s00436-012-2886-x
Source: PubMed


Malarial treatment is widely and readily available today. However, there was a time in the not-so-distant past when malaria was a deadly disease with no known cause or cure. In this article, we trace the origins of an antimalarial therapy from the discovery of the nature of the malarial parasite through the development of chloroquine. We dedicate this article to Johann "Hans" Andersag, the scientist who developed chloroquine, on the 110th anniversary of his birth, 16 February 1902.

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    • "Antimalarial medication, including chloroquine, has been the frontline choice in this battle. However, because of over-and inappropriate use, resistant strains of the malarial parasite started to evolve, diminishing the effects of the drug [6] [15]. Nevertheless, alternative uses of chloroquine include treatment of rheumatoid arthritis, discoid lupus erythematosus and amoebic hepatitis [5]. "
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    ABSTRACT: For many years chloroquine was used as a prophylactic agent against malaria, and more recently as a mild immunosuppressive. However, due to lengthy treatment periods, adverse effects have become apparent, which included retinopathy. The structurally related hydroxychloroquine is less toxic, thought to be owing to a lower tissue accumulation in melanin rich areas. This study primarily focused on quantifying melanin binding between chloroquine and hydroxychloroquine at physiological pH to investigate the potential link between binding and reported toxicity. In addition, for the first time this study quantified the actual extent of adsorption of chloroquine and hydroxychloroquine to melanin and examined the desorption profile of both drugs from melanin to demonstrate the affinity between the pigment and the solutes. The results suggest that there is a difference between the adsorption affinities of chloroquine and hydroxychloroquine, potentially explaining the differences in bioaccumulation in retinal tissue. In addition, both solutes displayed a strong physical attraction to the absorbent.
    Toxicology Reports 11/2014; 1. DOI:10.1016/j.toxrep.2014.10.019
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    • "For many years it was the first-line antimalarial drug. However, as for many antimicrobial drugs, eventually (two decades later) drugresistant strains developed (Krafts et al. 2012). In the second half of the twentieth century, another important antimalarial drug was also developed in a time of war: mefloquine was number 142,490 of a total of 250,000 antimalarial compounds screened during the US Army's antimalarial drug discovery program. "
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    ABSTRACT: Malaria is an ancient disease continuing to pose an enormous health, social, and economic burden. It is caused by infection with protozoan parasites belonging to the genus Plasmodium transmitted via the bite of female Anopheles species mosquitoes. Of more than 100 different species infecting a wide range of animals from rodents and birds to mammals, five species of malaria parasites are known to infect humans: Plasmodium falciparum, P. vivax, P. ovale (now being recognized as consisting of two subspecies), P. malariae and P. knowlesi. P. falciparum is most likely to cause severe disease and, if not promptly treated, may lead to death. References to the disease occur in the Chinese canon of medicine, clay tablets from Mesopotamia, Egyptian papyri and Indian medical works. Descriptions of malaria from classic Greece and the Roman Empire are abundant. It was commonly believed that malaria was caused by marsh water and foul vapors emanating from swamps, hence the word mal’aria, from the Italian for “bad air”. For thousands of years, no effective treatment was available. This changed with the discovery of Artemisia annua (sweet wormwood) in China and the use of quinine from Peruvian bark as potent and effective drugs against malaria. The current understanding of the malaria parasites and their lifecycle starts in the end of the nineteenth century with the discovery of the malaria parasites in the blood of malaria patients by Alphonse Laveran in 1880. Subsequently, Ronald Ross discovered in 1897 that a bird malaria parasite was transmitted by mosquitoes. In 1898 Giovanni Grassi, Camillo Golgi, Ettore Marchiafava, Amico Bignami, Angelo Celli and Giuseppe Bastianelli confirmed that malaria in humans was also a mosquito-borne disease, in this case Anopheles species. Grassi and Filetti introduced the names of P. vivax and P. malariae in 1890. The causative agent of what was dubbed ‘malignant malaria’ was baptized P. falciparum by William Welch in 1897 and P. ovale by John Stephens in 1922. The discovery of a liver stage before malaria enters the bloodstream was made by Henry Shortt and Cyril Garnham in 1948. The existence of dormant stages, in P. vivax and P. ovale was shown in 1982 by Wojciech Krotoski. This article describes the key discoveries and provides a short overview of the multifaceted history of malaria.
    Discoveries in Modern Science: Exploration, Invention, Technology, 1st Edition edited by James Trefil, Patricia Daniels, Donna McPhie, Craig Schiffries, 10/2014: chapter Malaria Is Transmitted by Mosquitoes: pages 640-647; Macmillan Reference USA., ISBN: 0028662482
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    • "Chloroquine is an antimalarial drug that has been used in humans for many years [1]. In recent years, Chloroquine has been shown to inhibit autophagy and induce apoptosis in malignant cells and thus has been tested in various experimental model systems [2] and in human clinical trials [3], [4]. "
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    ABSTRACT: Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.
    PLoS ONE 10/2014; 9(10):e109180. DOI:10.1371/journal.pone.0109180 · 3.23 Impact Factor
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