Effect of halofantrine and its desbutyl metabolite on lymphocyte proliferation dynamics |
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| Institution: | 1. Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany;2. Martin-Luther-University Halle-Wittenberg, Department of Radiotherapy, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany;1. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA;2. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4849 Calhoun Road, Health Building 2, Room, 7036, Houston, TX 77204, USA;3. Brigham and Women’s Hospital and Harvard Medical School, Division of Cardiovascular Medicine, 20 Shattuck Street, Thorn Biosciences 1219, Boston, MA 02115, USA;1. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China;2. N.D. Zelinsky Institute of Organic Chemistry, 47 Leninsky Prospect, Moscow 119991, Russia;3. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China;1. Department of Chemistry, 467 Hunter Laboratories, Clemson University, Clemson, SC 29634, USA;2. Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, 249 Life Sciences Building, Clemson University, Clemson, SC 29634, USA;3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, 777 Highland Ave., Madison, WI 53705-2222, USA |
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| Abstract: | Halofantrine hydrochloride (HF), one of the latest antimalarial agents currently undergoing clinical trials, and its active metabolite, N-desbutylhalofantrine (DHF), were examined for their effects on human and rat lymphocytes. HF has a biphasic concentration-dependent effect on phytohemagglutinin stimulated proliferation of human lymphocytes. Concentrations lower than 2.25 μM enhance, while higher concentrations inhibit proliferation. The IC50 values were 9.4 μM for HF, 4.5 μM for DHF and 14.7 μM for chloroquine. In human lymphocytes, enhanced proliferation was not detected for DHF unlike for HF. Combined achievable plasma concentrations of HF and DHF may sometimes be in the range where reduced lymphocyte proliferation occurs in vitro when based on simple additive dynamics. It remains to be confirmed if malarial treatment with HF leads to reduced T-cell responsiveness to antigenic challenges since HF and DHF persist for several days. |
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