{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:08:14Z","timestamp":1791036494274,"version":"4.1.0"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2008,6,1]],"date-time":"2008-06-01T00:00:00Z","timestamp":1212278400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2008,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this class, (\u00b1)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (NPC1161C), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. This racemic mixture was separated into its component enantiomers by chemical and chromatographic means. The enantiomers were evaluated for antiparasitic activity in murine models of\n            <jats:italic>Plasmodium berghei<\/jats:italic>\n            ,\n            <jats:italic>Pneumocystis carinii<\/jats:italic>\n            , and\n            <jats:italic>Leishmania donovani<\/jats:italic>\n            infection, as well as the propensity to elicit hematotoxicity in dogs. The (\u2212)-enantiomer NPC1161B was found to be more active (by severalfold, depending on the dosing regimen) than the (+)-enantiomer NPC1161A in all of these murine models. In addition, the (\u2212) enantiomer showed markedly reduced general toxicity in mice and reduced hematotoxicity in the dog model of methemoglobinemia. It is concluded that the configuration at the asymmetric center in the 8-amino side chain differentially affects efficacy and toxicity profiles and thus may be an important determinant of the \u201ctherapeutic window\u201d for compounds in this class.\n          <\/jats:p>","DOI":"10.1128\/aac.00645-07","type":"journal-article","created":{"date-parts":[[2008,4,1]],"date-time":"2008-04-01T00:46:09Z","timestamp":1207010769000},"page":"2130-2137","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":60,"title":["Antiparasitic Activities and Toxicities of Individual Enantiomers of the 8-Aminoquinoline 8-[(4-Amino-1-Methylbutyl)Amino]-6-Methoxy-4-Methyl-5-[3,4-Dichlorophenoxy]Quinoline Succinate"],"prefix":"10.1128","volume":"52","author":[{"given":"N. P. Dhammika","family":"Nanayakkara","sequence":"first","affiliation":[{"name":"National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Arba L.","family":"Ager","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn S.","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Yardley","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikhlas A.","family":"Khan","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences"},{"name":"Departments of Pharmacognosy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"McChesney","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences"},{"name":"Departments of Pharmacognosy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry A.","family":"Walker","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences"},{"name":"Pharmacology, School of Pharmacy, the University of Mississippi, University, Mississippi"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"4605","DOI":"10.1016\/0006-2952(88)90327-9","volume":"37","year":"1988","unstructured":"Agarwal, S., U. R. Gupta, R. C. Gupta, N. Anand, and S. S. Agarwal. 1988. Susceptibility of glucose-6-phosphate dehydrogenase-deficient red cells to primaquine enantiomers and two putative metabolites. I. Effect on reduced glutathione, methemoglobin content and release of hemoglobin. Biochem. Pharmacol.37:4605-4609.","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/424663"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/0006-2952(86)90145-0","volume":"35","year":"1986","unstructured":"Baird, J. K., G. J. McCormick, and C. J. Canfield. 1986. Effects of nine synthetic putative metabolites of primaquine on activity of the hexose monophosphate shunt in intact human red blood cells in vitro. Biochem. Pharmacol.35:1099-1106.","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/jps.2600770503","volume":"77","year":"1988","unstructured":"Baker, J. K., and J. D. McChesney. 1988. Differential metabolism of the enantiomers of primaquine. J. Pharm. Sci.77:380-382.","journal-title":"J. Pharm. Sci."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.35.2.277"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0732-8893(92)90036-S"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"51S","DOI":"10.1111\/j.1550-7408.1997.tb05772.x","volume":"44","year":"1997","unstructured":"Bartlett, M. S., S. F. Queener, M. M. Shaw, P. J. Durant, C. H. Lee, and J. W. Smith. 1997. In vitro and in vivo models of Pneumocystis carinii. J. Eukaryot. Microbiol.44:51S.","journal-title":"J. Eukaryot. Microbiol."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1990.42.532"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2003.09.011"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/BF01964465","volume":"10","year":"1991","unstructured":"Black, J. R., J. Feinberg, R. L. Murphy, R. J. Fass, J. Carey, and F. R. Sattler. 1991. Clindamycin and primaquine as primary treatment for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS. Eur. J. Clin. Microbiol. Infect. Dis.10:204-207.","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/clinids\/18.6.905","volume":"18","year":"1994","unstructured":"Black, J. R., J. Feinberg, R. L. Murphy, R. J. Fass, D. Finkelstein, B. Akil, S. Safrin, J. T. Carey, J. Stansell, and J. F. Plouffe. 1994. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044. Clin. Infect. Dis.18:905-913.","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1124\/jpet.102.041459","volume":"303","year":"2002","unstructured":"Bolchoz, L. J. C., A. K. Gelasco, D. J. Jollow, and D. C. McMillan. 2002. Primaquine-induced hemolytic anemia: formation of free radicals in rat erythrocytes exposed to 6-methoxy-8-hydroxylaminoquinoline. J. Pharmacol. Exp. Ther.303:1121-1129.","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1124\/jpet.103.062984","volume":"309","year":"2004","unstructured":"Bowman, Z. S., J. E. Oatis, Jr., J. L. Whelan, D. J. Jollow, and D. C. McMillan. 2004. Primaquine-induced hemolytic anemia: susceptibility of normal versus glutathione-depleted rat erythrocytes to 5-hydroxyprimaquine. J. Pharmacol. Exp. Ther.309:79-85.","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0014-5793(87)80072-8","volume":"214","year":"1987","unstructured":"Brossi, A., P. Millet, I. Landau, M. E. Bembenek, and C. W. Abell. 1987. Antimalarial activity and inhibition of monoamine oxidases A and B by exo-erythrocytic antimalarials. Optical isomers of primaquine, N-acylated congeners, primaquine metabolites and 5-phenoxy-substituted analogs. FEBS Lett.214:291-294.","journal-title":"FEBS Lett."},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1021\/ja01212a051","volume":"68","year":"1946","unstructured":"Campbell, K. N., A. H. Sommers, J. H. Kerwin, and B. K. Campbell. 1946. Quinoline series. III. Preparation of some 8-(\u03c9-alkylaminoalkylamino)quinolines. J. Am. Chem. Soc.68:1556-1559.","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196811212792102"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2001.65.685"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1365\/s10337-006-0015-7","volume":"64","year":"2006","unstructured":"Elsohly, M. A., W. Gul, S. Feng, N. P. D. Nanayakkara, A. M. Clark, S. Khan, F. B. Cogswell, and L. A. Walker. 2006. GC-MS analysis of the 8-aminoquinoline antimalarial [NPC1161] and its carboxy metabolite in plasma and red blood cells of primates. Chromatographia64:199-205.","journal-title":"Chromatographia"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1016\/0006-2952(88)90263-8","volume":"37","year":"1988","unstructured":"Fletcher, K. A., P. F. Barton, and J. A. Kelly. 1988. Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine. Biochem. Pharmacol.37:2683-2690.","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_2_21_2","first-page":"154","volume":"12","year":"1994","unstructured":"Garces, J. L., J. Arrizabalaga, J. A. Iribarren, F. Rodriguez, C. Garde, and A. Garcia. 1994. Clindamycin-primaquine in the treatment of Pneumocystis carinii pneumonia. Enferm. Infecc. Microbiol. Clin.12:154-157.","journal-title":"Enferm. Infecc. Microbiol. Clin."},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2005.73.1005"},{"key":"e_1_3_2_23_2","first-page":"1461","volume":"327","year":"1992","unstructured":"Kantor, G. S. 1992. Primaquine-induced methemoglobinemia during treatment of Pneumocystis carinii pneumonia. N. Engl. J. Med.327:1461.","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_2_24_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1097\/00007611-199004000-00010","volume":"83","year":"1990","unstructured":"Kay, R., and R. E. DuBois. 1990. Clindamycin\/ primaquine therapy and secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS. South. Med. J.83:403-404.","journal-title":"South. Med. J."},{"key":"e_1_3_2_25_2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/00034983.1996.11813071","volume":"90","year":"1996","unstructured":"Kinnamon, K. E., B. T. Poon, W. L. Hanson, and V. B. Waits. 1996. Primaquine analogs that are potent anti-Trypanosoma cruzi agents in a mouse model. Ann. Trop. Med. Parasitol.90:467-474.","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1978.27.751"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00351a017"},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/0041-008X(85)90155-3","volume":"81","year":"1985","unstructured":"Link, C. M., A. D. Theoharides, J. C. Anders, H. Chung, and C. J. Canfield. 1985. Structure-activity relationships of putative primaquine metabolites causing methemoglobin formation in canine hemolyzates. Toxicol. Appl. Pharmacol.81:192-202.","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"748","DOI":"10.2307\/3282248","volume":"74","year":"1988","unstructured":"McCabe, R. E. 1988. Primaquine is lethal for intracellular but not extracellular Trypanosoma cruzi. J. Parasitol.74:748-753.","journal-title":"J. Parasitol."},{"key":"e_1_3_2_30_2","unstructured":"8-Aminoquinolines. U.S. patent 6 376 511. 2002"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1016\/0006-2952(87)90312-1","volume":"36","year":"1987","unstructured":"Nicholl, D. D., G. Edwards, S. A. Ward, M. L. Orme, and A. M. Breckenridge. 1987. The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite. Biochem. Pharmacol.36:3365-3369.","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6468(08)70362-X"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.10.2166"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.32.6.807"},{"key":"e_1_3_2_35_2","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1093\/infdis\/165.4.764","volume":"165","year":"1992","unstructured":"Queener, S. F., R. A. Deen, M. S. Bartlett, W. K. Milhous, J. D. Berman, W. Y. Ellis, and J. W. Smith. 1992. Efficacy of intermittent dosage of 8-aminoquinolines for therapy or prophylaxis of Pneumocystis carinii pneumonia in rats. J. Infect. Dis.165:764-768.","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2002.67.39"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.12.1.51"},{"key":"e_1_3_2_38_2","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1093\/clinids\/19.6.1034","volume":"19","year":"1994","unstructured":"Sherwood, J. A., G. S. Gachihi, R. K. Muigai, D. R. Skillman, M. Mugo, J. R. Rashid, K. M. Wasunna, J. B. Were, S. K. Kasili, and J. M. Mbugua. 1994. Phase 2 efficacy trial of an oral 8-aminoquinoline (WR6026) for treatment of visceral leishmaniasis. Clin. Infect. Dis.19:1034-1039.","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_39_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1023\/A:1014853421871","volume":"232","year":"2002","unstructured":"Srivastava, S., A. S. Alhomida, N. J. Siddiqi, S. K. Puri, and V. C. Pandey. 2002. Methemoglobin reductase activity and in vitro sensitivity towards oxidant induced methemoglobinemia in Swiss mice and beagle dogs erythrocytes. Mol. Cell. Biochem.232:81-85.","journal-title":"Mol. Cell. Biochem."},{"key":"e_1_3_2_40_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0378-5173(93)90208-W","volume":"96","year":"1993","unstructured":"Stjaernkvist, P. 1993. Biodegradable microspheres: XIV. Effect of microparticle-bound primaquine on Leishmania donovani in mice. Int. J. Pharm.96:23-32.","journal-title":"Int. J. Pharm."},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1962.03620140081013"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e328010b848"},{"key":"e_1_3_2_43_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4269\/ajtmh.1967.16.133","volume":"16","year":"1967","unstructured":"Thompson, P. E., B. Olszewski, A. Bayles, and J. A. Waitz. 1967. Relations among antimalarial drugs: results of studies with cycloquanil-, sulfone-, or chloroquine-resistant Plasmodium berghei in mice. Am. J. Trop. Med. Hyg.16:133-145.","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"e_1_3_2_44_2","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/BF01964467","volume":"10","year":"1991","unstructured":"Toma, E. 1991. Clindamycin\/primaquine for treatment of Pneumocystis carinii pneumonia in AIDS. Eur. J. Clin. Microbiol. Infect. Dis.10:210-213.","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"e_1_3_2_45_2","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1093\/clinids\/17.2.178","volume":"17","year":"1993","unstructured":"Toma, E., S. Fournier, M. Dumont, P Bolduc, and H. Deschamps. 1993. Clindamycin\/primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial. Clin. Infect. Dis.17:178-184.","journal-title":"Clin. Infect. Dis."},{"key":"e_1_3_2_46_2","first-page":"1046","year":"1989","unstructured":"Toma, E., S. Fournier, M. Poisson, R. Morisset, D. Phaneuf, and C. Vega. 1989. Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lanceti:1046-1048.","journal-title":"Lancet"},{"key":"e_1_3_2_47_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0006-2952(97)00140-8","volume":"54","year":"1997","unstructured":"Trepanier, L. A., K. Ray, N. J. Winand, S. P. Spielberg, and A. E. Cribb. 1997. Cytosolic arylamine N-acetyltransferase (NAT) deficiency in the dog and other canids due to an absence of NAT genes. Biochem. Pharmacol.54:73-80.","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00402a001"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1086\/424508"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2005.73.871"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00645-07","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00645-07","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T19:39:30Z","timestamp":1645472370000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00645-07"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,6]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2008,6]]}},"alternative-id":["10.1128\/AAC.00645-07"],"URL":"https:\/\/doi.org\/10.1128\/aac.00645-07","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,6]]},"assertion":[{"value":"2007-05-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-03-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-06-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}