{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:58:20Z","timestamp":1790488700129,"version":"4.1.0"},"reference-count":25,"publisher":"Cambridge University Press (CUP)","issue":"5","license":[{"start":{"date-parts":[[2005,1,6]],"date-time":"2005-01-06T00:00:00Z","timestamp":1104969600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/www.cambridge.org\/core\/terms"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Parasitology"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:p><jats:italic>Plasmodium knowlesi<\/jats:italic> (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80\u2013160 mg\/kg total dose over 3\u20134 days. Ketoconazole, at a dose of 75 mg\/kg\/day\u00d710 days given orally to <jats:italic>P. knowlesi-<\/jats:italic>infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg\/kg\/day\u00d710 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg\/kg\/day\u00d710 days) treatment was combined with mefloquine (20 mg\/kg\/day\u00d74), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg\/kg\/day\u00d710 days) with mefloquine (20 mg\/kg\/day\u00d74), had a complete curative effect on <jats:italic>P. knowlesi<\/jats:italic> infection in all the treated monkeys (7\/7). Besides exerting direct antimalarial action against a mefloquine-resistant <jats:italic>P. knowlesi<\/jats:italic>, ketoconazole also acts as an inhibitor of hepatic microsomal CYP<jats:sub>450<\/jats:sub>3A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant <jats:italic>P. knowlesi<\/jats:italic>. The study shows a resistance reversal effect of a ketoconazole \u2013 mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of <jats:italic>P. knowlesi<\/jats:italic>. These findings can also be applied to reverse mefloquine resistance of <jats:italic>P. falciparum<\/jats:italic> in areas where mefloquine resistance is already established. The precise role of parasite CYP<jats:sub>450<\/jats:sub> in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.<\/jats:p>","DOI":"10.1017\/s0031182004006481","type":"journal-article","created":{"date-parts":[[2005,4,12]],"date-time":"2005-04-12T13:07:42Z","timestamp":1113311262000},"page":"475-479","source":"Crossref","is-referenced-by-count":19,"title":["Mefloquine resistance reversal action of ketoconazole \u2013 a cytochrome P<sub>450<\/sub> inhibitor, against mefloquine-resistant malaria"],"prefix":"10.1017","volume":"130","author":[{"given":"R.","family":"TRIPATHI","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"AWASTHI","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. P.","family":"DUTTA","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2005,1,6]]},"reference":[{"key":"S0031182004006481_ref006","unstructured":"DHAWAN, S. , AWASTHI, A. , TRIPATHI, R. , PURI, S. K. & DUTTA, G. P. (2000).Reversal of chloroquine\/mefloquine resistance of Plasmodium yoelii nigeriensis (MDR) by IFN-gamma and chloroquine resistance by Poly ICLC.Journal of Parasitic Diseases 24,195\u2013201."},{"key":"S0031182004006481_ref021","unstructured":"SALYANIK, R. I. , PANKOVA, T. G. , CHEKHONADSKIKH, T. V. & IGONINA, T. M. 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(1991).Mefloquine resistant P. falciparum malaria in Thai Burmese border.Lancet 337,1140\u20131143.","DOI":"10.1016\/0140-6736(91)92798-7"},{"key":"S0031182004006481_ref011","unstructured":"KYLE, D. E. , MILHOUS, W. K. & ODULA, M. M. J. (1988).Reversal of mefloquine resistance in Plasmodium falciparum in vitro. The 37th Annual Meeting of the American Society of Tropical medicine and Hygiene, Washington, D.C. 4\u20138 December, 1988, p. 218."},{"key":"S0031182004006481_ref017","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(98)90750-7"},{"key":"S0031182004006481_ref007","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(03)00049-X"},{"key":"S0031182004006481_ref003","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90638-Y"},{"key":"S0031182004006481_ref025","unstructured":"WORLD HEALTH ORGANIZATION(1996). WHO Fact Sheet NX94 Revised December 1996. Malaria. 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(1981).Antimalarial activity of mefloquine and chloroquine against blood induced Plasmodium knowlesi infection in rhesus monkeys.Indian Journal of Medical Research 73 (Suppl.),23\u201328."}],"container-title":["Parasitology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S0031182004006481","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T23:07:43Z","timestamp":1750460863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S0031182004006481\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,1,6]]},"references-count":25,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2005,2]]}},"alternative-id":["S0031182004006481"],"URL":"https:\/\/doi.org\/10.1017\/s0031182004006481","relation":{},"ISSN":["0031-1820","1469-8161"],"issn-type":[{"value":"0031-1820","type":"print"},{"value":"1469-8161","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,1,6]]}}}