In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum
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A 48 h in vitro test was conducted to compare the susceptibility of two strains of Plasmodium falciparum to chloroquine, the two enantiomers of chloroquine, desethylchloroquine and the new antimalarial drug pyronaridine. The five compounds similarly inhibited the chloroquine sensitive strain. However, desethylchloroquine was less active and pyronaridine was much more active than chloroquine and its enantiomers against the chloroquine resistant strain.Keywords:
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Pyronaridine, a 9-substituted 1-aza-acridine, was assayed for in vitro activity against clinical and field isolates as well as characterized clones of Plasmodium falciparum. The in vitro antimalarial activity of pyronaridine was compared to activities of standard antimalarials against multidrug-resistant isolates of P. falciparum from eastern and northern Thailand using an assay based on the inhibition of schizont maturation. Isolates from eastern Thailand (n = 30) were susceptible to pyronaridine (IC50 8.40 nM), mefloquine (IC50 6.97 nM), and amodiaquine (IC50 12.7 nM) and resistant to chloroquine (IC50 361 nM), quinine (IC50 388 nM), and pyrimethamine (IC50 11,800 nM). The isolates from northern Thailand (n = 7) showed no statistical difference in susceptibility to pyronaridine (IC50 10.1 nM), amodiaquine (IC50 7.29 nM), and mefloquine (IC50 5.48 nM); however, isolates were significantly more susceptible to chloroquine (IC50 167 nM), quinine (IC50 248 nM), and pyrimethamine (IC50 1,980 nM). These data suggest a lack of cross-resistance between pyronaridine and either chloroquine, quinine, or pyrimethamine. Using the same assay system the in vitro activity of pyronaridine was evaluated against isolates from treatment failures of mefloquine or enpiroline from eastern Thailand. The IC50 values for mefloquine against five recrudescent isolates were significantly higher (IC50 16.4 nM) than the field isolates collected from the same region (IC50 6.97 nM); however, there was no significant difference in the pyronaridine susceptibility between the isolates from the field study (IC50 8.89 nM) and the isolates from the treatment failures (IC50 8.40 nM). These observations suggest a lack of cross-resistance to mefloquine following treatment failure with either mefloquine or enpiroline. Using an in vitro assay based on the measurement of the inhibition of nucleic acid synthesis the high levels of antimalarial activity of pyronaridine was further evidenced by the comparatively low IC50 values of the drugs against two reference clones, D-6 African (IC50 4.73 nM) and the W-2 Indochina (IC50 15.4 nM).
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The in-vitro activities of pyronaridine, amodiaquine, chloroquine and quinine were evaluated against 161 isolates of Plasmodium falciparum from Senegal (Dielmo, Ndiop and Pikine), using an isotopic, micro, drug susceptibility test. The mean IC50 values (50% inhibitory concentration) for pyronaridine and amodiaquine were 3.8 nM (95% confidence interval (95% CI), 3.1-4.4) and 12.0 nM (95% CI, 10.0-14.0 nM), respectively. Pyronaridine and amodiaquine were more active than chloroquine against susceptible parasites. However, both drugs were significantly less active (P < 0.002 and P < 0.025) against chloroquine-resistant isolates than against chloroquine-susceptible isolates. Based on statistical calculation using the present data (mean IC50 + 2 S.D.), the cut-off value for in-vitro susceptibility to pyronaridine is IC50 < 15 nM; for eight isolates (5%) the IC50 was > 15 nM. No isolates tested showed resistance to amodiaquine (IC50 > 80 nM). Significant positive correlations, suggesting cross-resistance among these drugs in vitro, were found between pyronaridine and chloroquine (r2 = 0.19, P < 0.001), pyronaridine and quinine (r2 = 0.44, P < 0.001), pyronaridine and amodiaquine (r2 = 0.34, P < 0.001), amodiaquine and chloroquine (r2 = 0.14, P < 0.001), and amodiaquine and quinine (r2 = 0.21, P < 0.001). The present in-vitro findings require comparison with clinical studies.
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The in vitro activity of pyronaridine was evaluated against 62 isolates of Plasmodium falciparum from Libreville, Gabon using an isotopic, drug susceptibility microtest and was compared with amodiaquine, chloroquine, quinine, and halofantrine activities. The mean 50% inhibitory concentration (IC50) values of the 62 isolates from Gabon to pyronaridine was 3.0 nM (95% confidence interval [CI] = 2.1-3.9). Pyronaridine was less potent against chloroquine-resistant isolates than chloroquine-susceptible isolates but more potent than chloroquine against chloroquine-resistant parasites. The cut-off value for in vitro reduced susceptibility to pyronaridine was an IC50 > 15 nM. Two isolates (3%) showed an IC50 > 15 nM. A significant positive correlation was found between the activities of pyronaridine and chloroquine (r2 = 0.26, P < 0.001), pyronaridine and quinine (r2 = 0.36, P < 0.001), pyronaridine and amodiaquine (r2 = 0.55, P < 0.001), and pyronaridine and halofantrine (r2 = 0.50, P < 0.001). This correlation suggests in vitro cross-resistance or at least in vitro cross-susceptibility, which is not necessarily predictive of cross-resistance in vivo. The present in vitro findings require comparison with those of clinical studies.
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Summary: An enantioselective high-performance liquid chromatographic method for chloroquine and desethylchloroquine was developed using a chiral α1-acid glycoprotein column. This method was used to determine concentrations of chloroquine and desethylchloroquine enantiomers in plasma and urine from volunteers given single oral doses of racemic chloroquine. The disposition of the enantiomers was different. The renal clearance of the chloroquine enantiomers was indicative of stereoselective renal secretion of the drug, and evidence for stereoselective metabolism also was found.
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A 48 hour in vitro test was conducted to compare the susceptibility of chloro quine-sensitive strain and chloroquine-resistant strain of Plamodium falciparum to chloroquine, two enantiomers of chloroquine, desethyl-chloroquine and the new antimalarial drug pyronaridine. All the 5 compounds similarly inhibited the chloroquine sensitive-strain. However, pyronaridine was much more active than chloroquine and its enantiomers against the chloroquine-resistant strain, whereas desethylchloroquine was less active.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAbsolute configuration of the enantiomers of 7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]quinoline (chloroquine)J. Cymerman Craig, Hemendra N. Bhargava, E. Thomas Everhart, Bruce LaBelle, Ulrich Ohnsorge, and Richard V. WebsterCite this: J. Org. Chem. 1988, 53, 6, 1167–1170Publication Date (Print):March 1, 1988Publication History Published online1 May 2002Published inissue 1 March 1988https://doi.org/10.1021/jo00241a009RIGHTS & PERMISSIONSArticle Views890Altmetric-Citations24LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (578 KB) Get e-Alerts Get e-Alerts
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Optically pure d- and l-Chloroquine Diphosphate were examined for their efficacy against Plasmodium berghei in mice. The d-enantiomer is significantly more effective than the corresponding l-enantiomer, and in subcurative doses the d-enantiomer is also signficantly more active than the racemate. This increased activity has however no influence upon Chloroquine-resistant strains of P. berghei. The LD50 in non-infected mice is higher for the d-enantiomer than for either the racemate or the l-enantiomer when mice were treated orally one and 4 times. These differences in efficacy and toxicity between the d- and l-enantiomer of Chloroquine are however not as pronounced as those found for the enantiomers of many other drugs and furthermore these differences are limited to subcurative doses.
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Journal Article Positive relationship between the response of Plasmodium falciparum to chloroquine and pyronaridine Get access M. Warsame, M. Warsame ∗ 1Division of Parasitology, Department of Morphology and Pathology, Faculty of Medicine, Somali National University, Mogadishu, Somalia2Department of Infectious Diseases, Karolinska Institute, Roslagstull Hospital, Stockholm, Sweden ∗Correspondence to Dr M. Warsame Yusuf, c/o A. Björkman, Roslagstull Hospital, Box 5651, S-11489 Stockholm, Sweden. Search for other works by this author on: Oxford Academic PubMed Google Scholar W.H. Wernsdorfer, W.H. Wernsdorfer 3Institute of Specific Prophylaxis and Tropical Medicine, University of Vienna, Austria Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Payne, D. Payne 4Control of Tropical Diseases, Malaria Unit, World Health Organization, Geneva, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Björkman A. Björkman 2Department of Infectious Diseases, Karolinska Institute, Roslagstull Hospital, Stockholm, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 85, Issue 5, September-October 1991, Pages 570–571, https://doi.org/10.1016/0035-9203(91)90345-Y Published: 01 September 1991 Article history Received: 21 January 1991 Accepted: 13 March 1991 Published: 01 September 1991
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