Two cases of mefloquine resistant malaria in Thailand

Kârwacki, Jerome J.; Webster, H. K.; Limsomwong, Nipon; Shanks, G. Dennis

doi:10.1016/0035-9203(89)90620-2

Cited by 19 publications

(4 citation statements)

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“…In 1999, Alecrim et al [5] reported a case of a patient with P. vivax malaria who showed resistance to chloroquine and mefloquine in the Brazilian Amazon region. CQ and MQ-resistance overlap have also had commonly reported from Thailand [20]. Nomura [21] pointed to different mechanisms of resistance between the two species, however some data including results presented here show that caution is required.…”

Section: Discussionsupporting

confidence: 58%

In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon

Chehuan

Costa

et al. 2013

Malar J

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BackgroundChloroquine (CQ) and primaquine (PQ) are still the drugs of choice to treat Plasmodium vivax malaria in many endemic areas, Brazil included. There is in vivo evidence for the P. vivax resistance to CQ in the Brazilian Amazon, where the increase in the proportion of P. vivax malaria parallels the increase of unusual clinical complications related to this species. In this study, in vitro CQ and mefloquine (MQ)-susceptibility of P. vivax isolates from the Western Brazilian Amazon was tested using the double-site enzyme-linked lactate dehydrogenase immunodetection (DELI) assay.MethodsA total of 112 P. vivax isolates were tested in vitro for CQ-susceptibility and out of these 47 were also tested for MQ-susceptibility. The DELI assay was used to detect P. vivax growth at 48-hour short-term culture in isolates with ring stages ranging from 50 to %. Each isolate was tested in triplicate and geometric means of IC50’s was obtained. Nineteen isolates were genetically characterized for pvdhfr, pvmrp1, pvmdr1 and pvdhps candidate genes likely related to CQ resistance (10 with IC50<40 nM and 9 with IC50 >100 nM).ResultsTwelve out of 112 isolates were considered resistant to CQ, resulting in 10.7% (IC95% 5.0-16.4), while 3 out of 47 (6.4%; IC95% 0.0-12.8) were resistant to MQ. A discrete correlation was observed between IC50’s of CQ and MQ (Spearman=0.294; p=0.045). For pvdhps gene, a non-synonymous mutation was found at codon 382 (S→C) in 5/8 CQ-sensitive samples and 1/9 CQ-resistant samples (p=0.027). The other molecular markers were not associated to CQ-susceptibility.ConclusionsIn vitro CQ-resistance estimated in this study, estimated by the DELI test, was very similar to that observed in clinical trials, suggesting that in vitro procedures developed by capable local laboratories are useful in the surveillance of CQ-resistance in the Amazon; concurrent Amazon P. vivax strains with both CQ and MQ resistance may be common; and a non-synonymous mutation at pvdhps codon 382 (S→C) was associated to in vitro susceptibility to CQ, needing further studies to be confirmed.

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Section: Discussionsupporting

confidence: 58%

In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon

Chehuan

Costa

et al. 2013

Malar J

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“…Mefloquine hydrochloride was developed by the Walter Reed Army Institute of Research and Roche Laboratories (Nutley, N.J.) as an alternate choice for the treatment of chloroquine-resistant malaria and is marketed under the trade name Lariam. However, since pockets of clinical resistance to mefloquine have been reported in both Africa (8) and southeastern Asia (2,11), new drug therapies which overcome the resistance problem need to be developed.…”

mentioning

confidence: 99%

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor

Karle

1991

Antimicrob Agents Chemother

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The crystal structure of (+)-mefloquine methylsulfonate monohydrate was determined by X-ray diffraction and was compared with the crystal structures of mefloquine hydrochloride and mefloquine free base. The conformation of mefloquine was essentially the same in all three crystalline environments and was not dependent on whether mefloquine was a salt or a free base. In mefloquine methylsulfonate monohydrate, the angle between the average plane of the quinoline ring and the average plane of the piperidine ring was 76.90. The intramolecular aliphatic N-13. 0-1 distance was 2.730 ± 0. 3a (F).Since the mechanism of antimalarial action and the mechanism of mefloquine resistance may involve hydrogen bond formation between mefloquine and a cellular effector or transport proteins, the common conformation of mefloquine found in each crystalline environment may define the orientation in which mefloquine forms these potentially critical hydrogen bonds with cellular constituents.The continuing spread of multi-drug-resistant Plasmodium falciparum malaria (22) Understanding the mode of action and mode of resistance of mefloquine on a molecular level should aid the development of new treatment strategies. Although mefloquine alters the pH of the parasite's acid vesicles at nanomolar concentrations (13), the precise mode of action of mefloquine is not well defined. Structure-activity studies demonstrate that mefloquine loses its antimalarial activity if the amine and hydroxyl groups of mefloquine are acetylated (26). Formation of an 0-methyl or O-ethyl derivative as well as conversion of the saturated 2-piperidyl group to an unsaturated 2-pyridyl group also abolishes activity (26). This apparent structural requirement to have underivatized amine and hydroxyl groups suggests that these groups need to be free to hydrogen bond to cellular constituents. Thus, antimalarial activity may depend upon the ability of mefloquine * Corresponding author.to hydrogen bond to a cellular "effector." In addition, structure-activity studies (5, 6, 26) on the 3-and 4-piperidyl isomers of mefloquine and of the 3,6-bis(trifluoromethyl)-9-phenanthryl analog of mefloquine show that the physical placement of the hydroxyl and the amine groups with respect to each other is critical to antimalarial activity. These data further support the hypothesis that these compounds must hydrogen bond to cellular constituents to effect antimalarial activity and must do so with a specific geometry. At present, the mechanism(s) of resistance to mefloquine has not been elucidated (21).The three-dimensional structure of mefloquine defines how the mefloquine molecule physically interacts with a cellular effector or transport proteins. In order to determine the preferred conformation(s) of mefloquine, we undertook the comparison of the structure of mefloquine as both a free base and a salt in three different crystalline environments. The crystal structure of mefloquine methylsulfonate monohydrate (Fig. 1) was determined by X-ray diffraction and was compared with the crysta...

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“…The first report of mefloquine treatment failure (RII resistance: high grade resistance with initial clearance or substantial reduction of parasitemia of less than 25% of the initial count on day 2, but with persistence or recrudescence of parasitemia during days 4-7) was reported in Thailand in a non-immune patient as early as 1982, also on the ThaiCambodian border (Boudreau et al 1982), and since then several falciparum isolates from that area were documented to have decreased in vitro susceptibility to mefloquine (Webster et al 1985). Clinical resistance was also reported from Mae Sot on the Thai-Myanmar border in 1987 (Karwacki et al 1989). The actual epidemic centre of malaria outbreak of the Bo Rai on the Thai-Cambodian border was in the high-transmission areas of western Cambodia.…”

Section: Emergence Of Drug Resistance In Thailandmentioning

confidence: 94%

Current Malaria Status and Distribution of Drug Resistance in East and Southeast Asia with Special Focus to Thailand

Na‐Bangchang

Congpuong²

2007

Tohoku J. Exp. Med.

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Two cases of mefloquine resistant malaria in Thailand

Cited by 19 publications

References 4 publications

In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon

In vitro chloroquine resistance for Plasmodium vivax isolates from the Western Brazilian Amazon

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor

Current Malaria Status and Distribution of Drug Resistance in East and Southeast Asia with Special Focus to Thailand

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