Effectiveness of Amodiaquine as Treatment for Chloroquine-Resistant Plasmodium Falciparum Infections in Kenya

Watkins, William M.; Spencer, Harrison C.; Kariuki, D.M.; Sixsmith, David; Boriga, David A.; Kipingor, Tamara; Koech, Davy K.

doi:10.1016/s0140-6736(84)90410-0

Cited by 142 publications

(48 citation statements)

References 9 publications

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“…Unfortunately, resistance to pyrimethamine-sulfadoxine is already spreading at an alarming rate in East Africa (14,17,20,30,33,38). In Kenya, for instance, when the rate of resistance to chloroquine (parasitological failure on days 7 to 14 after treatment) in the 1980s was more than 30% in most areas where malaria is endemic (18,19,43), parasites in the same areas were fully susceptible to pyrimethamine-sulfadoxine (15,29). However, at present, the rate of resistance to pyrimethamine-sulfadoxine is greater than 30% (17,20,33,38) in these areas in Kenya.…”

mentioning

confidence: 99%

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

Nzila

Mberu

Bray

et al. 2003

Antimicrob Agents Chemother

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Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P. falciparum. In the present study we tested the ability of probenecid to reverse antifolate resistance in P. falciparum in vitro. Probenecid, at concentrations that had no effect on parasite viability alone (50 M), was shown to increase the sensitivity of a highly resistant parasite isolate to the antifolates pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and threefold, respectively. The equivalent effects against an antifolate-sensitive isolate were activity enhancements of approximately 3-, 6-, 1.2-, and 19-fold, respectively. Probenecid decreased the level of uptake of radiolabeled folic acid, suggesting a transport-based mechanism linked to folate salvage. When probenecid was tested with chloroquine, it chemosensitized the resistant isolate to chloroquine (i.e., enhanced the activity of chloroquine). This enhancement of activity was associated with increased levels of chloroquine accumulation. In conclusion, we have shown that probenecid can chemosensitize malaria parasites to antifolate compounds via a mechanism linked to reduced folate uptake. Notably, this effect is observed in both folate-sensitive and -resistant parasites. In contrast to the activities of antifolate compounds, the effect of probenecid on chloroquine sensitivity was selective for chloroquine-resistant parasites (patent P407595GB [W. P. Thompson & Co., Liverpool, United Kingdom] has been filed to protect this intellectual property).

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mentioning

confidence: 99%

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

Nzila

Mberu

Bray

et al. 2003

Antimicrob Agents Chemother

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“…When compounds are soluble in both chloroform and methanol, the spectrum in both solvents, CDCl 3 Table 1.…”

Section: H Nmr Studiesmentioning

confidence: 99%

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

et al. 2007

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Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their N ω -oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC 50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC 50 ) 0.7-6 µg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC 50 ) 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives. IntroductionMalaria is one of the most widespread diseases in many regions of the world, exposing millions of people to risk of infection and death. The 4-aminoquinolines such as chloroquine (CQ) are the most important and widely used class of drugs for treatment of malaria. Chloroquine has been the drug of choice for malaria treatment since the early 1950s, providing effective and safe treatment for millions of Plasmodium falciparum infected patients a year. Development of drug resistance to chloroquine in malaria has become a major health concern in malaria endemic areas, which has prompted a search for alternative antimalarials against the CQ-resistant strains. 1,2 As a result, several new classes of antimalarial drugs were developed; none has reached the same status of recognition as the drug of choice in malaria therapy as CQ.Amodiaquine (AQ), a new Mannich base 4-aminoquinoline, is effective against chloroquine-resistant strains of P. falciparum. 3 However, the clinical use of AQ has been severely restricted because of the hepatoxicity and agranulocytosis side effects associated with its long term use. 4,5 Recent reports indicate that AQ was metabolized by cytochrome P-450 oxidation to form reactive quinoneimine metabolite with subsequent conjugate addition of glutathione or cysteinyl function of the enzymes. 6,7 Lysosomal accumulation and bioactivation of reactive quinoneimine metabolite are implicated to be the cause of the observed AQ in vivo toxicity. 8,9 To avoid the quinoneimine metabolite formation, a series of isoquine and related analogues were reported in the literature. 10-12 Isoquine (IQ) is an analogue of AQ, in which the 4′-hydroxy group on the aniline ring of AQ is int...

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“…After stirring the mixture for 7 h at room temperature, the solvent was evaporated, the solid residue washed with 1 M NaHCO 3 …”

Section: N-{3-[(7-chloro-4-quinolyl)amino]-5-[hydroxymethyl]phenyl}-nmentioning

confidence: 99%

“…After stirring the mixture for 12 h at room temperature, the appropriate amine (4 mmol, 8 eq) was added. Following reflux of the mixture for 5 h, the solvent was evaporated, the solid residue washed with 1 M NaHCO 3 …”

Section: General Procedures For Synthesis Of Compounds 3-6mentioning

confidence: 99%

“…After stirring the mixture for 12 h at room temperature, piperidine was added (145 ml, 1.47 mmol, 4 eq). Following reflux of the mixture for 5 h, the solvent was evaporated, the solid residue washed with 1 M NaHCO 3 In Vitro P. falciparum Culture and Drug Assays P. falciparum strains were maintained continuously in culture on human erythrocytes as described by Trager and Jensen. 17) In vitro antiplasmodial activity was determined using a modification of the semi-automated microdilution technique of Desjardins et al 18) P. falciparum CQ-sensitive (F32a/Tanzania) and CQ-resistant (FcB1R/Colombia, PFB/Brazil) strains were used in sensitivity testing.…”

Section: N-{3-[(7-chloro-4-quinolyl)amino]-5-[(piperidinomethylidene)mentioning

confidence: 99%

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"One-Pot" Synthesis and Antimalarial Activity of Formamidine Derivatives of 4-Anilinoquinoline.

Delarue

Girault

Ali³

et al. 2001

Chem. Pharm. Bull.

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Amodiaquine (AQ) is an antimalarial which is effective against chloroquino-resistant strains of Plasmodium falciparum but whose clinical use is severely restricted because of associated hepatotoxicity and agranulocytosis. "One-pot" synthesis of formamidines likely to be transformed into AQ derivatives is reported. Compared with AQ, the new compounds were devoid of in vitro cytotoxicity upon human embryonic lung cells and mouse peritoneal macrophages. One showed a potent in vivo activity in mice infected with P. berghei. Transformation of this compound by reductive amination led to a new type of AQ derivatives that displayed an in vitro activity similar to that of AQ but did not lead to toxic quinone-imines.

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Effectiveness of Amodiaquine as Treatment for Chloroquine-Resistant Plasmodium Falciparum Infections in Kenya

Cited by 142 publications

References 9 publications

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

Synthesis and Antimalarial Activity of New Isotebuquine Analogues

"One-Pot" Synthesis and Antimalarial Activity of Formamidine Derivatives of 4-Anilinoquinoline.

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