Roxithromycin potentiates the effects of chloroquine and mefloquine on multidrug-resistant Plasmodium falciparum in vitro

Min, Taesun; Khairul, Mohd Fadzli Mustaffa; Low, Jonathan; Nasriyyah, C.H. Che; A'shikin, A.Noor; Nor, Norazmi Mohd; Ravichandran, M.; Sugavasi, Raju

doi:10.1016/j.exppara.2006.10.004

Cited by 7 publications

(3 citation statements)

References 22 publications

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“…The most pronounced effect was observed with DEAQ and QN, with a FIC of Ͻ0.5 (Table 1). No chemosensitization was observed when 3D7 was used.The ability of VPM to chemosensitize parasites to CQ and CQ-related drugs in CQ-resistant strains is well established (20, 27); however, this effect is commonly found to be moderate (mean FICs Ͼ 0.5) (10,12,13,15), in line with our data. The molecular mechanism of this chemosensitization is well understood.…”

supporting

confidence: 82%

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Masseno

Muriithi

Nzila

2009

Antimicrob Agents Chemother

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We tested the effect of probenecid and verapamil in chemosensitizing Plasmodium falciparum to 14 antimalarials using the multidrug-resistant strain V1S and the drug-sensitive 3D7. Verapamil chemosensitizes V1S to quinine and chloroquine. Interestingly, probenecid profoundly chemosensitizes V1S to piperaquine. Thus, probenecid could be used to increase piperaquine efficacy in vivo.The modulation of chloroquine (CQ) resistance with the calcium channel blocker verapamil (VPM), antipsychotic drugs, histamine receptor antagonists, and antidepressant agents among others was the first case of resistance modulation to be reported (reviewed in references 6, 8, and 28).Clinical evaluation of some of these agents has been carried out in areas where CQ resistance is moderate (22,(24)(25)(26). However, these agents have the disadvantage of being pharmacologically active, with systemic effects that may result in a variety of side effects. In addition, the minimum concentrations of these agents needed to chemosensitize parasites to CQ (usually more than 1 M of free drug) (1, 4, 11-13) are not achievable in vivo when normal doses are used; therefore, high doses have to be used, with all of the attendant risks of toxicity. All of these limitations may explain why the reversal of CQ resistance has never attained widespread application.We have demonstrated that the uricosuric drug probenecid (PBN) chemosensitizes parasites to antifolate and CQ (16,18).In this study, we tested the effect of PBN against the aminoquinolines CQ, piperaquine (PPRQ), primaquine (PMQ), desethylamodiaquin (DEAQ), and amodiaquin (AQ); the amino alcohols lumefantrine (LM), mefloquine (MFQ), halofantrine (HLF), and quinine (QN); the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), and methotrexate (MTX); the benzonaphthyridine pyronaridine (PRN); and the sesquiterpene dihydroartemisinin (DHA). We used the chemosensitizer VPM as a comparator.CQ, PMQ, AQ, MFQ, QN, MTX, PBN, and VPM were purchased from Sigma (Poole, Dorset, United Kingdom). PPRQ was a gift from Universal Corporation Limited, Kikuyu, Kenya. DEAQ, DHA, LM, PRN, and HLF were gifts from Steve Ward, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. Drugs were dissolved as suggested by manufacturers. For PBN, after dilution in dimethyl sulfoxide (500 mg/ml), a subsequent serial dilution was carried out; this consisted of fivefold dilution in absolute ethanol followed by twofold dilution in 2% sodium bicarbonate and then dilution in RPMI 1640 medium (PBN crystallizes when diluted directly from dimethyl sulfoxide to RPMI 1640 medium).We employed two reference P. falciparum laboratory strains: V1S, a multidrug-resistant strain (resistant to CQ, PM, and QN) and 3D7, a strain fully sensitive to all tested antimalarials, except LM and PMQ. Cultures were carried out in RPMI 1640 (GIBCO BRL, United Kingdom), and antimalarial activities were expressed as the drug concentration required for 50% inhibition of [ 3 H]hypoxanthine incorporation (IC 50 ) during the 66-h assay (19).Chemosensit...

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supporting

confidence: 82%

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Masseno

Muriithi

Nzila

2009

Antimicrob Agents Chemother

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“…Roxithromycin showed synergy with chloroquine and to a lesser extent also with mefloquine. It has been suggested that a resistance reversing effect due to the inhibition of the MDR1 transporter could be a factor in the synergy between azithromycin or roxithromycin and chloroquine [131,132]. The ketolide telithromycin (12, Fig.…”

Section: Macrolidesmentioning

confidence: 99%

Antibiotics in Malaria Therapy and their Effect on the Parasite Apicoplast

Pradel¹,

Schlitzer

2010

CMM

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The impact of selected antibiotics on combating malaria infections was discovered in the mid of last century. Only recently, studies on their modes of action in malaria parasites have been initiated, prompted by the discovery of a prokaryotic organelle, the apicoplast. This plastid-derived structure, which originates from a secondary endosymbiotic event, possesses important metabolic as well as housekeeping functions, including fatty acid and heme biosynthesis. Due to its indispensability for parasite survival it represents a promising target for the use of antibiotics in malaria therapy. Most antibiotics cause a delayed death phenotype, which manifests in the late onset of antimalarial activity during the second replication cycle of the pathogen. This review will describe the effect of classical antibacterial agents against malaria parasites and the use of some of these compounds in clinical settings. Firstly we discuss the current knowledge about the physiological and morphological effects of antibiotics on the parasite and the apicoplast in particular, with special focus on the delayed death effect. Secondly antimalarial antibiotics are specified and their effects in vitro are compared with available in vivo data and clinical studies. Major precautions and side effects are described.

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“…A resistance-reversing effect due to the inhibition of the MDR1 transporter could be a factor in this synergy. [361] In clinical trials, azithromycin (100) was well tolerated as a prophylactic agent, [362] but less effective than doxycycline (97) against P. falciparum malaria. [363,364] Against P. vivax malaria, both were equally effective.…”

Section: Macrolidesmentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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Roxithromycin potentiates the effects of chloroquine and mefloquine on multidrug-resistant Plasmodium falciparum in vitro

Cited by 7 publications

References 22 publications

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

In Vitro Chemosensitization ofPlasmodium falciparumto Antimalarials by Verapamil and Probenecid

Antibiotics in Malaria Therapy and their Effect on the Parasite Apicoplast

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

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