Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of
            <i>Plasmodium falciparum</i>

Fivelman, Quinton L.; Adagu, I. S.; Warhurst, David C.

doi:10.1128/aac.48.11.4097-4102.2004

Cited by 262 publications

(304 citation statements)

References 32 publications

(36 reference statements)

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“…SB1-A6 is similarly sensitive to proguanil in the presence of 100nM 6-NH 2 Ac (data not shown). No such effect is evident in TM90C2B (proguanil IC 50 >5μM with or without atovaquone or 6-NH 2 Ac), consistent with previous results in the TM90C2B [14] and other [23] atovaquone-resistant parasites with identified mutations at codon 268 of cyt b. A hypothesis to account for parasitespecific synergy between proguanil and atovaquone has been proposed, but remains speculative [20].…”

supporting

confidence: 78%

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Smilkstein

Forquer

Kanazawa

et al. 2008

Molecular and Biochemical Parasitology

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Mitochondrial electron transport is essential for survival in Plasmodium falciparum, making the cytochrome (cyt) bc 1 complex an attractive target for antimalarial drug development. Here we report that P. falciparum cultivated in the presence of a novel cyt bc 1 inhibitor underwent a fundamental transformation in biochemistry to a phenotype lacking a requirement for electron transport through the cyt bc 1 complex. Growth of the drug-selected parasite clone (SB1-A6) is robust in the presence of diverse cyt bc 1 inhibitors, although electron transport is fully inhibited by these same agents. This transformation defies expected molecular-based concepts of drug resistance, has important implications for the study of cyt bc 1 as an antimalarial drug target, and may offer a glimpse into the evolutionary future of Plasmodium.Unlike most other eukaryotic cells, Plasmodia do not rely on mitochondrial electron transport for energy production. Nonetheless, inhibition of cyt bc 1 complex electron transport is normally lethal to the parasite, presumably by interruption of essential links to de novo pyrimidine biosynthesis, via dihydroorotate dehydrogenase (DHODH), and to maintenance of the mitochondrial membrane potential. Although these interrelationships determine the viability of the parasite and our ability to reduce that viability, they are only generally understood. Review of Plasmodial electron transport and cyt bc 1 complex function are beyond the scope of this report, but in-depth discussions are available [1][2][3].The anti-malarial drug atovaquone occupies the quinol oxidase (Q o ) site of mitochondrial cyt b, inhibiting electron flux through the cyt bc 1 complex (ubiquinol:cytochrome c oxidoreductase or complex III) and collapsing mitochondrial membrane potential with a potency 1000-fold greater in Plasmodium than mammalian cells [4,5]. Unfortunately, high rates of recrudescent infection and treatment failure were seen after anti-malarial use of atovaquone alone [6], and treatment failures after atovaquone-proguanil combination therapy (Malarone®) were soon evident [7,8] despite only limited worldwide anti-malarial use. The rapid development and the diversity of atovaquone-resistant phenotypes and genotypes (perhaps a consequence of its mechanism of action [9]), the parallel evolution of resistance-encoding mutations [10] and their appearance with or without atovaquone exposure [11] in dispersed geographic locations, all indicate the strong propensity for atovaquone resistance. The hope that this risk can be overcome by appropriate combination therapy or by novel inhibitors continues to drive efforts to discover and develop cyt bc 1 inhibitor anti-malarials [12].Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that ...

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supporting

confidence: 78%

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Smilkstein

Forquer

Kanazawa

et al. 2008

Molecular and Biochemical Parasitology

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“…4) is active against chloroquine-resistant plasmodium strains [51] but is associated with a high risk of cardiac arrhythmias (prolongation of QT-interval caused by an inhibition of the inward K + -current) [23, 52 -54]. Therefore, halofantrine 5 has been withdrawn from the market in several countries.…”

Section: Halofantrinementioning

confidence: 99%

“…This pathway is inhibited by proguanil 15 resulting in a rapid breakdown of membrane potential [107]. Through this synergism, the selection of resistant strains during therapy is reduced, but once a strain has become resistant to atovaquone 19, it is also resistant against the combination with proguanil 15 [51]. The combination of atovaquone 19 and proguanil 15 (Malaronem) is used for prophylaxis and therapy of uncomplicated malaria tropica [102,108,109].…”

Section: Inhibitors Of the Respiratory Chain Atovaquone/proguanilmentioning

confidence: 99%

Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer¹

2008

Archiv der Pharmazie

131

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Malaria continues to be a potentially fatal threat to almost half of the world's population. In light of this threat, the armory to fight this disease is rather limited. Resistance against the most common and affordable antimalarials is widespread. Only few new drugs are in clinical development, most of them belong to long used classes of antimalarial drugs. This review will concisely cover the drugs which are currently in use, and describe the drug candidates which are in clinical evaluation.

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“…The detection of synergism may also be useful in illuminating mechanism of drug action and in the development of new theories. 14,15 It is therefore possible to upsurge the analgesic efficacy and potency of xylopic acid and pregabalin and correspondingly decrease their side effects via combination therapy.…”

Section: Introductionmentioning

confidence: 99%

Anti-Nociceptive Synergism of Pregabalin and Xylopic acid Co-administration in Paclitaxel induced Neuropathy: Isobolographic Analysis

Ofori¹,

Woode²,

Kyei³

et al. 2015

Phcog J

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Background: Paclitaxel-induced neuropathy still remains a clinical problem for patients undergoing chemotherapy. Objective: The objective of the study was to determine the interaction between xylopic acid and pregabalinco-administration as well as their toxicity in paclitaxel-induced neuropathy. Materials and Methods: Neuropathic pain was induced in rats with 2 mg/ kg of paclitaxel on four alternate days (days 0, 2, 4 and 6). Equi effective doses of xylopic acid and pregabalin that produced 50% anti-nociception (ED 50 ) were determined from their log-dose response curves in the cold allodynia and thermal pain tests. Xylopic acid and pregabalin were again administered to rats in a fixed ratio combination (1:1) of their ED 50 's in order to determine the experimental ED 50 (Z exp ) of the co-administered compounds. Isobolograms were constructed to compare the Z exp to a theoretical ED 50 (Z add ). Blood samples from the various treatment groups of rats were collected for toxicological assessment of the co-administered compounds. Results: The Z exp lay below the Z add on the isobologram of the cold allodnia test. The co-administration exhibited additivity in the thermal pain test. The co-administration did not produce significant (p>0.05) toxicity in rats. The co-administration may be beneficial in paclitaxel-induced neuropathy.Key words: Isobolograms, Neuropathic pain, Paclitaxel, xylopic acid, Toxicity. SUMMARY• Paclitaxel-induced neuropathy is still a clinical problem.• Pregabalin and Xylopic acid co-administration produced anti-nociceptive synergism against this pain type.• The co-administration was fairly safe in animals. PICTORIAL ABSTRACTAbbreviations used: XA: Xylopic acid, PG: Pregabalin, Z add : Theoritical ED 50 , Z exp : Experimental ED 50 .

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Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

Cited by 262 publications

References 32 publications

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

A drug-selected Plasmodium falciparum lacking the need for conventional electron transport

Antimalarial Drugs – What is in Use and What is in the Pipeline

Anti-Nociceptive Synergism of Pregabalin and Xylopic acid Co-administration in Paclitaxel induced Neuropathy: Isobolographic Analysis

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