Bruno Pradines - Academia.edu (original) (raw)

Papers by Bruno Pradines

Research paper thumbnail of Antibody Responses to Several Malaria Pre-Erythrocytic Antigens as a Marker of Malaria Exposure Among Travelers

The American Journal of Tropical Medicine and Hygiene, 2006

Research paper thumbnail of In Vitro Activities of Benflumetol against 158 Senegalese Isolates of Plasmodium falciparum in Comparison with Those of Standard Antimalarial Drugs

Antimicrobial Agents and Chemotherapy, 1999

The 50% inhibitory concentration (IC 50 s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) ... more The 50% inhibitory concentration (IC 50 s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates ( P < 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Malaria Prophylaxis Failure with Doxycycline, Central African Republic, 2014

Emerging Infectious Diseases, 2015

Human spotted fever group rickettsioses are underappreciated in southern Taiwan, particularly for... more Human spotted fever group rickettsioses are underappreciated in southern Taiwan, particularly for the species closely-related to Rickettsia felis.

Research paper thumbnail of Multinormal in vitro distribution of Plasmodium falciparum susceptibility to piperaquine and pyronaridine

Malaria journal, Jan 5, 2015

In 2002, the World Health Organization recommended that artemisinin-based combination therapy (AC... more In 2002, the World Health Organization recommended that artemisinin-based combination therapy (ACT) be used to treat uncomplicated malaria. Dihydroartemisinin-piperaquine and artesunate-pyronaridine are two of these new combinations. The aim of the present work was to assess the distribution of the in vitro values of pyronaridine (PND) and piperaquine (PPQ) and to define a cut-off for reduced susceptibility for the two anti-malarial drugs. The distribution and range of the 50% inhibitory concentration values (IC50) of PND and PPQ were determined for 313 isolates obtained between 2008 and 2012 from patients hospitalized in France for imported malaria. The statistical Bayesian analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to PND and PPQ. The PND IC50 values ranged from 0.6 to 84.6 nM, with a geometric mean of 21.1 ± 16.0 nM (standard deviation). These values were classified into three components. The P...

Research paper thumbnail of Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs

Malaria journal, Jan 14, 2011

The aim of this study was to evaluate the cultivation system in which the proper atmospheric cond... more The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine) by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2 and 10% O2). The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2) were significantly higher than those of Genbag® conditions ...

Research paper thumbnail of Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure

Malaria journal, Jan 7, 2006

Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. ... more Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated. The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed. The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In ...

Research paper thumbnail of Ferroquine: A Concealed Weapon

Molecular Approaches toward Targeted Drug Development, 2011

ABSTRACT The development of ferroquine (FQ; SR97193) is the result of a successful strategy consi... more ABSTRACT The development of ferroquine (FQ; SR97193) is the result of a successful strategy consisting of the incorporation of a ferrocene moiety into the structure of chloroquine (CQ) to overcome the resistance of Plasmodium falciparum to the parent drug, or to improve its antimalarial action. This approach has been applied to several classes of known antimalarials (arylaminoalcohols, artemisinin derivatives, naphthoquinones), without any real gain of activity. Nevertheless, the modification of amino-4-quinolines and, more recently, of fluoroquinolones has provided highly significant results. The efficacy of ferrocene-quinoline antimalarials is directly dependent not only on the position of ferrocene in the molecule, but also on several other properties of the drugs. Among numerous molecules synthesized, FQ appears so far to be the most promising among antimalarials currently in development. The potent activity of FQ and the absence of cross-resistance with other antimalarials were demonstrated both in vitro on a large number of clones and field isolates of P. falciparum, and in vivo on rodent models that demonstrated the high bioavailability of the product. Excellent properties of FQ were observed during a pharmacology survey. The drug has been developed by Sanofi-Aventis, and is currently in Phase IIb clinical trials.

Research paper thumbnail of Paludisme d’aéroport

La Presse Médicale, 2009

Airport malaria is a particular form of autochthonous malaria: it happens when the Plasmodium inf... more Airport malaria is a particular form of autochthonous malaria: it happens when the Plasmodium infected Anopheles genus mosquito travels from an endemic area to a malaria free airport. Since 1969, 30 cases of airport malaria have been reported in France, 2 during summer 2008. The severity of airport malaria is explained by the frequency of Plasmodium falciparum infecting non immune individuals and an often important diagnosis delay. It is a compulsory notification disease in France. The International Health Regulations (IHR) require states to check that airplanes coming from malaria or arboviral endemic area are systematically disinsected. Vector control measures have to be implemented within a distance of at least 400 meters around the perimeter of airports in malaria or arboviral endemic areas. In France, this measure applies to all airports of French overseas territories, except for the island of Saint-Pierre and Miquelon.

Research paper thumbnail of Apport de la biologie moléculaire dans le diagnostic de la toxoplasmose chez le transplanté rénal

Revue Française des Laboratoires, 2003

Research paper thumbnail of Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the Republic of Ivory Coast

The increased spread of drug-resistant malaria highlights the need for alternative drugs for trea... more The increased spread of drug-resistant malaria highlights the need for alternative drugs for treatment and chemoprophylaxis. The combination of atovaquone-proguanil (Malarone W) has shown high efficacy against Plasmodium falciparum with only mild side-effects. Treatment failures have been attributed to suboptimal dosages or to parasite resistance resulting from a point mutation in the cytochrome b gene. In this paper, a case of early treatment failure was reported in a patient treated with atovaquone-proguanil; this failure was not associated with a mutation in the parasite cytochrome b gene, with impaired drug bioavailability, or with re-infection.

Research paper thumbnail of Albumin-bound nanoparticles of practically water-insoluble antimalarial lead greatly enhance its efficacy

International Journal of Pharmaceutics, 2014

We recently showed that the indolone-N-oxides can be promising candidates for the treatment of ch... more We recently showed that the indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30 min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25 mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.

Research paper thumbnail of 1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-β-lactam conjugates: Synthesis and antimalarial evaluation

European Journal of Medicinal Chemistry, 2014

A series of ferrocenylchalcone-b-lactam conjugates were synthesized and evaluated against 3D7 (CQ... more A series of ferrocenylchalcone-b-lactam conjugates were synthesized and evaluated against 3D7 (CQ-Sensitive) and W2 (CQ-Resistant) strains of Plasmodium falciparum. The SAR studies revealed the dependence of activities at N-1 substituent of b-lactam ring with compounds being more potent on resistant strain. The compound 9f and 9l with N-cyclohexyl substituent proved to be the most potent and non-cytotoxic among the series exhibiting IC 50 values of 2.36 and 2.43 mM respectively, against W2 strain of P. falciparum.

Research paper thumbnail of Response to: Chemoresistance in falciparum malaria

Trends in Parasitology, 2003

Abstract In Senegal and Gabon, in addition to malaria imported into France from West and Central ... more Abstract In Senegal and Gabon, in addition to malaria imported into France from West and Central Africa, there is no evidence of frequency variation of in vitro chloroquine-resistance of Plasmodium falciparum in the past ten years.

Research paper thumbnail of In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger transporter (Pfnhe-1) gene in 393 isolates from Dakar, Senegal

Malaria Journal, 2013

Background Although the World Health Organization recommends replacing quinine (QN) by artesunate... more Background Although the World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa. Investigations of microsatellite Pfnhe-1 ms4760 polymorphisms in culture-adapted isolates from around the world have revealed that an increase in the number of DNNND amino acid motifs was associated with decreased QN susceptibility, whereas an increase in the number of DDNHNDNHNND motifs was associated with increased QN susceptibility. Methods In this context, to further analyse associations between Pfnhe-1 ms4760 polymorphisms and QN susceptibility, 393 isolates freshly collected between October 2009 and January 2010 and July 2010 and February 2011, respectively, at the Hôpital Principal de Dakar, Senegal were assessed ex vivo for QN susceptibility, and their genes were amplified and sequenced. Results Of the 393 Pla...

Research paper thumbnail of Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

Malaria Journal, 2012

Background The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) an... more Background The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN). Methods The susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method. Results The IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM) and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM). A significant positive correlation was shown between responses to PPQ and PND responses (rho =...

Research paper thumbnail of Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000–2011

Malaria Journal, 2013

Background: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990... more Background: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. Methods: The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. Results: A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC 50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = −0.3, p < 10-3). Conclusions: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011and they correlated to the decrease of the drug pressure.

Research paper thumbnail of Remote Sensing and Malaria Risk for Military Personnel in Africa

Journal of Travel Medicine, 2008

N onimmune civilians and military personnel traveling in malaria-endemic areas are exposed to tra... more N onimmune civilians and military personnel traveling in malaria-endemic areas are exposed to transmission and may experience clinical malaria attacks during or after their travel. In the French armies, individual malaria control is based on the use of diethyltoluamide-based insect repellents, clothing that covers the arms and legs (long clothes), deltamethrin-impregnated bed nets, and

Research paper thumbnail of Modeling ofPlasmodium falciparum–Infected Erythrocyte Cytoadhesion in Microvascular Conditions: Chondroitin‐4‐Sulfate Binding, A Competitive Phenotype

The Journal of Infectious Diseases, 2003

Although chondroitin-4-sulfate (CSA) is expressed throughout the microvasculature and CSA-binding... more Although chondroitin-4-sulfate (CSA) is expressed throughout the microvasculature and CSA-binding infected erythrocytes (IE CSA) cytoadhere to lung and brain endothelial cells and sequester in male Saimiri sciureus, this phenotype seems to be dependent on the presence of a placenta to develop. This contradiction was investigated by modeling the interactions and cytoadhesion parameters in the microvasculature. Mixtures of IEs interacting with CSA, CD36, or intercellular adhesion molecule 1 were incubated with endothelial cells expressing the corresponding receptors, at physiological pH, under flow conditions. By use of suspensions composed of equal proportions of the phenotypes, cytoadhesion of ∼10 times as many IE CSA as of any other IE tested was observed. Adherent IE CSA resisted microvascular wall shear stresses 3-15 times more effectively than did the others. These results, which require confirmation with field isolates, demonstrate that the CSA phenotype is competitive and are consistent with this phenotype initiating microvessel occlusion and with CSA-mediated sequestration in microvessel conditions.

Research paper thumbnail of Susceptibility ofPlasmodium falciparumIsolates to Doxycycline Is Associated withpftetQSequence Polymorphisms andpftetQandpfmdtCopy Numbers

The Journal of Infectious Diseases, 2010

Research paper thumbnail of Molecular surveillance of drug-resistant Plasmodium vivax using pvdhfr, pvdhps and pvmdr1 markers in Nouakchott, Mauritania

Journal of Antimicrobial Chemotherapy, 2011

Plasmodium falciparum and Plasmodium vivax occur in Mauritania. Drug-resistant P. falciparum has ... more Plasmodium falciparum and Plasmodium vivax occur in Mauritania. Drug-resistant P. falciparum has been reported, but the drug-resistance status of P. vivax is unknown. The aims of the present study were to determine the prevalence of mutant pvdhfr, pvdhps and pvmdr1 genes and of pvmdr1 gene amplification in P. vivax isolates in Nouakchott, the capital city of Mauritania, and to establish a baseline for molecular surveillance of drug-resistant P. vivax in the country. Patients and methods: Between 2007 and 2009, 439 febrile patients were screened for malaria in Nouakchott. The sequences of pvdhfr, pvdhps and pvmdr1 markers in 110 P. vivax isolates were determined by direct sequencing of PCR products. The pvmdr1 gene copy number was determined by real-time PCR. The majority of the isolates with a successful PCR amplification (76/86, 88%) were characterized to be of the wild-type pvdhfr genotype, while the remaining 10 isolates carried the S58R and S117N double mutations. All isolates had the wild-type pvdhps genotype SAKAV. For pvmdr1, 75 of 103 (73%) had the wild-type Y976, and 28 (27%) carried the mutant F976. Most (98%) carried the mutant L1076 codon. Of 105 isolates, 102 (97%) had one copy and 3 (3%) had two copies of the pvmdr1 gene. The prevalence of mutations associated with antifolate resistance is low in Mauritania. Further studies are required to determine the roles of pvmdr1 mutations and gene amplification in conferring drug resistance. These data will serve as a baseline for further monitoring of drug-resistant malaria.

Research paper thumbnail of Antibody Responses to Several Malaria Pre-Erythrocytic Antigens as a Marker of Malaria Exposure Among Travelers

The American Journal of Tropical Medicine and Hygiene, 2006

Research paper thumbnail of In Vitro Activities of Benflumetol against 158 Senegalese Isolates of Plasmodium falciparum in Comparison with Those of Standard Antimalarial Drugs

Antimicrobial Agents and Chemotherapy, 1999

The 50% inhibitory concentration (IC 50 s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) ... more The 50% inhibitory concentration (IC 50 s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates ( P < 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Research paper thumbnail of Malaria Prophylaxis Failure with Doxycycline, Central African Republic, 2014

Emerging Infectious Diseases, 2015

Human spotted fever group rickettsioses are underappreciated in southern Taiwan, particularly for... more Human spotted fever group rickettsioses are underappreciated in southern Taiwan, particularly for the species closely-related to Rickettsia felis.

Research paper thumbnail of Multinormal in vitro distribution of Plasmodium falciparum susceptibility to piperaquine and pyronaridine

Malaria journal, Jan 5, 2015

In 2002, the World Health Organization recommended that artemisinin-based combination therapy (AC... more In 2002, the World Health Organization recommended that artemisinin-based combination therapy (ACT) be used to treat uncomplicated malaria. Dihydroartemisinin-piperaquine and artesunate-pyronaridine are two of these new combinations. The aim of the present work was to assess the distribution of the in vitro values of pyronaridine (PND) and piperaquine (PPQ) and to define a cut-off for reduced susceptibility for the two anti-malarial drugs. The distribution and range of the 50% inhibitory concentration values (IC50) of PND and PPQ were determined for 313 isolates obtained between 2008 and 2012 from patients hospitalized in France for imported malaria. The statistical Bayesian analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to PND and PPQ. The PND IC50 values ranged from 0.6 to 84.6 nM, with a geometric mean of 21.1 ± 16.0 nM (standard deviation). These values were classified into three components. The P...

Research paper thumbnail of Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti-malarial drugs

Malaria journal, Jan 14, 2011

The aim of this study was to evaluate the cultivation system in which the proper atmospheric cond... more The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag® system associated with the atmospheric generators for capnophilic bacteria Genbag CO2® was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine) by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2® system and compared to controlled incubator conditions (5% CO2 and 10% O2). The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2) were significantly higher than those of Genbag® conditions ...

Research paper thumbnail of Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure

Malaria journal, Jan 7, 2006

Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. ... more Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated. The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed. The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In ...

Research paper thumbnail of Ferroquine: A Concealed Weapon

Molecular Approaches toward Targeted Drug Development, 2011

ABSTRACT The development of ferroquine (FQ; SR97193) is the result of a successful strategy consi... more ABSTRACT The development of ferroquine (FQ; SR97193) is the result of a successful strategy consisting of the incorporation of a ferrocene moiety into the structure of chloroquine (CQ) to overcome the resistance of Plasmodium falciparum to the parent drug, or to improve its antimalarial action. This approach has been applied to several classes of known antimalarials (arylaminoalcohols, artemisinin derivatives, naphthoquinones), without any real gain of activity. Nevertheless, the modification of amino-4-quinolines and, more recently, of fluoroquinolones has provided highly significant results. The efficacy of ferrocene-quinoline antimalarials is directly dependent not only on the position of ferrocene in the molecule, but also on several other properties of the drugs. Among numerous molecules synthesized, FQ appears so far to be the most promising among antimalarials currently in development. The potent activity of FQ and the absence of cross-resistance with other antimalarials were demonstrated both in vitro on a large number of clones and field isolates of P. falciparum, and in vivo on rodent models that demonstrated the high bioavailability of the product. Excellent properties of FQ were observed during a pharmacology survey. The drug has been developed by Sanofi-Aventis, and is currently in Phase IIb clinical trials.

Research paper thumbnail of Paludisme d’aéroport

La Presse Médicale, 2009

Airport malaria is a particular form of autochthonous malaria: it happens when the Plasmodium inf... more Airport malaria is a particular form of autochthonous malaria: it happens when the Plasmodium infected Anopheles genus mosquito travels from an endemic area to a malaria free airport. Since 1969, 30 cases of airport malaria have been reported in France, 2 during summer 2008. The severity of airport malaria is explained by the frequency of Plasmodium falciparum infecting non immune individuals and an often important diagnosis delay. It is a compulsory notification disease in France. The International Health Regulations (IHR) require states to check that airplanes coming from malaria or arboviral endemic area are systematically disinsected. Vector control measures have to be implemented within a distance of at least 400 meters around the perimeter of airports in malaria or arboviral endemic areas. In France, this measure applies to all airports of French overseas territories, except for the island of Saint-Pierre and Miquelon.

Research paper thumbnail of Apport de la biologie moléculaire dans le diagnostic de la toxoplasmose chez le transplanté rénal

Revue Française des Laboratoires, 2003

Research paper thumbnail of Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the Republic of Ivory Coast

The increased spread of drug-resistant malaria highlights the need for alternative drugs for trea... more The increased spread of drug-resistant malaria highlights the need for alternative drugs for treatment and chemoprophylaxis. The combination of atovaquone-proguanil (Malarone W) has shown high efficacy against Plasmodium falciparum with only mild side-effects. Treatment failures have been attributed to suboptimal dosages or to parasite resistance resulting from a point mutation in the cytochrome b gene. In this paper, a case of early treatment failure was reported in a patient treated with atovaquone-proguanil; this failure was not associated with a mutation in the parasite cytochrome b gene, with impaired drug bioavailability, or with re-infection.

Research paper thumbnail of Albumin-bound nanoparticles of practically water-insoluble antimalarial lead greatly enhance its efficacy

International Journal of Pharmaceutics, 2014

We recently showed that the indolone-N-oxides can be promising candidates for the treatment of ch... more We recently showed that the indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30 min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25 mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.

Research paper thumbnail of 1H-1,2,3-triazole tethered mono- and bis-ferrocenylchalcone-β-lactam conjugates: Synthesis and antimalarial evaluation

European Journal of Medicinal Chemistry, 2014

A series of ferrocenylchalcone-b-lactam conjugates were synthesized and evaluated against 3D7 (CQ... more A series of ferrocenylchalcone-b-lactam conjugates were synthesized and evaluated against 3D7 (CQ-Sensitive) and W2 (CQ-Resistant) strains of Plasmodium falciparum. The SAR studies revealed the dependence of activities at N-1 substituent of b-lactam ring with compounds being more potent on resistant strain. The compound 9f and 9l with N-cyclohexyl substituent proved to be the most potent and non-cytotoxic among the series exhibiting IC 50 values of 2.36 and 2.43 mM respectively, against W2 strain of P. falciparum.

Research paper thumbnail of Response to: Chemoresistance in falciparum malaria

Trends in Parasitology, 2003

Abstract In Senegal and Gabon, in addition to malaria imported into France from West and Central ... more Abstract In Senegal and Gabon, in addition to malaria imported into France from West and Central Africa, there is no evidence of frequency variation of in vitro chloroquine-resistance of Plasmodium falciparum in the past ten years.

Research paper thumbnail of In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger transporter (Pfnhe-1) gene in 393 isolates from Dakar, Senegal

Malaria Journal, 2013

Background Although the World Health Organization recommends replacing quinine (QN) by artesunate... more Background Although the World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa. Investigations of microsatellite Pfnhe-1 ms4760 polymorphisms in culture-adapted isolates from around the world have revealed that an increase in the number of DNNND amino acid motifs was associated with decreased QN susceptibility, whereas an increase in the number of DDNHNDNHNND motifs was associated with increased QN susceptibility. Methods In this context, to further analyse associations between Pfnhe-1 ms4760 polymorphisms and QN susceptibility, 393 isolates freshly collected between October 2009 and January 2010 and July 2010 and February 2011, respectively, at the Hôpital Principal de Dakar, Senegal were assessed ex vivo for QN susceptibility, and their genes were amplified and sequenced. Results Of the 393 Pla...

Research paper thumbnail of Ex vivo activity of the ACT new components pyronaridine and piperaquine in comparison with conventional ACT drugs against isolates of Plasmodium falciparum

Malaria Journal, 2012

Background The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) an... more Background The aim of the present work was to assess i) ex vivo activity of pyronaridine (PND) and piperaquine (PPQ), as new components of artemisinin-based combination therapy (ACT), to define susceptibility baseline, ii) their activities compared to other partner drugs, namely monodesethylamodiaquine (MDAQ), lumefantrine (LMF), mefloquine (MQ), artesunate (AS) and dihydroartemisinin (DHA) against 181 Plasmodium falciparum isolates from African countries, India and Thailand, and iii) in vitro cross-resistance with other quinoline drugs, chloroquine (CQ) or quinine (QN). Methods The susceptibility of the 181 P. falciparum isolates to the nine anti-malarial drugs was assessed using the standard 42-hours 3H-hypoxanthine uptake inhibition method. Results The IC50 values for PND ranged from 0.55 to 80.0 nM (geometric mean = 19.9 nM) and from 11.8 to 217.3 nM for PPQ (geometric mean = 66.8 nM). A significant positive correlation was shown between responses to PPQ and PND responses (rho =...

Research paper thumbnail of Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000–2011

Malaria Journal, 2013

Background: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990... more Background: Chloroquine (CQ) was the main malaria therapy worldwide from the 1940s until the 1990s. Following the emergence of CQ-resistant Plasmodium falciparum, most African countries discontinued the use of CQ, and now promote artemisinin-based combination therapy as the first-line treatment. This change was generally initiated during the last decade in West and Central Africa. The aim of this study is to describe the changes in CQ susceptibility in this African region, using travellers returning from this region as a sentinel system. Methods: The study was conducted by the Malaria National Reference Centre, France. The database collated the pfcrtK76T molecular marker for CQ susceptibility and the in vitro response to CQ of parasites from travellers' isolates returning from Senegal, Mali, Ivory Coast or Cameroon. As a proxy of drug pressure, data regarding CQ intake in febrile children were collated for the study period. Logistic regression models were used to detect trends in the proportions of CQ resistant isolates. Results: A total of 2874 parasite isolates were genotyped between 2000-2011. The prevalence of the pfcrt76T mutant genotype significantly decreased for Senegal (from 78% to 47%), Ivory Coast (from 63% to 37%), Cameroon (from 90% to 59%) and remained stable for Mali. The geometric mean of the 50% inhibitory concentration (IC 50) of CQ in vitro susceptibility and the proportion of resistant isolates (defining resistance as an IC50 value > 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = −0.3, p < 10-3). Conclusions: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011and they correlated to the decrease of the drug pressure.

Research paper thumbnail of Remote Sensing and Malaria Risk for Military Personnel in Africa

Journal of Travel Medicine, 2008

N onimmune civilians and military personnel traveling in malaria-endemic areas are exposed to tra... more N onimmune civilians and military personnel traveling in malaria-endemic areas are exposed to transmission and may experience clinical malaria attacks during or after their travel. In the French armies, individual malaria control is based on the use of diethyltoluamide-based insect repellents, clothing that covers the arms and legs (long clothes), deltamethrin-impregnated bed nets, and

Research paper thumbnail of Modeling ofPlasmodium falciparum–Infected Erythrocyte Cytoadhesion in Microvascular Conditions: Chondroitin‐4‐Sulfate Binding, A Competitive Phenotype

The Journal of Infectious Diseases, 2003

Although chondroitin-4-sulfate (CSA) is expressed throughout the microvasculature and CSA-binding... more Although chondroitin-4-sulfate (CSA) is expressed throughout the microvasculature and CSA-binding infected erythrocytes (IE CSA) cytoadhere to lung and brain endothelial cells and sequester in male Saimiri sciureus, this phenotype seems to be dependent on the presence of a placenta to develop. This contradiction was investigated by modeling the interactions and cytoadhesion parameters in the microvasculature. Mixtures of IEs interacting with CSA, CD36, or intercellular adhesion molecule 1 were incubated with endothelial cells expressing the corresponding receptors, at physiological pH, under flow conditions. By use of suspensions composed of equal proportions of the phenotypes, cytoadhesion of ∼10 times as many IE CSA as of any other IE tested was observed. Adherent IE CSA resisted microvascular wall shear stresses 3-15 times more effectively than did the others. These results, which require confirmation with field isolates, demonstrate that the CSA phenotype is competitive and are consistent with this phenotype initiating microvessel occlusion and with CSA-mediated sequestration in microvessel conditions.

Research paper thumbnail of Susceptibility ofPlasmodium falciparumIsolates to Doxycycline Is Associated withpftetQSequence Polymorphisms andpftetQandpfmdtCopy Numbers

The Journal of Infectious Diseases, 2010

Research paper thumbnail of Molecular surveillance of drug-resistant Plasmodium vivax using pvdhfr, pvdhps and pvmdr1 markers in Nouakchott, Mauritania

Journal of Antimicrobial Chemotherapy, 2011

Plasmodium falciparum and Plasmodium vivax occur in Mauritania. Drug-resistant P. falciparum has ... more Plasmodium falciparum and Plasmodium vivax occur in Mauritania. Drug-resistant P. falciparum has been reported, but the drug-resistance status of P. vivax is unknown. The aims of the present study were to determine the prevalence of mutant pvdhfr, pvdhps and pvmdr1 genes and of pvmdr1 gene amplification in P. vivax isolates in Nouakchott, the capital city of Mauritania, and to establish a baseline for molecular surveillance of drug-resistant P. vivax in the country. Patients and methods: Between 2007 and 2009, 439 febrile patients were screened for malaria in Nouakchott. The sequences of pvdhfr, pvdhps and pvmdr1 markers in 110 P. vivax isolates were determined by direct sequencing of PCR products. The pvmdr1 gene copy number was determined by real-time PCR. The majority of the isolates with a successful PCR amplification (76/86, 88%) were characterized to be of the wild-type pvdhfr genotype, while the remaining 10 isolates carried the S58R and S117N double mutations. All isolates had the wild-type pvdhps genotype SAKAV. For pvmdr1, 75 of 103 (73%) had the wild-type Y976, and 28 (27%) carried the mutant F976. Most (98%) carried the mutant L1076 codon. Of 105 isolates, 102 (97%) had one copy and 3 (3%) had two copies of the pvmdr1 gene. The prevalence of mutations associated with antifolate resistance is low in Mauritania. Further studies are required to determine the roles of pvmdr1 mutations and gene amplification in conferring drug resistance. These data will serve as a baseline for further monitoring of drug-resistant malaria.