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Biomedical subjects

B Pradines

Publications and source records attributed to B Pradines.

At least 19 recordsLinked to original sources
PubMed2006

[Malaria vaccines: prospects and reality].

The development of a malaria vaccine has been accelerating in the last ten years. The number of clinical trials has increased and some malaria antigens have been tested in endemic areas. No potential vaccine has yet shown sufficient and lasting efficacy to justify its inclusion in a public health program. However, trials have unambiguously shown that some level of anti-malaria clinical immunity can be achieved by vaccination, both in experimental and in field conditions. Advances in malaria vaccine development are presented.

Animals↗
PubMed2006

In vitro activity of iron-binding compounds against Senegalese isolates of Plasmodium falciparum.

OBJECTIVES: The in vitro activities of FR160, a synthetic catecholate siderophore, and two iron-binding agents, desferrioxamine and doxycycline, were evaluated against Plasmodium falciparum isolates. Correlations between these compounds and standard antimalarial drugs (chloroquine, quinine, amodiaquine, pyronaridine, artemether, artesunate, atovaquone, cycloguanil and pyrimethamine) were assessed to determine any degree of cross-resistance. METHODS: Between October 1997 and February 1998, and September and November 1998, 189 P. falciparum isolates were obtained in Dielmo and Ndiop (Dakar). Their susceptibilities were assessed using an isotopic, microwell format, drug susceptibility test. RESULTS: The 137 inhibitory concentrations (IC(50)) values of FR160 ranged from 0.1 to 10 microM and the geometric mean IC(50) was 1.48 microM (95% CI = 1.29-1.68 microM). The geometric mean IC(50) of doxycycline for 121 isolates was 18.9 microM (95% CI = 16.8-21.3 microM) and that of desferrioxamine for 73 isolates was 20.7 microM (95% CI = 17.3-24.8 microM). FR160 was significantly less active against the chloroquine-resistant isolates (P < 0.0001). The mean IC(50)s of doxycycline were significantly higher for the chloroquine-susceptible isolates than for the resistant parasites (P = 0.0447). There was a weak correlation between the responses to FR160, desferrioxamine or doxycycline and those to the other antimalarial compounds (r(2) < 0.22). CONCLUSIONS: The activities of FR160 and desferrioxamine, determined for P. falciparum clones, were confirmed against 137 isolates. The coefficients of determination between the responses to FR160, doxycycline or desferrioxamine and those to all the antimalarial drugs tested are too weak to suggest cross-resistance. FR160 could be a rationale partner to use in combination with doxycycline.

Animals↗
PubMed2005

[Chemosusceptibility analysis of Plasmodium falciparum imported from Comoros to Marseilles, France in 2001-2003].

OBJECTIVES: The aim of this work was to study the chemosensitivity of Plasmodium falciparum strains isolated from patients presenting with malaria after having returned from Comoros Islands in 2002-2003, and hospitalized at the North University Hospital, in Marseilles, France. MATERIALS AND METHODS: In vitro drug susceptibility (for strains maintained in culture) and mutation-specific polymerase chain reaction (PCR) assays (for all strains) were performed. RESULTS: Out of 23 strains kept in culture, 50% were shown to be resistant in vitro to chloroquine, 50% were resistant to pyrimethamine, 40% to cycloguanil, 25% to atovaquone, and 7% to mefloquine. However all these strains were susceptible to quinine, halofantrine, and artemether. Moreover, 48 strains were tested by molecular methods. As a result, 69% were shown to have the Asp108 mutation in the dihydrofolate reductase gene (Pfdhfr), the basic mutation associated with antifolate resistance, and 54% had additional mutations Ile51 plus Arg59, associated with a high level of resistance. Furthermore, 90% of the 20 strains tested in 2003 were shown to have the point mutation Pfcrt76 in the P. falciparum chloroquine resistance transporter (Pfcrt) gene recently proposed as a molecular marker of chloroquine-resistance. CONCLUSION: Obtaining plasmodium strains from Comoros to be tested in Marseilles, where all laboratory facilities are available, is a unique opportunity to establish a surveillance of falciparum drug resistance in the Comoros islands.

Animals↗
PubMed2005

[Metallocenes and malaria: a new therapeutic approach].

Rapid development of significant resistance to antimalarial drugs has been a major force driving research to identify and develop new compounds. The use of synthetic organometallic complexes seems to be promising for treatment of malaria infections. Recent progress in identification and development of new drugs promises to lead to a much greater range of antimalarial agents. Organometallic complexes and metalloporphyrins have shown in vitro activity against Plasmodium falciparum. Ferroquine (ferrocenyl chloroquine) is more active than chloroquine against strains and isolates of P. falciparum and shows efficacy against murine parasites.

Animals↗
PubMed2005

[Evaluating malaria attributable morbidity in endemic areas].

There are no specific clinical signs or symptoms of malaria. Fever attacks, anemia, or signs of severity like coma or respiratory distress cannot easily be attributed to malaria in people who are infected most of the time. Ascribing clinical manifestations to malaria is problematic in populations that are regularly exposed to the transmission of human plasmodia. The more transmission is intense and regular, the higher the prevalence of asymptomatic infections. In areas of intense and perennial malaria transmission, more than 90% of the population may be infected and the simple detection of a plasmodial infection is not enough to attribute clinical manifestations to malaria. Naturally acquired anti-malaria immunity permitting asymptomatic infections is incomplete and temporary. It is an obstacle to the estimation of the malaria burden in endemic areas. The positive association between parasite density and fever allows the attribution of clinical attacks to malaria. The relationship between parasitaemia and the risk of fever is not continuous. An age- and endemicity-dependent threshold effect of parasite density has been demonstrated and can be used to distinguish clinical attacks due to malaria from others. Clinical diagnosis and evaluation of malaria are problematic in three situations: in public health to estimate the malaria burden for health services, in clinical research to evaluate treatments or prophylactic measures (drug, vaccine, anti-vectorial devices), and in basic research on pathophysiology, immunology or genetic susceptibility to clinical malaria. No one diagnostic definition nor procedure for detecting cases is adequate for all three purposes. Case detection may be passive (in health structures for example) or active (in population). The choice of methods for diagnosis and recruitment depends on the objectives and whether a "pragmatic" or "explicative" approach is used. The radical differences between these approaches are often unsuspected or ignored.

Adult↗
PubMed2003

[Malaria prophylaxis and treatment: problems, recent developments and perspectives].

Rapid development of significant resistance to antimalarials has been a major force driving research to identify and develop new drugs. Recent progress in this field promises to lead to a much greater range of antimalarial agents. The availability of a broader battery of drugs should provide a partial solution to the dilemma faced by malarial control agencies, i.e., distributing antimalarial drugs as widely as possible without enhancing resistance. Avenues of research for development of new antimalarials include lipid metabolism, degradation of hemoglobin and proteins, interaction with molecule transport, iron metabolism, apicoplasty and signal transduction. Throughout the course of evolution, micro-organisms have thwarted traps set by the environment including those designed by man. One can but hope that the different approaches now being implemented on a worldwide bases will overcome the defense mechanisms that Plasmodium have deployed in their long co-evolution with humans and anopheles.

Animals↗
PubMed2003

[Iron chelation in antimalarial therapy].

Rapid development of significant resistance to antimalarial drugs has been a major force driving research to identify and develop new compounds. A number of iron(III)-chelating compounds designed for purposes other than treating malaria have in vitro antimalarial activity stemming from iron deprivation or toxic effects related to free radical release. Several of the iron(III) chelators have been effective in animal models of plasmodial infection. Desferrioxamine has been used successfully against both uncomplicated and severe malaria in humans. Iron-chelating agents seem to be promising therapeutic adjuvants for treatment of severe Plasmodium falciparum malaria infection.

Animals↗
PubMed2002

In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs.

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, artesunate, atovaquone, cycloguanil and pyrimethamine were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo, Ndiop), using an isotopic micro-drug susceptibility test. The IC50 values for ferrochloroquine ranged from 0.55 to 28.2 nM and the geometric mean IC50 for the 55 isolates was 7.9 nM (95% CI, 6.5-9.7 nM). Ferrochloroquine was 35 times more active than chloroquine (35-fold greater against chloroquine-resistant isolates), quinine, mefloquine, amodiaquine, cycloguanil and pyrimethamine. Weak positive correlations were observed between the responses to ferrochloroquine and that to chloroquine, quinine, and amodiaquine, but not compulsorily predictive of cross-resistance. There was no significant correlation between the response to ferrochloroquine and that to mefloquine, halofantrine, artesunate, atovaquone, cycloguanil and pyrimethamine. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Animals↗
PubMed2002

Iron chelators as antimalarial agents: in vitro activity of dicatecholate against Plasmodium falciparum.

The present study was undertaken to explore the antimalarial effect of a series of dicatecholate iron chelators. They may be made more or less lipophilic by increasing or reducing the length of the R substituent on the nitrogen. In vitro activity against the W2 and 3D7 clones of Plasmodium falciparum, toxicity on Vero cells and toxicity on uninfected erythrocytes by measure of the released haemoglobin were assessed for each compound. These findings were compared with the ability of iron(III), iron(II) and ferritin to reverse the inhibitory effect of catecholates. This study shows that increased lipid solubility of catecholate iron chelators does not lead to improved antimalarial activity. However, their activity is well correlated with their interaction with iron and with their toxicity against Vero cells. This study demonstrates a potent antimalarial effect of FR160 (R = C9H19) on five different strains of P. falciparum in vitro. FR160 inhibited parasite growth with an IC50 between 0.8 and 1.5 micro M. The effects of FR160 on mammalian cells were minimal compared with those obtained with malaria parasites. FR160 acted on parasites at considerably higher rates than desferrioxamine, and at all stages of parasite growth. The drug was more effective at the late trophozoite and young schizont stages, although FR160 affected rings and schizonts as well. Ascorbic acid, a free radical scavenger, reduced the activities of FR160 and artesunate. FR160 might induce formation of free radicals, which could explain why FR160 antagonized the effects of artesunate and dihydroartemisinin.

Animals↗
PubMed2002

Profile and evolution of the chemosusceptibility of falciparum malaria imported into France in 2000.

In 2000, the chemosusceptibility of imported malaria was stable in France. All countries of infection considered, the bi-resistance to chloroquine and cycloguanil has not changed from 1996 to 2000. The monotherapy using quinine or mefloquine remains the first-line treatment to falciparum malaria. Resistance to these two antimalarials is rare in Africa and has not evolved over the past 15 years.

Adolescent↗
PubMed2002

[Mechanism of action of antimalarials. Value of combined atovaquone/proguanil].

Determining the mode of action of different antimalarial drugs at the cellular level is essential to optimizing their use and to understanding the mechanisms underlying plasmodial resistance. The main targets for antimalarial drugs in Plasmodium falciparum have been the food vacuole and mitochondrial system. A new target is recently discovered organelle named the apicoplast. The apicoplast is the site of a number of metabolic pathways crucial to the survival of the parasite. It may also be involved in DNA replication and transcription. Antimalarial drugs are classified into three groups according to site of action, i.e., drugs that act on the food vacuole, drugs that block metabolic synthesis and oxidative processes, and drugs that interfere with membrane processes. Knowledge of these sites of action has enabled identification of new drugs with the most promising potential for development. Current antimalarial strategies prioritize combination therapies such as atovaquone/proguanil or artemether/lumefantrine and prolonged treatments to limit the risk of inducing drug resistant Plasmodium.

Animals↗
PubMed2002

[Re-assessment of culture inhibition assays and reinvasion of P. falciparum for the appraisal of immunity of individuals living in an endemic area].

We conducted an analysis to reevaluate the in vitroculture inhibition assays as a reliable criteria of functional activity of anti-P. falcipanrm antibodies in premunized individuals. Several strains of P. falcipanrm adapted to in vitro culture were compared, and various technical conditions of parasite growth factors such as culture medium or incubation conditions were explored. A subsequent degree of variation was evidenced related to the parasite strain used and the culture conditions. The culture inhibition and the merozoite reinvasion inhibition assays were performed using a collection of plasma from premunized individuals living in two different endemic area of transmission in Senegal. High levels of inhibition were evidenced with a limited degree of variation according to the two different locations of individual's samples. A Significant relationship between anti-merozoite Ab levels and the culture inhibition assays was found contrary to the merozoite re-invasion inhibition assays. Taken together, our results show that such inhibition assays can be managed in facilities of southern laboratories near endemic areas. However, strictly defined culture conditions, homogeneous withdrawals of patients and standardized protocols are necessary for the assessment of such functional assaysas a potential markerof protection-associated mechanisms in longitudinal studies.

Adolescent↗
PubMed2001

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Animals↗
PubMed2001

In vitro activities of antibiotics against Plasmodium falciparum are inhibited by iron.

The in vitro activities of cyclines (tetracycline, doxycycline, minocycline, oxytetracycline, and rolitetracycline), macrolides (erythromycin, spiramycin, roxithromycin, and lincomycin), quinolones (norfloxacin and ofloxacin), rifampin, thiamphenicol, tobramycin, metronidazole, vancomycin, phosphomycin, and cephalosporins (cephalexin, cefaclor, cefamandole, cefuroxime, ceftriazone, cefotaxime, and cefoxitin) were evaluated on Plasmodium falciparum clones, using an isotopic, micro-drug susceptibility test. Only tetracyclines, macrolides, quinolones, and rifampin demonstrated in vitro activity against P. falciparum, which increased after a prolonged exposure (96 or 144 h). In the presence of iron (FeCl(3)), only the activities of tetracyclines and norfloxacin were decreased. Their in vitro activity against intraerythrocytic stages of multidrug-resistant P. falciparum and their efficacy in vivo favor the use of antibiotics as antimalarial drugs. However, due to their slow antimalarial action and to the fact that they act better after prolonged contact, they probably need to be administered in conjunction with a rapidly acting antimalarial drug, such as a short course of chloroquine or quinine.

Animals↗
PubMed2001

[Prevention and treatment of malaria: in vitro evaluation of new compounds].

One of the current options for reducing the morbidity and mortality of malaria are chemoprophylaxis and chemotherapy. For this reason, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria. There is an urgent need to find and develop novel compounds and to identify novel chemotherapeutic targets. Different approaches to discover new compounds are presented from examples of molecules studied in the Tropical Medicine Institute of the French Army Health Service (IMTSSA) evaluation against isolates of compounds in pharmaceutical development in collaboration with pharmaceuticals (pyronaridine, benflumetol, ferrochloroquine), screening of molecules which are still registered for other pathologies (antibiotics), screening of new synthesized compounds (artemisinin derivatives) and identification of parasitical targets and essential metabolic ways for parasite, and identification of molecules acting on these targets (reversal of resistance to chloroquine, iron chelators).

Animals↗
PubMed2000

Antibiotics for prophylaxis of Plasmodium falciparum infections: in vitro activity of doxycycline against Senegalese isolates.

The in vitro activities of doxycycline, chloroquine, quinine, amodiaquine, artemether, pyrimethamine, and cycloguanil were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro, drug susceptibility test. The 71-50% inhibitory concentration (IC50) values for doxycycline ranged from 0.7 to 108.0 microM and the geometric mean IC50 for the 71 isolates was 11.3 microM (95% confidence interval = 9.5-13.4 microM). The activity of doxycycline did not differ significantly (P = 0.0858) between the chloroquine-susceptible isolates and the chloroquine-resistant isolates. There was no in vitro correlation between the responses to doxycycline and those to artemether, chloroquine, quinine, amodiaquine, pyrimethamine, and cycloguanil, suggesting no in vitro cross-resistance among these drugs. Potency was increased by prolonged exposure. In 96-hr incubations, the activity of doxycycline was 4-5-fold more increased than in 48-hr incubations. The in vitro activity of doxycycline against intraerythrocytic stages of multidrug-resistant P. falciparum, its action against the preerythrocytic forms, the lack of correlation between the responses in vitro of P. falciparum to doxycycline and the other antimalarial drugs, and its original potential site of action are factors that favor its use as antimalarial drug.

Amodiaquine↗