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Biomedical subjects

J Le Bras

Publications and source records attributed to J Le Bras.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Human transmission and plasmodium resistance].

There is no longer malaria transmission in Europe and North America, while the transmission decreases in sub-tropical areas and increases in tropical countries. Most of malarias are now due to Plasmodium falciparum and happen in Africa. In the regions where the transmission is high, malaria is stable, baby mortality is high, and protective immunity is achieved in early childhood. Falciparum resistant malaria originates from mutations on drug target decreasing affinity to antifols, or mutations preventing accumulation of chloroquine in parasitized red blood cells. Resistance is a rapid event following large use of antifols, even associated, while falciparum chloroquine resistance is now widespread. Resistance to quinine, mefloquine and halofantrine is still at low levels out of Thailand, as their use remains through medical hands. Non resistance was observed yet with artemisinin derivatives.

Africa↗
PubMed1998

[Resistance to chloroquine and cycloguanil of Plasmodium falciparum in patients arriving in France after travel in Africa without chemoprophylaxis].

The in vitro susceptibility of chloroquine and the genomic profile of dihydrofolate reductase (DHFR) codon 108 was determined against african isolates of P. falciparum (Pf) from imported malaria cases without previous drug intake by an isotopic microtest or PCR + RFLP. Pf resistance to chloroquine or to the DHFR inhibitor was present in 49% and 46% of isolates, respectively. Pf drug resistance was more frequent in permanent than in seasonal malarial transmission areas and chloroquine plus DHFR resistance reached 28% in years 1995-97. Updating the guidelines for the prevention of malaria in travellers to Africa is necessary.

Africa↗
PubMed1998

In vitro susceptibility of African Plasmodium falciparum isolates to dihydroartemisinin and the risk factors for resistance to qinghaosu.

In vitro susceptibility to dihydroartemisinin (DHART) and to artemether of 476 Plasmodium falciparum fresh clinical isolates obtained from non immune travellers returning from Africa to France in 1993-1996 were analysed to search for natural resistance and cross resistance of these compounds with available antimalarials. The mean median inhibitory concentration (IC50) values for artemether and DHART were 2.69 nM and 1.17 nM, respectively. Nineteen isolates presented with a decreased IC50 to artemether or DHART. Chloroquine-resistant isolates were more susceptible to artemether (2.15 versus 3.26 nM) and DHART (0.876 versus 1.51 nM) than chloroquine-susceptible ones. Artemether and DHART responses were correlated (r2 = 0.599). The isolates identified as resistant to DHART or artemether in this study had IC50's close to the cut-off and limited cross-resistant profiles.

Africa↗
PubMed1997

In vitro sensitivity of Plasmodium falciparum to anti-folinic agents (trimethoprim, pyrimethamine, cycloguanil): a study of 29 African strains.

The in vitro drug sensitivity of three dihydrofolate reductase inhibitors (pyrimethamine, cycloguanil, trimethoprim) was determined against 29 strains and isolates of Plasmodium falciparum by an isotopic semi-microtest. Trimethoprim is less active than pyrimethamine or cycloguanil and its activity is correlated with that of two other inhibitors, suggesting cross-resistance in vitro among the dihydrofolate reductase inhibitors.

Animals↗
PubMed1997

[Drug sensitivity of falciparum malaria imported into France in 1995].

The National Reference Centre for Malaria Chemosusceptibility (CNRCP) and the Tropical Medicine Institute of the Health Department for the Army (IMTSSA) monitor the chemosusceptibility of falciparum malaria introduced in France. In 1995, 353 isolates of P. falciparum are sent to the CNRCP and IMTSSA from malaria cases presenting in 49 civil and military hospitals distributed all over the french country. The patients are mostly Africans living in France and have mainly stayed in West Africa. Half of them did not take any chemoprophylaxis and a quarter took only chloroquine more or less regularly. The curative treatment, when known, is halofantrine alone in 52% of cases and quinine alone in 28% of cases. Three halofantrine failures are reported including 1 incorrect regimen and 4 quinine failures including 3 incorrect regimens. In 1995, in vitro resistance of P. falciparum isolates imported in France to the chemoprophylactic and therapeutic drugs is not worsening. In vitro quinine resistance is rare (1/108), mefloquine resistance (2/20) and halofantrine resistance (12/211) are limited, cycloguanil resistance (42/185) is stable and chloroquine resistance (84/230) is even decreasing (less selective pressure in Africa?).

Adolescent↗
PubMed1997

[Optimum quinine therapy in falciparum malaria attacks contracted in Africa].

A review about the use of quinine for uncomplicated falciparum malaria contracted in Africa is proposed. The dose of 8 mg/kg of quinine base 3 times a day seems to be admitted by all. On the other way, the duration of treatment fluctuates from 2 to 10 days without evidence of difference in efficacy between 3, 5 and 7 days. The pharmacodynamic and pharmacokinetic properties of quinine are reviewed and suggest that 3, 5 and 7 days are efficient at least on, respectively, 1, 2 and 3 parasite cycles and suggest that a five day treatment may be curative for all kind of patients infested with a quinine-sensitive strain of P. falciparum in Africa.

Africa↗
PubMed1996

Plasmodium falciparum: molecular characterization of multidrug-resistant Cambodian isolates.

Clinical resistance to many therapies for malaria is a rapidly evolving problem in most endemic areas, particularly, Southeast Asia. Recent studies have suggested linkages between the mdr-like genes of Plasmodium falciparum and resistance to quinoline containing compounds. Other studies have found an association between allelic polymorphisms in the DHFR gene and antifol resistance in these parasites. The purpose of this study was to further examine these associations in recent isolates from Cambodia. DNA sequences and gene copy number of the pfmdrl and the DHFR-TS gene in 10 Cambodian isolates were analyzed and correlated with the drug sensitivity pattern. No new intragenic alleles were detected in the pfmdrl gene by a full-length DNA sequence analysis of the L-14/Cambodia clone. The allelic variations seen in pfmdrl in these isolates did not correlate with chloroquine resistance as previously reported. The full-length sequence of the DHFR latter findings may be correlated with high-level resistance to the antifolate drugs as has been previously described. None of the Cambodian isolates presented gene amplification in either pfmdrl or DHFR-TS genes.

Alleles↗
PubMed1996

In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.

Animals↗
PubMed1996

[Diagnostic and prognostic importance of laboratory tests in malaria in airports. Study of six recent cases].

During the summer 1994, six cases of airport malaria occurred in France, near the Roissy-Charles-de-Gaulle airport. Due to Plasmodium falciparum, all cases underwent rapid and severe deterioration, and in one case, the patient died. The role of laboratory tests is essential to establish the diagnosis of persons who have never resided in the endemic malaria areas and follow up with the patients already under treatment to detect possible complications.

Adult↗
PubMed1996

[Mechanisms and epidemiology of resistances to antimalarials].

Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazonia and South-East Asia and responsible for severe involvement of fever or anemia prompting more than a million death per year. Resistance originate from chromosomic mutations. Antimetabolite-resistant mutants (pyrimethamine and proguanil) are highly prevalent in Asia, America and East Africa. One to 3 point mutations on the dihydrofolate-reductase gene, the target enzyme, give moderate to high level of resistance. Molecular biology furnishes sensitive tools for population-based studies of resistance to these compounds. Four-aminoquinolines resistant mutants (chloroquine and amodiaquine) were encountered more than 10 years after a huge amount of these drugs has been sold. The level of resistance varies among parasites isolates populations. Impaired uptake of the drug by the parasite vacuole is a common characteristic of resistant strains. This phenotype is poorly correlated with PfMDR1 gene mutations on chromosome 5 but is strongly associated with a particular RFLP profile on chromosome 7. Amino-alcohol resistant falciparum malaria is scarce (quinine, mefloquine, halofantrine) and supposed to be associated with impaired uptake of the drug by the parasite, the mechanism of which is still unclear. In each of these three antimalarial drugs groups, the highly resistant level to a peticular compound, the highly prevalence of cross resistance of the malaria isolate. An established and strong drug pressure probably explains the multi-chemoresistance encoutered in South-East Asia and forests of South America. In Africa, frequent genetic recombinations in Plasmodium originates from a high level of malaria transmission, and falciparum chloroquine-resistance prevalence seems to stabilize at an equal level as chloroquine-sensitive malaria.

Animals↗
PubMed1996

[Contribution of Trichrome Blue in the diagnosis of microsporidiosis].

Detection of microsporidia belongs to the usual coprologic and urine detection of parasites from HIV seropositive patients. To improve the identification of microsporidial spores, several stains have been used. Trichrome Blue stain has been evaluated in this study. We first compared Trichrome Blue stain to Weber's trichrome for the detection of microsporidia in smears of stools received from HIV seropositive patients. No difference of sensibility has been demonstrated between the two stains, and Uvitex 2B used on the same samples has confirmed these results. Then, Trichrome Blue stain has been used for the detection of microsporidial spores in other specimens (40 samples of nasal mucus, conjonctival samples, duodenal biopsy and urine), also Giemsa and Uvitex 2B. The advantage of Trichrome Blue stain is its ready-to-use presentation, and faster realisation at higher temperature. Trichrome Blue stain is interesting as a confirmation technique or for laboratories which do not have fluorescent microscopy equipment.

Animals↗
PubMed1995

Plasmodium falciparum and Plasmodium vivax: lactate dehydrogenase activity and its application for in vitro drug susceptibility assay.

Lactate dehydrogenase, the terminal enzyme of anerobic Embden-Meyerhoff glycolysis, plays an important role in the carbohydrate metabolism of human malaria parasites. Based on the ability of malarial lactate dehydrogenase to use 3-acetylpyridine NAD as a coenzyme in a reaction leading to the formation of pyruvate from L-lactate, the enzymatic activity of fresh clinical isolates of Plasmodium falciparum and Plasmodium vivax was determined in relation to incubation time, asexual stages, and parasitemia and applied to a drug susceptibility assay. Lactate dehydrogenase activity was detectable at a parasitemia > 0.4%, at a hematocrit of 1.5%, and increased with parasitemia. Maximal lactate dehydrogenase activity was generally observed between 36 and 48 hr, when the trophozoites and schizonts predominated. The results of the in vitro drug susceptibility assays based on the inhibition of lactate dehydrogenase activity and on the incorporation of tritium-labeled hypoxanthine were correlated. For an optimal performance against fresh clinical malaria isolates, however, the enzymatic assay requires an initial parasitemia between 1 and 2% at a hematocrit of 1.5%.

Animals↗
PubMed1995

Plasmodium falciparum: detection of antifolate resistance by mutation-specific restriction enzyme digestion.

We describe here a rapid procedure to predict the resistance of Plasmodium falciparum to pyrimethamine or cycloguanil. The method consists of amplification by PCR of the DHFR gene followed by restriction enzyme digestion of codons 16 and 108. Three different enzymes are used to cut the wild-type, 108-threonine mutant, and 108-asparagine mutant gene. Since every natural antifolate-resistant isolate identified until now carries a mutation in codon 108, determination of the nature of this codon can predict the sensitivity of any P. falciparum isolate.

Animals↗
PubMed1995

Plasmodium falciparum: detection of P-glycoprotein in chloroquine-susceptible and chloroquine-resistant clones and isolates.

Recent studies have suggested the potential involvement of multidrug resistance (mdr) genes in resistance to quinoline-containing compounds in Plasmodium falciparum parasites. Three different antibodies were used to detect the malarial mdr 1 protein product by indirect immunofluorescence and/or immunoblot in fresh clinical isolates and clones of P. falciparum from different geographic origins. A 160-kDa protein was detected in all five parasite clones by immunoblot and around the food vacuole by IFA, regardless of the level of sensitivity to chloroquine and the modulation by desipramine of chloroquine accumulation. Our results suggest that chloroquine resistance is not correlated with the presence of the Pfmdr1 product.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa.

Resistance of Plasmodium falciparum to many therapeutic agents is an increasing problem in most endemic areas. The role of the mdr-like gene products of P. falciparum in resistance to quinoline-containing compounds is not clear. The purpose of this study was to further examine the role of pfmdr1 in drug resistance in fresh clinical isolates originating from Africa. Drug susceptibility testing (chloroquine, mefloquine, halofantrine and quinine) and a molecular analysis of pfmdr1 was completed for 51 fresh clinical isolates. A statistical association between the chloroquine sensitivity phenotype and an intragenic allele of pfmdr1 was noted at a position, amino acid 86, which was previously associated with chloroquine resistance. There was little variation in the other intragenic alleles previously associated with chloroquine resistance. No correlation between pfmdr1 intragenic allelic variation and susceptibility to mefloquine, halofantrine or quinine was found. There was no association between gene copy number of pfmdr1 and any drug resistant phenotype in an analysis of selected isolates. This, along with other data, suggests that mefloquine resistance may have arisen by two different mechanisms in African and Southeast Asian isolates. Much more variability in the polyasparaginated region of the pfmdr1 gene was noted in this study than previously reported. In addition, fingerprint analysis using multiplex PCR revealed considerable genetic variability among these isolates.

Africa South of the Sahara↗
PubMed1995

In vitro activity of atovaquone against the African isolates and clones of Plasmodium falciparum.

The in vitro activity of atovaquone (566C80) was evaluated and compared with that of chloroquine, quinine, mefloquine, halofantrine, artemether, pyrimethamine, and cycloguanil against African isolates and clones of Plasmodium falciparum using an isotopic, semimicro, drug susceptibility test. Atovaquone was highly active against the chloroquine-susceptible L-3 (geometric mean 50% inhibitory concentration [IC50] = 0.978 nM) and L-16 clones (mean IC50 = 0.680 nM) and against the multidrug-resistant FCM 29 clone (mean IC50 = 1.76 nM). Similar low IC50 values for atovaquone were observed against the chloroquine-susceptible isolates (n = 35; geometric mean IC50 = 0.889 nM) and the chloroquine-resistant parasites (n = 26; geometric mean IC50 = 0.906 nM). The in vitro responses between atovaquone and the other antimalarial drugs were not correlated, indicating the absence of in vitro cross-resistance. The high in vitro activity of atovaquone without any in vitro evidence for cross-resistance with other antimalarial drugs against the naturally occurring malaria parasites is a factor that favors further development of the drug for clinical use.

Animals↗