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PubMed2000

Protein tyrosine kinase activity in human malaria parasite Plasmodium falciparum.

Protein tyrosine kinases (PTKs) are believed to be implicated in the parasite growth, maturation and differentiation functions. Protein tyrosine kinase activity was found to be distributed in all the stages of P. falciparum parasite maturation. Membrane bound PTK activity was found to be increased during maturation process (ring stage to trophozoite stage) in chloroquine sensitive strains. In vivo conversion of the schizont stage to ring stage via release of merozoites was associated with a decrease in PTK activity. Chloroquine inhibited the membrane bound PTK activity in a dose dependent manner (IC50 = 45 microM). Kinetic studies show that chloroquine is a competitive inhibitor of PTK with respect to peptide substrate and noncompetitive with respect to ATP indicating that chloroquine inhibits PTK activity by binding with protein substrate binding site. The results suggest that maturation of malaria parasite is related to PTK and inhibition of this activity by chloroquine could provide a hypothesis to explain the mechanism of action of chloroquine.

Animals↗
PubMedDate not supplied

[Monitoring the chemoresistance of Plasmodium falciparum malaria in Yopougon (Abidjan): in vivo study of chloroquine sensitivity and evaluation of pyrimethamine resistance following the analysis of point mutation in the dihydrofolate reductase gene].

A major endemic in Côte d'Ivoire, malaria is the first cause of hospital admissions and mortality in tropical Africa. The decrease of morbidity and mortality depends on early diagnosis and relevant treatment. This situation is hampered by an emerging resistance of P. falciparum to usual drugs such as chloroquine and sulfadoxine-pyrimethamine. In recognition of this problem, we established a monitoring system in the north of Abidjan (Yopougon) in order to better analyse P. falciparum resistance. The molecular basis of P. falciparum resistance to pyrimethamine is associated with point mutations in the dihydrofolate reductase (dhfr) gene. The presence of a wild-type codon 108-ser is defined by the presence of an Alu1 restriction site. A single base change resulting in the change of amino acid from 108-Ser to 108-Asn or 108-Thr results in the appearance of a Bsr1 or a Scrf1 restriction site respectively. In response to these needs, 42 children aged 6 to 59 months were enrolled in the study by using tests of therapeutic efficacy of chloroquine (14-day in vivo test of WHO). Before treatment, infected blood samples were stored at 20 C until P. falciparum DNA extraction. The results of the in vivo sensitivity of chloroquine showed 84.3% of plasmodic rate, 97.7 % of P. falciparum against 2.3% of P. malariae. However, 78.6% of adequate clinical response (ACR) was obtained and 21.4% of early therapeutic failure (ETF). At the end of the study, clearance of parasitemia and fever was obtained but the gametocytic rate was 4.8%. More, RFLP studies of amplified DNA fragment revealed that P. falciparum from 12 children (44.5%) had point mutation in the codon 108 of the dhfr gene. The mutation of these isolates was based on the change of amino-acid from 108-Ser to 108-Asn. Moreover, 51.8% of isolates were of the wild type. In conclusion, our results showed that chloroquine resistance is a reality in Abidjan just like anywhere else in West Africa. However, the number of isolates which had point mutation in the dhfr gene suggested that the future approach must be the study of possible correlation between the in vivo sulfadoxine-pyrimethamine test and point mutations in the dihydrofolate reductase and in the dihydropteroate synthase gene of P. falciparum from Côte d'Ivoire.

Animals↗
PubMed1992

Persistence of low levels of Plasmodium falciparum resistance to chloroquine in the autochthonous population of the Central African Republic.

In Central African Republic, the first cases of resistant P. falciparum to chloroquine occurred in 1983 in non immune expatriate residents on regular chemoprophylaxis. From 1984 to 1991, 950 in vivo tests with a seven days observation period were performed in semi-immune autochtonous children living in seven towns of the country. Chloroquine treatments were given at 25 mg/kg over 3 days period to children with P. falciparum parasitaemia > 500 (634 simplified methods) or > 1000/mm3 (316 WHO standard field tests), usually asymptomatic. Until 1988, the surveys show an absence or a low frequency of chloroquine resistance (usually below 10%) according to the town; since 1989, the resistance has been present in all towns but everywhere with a frequency under 20%. None cases of R III level resistance was observed and all children became or remained asymptomatic at day 7. Until further surveys demonstrate a decreased efficacity of chloroquine, it is advised that chloroquine be used at 25 mg/kg over 3 days period as the treatment of choice in uncomplicated acute malaria in the Central African Republic.

Animals↗
PubMed1959

The development of pyrimethamine resistance by Plasmodium falciparum.

Sixteen patent P. falciparum infections (McLendon and Panama strains) in non-immunes were treated with single doses of pyrimethamine. The schizontocidal and sporontocidal response to the initial dose was rapid.Seven blood-induced infections, of which three were treated with 100 mg and four with 50 mg, did not relapse. Of seven cases observed after 25-mg treatment, five relapsed.Delayed treatment of the relapsing infections (Panama strain) with single doses of 25 mg or 50 mg, and subsequently 100 mg, had virtually no schizontocidal or sporontocidal effect. In one case the resistant infection was transmitted by mosquitos to another patient; the subsequent infection was also highly resistant to the drug.It is concluded that under the experimental conditions of this study resistance to pyrimethamine by P. falciparum may occur rapidly after a single dose of 25 mg, being manifested during relapses on the second challenge with the drug. Increasing the drug dosage does not overcome the resistance. The resistant character is readily transmitted by mosquitos.

Antimalarials↗
PubMedDate not supplied

[A network RER rooted on in vitro readout assays of Plasmodium falciparum sensitivity to chloroquine in the Indian Ocean Region].

Chloroquine has been used as a first line drug to treat uncomplicated malaria cases during the last five decades in Madagascar and in the Comoros Union. The four plasmodial species known to infect humans occur on Madagascar Island. Chloroquine-resistant malaria cases, sometimes only suspected from presumptive malaria cases, have been reported in both countries. Thus, to redefine a strategy and a policy to cure malaria, there is a need to get relevant and updated data. In December 1999, the Madagascan Ministry of Health and the Institut Pasteur de Madagascar formed a network named RER for malaria resistance surveillance. In 2000 and 2001, 18 study sites (17 throughout Madagascar and 1 in Comoros) joined this network. Health-care workers were trained mainly for malaria diagnosis through the use of blood smear examination and for malaria case management. To alleviate the lack of competent medical teams within the health centres, and for technical and logistic reasons, as part of the network activities, it was decided to start with in vitro tests to assess the sensitivity of P.falciparum isolates to chloroquine by means of the isotopic method. Parasitized blood samples were collected from consenting patients. P.falciparum isolates were more predominant (989/1,036). Out of the 564 tests done, 432 (76.6%) could be assessed. Results demonstrated that 94.3% (381/404) of the Madagascan P.falciparum isolates were susceptible to chloroquine. In contrast, chloroquine-resistant isolates were prevalent in Comoros (8/28). The network set-up is presented. The usefulness of the in vivo approach and of the in vitro investigations (chemosusceptibility test and screening of mutations accounting for resistance to chloroquine) to monitor the emergence and the dissemination of chloroquine-resistant parasites is discussed.

Animals↗
PubMedDate not supplied

The detection and treatment of Plasmodium falciparum malaria: time for change.

In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT) seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance.

Animals↗
PubMed1992

Defence mechanisms and immune evasion in the interplay between the humane immune system and Plasmodium falciparum.

Immunity to P. falciparum malaria is developed as a result of long term exposure to the parasite and depends on immunological memory. The key directors in immune recognition and regulation of the immunological responses are the T-cells. It seems reasonable to propose that immunity is acquired when a critical mass of T-cells, recognizing relevant malaria antigens, has been developed. These T-cells mediate immunity by regulating macrophage and B-cell activity, but they may also act directly as cytotoxic cells on infected hepatocytes and through production of parasite-toxic cytokines. The potential immune effector mechanisms against P. falciparum are many. The relative importance of each in protection is unknown and protection seems to be mediated through different mechanisms according to the degree of exposure to malaria and the pattern of malaria transmission. Since immunity to malaria is not an absolute phenomenon, many effector mechanisms are probably working together in (partially) protected individuals. Immunity to P. falciparum is acquired after years of exposure to the parasite and several disease episodes. The protracted course to clinical immunity indicates that the parasite interfere with development of immunity. Several mechanisms seem to be operating. 1) Induction of the immune response to some macromolecules is avoided because the parasites are living inside host cells during part of their life cycle, and the reaction to other molecules is apparently avoided by mimicry of host molecules. 2) Immune recognition is hampered by the extraordinary diversity of antigen phenotypes in the parasite population. 3) Immune regulation is obstructed by immune suppression. During P. falciparum malaria such suppression is characterized by a profoundly diminished in vitro proliferative response to malaria antigens, which probably is precipitated by defects in the early events of T-cell activation and inhibition of IL-2 function elucidated, but soluble factors secreted either by the parasites, or by host cells as a result of exposure to the parasite, seem to be involved. 4) Immune effector mechanisms in the liver and the spleen are avoided by sequestration of the mature parasites to the vascular endothelium. The interplay between the human defence system and the malaria parasite governs the symptomatology, the pathology and the development of immunity to the disease. These interactions are extremely complex, and only partly understood. Figure 1 summarizes my view on how these interactions could explain the characteristics of acquired immunity to P. falciparum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Response of Plasmodium falciparum to cotrimoxazole therapy: relationship with plasma drug concentrations and dihydrofolate reductase and dihydropteroate synthase genotypes.

We assessed the efficacy of trimethoprim/sulfamethoxazole (TRM/SMX) in vivo in relation to the frequency of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) alleles in 45 Sudanese malaria patients. Plasma levels of TRM, SMX, and acetylsulfamethoxazole (AcSMX) were measured before treatment and at days 3, 7, and 14 or upon recrudescence to ascertain drug absorption. Forty patients (89%) had an adequate clinical response, one patient (2%) had an early treatment failure response, while four patients (8%) showed late treatment failure responses. Genotyping of merozoite surface protein 1, MSP-1, MSP-2, and glutamate-rich protein before treatment and upon recrudescence showed that all recurring parasites were recrudescences. The plasma levels of TRM, AcSMX, and SMX indicated adequate drug absorption in all patients. This suggests parasite resistance as a cause of treatment failure. The presence of dhfr Ile 51 and Asn 108 alone or coupled with dhps Ala-436 among parasites that were cleared after treatment indicates that these alleles alone are insufficient to cause in vivo resistance. However, the presence of the triple mutant dhfr (Ile-51/Arg-59/Asn-108) with the dhps Gly-437 genotype in all recurring infections, suggests the importance of codon 59 and 437 alleles in susceptibility to TRM/SMX. However, the number is too little to make firm conclusions.

Animals↗
PubMed2005

False-positive results of a Plasmodium falciparum histidine-rich protein 2-detecting malaria rapid diagnostic test due to high sensitivity in a community with fluctuating low parasite density.

The persistence of parasite histidine-rich protein 2 (HRP2) in the circulation after parasite clearance has been considered a drawback for rapid diagnostic tests (RDTs) targeting HRP2 and a major cause of false-positive results. This paper reports results of a study into whether a proportion of RDT HRP2 false-positive cases carried parasites using polymerase chain reaction analysis as the gold standard rather than microscopy. The high rate of RDT false-positive parasitemia results in comparison with microscopy was shown to predominantly represent cases that had a parasite density below the threshold for detection by microscopy. Despite the generally low disease-endemic prevalence of malaria in the area, there was a high prevalence of chronic infections with low, fluctuating, parasite densities that were better detected by RDT. Our results suggest that in areas known to have low-density parasitemias, RDTs targeting HRP2 may increase diagnostic sensitivity in comparison with microscopy. While microscopy remains the standard for comparison of malaria diagnostic accuracy, the limitations of microscopy, and the possibility that RDTs may have superior accuracy in some circumstances, should be taken into account when interpreting results of diagnostic trials.

Animals↗
PubMed2005

Therapeutic efficacy of sulfadoxine-pyrimethamine and amodiaquine among children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania.

The efficacy of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) was assessed at Kivunge and Micheweni in Zanzibar, Tanzania, in 2001. The main objective was to obtain baseline data after observations of high levels of chloroquine treatment failures. Children (6-59 months) were randomized to receive either drug. At Kivunge, SP and AQ were given to 64 and 63 cases, while for Micheweni, 61 and 70 cases were treated. Main findings were overall high rates (> 90%) of adequate clinical response (ACR) with AQ. A lower ACR was seen in the SP group at Kivunge (87.1%) compared with Micheweni (94.8%). Furthermore, in the ACR group, 16.7% AQ parasitological resistance (RI-RIII) was encountered at Kivunge. Most of the cases of SP parasitological resistance (14.5%; RI/RII) were seen at Micheweni. Notwithstanding this, the overall treatment failure was only 9.2% with SP and 5.5% with AQ. The Zanzibar Ministry of Health has since reviewed its antimalarial drug policy.

Amodiaquine↗
PubMed2006

[Prevalence, genetic diversity and multiplicity of Plasmodium falciparum infection in school children in central Cote d'Ivoire].

A study was carried out in the village of Taabo, located in the vicinity of a large man-made lake in central Côte d'Ivoire. The objectives were (i) to determine the level of prevalence, genetic diversity and multiplicity of Plasmodiumfakiparum infection in schoolchildren and (ii) to compare the diagnostic performance of light microscopy and polymerase chain reaction (PCR). A total of 424 schoolchildren ranging in age from 5 to 15 years underwent diagnostic testing using both light microscopy of blood smears and PCR. Multiplicity of P. falciparum infection was investigated in 196 children (46.2%). The prevalence of malaria was 54.7% based on light microscopy and 83.9% based on PCR. Genotyping based on polymorphism in the length of the restriction fragment of the gene encoding the merozoite surface protein-2 (msp2) showed that 86.5% of cases involved multiple infection with a geometric mean of 3.87 genotypes per positive child. There was a strong positive correlation between multipcity of infection and parasite density in the 56-year old age group. A total of 50 genotypes including six observed for the first time were identified and classified into families with similar-sized sequence groups: 26 x FC27 (52%) and 24 x 3D7 (48%). In comparison with PCR, the sensitivity and specificity of light microscopy for diagnosis of P. falciparum was 81.3% and 88.2% respectively. Data are discussed in the light of similar studies carried out in sub-Saharan Africa and elsewhere. These findings can serve as a basis for monitoring the longterm effect of major water resource management projects on the prevalence, genetic diversity and multiplicity of P. falciparum infection.

Adolescent↗
PubMed1992

Rheological analysis of the adhesive interactions of red blood cells parasitized by Plasmodium falciparum.

Adhesion of parasitized red blood cells (RBCs) to vascular endothelium is thought to be a key factor in the pathology of falciparum malaria. However, quantitative analyses of the intercellular forces and of the effects of flow on adhesion have been lacking. We have characterized cytoadhesion of RBCs parasitized by the strains ITO4 (which can bind to receptors ICAM-1 or CD36) and FCR3A2 (which can bind to CD36 only) using micropipette manipulation and flow chamber techniques. Target cells were unfixed or glutaraldehyde-fixed human umbilical vein endothelial cells (HUVEC, bearing ICAM-1 only) or human amelanotic melanoma cells (C32, bearing CD36 and ICAM-1). In the static, micropipette assay, 60% to 70% of parasitized cells would adhere when tested at up to three successive sites. The percentage of cells adhering and the force required for their detachment (approximately 10(-10) N) were similar for each combination of parasite strain and adhesion target (ITO4/HUVEC, ITO4/C32, FCR3A2/C32). In the flow chamber, efficiency of initial adhesion of parasitized cells was essentially constant (at about 1%) up to a stress of 0.1 Pa, and then decreased rapidly with increasing stress. Either receptor (ICAM-1 or CD36) could immobilize flowing cells at a physiologic flow stress (0.1 Pa), but the numbers of cells adhering varied for the different combinations (ITO4/C32 greater than ITO4/HUVEC greater than FCR3A2/C32). When flow was increased in steps, adhered cells were gradually washed off but many could withstand stresses at which they would not initially adhere. The force for detachment estimated in this way was similar to the pipette value, and again, was similar for the different combinations of strains and targets. Adhesion from flow depends on the affinity between surfaces being above a critical level, and once adhesion is established, the fracture energy determines resistance to disruption of adhesion. The results show that the fracture energy is greater than the affinity (ie, that adhesion becomes stabilized after it is initially established) and that the ratio of affinity to fracture energy is different for different receptor/ligand pairs, with ICAM-1 appearing to be the more efficient immobilizing receptor. Also, static and flow-based assays of adhesion clearly differ; the affinity is less critical in the static situation, so that most parasitized cells were capable of adhering in a static assay, but fewer did so under flow. Adhesiveness varied markedly from cell to cell, both for targets and parasitized cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗