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PubMed2004

Efficacy of herbal remedies used by herbalists in Oyo State Nigeria for treatment of Plasmodium falciparum infections--a survey and an observation.

In the course of evaluating the contribution of phytomedicine to possible drug discovery of antimalarial drugs, an ethnomedical survey of specialized children traditional clinics was done. In the observational multi center study, efficacy of eight different herbal remedies, each consisting of 3-8 ingredients and administered by herbalists were investigated in clients enrolled in the six traditional clinics in Oyo (urban center) and Otu (rural center) of Oyo State, Nigeria. The clients, aged between six months and fifteen years with clinical symptoms of malaria were enrolled in the clinics of the herbalists, as their usual practice. Oral informed consents were obtained from their parents or guardians. Microscopic diagnosis of malaria infection was used to evaluate parasitaemia and validate efficacy of herbal remedies. Results of the analysis showed that, of the 163 clients of the herbalists, only 62 (30 from Oyo, 32 from Otu) had microscopically confirmed P. falciparum infection. Only results from 54 clients (29/30 (Oyo) and 25/32 (Otu) with P. falciparum infection could be evaluated. Plasmodium falciparum infection in 88% (23/29) of clients from Oyo responded to treatment with the herbal remedies while cure rate in clients from Otu was 42% (13/25). Parasite densities ranged from 171 to 53,613 parasites/microl blood and 87 to 36,209 parasites/microl blood in patients from Oyo and Otu respectively. The herbalists administered the remedies and Gossypium arboreum, Anarcadium occidentalis, Citrus medica, Phyllanthus amarus and Lippia multiflora were the main ingredients in the efficacious remedies. The herbalists gave detailed descriptions of each of the 8 herbal remedies proffered. The results confirm the efficacy of two of the eight herbal remedies, thereby validating the role of ethnomedicine as a possible source for the discovery of new chemotherapeutic agents in the treatment of P. falciparum malaria.

Adolescent↗
PubMed2001

Reversal of chloroquine and mefloquine resistance in Plasmodium falciparum by the two monoindole alkaloids, icajine and isoretuline.

Eight naturally occurring monoindole alkaloids were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance of a chloroquine-resistant strain of Plasmodium falciparum. None of these indole alkaloids has significant intrinsic antiplasmodial activity (IC(50) > 10 microM or 5 microg/ml). Nevertheless, three alkaloids (icajine, isoretuline and strychnobrasiline) did reverse chloroquine resistance at concentrations between 2.5 and 25 microg/ml (IF of 12.82 for isoretuline on W2 strain). The Interaction Factor (IF) equals 2, < 2, or > 2 for additive, antagonistic or synergistic effects of alkaloids on chloroquine inhibition, respectively. Icajine and isoretuline were also assessed in vitro for their mefloquine potentiating activity on a mefloquine-resistant strain of Plasmodium falciparum. Only icajine proved to be synergistic with mefloquine (IF = 15.38).

Alkaloids↗
PubMed1999

Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand.

Parasite genotyping by the polymerase chain reaction was used to distinguish recrudescent from newly acquired Plasmodium falciparum infections in a Karen population resident on the northwestern border of Thailand where malaria transmission is low (one infection/person/year). Plasmodium falciparum infections were genotyped for allelic variation in three polymorphic antigen loci, merozoite surface proteins-1 and -2 (MSP-1 and -2) and glutamaterich protein (GLURP), before and after antimalarial drug treatment. Population genotype frequencies were measured to provide the baseline information to calculate the probability of a new infection with a different or the same genotype to the initial pretreatment isolate. Overall, 38% of the infections detected following treatment had an identical genotype before and up to 121 days after treatment. These post-treatment genotypes were considered recrudescent because of the low (< 5%) probability of repeated occurrence by chance in the same patient. This approach allows studies of antimalarial drug treatment to be conducted in areas of low transmission since recrudescences can be distinguished confidently from newly acquired infections.

Alleles↗
PubMed1995

Serum antibodies from malaria-exposed people recognize conserved epitopes formed by the two epidermal growth factor motifs of MSP1(19), the carboxy-terminal fragment of the major merozoite surface protein of Plasmodium falciparum.

The major merozoite surface protein of Plasmodium falciparum (PfMSP1) is a candidate antigen for a malaria vaccine. A 19-kDa C-terminal processing product of PfMSP1 (PfMSP1(19)) is composed of two domains sharing a cysteine-rich motif with epidermal growth factor (EGF) and is the target of monoclonal antibodies which block erythrocyte invasion in vitro. We have evaluated human antibody responses to PfMSP1(19) by using recombinant proteins representing the EGF motifs encoded by the two main alleles of the MSP1 gene. We find that both EGF motifs are antigenic but that only 10 to 20% of malaria-exposed individuals have serum antibodies that recognized either of the motifs. When both EGF motifs were expressed together as a single protein, they were recognized by more than 40% of sera from malaria-exposed individuals. Major epitopes recognized by human antibodies are dependent upon the correct tertiary structure of the protein and are cross-reactive between the different allelic sequences of PfMSP1(19). This suggests that antibodies induced by vaccination with one or the other allelic forms of the protein could recognize all strains of P. falciparum. Immunoglobulin G (IgG) subclass-specific enzyme immunoassays indicate that PfMSP1(19) antibodies are predominantly of the IgG1 subclass.

Adolescent↗
PubMed2002

Independent translocation of two micronemal proteins in developing Plasmodium falciparum merozoites.

Apical membrane antigen 1 of Plasmodium falciparum (PfAMA1) contains an N-terminal propeptide that is removed prior to the translocation of the mature protein onto the merozoite surface. We localized unprocessed PfAMA1 to the microneme organelles of the intraerythrocytic schizont. The results have suggested that the processed form of PfAMA1 translocates from the microneme compartment independently of another microneme protein, EBA175, which is also involved in the invasion of human erythrocytes.

Animals↗
PubMed2004

Comparative study of the in vitro sensitivity of Plasmodium falciparum to artemisinin in two border areas of Thailand.

Artesunate was introduced in Thailand in 1995 for the treatment of falciparum malaria in areas of multidrug resistance, where it is used in combination with mefloquine. The studies were conducted between May and August 1999, 2000 and 2001 in the provinces Mae Hong Son and Tak (Mae Sot District) in northwestern Thailand, both on the border to Myanmar. The province of Mae Hong Son is still largely unaffected by multidrug resistance and infections with Plasmodium falciparum are treated with mefloquine alone. In the district of Mae Sot, 350 km southwards, more than 60% of the Plasmodium falciparum isolates were found to be resistant to mefloquine. Between 1999 and 2001, a total of 227 fresh isolates of Plasmodium falciparum were successfully tested for their sensitivity to artemisinin using the WHO standard in vitro microtest. The weighted mean EC5o and EC90 values for 1999-2001 were 9.20 nM and 34.37 nM in Mae Hong Son and 11.18nM and 71.63nM in Mae Sot, respectively. The comparison of the sensitivity to artemisinin between Mae Hong Son and Mae Sot showed no significant difference in 1999, but significant differences in 2000 (p<0.05) and in 2001 (p<0.01). This phenomenon could be a consequence of different drug pressure. Furthermore, the lower sensitivity of Plasmodium falciparum to mefloquine in Mae Sot may play a minor (but amplifying) role, as the activities of artemisinin and mefloquine show a significant correlation.

Animals↗
PubMed1995

Antigenicity and immunogenicity of recombinant glutamate-rich protein of Plasmodium falciparum expressed in Escherichia coli.

A recombinant Plasmodium falciparum glutamate-rich protein (GLURP) was produced in Escherichia coli as a nearly full-length protein. In order to map immunodominant regions on GLURP, the nonrepetitive amino-terminal region (R0) as well as the central repeat region (R1) and the carboxy-terminal repeat region (R2) were also produced as separate products. All four purified gene products reacted specifically with serum samples from adults living in an area of Liberia where malaria is holoendemic. It appears that the human immune response against GLURP is primarily directed against the R2 region because 94% of the serum samples reacted with this region in an immunoassay. Antibody reactivity against the R0 region was also observed in 75% of the serum samples, while the R1 region showed only weak antibody-binding activity. When the nearly full-length GLURP molecule was adsorbed to Al(OH)3 it was found to be immunogenic in mice. In these experiments, the antibody response was almost exclusively directed against the R2 region. When anti-GLURP sera were obtained from rabbits immunized with the three regions, R0, R1, and R2, respectively, they recognized in immunoprecipitation experiments authentic GLURP from P. falciparum grown in vitro. These results demonstrate that GLURP produced in E. coli can induce a humoral immune response against GLURP derived from blood-stage parasites.

Amino Acid Sequence↗
PubMed1998

[Considering disparities in resistance of Plasmodium falciparum in Africa in chemoprevention decisions].

OBJECTIVES: Assess the efficacy of preventive and curative treatments of imported malaria. METHODS: The in vitro drug susceptibility of mefloquine, chloroquine and cycloguanil was determined against African isolates of Plasmodium falciparum from imported malaria cases by an isotopic in vitro test or a genomic approach. RESULTS: Plasmodium falciparum resistance to mefloquine, chloroquine or to the dihydrofolate reductase inhibitor was present in 5.2%, 46% and 42% of isolates respectively. Plasmodium falciparum drug resistance to chloroquine or antifolinics was more frequent in permanent than in seasonal malarial transmission areas. Simultaneous resistance to chloroquine and antifolinics was observed in 17% of isolates between 1991 and 1994 and in 28% between 1995 and 1997.

Africa↗
PubMed1987

Ultrastructural studies on the interaction of Plasmodium falciparum ookinetes with the midgut epithelium of Anopheles stephensi mosquitoes.

The interaction of Plasmodium falciparum ookinetes with the midgut epithelium of Anopheles stephensi is described by electron microscopy. Plasmodium falciparum ookinetes have been traced during the early stages of invasion and localization beneath the basal lamina of the midgut. It is generally assumed that ookinetes break through two membranes to reach the basal lamina of the midgut epithelium by an intracellular route. In the present study evidence is presented that the ookinete takes an intercellular route in traversing the epithelial layer. Compared to the mode of penetration and intracellular development of sporozoites and merozoites, an intercellular route for penetration of the ookinete is not inconsistent with its further extracellular development.

Animals↗
PubMed2003

Field application and evaluation of a rapid immunochromatographic test for detection of Plasmodium falciparum infection among the inhabitants of Lao PDR.

Field application and evaluation of a rapid immunochromatographic test (ICT) for detection of Plasmodium falciparum infection were performed in 13 villages in a southern province of Lao PDR in 1999. More than 2,000 inhabitants, accounting for 61.8% of the total estimated population, were examined. Malaria infection was confirmed in all villages surveyed by ICT and microscopic diagnosis. The positive rates of P. falciparum malaria by microscopy ranged from 9.7% to 59.2% (mean 27.2%), whereas by ICT they were from 11.6% to 64.5% (mean 29.8%). The positive rates by ICT were generally higher in 8 out of 13 villages. However, a significant difference between the positive rates by microscopy and ICT was not observed in all villages. Plasmodium falciparum infection was actually confirmed by microscopy in 84.1% of specimens that tested positive by ICT. The results by ICT were consistent with those of the microscopic diagnosis, the discrepancy of the results was less than 10% (141/2,066). The ICT was falsely-positive in 4.7% and falsely-negative in 2.1% of the test cases. These results showed the efficacy of ICT not only in the diagnosis of the respective cases, but also in the mass-examination in the field.

Animals↗
PubMed2005

Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT.

OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South American/PNG -haplotype (SVMNT) on mainland Southeast Asia. SVMNT-haplotype and others might be associated with a decreased efficacy of Amodiaquine and could therefore be potential markers for of amodiaquine resistance (AQR). If there is a correlation between AQR and the SVMNT-haplotype as suggested, 31% prevalence of a potential resistance marker is cause for concern.

Adolescent↗
PubMed1996

Plasmodium falciparum merozoite adhesion is mediated by sialic acid.

The invasion of host red blood cells by Plasmodium falciparum merozoites is a complex process requiring multiple receptor-ligand interactions. Glycophorin A, a sialic acid-rich integral membrane protein, is an important RBC receptor for merozoites. We stably expressed glycophorin A in wild type Chinese hamster ovary (CHO) cells and in Lec 2 CHO cells which have a defect in the ability to sialylate proteins. Malaria merozoites were assessed for the ability to adhere to CHO cells that were either untransfected or expressed recombinant glycophorin A. Merozoites only adhered to wild type CHO cells and they did so irrespective of the expression of glycophorin A. These results suggest that cellular adhesion, the earliest event in the malaria invasion process, is mediated by sialic acid residues. This model system will provide valuable molecular information regarding early events in the malaria invasion process.

Animals↗
PubMed1999

Effect of iron supplementation and malaria prophylaxis in infants on Plasmodium falciparum genotypes and multiplicity of infection.

During a randomized placebo-controlled trial of chemoprophylaxis against Plasmodium falciparum malaria and iron supplementation, in infants living under conditions of intense transmission, all samples of P. falciparum obtained from children aged 5 and 8 months were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis for the msp2 locus. One hundred and six blood samples were analysed for the number of concurrent infections (multiplicity), and the allelic family of each msp2 genotype was determined. Mean multiplicity of infection was, overall, 2.76 infections/child, and it was significantly reduced in infants receiving chemoprophylaxis. This finding might help to explain the rebound effect in morbidity observed after prophylaxis was ended. Iron supplementation did not affect multiplicity of infection. In infants receiving placebo only, or placebo and iron supplementation, a significant positive association was observed between the number of infections and parasite densities (Spearman's p = 0.25, P-0.047). This association was lost in the group receiving chemoprophylaxis alone, or in combination with iron. This study showed a significant association of FC27-like msp2 alleles with prospective risk of clinical malaria in children (relative risk = 1.487, P = 0.013). Such an association was also found for the present risk of clinical malaria in infants receiving prophylaxis (odds ratio = 3.84, P = 0.026), which might imply that chemoprophylaxis may impair the development of premunition.

Anemia, Iron-Deficiency↗
PubMed2000

Commitment to gametocytogenesis in Plasmodium falciparum.

To achieve transmission, a subpopulation of asexually dividing bloodstream forms of the human malaria parasite Plasmodium falciparum withdraws from the cell cycle to develop into gametocytes - cells specialized for sexual reproduction and invasion of the mosquito vector. For natural selection to maximize transmission to new hosts, a balance must have evolved between asexual replication and sexual differentiation. Here, Mike Dyer and Karen Day consider observations on the process of commitment to gametocytogenesis and use this information as the framework for a model that begins to explain the control of the dynamics between asexual and sexual development.

Animals↗
PubMed2000

In vitro sensitivity of Plasmodium falciparum and clinical response to lumefantrine (benflumetol) and artemether.

AIMS: To assess the sensitivity of 103 Plasmodium falciparum isolates to a combination of lumefantrine (benflumetol) and artemether (CGP 56697), with the objective of determining a correlation between in vitro drug sensitivity and therapeutic outcome. METHODS: Patients suffered from uncomplicated falciparum malaria and came from areas of Thailand affected by multidrug resistance. CGP 56697 was given in the form of tablets containing 20 mg artemether and 120 mg lumefantrine. The standard dose regimen, 4 doses of 4 tablets over 48 h, was compared with two lower dose regimens (4 x 2 tablets and 3 x 4 tablets). RESULTS: The parasites showed high resistance to chloroquine, fairly advanced resistance to mefloquine and compromised sensitivity to quinine. Sensitivity to artemisinin and lumefantrine prior to treatment was similar in all treatment groups. The 4 x 4 tablet regimen was more effective than the other regimens in coping with infections with relatively low sensitivity to artemisinin and/or lumefantrine. The EC90 for artemisinin is an important determinant of treatment success. Parasite density at the start of treatment was identified as another critical predictor of treatment outcome. CONCLUSIONS: The results indicate that parasite exposure to the drugs may have been inadequate and/or too short in the cases of treatment failure, particularly marked in the lower dose regimens. This could probably be remedied by expanding the dose regimen in areas affected by multidrug resistance and in the case of relatively high parasitaemia.

Animals↗
PubMed1999

Surprisingly little polymorphism in the merozoite-surface-protein-2 (MSP-2) gene of Indian Plasmodium falciparum.

The polymorphism in the merozoite-surface-protein-2 (MSP-2) gene of six Indian Plasmodium falciparum isolates was studied by PCR amplification, cloning and sequencing. One of the isolates showed a deletion of 63 bp and all showed point mutations, although some of these mutations were silent. All the isolates also exhibited 5' and 3' conserved regions, with the two 32-mer amino-acid repeats characteristic of the FC27 family, and none belonged to the IC-1/3D7 family. Although the MSP-2 genes of these isolates represent new allelic sequences, they belong to the FC27 family and show remarkably little variation.

Amino Acid Sequence↗
PubMed2003

Plasmodium falciparum is able to invade erythrocytes through a trypsin-resistant pathway independent of glycophorin B.

Plasmodium falciparum invades erythrocytes through multiple ligand-receptor interactions, with redundancies in each pathway. One such alternate pathway is the trypsin-resistant pathway that enables P. falciparum to invade trypsin-treated erythrocytes. Previous studies have shown that this trypsin-resistant pathway is dependent on glycophorin B, as P. falciparum strains invade trypsin-digested glycophorin B-deficient erythrocytes at a highly reduced efficiency. Furthermore, in a recent study, the P. falciparum 7G8 strain did not invade glycophorin B-deficient erythrocytes, a finding that was not confirmed in the present study. To analyze the degree of dependence on glycophorin B for invasion by P. falciparum through the trypsin-resistant pathway, we have studied the invasion phenotypes of five parasite strains, 3D7, HB3, Dd2, 7G8, and Indochina I, on trypsin-treated normal and glycophorin B-deficient erythrocytes. Invasion was variably reduced in glycophorin B-deficient erythrocytes. Four strains, 3D7, HB3, Dd2, and Indochina I, invaded trypsin-treated erythrocytes, while invasion by the 7G8 strain was reduced by 90%. Among the four strains, invasion by 3D7, HB3, and Dd2 of trypsin-digested glycophorin B-deficient erythrocytes was further reduced. However, Indochina I invaded trypsin-digested glycophorin B-deficient erythrocytes at the same efficiency as its invasion of trypsin-digested normal erythrocytes. This strongly suggests that the Indochina I strain of P. falciparum is not dependent on glycophorin B to invade through a trypsin-resistant pathway as are the strains 3D7, HB3, and Dd2. Thus, P. falciparum is able to invade erythrocytes through a glycophorin B-independent, trypsin-resistant pathway.

Animals↗
PubMed2006

Development, characterization and immunogenicity of a multi-stage, multi-valent Plasmodium falciparum vaccine antigen (FALVAC-1A) expressed in Escherichia coli.

A synthetic multistage, multi-epitope Plasmodium falciparum malaria antigen (FALVAC-1A) was designed and evaluated in silico, and then the gene was constructed and expressed in Escherichia coli. The FALVAC-1A protein was purified by inclusion body isolation, followed by affinity and ion exchange chromatography. Although FALVAC-1A was a synthetic antigen, it folded to a specific, but as yet incompletely defined, molecular conformation that was stable and comparable from lot to lot. When formulated with four different adjuvants, FALVAC-1A was highly immunogenic in rabbits, inducing not only ELISA reactivity to the cognate antigen and most of its component epitopes, but also in vitro activity against P. falciparum parasites as demonstrated by inhibition of sporozoite invasion, antibody dependent cellular inhibition and the immunofluorescence assay.

Amino Acid Sequence↗