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PubMed1999

Plasmodium falciparum and Plasmodium yoelii: effect of the iron chelation prodrug dexrazoxane on in vitro cultures.

To determine if an iron-chelating prodrug that must undergo intracellular hydrolysis to bind iron has antimalarial activity, we examined the action of dexrazoxane on Plasmodium falciparum cultured in human erythrocytes and P. yoelii cultured in mouse hepatocytes. Dexrazoxane was recently approved to protect humans from doxorubucin-induced cardiotoxicity. Using the fluorescent marker calcein, we confirmed that the iron-chelating properties of dexrazoxane are directly related to its ability to undergo hydrolysis. As a single agent, dexrazoxane inhibited synchronized cultures of P. falciparum in human erythrocytes only at suprapharmacologic concentrations (> 200 microM). In combination with desferrioxamine B, dexrazoxane in pharmacologic concentrations (100-200 microM) moderately potentiated inhibition by approximately 20%. In contrast, pharmacologic concentrations of dexrazoxane (50-200 microM) as a single agent inhibited the progression of P. yoelli from sporozoites to schizonts in cultured mouse hepatocytes by 45 to 69% (P < 0.001). These results are consistent with the presence of a dexrazoxane-hydrolyzing enzyme in hepatocytes but not in erythrocytes or malaria parasites. Furthermore, these findings suggest that dexrazoxane must be hydrolyzed to an iron-chelating intermediate before it can inhibit the malaria parasite, and they raise the possibility that the iron chelator prodrug concept might be exploited to synthesize new antimalarial agents.

Animals↗
PubMed2001

Contemporaneous and successive mixed Plasmodium falciparum and Plasmodium vivax infections are associated with Ascaris lumbricoides: an immunomodulating effect?

Following an investigation suggesting a protective role for Ascaris against cerebral malaria, possibly through immunomodulation, we examined whether Ascaris had any impact on mixed Plasmodium falciparum and Plasmodium vivax infections. We studied a cross section of 928 patient files between 1991 and 1999. Forty patients had contemporaneous mixed infections and 40 patients had P. falciparum infections, followed by P. vivax infections. There was a significant association between Ascaris infection and risk of having both contemporaneous or successive mixed P. falciparum and P. vivax infections (adjusted odds ratios respectively 6 [2-18] P = 0.001 and 3.6 [1.2-11.1] P = 0.02). There was a positive linear trend between the burden of Ascaris and the risk of mixed infections P < 0.0001. These results suggested the possibility that pre-existing Ascaris infection may increase tolerance of the host to different Plasmodium spp., thus facilitating their coexistence.

Animals↗
PubMed2002

Anemia in parasite- and recombinant protein-immunized aotus monkeys infected with Plasmodium falciparum.

Plasmodium falciparum-induced anemia was characterized in Aotus monkeys repeatedly immunized by infection with P. falciparum (FVO strain) parasites, then cross-challenged with CAMP strain, or in monkeys receiving blood stage challenges as part of malaria vaccine trials. In 4 studies, 25 (30.5%) of 82 monkeys had at least a 50% reduction in hematocrit; mean day of maximum parasitemia was 12.5, whereas the mean day of minimum hematocrit was 18.8 (P < 0.0009). Decreased hematocrit levels were not associated with reticulocytosis until parasite densities decreased significantly from peak levels. Direct antibody tests to detect IgG and C3d on the surface of erythrocytes were negative. Nonantibody/noncomplement-mediated lysis of uninfected erythrocytes seems to be the principal cause of the anemia, and it also seems that bone marrow suppression and lysis of infected erythrocytes contributed to the anemia. Partial immunity-whether induced by repeated immunization with whole parasites or with vaccine-seems important to the development of anemia.

Anemia↗
PubMed2002

Comparison of field and expert laboratory microscopy for active surveillance for asymptomatic Plasmodium falciparum and Plasmodium vivax in western Thailand.

Microscopy of Giemsa-stained thick and thin films by a skilled microscopist has remained the standard laboratory method for the diagnosis of malaria. However, diagnosis of malaria with this method is problematic since interpretation of results requires considerable expertise, particularly at low parasite levels. We compared the efficacy of "field" and "expert laboratory" microscopy for active surveillance of Plasmodium falciparum and P. vivax in western Thailand. Field microscopy consisted of an approximately five-minute read (50-100 fields) of a thick film at x700 using a natural light source, whereas expert laboratory microscopy consisted of a 20-minute read (number of parasites per 500 leukocytes) at x1,000 using a high-quality, well-maintained microscope with an artificial light source. All discordant and 20% of concordant results were cross-checked blindly. A total of 3,004 blood films collected between May and November 2000 were included in the study, of which 156 (5.2%) were positive for P. falciparum, 177 (5.9%) for P. vivax, and 4 (0.1%) for both P. falciparum and P. vivax by expert microscopy. A total of 84.4% (135 of 160) of the P. falciparum-positive slides and 93.9% of the P. vivax-positive slides had a parasitemia of less than 500/microL. Field microscopy was specific (99.3%) but not sensitive (10.0%) for the diagnosis of P. falciparum malaria, with a positive predictive value (PPV) of 43.2% and a negative predictive value (NPV) of 95.1%. The corresponding specificity and sensitivity for the diagnosis of P. vivax malaria were 99.2% and 7.1%, respectively, with a PPV of 38.7% and an NPV of 93.9%. Field microscopy, as defined in this study, is not an effective method for active malaria surveillance in western Thailand, where prevalence and parasitemia rates are low.

Adolescent↗
PubMed1997

Laboratory and field comparisons of adenosine influx in Plasmodium falciparum and Plasmodium vivax infected erythrocytes with genetic abnormalities from patients in Myanmar.

Influx of the purine nucleoside, adenosine, was assessed in erythrocytes from both normal subjects and from subjects with a range of genetically determined erythrocyte disorders from Myanmar. The latter included alpha-thalassemia major (Myanmar variant), beta-thalassemia major (Myanmar variant), beta-thalassemia trait, HbEE and HbAE erythrocytes and two variants of glucose-6-phosphate dehydrogenase (G6PDH) deficiency. Significant reductions (p < 0.01) of adenosine influx were observed in erythrocytes from individuals with alpha- and beta-thalassemia major and severe G6PDH deficiency. Abnormal erythrocytes infected with the malarial parasites, Plasmodium falciparum or Plasmodium vivax, demonstrated a reduction in adenosine transport which correlated with the proportion of abnormal erythrocytes present in the samples obtained. The effect of nitrobenzylthioinosine (NBMPR) on adenosine influx was explored in normal and abnormal erythrocytes. In all these cases, NBMPR completely inhibited the transport of adenosine. However, transport of adenosine into P. falciparum and P. vivax-infected normal erythrocytes and abnormal cells was only inhibited 50-60% by NBMPR. The combination of tubercidin and NBMPR completely blocked adenosine transport into both normal and abnormal erythrocytes infected with either P. falciparum or P. vivax.

Adenosine↗
PubMed2002

Time course of in vitro maturation of intra-erythrocytic malaria parasite: a comparison between Plasmodium falciparum and Plasmodium knowlesi.

The schizont maturation assay for in vitro drug sensitivity tests has been a standard method employed in the global baseline assessment and monitoring of drug response in Plasmodium falciparum. This test is limited in its application to synchronous plasmodial infections because it evaluates the effect of drug on the maturation of parasite especially from ring to schizont stage and therefore synchronized P. falciparum cultures are required. On the other hand, P. knowlesi, a simian malaria parasite has a unique 24-h periodicity and maintains high natural synchronicity in monkeys. The present report presents the results of a comparative study on the course of in vitro maturation of sorbitol synchronized P. falciparum and naturally synchronous P. knowlesi. Ring stage parasites were incubated in RPMI medium supplemented with 10-15% pooled homologous serum in flat-bottomed 96-well micro plates using a candle jar at 37 degrees C. The results suggest that the ideal time for harvesting the micro-assay plates for in vitro drug sensitivity test for sorbitol-synchronized P. falciparum and naturally synchronous P. knowlesi are from 26 to 30 h and from 22 to 25 h, respectively. The advantages of using P. knowlesi in chemotherapeutic studies are discussed.

Animals↗
PubMed1994

A highly sensitive, rapid, and simple polymerase chain reaction-based method to detect human malaria (Plasmodium falciparum and Plasmodium vivax) in blood samples.

A highly sensitive, rapid and simple method to detect human malaria in blood samples was developed. Malaria parasite DNA in blood from a fingerprick was directly amplified by the polymerase chain reaction (PCR) using two sets of primers to yield a 206-basepair (bp) product for Plasmodium falciparum and a 183-bp product for P. vivax. Both were easily visualized in an ethidium bromide-stained agarose gel, allowing identification of the two human malaria species in a single amplification reaction. As little as a one P. falciparum and/or P. vivax parasite per microliter of blood was detectable by this method, a sensitivity superior to that of thick blood film microscopy. The total time required for diagnosis of 48 blood samples, starting from fingerprick blood collection, was approximately 4 hr. When compared with microscopic examination by an expert microscopist, results showed a sensitivity of 89% for P. falciparum and 91% for P. vivax and an overall specificity of 94%. Six infected blood samples classified by microscopy as single species were diagnosed by the PCR method as being mixed P. falciparum and P. vivax infections. The high sensitivity, rapidity, and simplicity of the method should make it attractive for a large-scale epidemiology study, follow-up of drug treatment, and immunization trials.

Animals↗
PubMed2006

Assessing the genetic diversity of the aldolase genes of Plasmodium falciparum and Plasmodium vivax and its potential effect on performance of aldolase-detecting rapid diagnostic tests.

Malaria-specific rapid diagnostic tests (RDTs) targeting aldolase show highly variable sensitivities. We assessed diversity in Plasmodium falciparum and P. vivax aldolases by sequencing the coding genes from parasites of various origins. The results show that aldolases are highly conserved, indicating that antigenic diversity is not a cause of variable RDT sensitivity.

Aldehyde-Lyases↗
PubMed1975

The indirect hemagglutination test for malaria. Evaluation of antigens prepared from Plasmodium falciparum and Plasmodium vivax.

Soluble antigens were prepared from Plasmodium falciparum and P. vivax and were evaluated in the indirect hemagglutination test. These antigens, attached to aldehyde-fixed type "O" erythrocytes, detected antibodies in more than 91% of infections with the homologous Plasmodium species. Detection rates in infections caused by the heterologous species ranged from 72% to 76%. Positive reactions occurred in less than 2% of sera from persons without malaria infection.

Animals↗
PubMed1993

T-cell recognition of a cross-reactive antigen(s) in erythrocyte stages of Plasmodium falciparum and Plasmodium yoelii: inhibition of parasitemia by this antigen(s).

In the current study, we investigated the presence of a cross-reactive antigen(s) in the erythrocyte stage from Plasmodium yoelii (265 BY strain) and Plasmodium falciparum through recognition by T cells primed in vivo with antigens from each of these parasites. BALB/c mice are naturally resistant to P. falciparum but are susceptible to P. yoelii infection. Mice that had recovered from P. yoelii primary infection became resistant to a second infection. A higher in vitro proliferative response to a soluble blood stage preparation of P. falciparum was observed in splenic cells from immune animals than in those from mice with a patent P. yoelii infection. The antigen-induced proliferative response was enhanced when animals were exposed to a secondary infection. Animals exposed to a challenge infection were treated with anti-CD4 or anti-CD8 monoclonal antibodies to deplete the corresponding subset of T cells. There was a marked diminution in P. falciparum antigen-induced proliferative response in the total splenic cell populations from CD8-depleted but not from CD4-depleted mice. In CD8-depleted and nondepleted animals, the antigen-induced proliferation in the total cell populations was markedly lower than in the T-cell-rich populations, indicating inhibitory activities of B cells and/or macrophages. There was no such difference in the stimulation between total and T-enriched cell populations from CD4-depleted animals. Flow cytometry analysis demonstrated the presence of an almost equal percentage of CD8+ (59.6%) and CD4+ (64%) T cells in the spleen preparations following in vivo depletion of CD4- and CD8-bearing T cells, respectively. When cultured with P. yoelii blood stage antigen, splenocytes from animals immunized with P. falciparum antigen displayed a significant proliferative response which was markedly diminished by treatment with anti-Thy-1.2 antibody plus complement. Animals immunized with P. falciparum antigen and then challenged with P. yoelii blood stage parasites displayed about a 50% lower level of parasitemia. These results demonstrated the existence of a cross-reactive antigen(s) between a murine and a human Plasmodium species, as determined from both in vivo and in vitro biological assays, and indicated the reactivity of mainly CD8+ T cells with this antigen.

Animals↗
PubMed1978

Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus). II. Responses to chloroquine, quinine, and pyrimethamine.

The studies described in this report were designed to determine the responses of established infections with eight strains of Plasmodium falciparum and two strains of P. vivax in owl monkeys to treatment with chloroquine, quinine, and pyrimethamine. Responses with these different strains ranged from cure via application of well-tolerated doses of two of the above drugs and refractoriness to treatment with maximally tolerated doses of the third, to complete resistance to maximally tolerated doses of all three compounds. The results of treatment exhibited in infected owl monkeys correlated well in two respects with those reported in humans infected with the same plasmodial species. First, calculated on a milligram per M2 basis, the doses of chloroquine, quinine, or pyrimethamine required for a CD90 response in owl monkeys infected with strains susceptible to these drugs were remarkably similar to the doses required and/or employed for cure of infections with so-called drug-susceptible strains in human patients. Secondly, with few exceptions, the responses to the above drugs in owl monkeys infected with the ten specially selected strains were essentially identical with those exhibited by human volunteers or patients infected with the same strains. Together, these findings and correlations provide strong support for use of owl monkeys infected with appropriate strains of P. falciparum and P. vivax in the search for more broadly effective antimalarial drugs.

Animals↗
PubMed1988

[Efficacy of halofantrine in Plasmodium falciparum or Plasmodium vivax malaria in a resistance area (French Guiana)].

Halofantrine (WR 171.669) is a phenanthrene methanol derivative effective against the multidrug resistant strains of Plasmodium falciparum. One hundred and one patients, 48 men and 53 women, 53 adults and 48 children (less than or equal to 12 years old) aged from 1.5 to 57 years were treated. Fifty-one patients received a single 16 mg/kg dose and 50 patients received 24 mg/kg/day in 3 doses at 6-hour intervals. Parasite counts with examination of both thin and thick smears were performed twice daily for 5 to 6 days following treatment, or until smears were negative for parasites for 24 hours, and then weekly for 4 weeks. Thirteen patients reported clinical side effects. Six treated patients had no parasites. One patient had mixed parasitemia. Eighty three patients had P. falciparum malaria, with mean parasitemias between 26,850 +/- 36,679 and 35,412 +/- 50,527 per cubic millimeter. Halofantrine was very effective in the two doses tested from 87.5 to 100 p. 100. Eleven patients had in vivo resistant strains; ten in vitro tests were successful and nine were resistant to chloroquine. Thirteen patients with P. vivax and a mean parasitemia of 13,858 +/- 10,835 per cubic millimeter were cured but 3 had a relapse 3 to 4 weeks after treatment. At the 2 dosage levels tested halofantrine proved highly effective in the treatment of malaria caused by resistant and sensitive strains to P. falciparum.

Adolescent↗
PubMed2002

The population structure of Plasmodium falciparum and Plasmodium vivax during an epidemic of malaria in the Eastern Highlands of Papua New Guinea.

Although most of the Papua New Guinea highlands are too high for stable malaria transmission, local epidemics are a regular feature of the region. Few detailed descriptions of such epidemics are available, however. We describe the investigation of a malaria epidemic in the Obura Valley, Eastern Highlands Province, Papua New Guinea. Of the 244 samples examined by microscopy, 6.6% were positive for Plasmodium falciparum only, 9.4% were positive for Plasmodium vivax only, and 1.2% were mixed infections. MSP2 and MSP3alpha genotyping and AMA1 sequencing were used to determine the genetic variation present in a sample of P. falciparum and P. vivax infections. The P. vivax infections were found to be genetically highly diverse. In contrast, all P. falciparum samples were of a single genotype. This striking difference in genetic diversity suggests endemic, low-level local transmission for P. vivax but an outside introduction of P. falciparum as the most likely source of the epidemic.

Adolescent↗
PubMed1980

Chemosuppressive field trials in Thailand. IV. The suppression of Plasmodium falciparum and Plasmodium vivax parasitemias by mefloquine (WR 142,490, A 4-quinolinemethanol).

The effect of various dosages of mefloquine hydrochloride (WR 142,490) and sulfadoxine-pyrimethamine in the suppression of malaria infections was studied in an area of northeastern Thailand highly endemic for both chloroquine-resistant Plasmodium falciparum and for P. vivax. Both preparations, in all regimens studied, were effective in greatly reducing the incidence of falciparum infections. Mefloquine was more active in preventing vivax parasitemia than sulfadoxine-pyrimethamine; however, this combination remains the commercially available regimen of choice where both parasites occur and P. falciparum is resistant to chloroquine.

Adolescent↗
PubMed1978

Plasmodium falciparum and Plasmodium vivax infections in the owl monkey (Aotus trivirgatus). III. Methods employed in the search for new blood schizonticidal drugs.

This report describes, illustrates, and validates the major features of a procedure designed to provide primary assessments of the activities of potential antimalarial drugs against infections with chloroquine-resistant or pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys of Colombian origin. Studies with 14 specially selected compounds have shown that the test method has the capacity to identify and quantify diverse levels of therapeutic efficacy among agents that differ widely in chemical structure. Extended studies with two of the above compounds indicate that such assessments have an acceptable level of reproducibility. Experiments with two other agents, structurally different from those in the selected group, have shown that the impacts of pyrimethamine resistance (or chloroquine resistance) on the activity of a compound can be readily identified during routine application of the test procedure, as can emergence of parasites resistant to the test agent. The above body of information can usually be acquired in infections with two strains of P. falciparum, one chloroquine-resistant, the other pyrimethamine-resistant, with commitments of no more than 1.5 g of test compound and 12 owl monkeys. These modest requirements have made it possible to utilize human plasmodial infections in the owl monkey in the search for new blood schizonticidal drugs more broadly effective than those currently available.

Animals↗
PubMed1979

Studies on the 2,4-diamino-6-substituted quinazolines. II. Activities of selected derivatives against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.

Four 6-thio-, one 6-sulfinyl-, and two 6-sulfonyl-substituted 2,4-diaminoquinazolines were evaluated for capacities to cure established infections with the chloroquine-resistant Vietnam Oak Knoll and pyrimethamine-resistant Malayan Camp-CH/Q strains of Plasmodium falciparum in owl monkeys. As compared with the doses of standard drugs required for cure of infections with drug-susceptible strains or doses of the newly developed aminoalcohols required for cure of either drug-susceptible or drug-resistant strains, each of these quinazolines effected cure of infections with the Oak Knoll strain at a remarkably small daily dose. However, doses required for cure of infections with the Camp-CH/O strain were from 4-48 times those required for cure of infections with the Oak Knoll strain, suggesting that the activities of these quizanolines, like those of 6-amino-substituted derivatives, were compromised by pyrimethamine resistance. This suggestion received support from expanded studies involving WR-158,122 and WR-159,412, the most active of the agents examined, and the multidrug-resistant Vietnam Smith strain of P. falciparum and Vietnam Palo Alto strain of P. vivax, as well as the Oak Knoll and Camp-CH/Q strains. These studies also showed that significant fractions of infections with the Oak Knoll, Camp-CH/Q, and Palo Alto strains treated previously with subcurative doses of the above derivatives failed to respond to doses that regularly cured previously untreated infections. These treatment failures proved to be due to emergence of parasites resistant to the quinazolines.

Animals↗
PubMed2005

Dramatic difference in diversity between Plasmodium falciparum and Plasmodium vivax reticulocyte binding-like genes.

Malaria parasite proteins involved in erythrocyte invasion are considered important vaccine targets. Members of the reticulocyte binding-like (RBL) family of Plasmodium merozoite proteins are found in human, simian, and rodent malaria parasites and function in the initial steps of erythrocyte selection and invasion. The RBL genes are large, ranging in size from 7.7 to 10 kb, and the extent of any sequence diversity in parasite populations is unknown. We present the first assessment of sequence diversity within RBL genes from the two major human malaria parasites: Plasmodium falciparum and P. vivax. Polymorphism within the RBL genes is generally limited, except for P. vivax reticulocyte binding protein 2 (PvRBP2), which has nucleotide diversity levels 25-fold higher than the other RBL genes. The PvRBP2 haplotypes appear to fall into two distinct classes of alleles, suggesting large-scale dimorphism in this gene. Polymorphisms were frequently clustered, suggesting that different RBL domains may be evolving under different selection and functional pressures.

Amino Acid Sequence↗