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Biomedical subjects

H K Webster

Publications and source records attributed to H K Webster.

At least 91 records · Page 5Linked to original sources
PubMed1991

Halofantrine for the treatment of mefloquine chemoprophylaxis failures in Plasmodium falciparum infections.

Thai soldiers who became slide-positive for malaria while receiving mefloquine chemoprophylaxis were treated with halofantrine to study its efficacy against mefloquine-resistant falciparum malaria. Thirty-two patients received three doses of 500 mg (1,500 mg total) of halofantrine at six-hr intervals, and were then observed for four weeks. Parasite recrudescence following treatment (median 21 days) occurred in seven of 23 patients (30%) who had mefloquine serum concentrations indicative of regular prophylaxis (greater than 500 ng/ml). Serum concentrations of mefloquine in all 32 patients averaged 950 ng/ml (range 26-2,515) prior to halofantrine treatment. The halofantrine serum concentrations were higher in patients cured by halofantrine than in patients with drug failure, but this was not statistically significant. Patients who were cured by halofantrine had parasites that were more sensitive in in vitro testing to mefloquine (mean [inhibitory concentration] IC50 = 12.5 ng/ml) than in patients whose parasitemias recrudesced (mean IC50 = 23.8 ng/ml) (P less than 0.01, by Wilcoxon rank sum test). These observations suggest that the current formulation and regimen of halofantrine are not optimal for the treatment of multiple drug-resistant falciparum malaria from Thailand.

Animals↗
PubMed1991

Characterization of naturally acquired antibody responses to a recombinant fragment from the N-terminus of Plasmodium falciparum glycoprotein 195.

Antibody responses to the glycoprotein precursor of the major merozoite surface antigens of Plasmodium falciparum (gp195) were investigated in acutely infected Thai adults. Specific IgG antibody was assayed by enzyme-linked immunosorbent assay using a recombinant fragment derived from the N-terminal region of gp195 as the capture antigen. Two control groups were found to be without significant cross-reacting antibody. Among occupationally exposed soldiers, 84 of 85 men developed positive antibody responses during acute falciparum malaria. Mean antibody levels began to increase at the time of diagnosis, peaking, often at high titers, within two weeks, and then decreased with an initial serum half-life of less than one month. The high frequency of gp195 antibody responses underscores a potential role in serodiagnosis, whereas the dynamic nature of the response suggests that a rigorous schedule of prospective serum sampling will be required to accurately assess the relationship between these antibodies and protection.

Adolescent↗
PubMed1990

Prevalence of antibody to heterologous circumsporozoite protein of Plasmodium vivax in Thailand.

The distribution in Thailand of antibody to a recently discovered variant of circumsporozoite proteins of Plasmodium vivax was determined by enzyme-linked immunosorbent assay (ELISA). The ELISA capture antigens were a synthetic peptide of the principal variant sequence ANGAGNQPG and a candidate P vivax vaccine that contained the predominant repeat sequence GDRAA/DGQPA. Serological evidence of recent inoculation with the variant was found throughout Thailand and in migrants from Cambodia, Malaysia, and Burma. IgG antibody to the two P vivax circumsporozoite proteins was detected in 217 of 804 test sera (27%). Within the regions studied the proportion of positive sera specific for the variant epitope ranged from 28% to 66%. A vaccine against the predominant repeat domain may rapidly select for the variant, which already appears to be widespread within Thailand.

Amino Acid Sequence↗
PubMed1990

T cell responses in acute falciparum malaria.

T lymphocyte responses to malaria-specific antigens during acute falciparum malaria were studied to determine host-parasite interaction and its relation to the manifestations of the disease. The results indicate that while there is antigen-specific immunodepression, markedly elevated levels of soluble factors such as IL2 receptor, CD8 antigen and IFN-gamma suggest that there is intense concurrent cellular activation which however does not seem to be effective in controlling the infection. It is proposed that the cellular activation is to a large extent non-specific and polyclonal, and leads to the exaggerated production of cytokines and eventually immunopathology. Various mechanisms of immunodepression are discussed.

Acute Disease↗
PubMed1990

Increased gamma delta T cells in acute Plasmodium falciparum malaria.

The T cell receptor of gamma delta is normally expressed on a small percentage of peripheral lymphocytes. Although the role of gamma delta T cells in the physiologic immune response is still unknown, there is accumulating evidence that gamma delta T cells may participate in the immune response to mycobacterial and other infectious organisms. In this study, we have quantitated the number of circulating gamma delta T cells during acute Plasmodium falciparum malaria. The results indicate that gamma delta T cells are elevated during the acute infection and remain elevated for at least 4 weeks during convalescence. T cells may participate in the immune response against P. falciparum by functioning as non-MHC restricted cytotoxic cells against intraerythrocytic parasites. Alternatively, lymphokines may be produced on antigen stimulation which may have antiparasitic activity.

Acute Disease↗
PubMed1990

Folate and cobalamin metabolism in Plasmodium falciparum.

During the past several years, Jerapan Krungkrai, H. Kyle Webster and Yongyuth Yuthavong have characterized the metabolic pathway of folate biosynthesis and folate-dependent reactions, including the cobalamin-dependent activity of methionine synthase, in P. falciparum grown in vitro. In this review, they discuss the implications of this work for understanding the mechanism of pyrimethamine resistance and the importance of cloning the dihydrofolate reductase gene. In addition, the role of cobalamin in P. falciparum will be considered. Interference with cobalamin use may represent a new target for combating the parasite.

Journal Article↗
PubMed1990

Simultaneous measurement of quinine and quinidine in human plasma, whole blood, and erythrocytes by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method with fluorescence detection is described for the simultaneous measurement of quinine and quinidine in plasma, whole blood, and erythrocytes. The compounds were separated on an Ultrasphere C18 reversed-phase column (25 cm x 4.6 mm inside diameter, 5 microns particle size) using a mobile phase of acetonitrile/water/triethylamine (11:88:1, vol/vol) at pH 2.5. The method, simple, accurate, and selective, requires only a single-step liquid-liquid extraction and uses the structurally similar alkaloid, cinchonine, as the internal standard. The commercial impurities, dihydroquinine and dihydroquinidine, and unknown metabolites were well resolved from the parent drugs. The assay is precise, with interassay coefficients of variation less than or equal to 7.0% and an accuracy of less than or equal to 7.3% over a concentration range of 0.125 to 4.0 micrograms/0.25 ml. The extraction recoveries of the two drugs were similar, averaging 82.9% for quinine and 79.3% for quinidine from the three biological fluids. The clinical application of the method for routine drug monitoring and for estimating the pharmacokinetics of quinine and quinidine in man are discussed.

Chromatography, High Pressure Liquid↗
PubMed1990

Macrophage activation in falciparum malaria as measured by neopterin and interferon-gamma.

Macrophage activation during acute falciparum malaria in 71 Thai adults was investigated by measuring urinary neopterin and serum interferon-gamma (IFN-gamma). Neopterin, a product of IFN-gamma-activated macrophages, was elevated in 94% of patients upon admission (day 0, prior to treatment) and in all at some time during the period of study. Neopterin levels tended to rise further (days 1-5) before falling back towards the normal range as patients recovered following effective chemotherapy (days 6-8). IFN-gamma was measured in 32 patients and found to be directly related to neopterin concentration. Both neopterin and IFN-gamma values were highest in patients experiencing a first malaria infection. Among those with histories of prior malaria, neopterin and IFN-gamma levels were inversely related to the number of previous infections. Morbidity, as assessed by degree and duration of fever, was directly related to neopterin concentration. This longitudinal study quantitatively describes the extent and duration of macrophage activation in falciparum malaria. The data also suggest that with repeated malaria infection and antigen exposure, there is a progressive decrease or possibly suppression of the T cell-macrophage interaction mediated by IFN-gamma.

Adult↗
PubMed1990

Occupational malaria in Thai Rangers: epidemiological, clinical and immunological features.

Malaria continues to be a serious disease threat to soldiers deployed in tropical environments. Distinct features of the disease and the host immune response require that malaria occurring in occupational groups be investigated separately from the infection as found in endemic populations. For the first time since the Vietnam War, malaria has been systematically studied in soldiers under combat conditions. In this report we describe characteristics of malaria as experienced by Thai Rangers operating on the Lao-Cambodian border.

Animals↗
PubMed1989

High-performance liquid chromatographic assay for thymidylate synthase from the human malaria parasite, Plasmodium falciparum.

A rapid and highly sensitive high-performance liquid chromatographic assay for thymidylate synthase activity is described. The assay is based on the separation of the substrate, deoxyuridylate (dUMP), and its product, deoxythymidylate (dTMP), on a LiChrosorb RP-8 reversed-phase column with 44 mM triethylammonium phosphate (pH 7.0) as mobile phase and a flow-rate of 1.0 ml/min. In addition, using a mu Bondapak C18 reversed-phase column with 10 mM potassium phosphate (pH 4.0) and a gradient of 0-28% methanol, dUMP, dTMP and deoxythymidine (dTdR) are well separated within 30 min. The latter system is also applied to assay thymidine kinase activity with dTdR and dTMP as substrate and product, respectively. This method is sensitive enough to measure dTMP at concentrations as low as 25 pmol, and it was used to show that crude extracts of the human malaria parasite Plasmodium falciparum contain thymidylate synthase but not thymidine kinase activity.

Animals↗
PubMed1989

De novo and salvage biosynthesis of pteroylpentaglutamates in the human malaria parasite, Plasmodium falciparum.

Plasmodium falciparum was shown to synthesize pteroylpolyglutamate de novo from guanosine 5'-triphosphate (GTP), p-aminobenzoate (PABA), and L-glutamate (L-Glu). The parasite also had the capacity to synthesize pteroylpolyglutamate from both intact and degradation moieties (p-aminobenzoylglutamate and pterin-aldehyde) of exogenous folate added into the growth medium. The major product was identified as 5-methyl-tetrahydroteroylpentaglutamate following exposure to pteroylpolyglutamate hydrolase and oxidative degradation of the C9-N10 bond in the molecule and identification of products by reversed-phase high performance liquid chromatography. Inhibition of pteroylpentaglutamate synthesis from the radiolabelled metabolic precursors (GTP, PABA, L-Glu) and folate by the antifolate antimalarials, pyrimethamine and sulfadoxine at therapeutic concentrations, may suggest the existence of a unique biosynthetic pathway in the malaria parasite.

Animals↗
PubMed1989

Characterization of cobalamin-dependent methionine synthase purified from the human malarial parasite, Plasmodium falciparum.

Methionine synthase, which catalyzes the reaction, 5-methyltetrahydrofolate (5-CH3-H4PteGlu) + homocysteine----methionine + tetrahydrofolate, was detected and partially purified from the human malarial parasite, Plasmodium falciparum (K1 isolate). Partial purification was achieved using high-performance size-exclusion and anion-exchange chromatography. The apparent relative molecular weight of the enzyme was estimated as 105,000 daltons, and the apparent Km for 5-CH3-H4PteGlu was 24.2 microM. The enzyme was dependent on adenosylcobalamin or methylcobalamin but not on cobalamin, cyanocobalamin, or hydroxocobalamin in either the absence or presence of S-adenosylmethionine. Preincubation with nitrous oxide markedly inhibited the enzyme. Methionine synthase in P. falciparum may play a role in the supply of methionine and in folate salvage using exogenous 5-CH3-H4PteGlu for tetrahydrofolate metabolism.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1989

Immune responses to the circumsporozoite protein of Plasmodium falciparum in relation to HLA-DR type.

Associations between HLA-DR/DQ phenotypes and immune responses to the circumsporozoite (CS) protein of the human malaria parasite, Plasmodium falciparum, were investigated in Thai adults. The frequency of DR and DQ types did not differ between 15 high antibody responders and 16 antibody non-responders. Initial results which suggested that lymphocyte responses to a CS-derived peptide (R32tet32) might be HLA-DR associated were not confirmed by subsequent extension of the study. Thus, MHC restriction appears not to be a major factor in the frequently observed unresponsiveness of the immune system to the P. falciparum sporozoite. Based on these results, it is expected that MHC restriction will not be a major obstacle to the application of a malaria vaccine in outbred human populations.

Adult↗