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Biomedical subjects

H K Webster

Publications and source records attributed to H K Webster.

At least 55 records · Page 3Linked to original sources
PubMed1993

Response of Plasmodium vivax variants to chloroquine as determined by microscopy and quantitative polymerase chain reaction.

Genotypic heterogeneity in the repetitive portion of the circumsporozoite (CS) protein of Plasmodium vivax has been reported from many P. vivax-endemic areas. The objective of this study was to determine if the VK210 and VK247 CS variants of P. vivax differed in their clearance rates following chloroquine (CQ) therapy. One hundred seventy-one cases of P. vivax infection occurring in patients presenting to a research treatment center in Thailand were analyzed. Finger-prick blood samples were collected for microscopy and spotted onto filter paper at presentation and on each of five days of observation through supervised CQ therapy. A portion of the CS gene was amplified from filter paper samples by the polymerase chain reaction (PCR) and genotyped by oligoprobes specific for the VK210 and VK247 CS repeat regions. The mean time to clear parasitemia as determined by thick blood smear was significantly longer for pure VK210 infections (51 hr; 95% confidence interval [CI] 47.4-54, P = 0.006) and mixed infections (53 hr; 95% CI 49.2-56.7, P = 0.0009) as compared with VK247 infections (44 hr; 95% CI 39.8-47.9). Five patients matched for parasitemia, age, sex, and previous malaria experience were selected from each of the three genotype groups in the larger study for further analysis by quantitative PCR of P. vivax genotype-specific DNA during a treatment course. The mean time to clear parasite DNA, as determined by PCR, was significantly slower for VK210 parasites (65 hr; 95% CI 51-79) than for VK247 parasites (47 hr; 95% CI 30-63, P = 0.045).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Sequestration pattern of parasitized erythrocytes in cerebrum, mid-brain, and cerebellum of Plasmodium coatneyi-infected rhesus monkeys (Macaca mulatta).

Six rhesus monkeys (Macaca mulatta) infected with Plasmodium coatneyi were studied for parasitized red blood cell (PRBC) sequestration in microvessels of the brain. The degree of PRBC sequestration is different in the cerebral, mid-brain, and cerebellar microvessels, with sequestration occurring preferentially in the cerebellum. This pattern resembles that of PRBC sequestration in cerebral and cerebellar microvessels in human falciparum malaria. The morphologic appearance of sequestered cells under light and electron microscopy as well as the PRBC sequestration pattern bolsters the contention that the rhesus monkey infected with P. coatneyi is an appropriate primate model for the experimental study of human cerebral malaria.

Animals↗
PubMed1993

Amplification of quinine cardiac effects by the resistance-reversing agent prochlorperazine in falciparum malaria.

The use of reversing agents to overcome drug resistance is a potential new treatment strategy for both malaria and cancer. Laboratory studies have raised questions about the safety of this therapeutic approach, but data in humans are lacking. We therefore assessed the toxic potential of reversing agent therapy in Thai patients receiving quinine (17 mg/kg given over 4.5 hr) for falciparum malaria by serial measurements of the QTc interval, an electrocardiographic (ECG) marker of the effect of quinine. Six patients were randomly assigned to receive intravenous quinine alone while another six received one intramuscular injection of 12.5 mg of the reversing agent prochlorperazine (PC; compazine, stemetil) 2.5 hr after the quinine infusion had begun. Compared with baseline values at 2.5 hr, there was prolongation of the QTc interval 30, 60, 90, and 120 min after PC was injected (P < 0.05) but no further lengthening with quinine alone (P > 0.2). Prochlorperazine alone did not lengthen the QTc interval in six healthy volunteers. Neither total nor free quinine plasma levels increased after PC was injected, suggesting that ECG changes may have been due to PC-induced intracellular accumulation of quinine. Although only minor quinine ECG effects were amplified by the reversing agent PC in this study, resistance-reversing therapy could potentiate more serious drug effects. The possibility that more serious toxic effects could be produced by this therapeutic approach should be investigated further.

Electrocardiography↗
PubMed1993

A nonhuman primate model for human cerebral malaria: effects of artesunate (qinghaosu derivative) on rhesus monkeys experimentally infected with Plasmodium coatneyi.

We studied the effects of artesunate on rhesus monkeys infected with Plasmodium coatneyi. Sixteen rhesus monkeys were divided in four groups. Group I consisted of three monkeys that were splenectomized and were treated with three doses (loading dose: 3.3 mg/kg, maintenance doses: 1.7 mg/kg) of artesunate, group II consisted of three monkeys that were treated with three doses of artesunate (same as group I), group III consisted of two monkeys that were treated with one dose (3.3 mg/kg) of artesunate, and group IV consisted of five untreated monkeys. Parasitemias of these groups ranged from 13.3% to 19.5% before treatment. Twenty-four hours after administration, the parasitemia was reduced to 2.2% in group I and to < 0.1% in group II; parasitemia was lowered to 10.6% in group III only 3 hr after drug administration. The rate of sequestration in the cerebral microvessels, which was 29.4% in untreated animals, was < 0.1% in groups I and II (24 hr after treatment), and 2.0% in group III (3 hr after treatment). These data clearly indicate that artesunate not only reduced parasitemia, but also reduced the rate of parasitized red blood cell (PRBC) sequestration in cerebral microvessels. In an immunohistologic study, endothelial-leukocyte adhesion molecule-1 (ELAM-1) was not detected in group I after treatment with artesunate, although the presence of CD36, thrombospondin, intercellular adhesion molecule-1, IgG, and C3 in the cerebral microvessels was not altered. This is the first in vivo study to show that artesunate interferes with continued PRBC sequestration in the cerebral microvessels in cerebral malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Prevention of Plasmodium falciparum malaria by Fansimef and Lariam in the northeastern part of Thailand.

Two studies were conduct in Thailand in order to find appropriate falciparum malaria prophylactic drug regimens. The first study was done during June - September 1987 with 363 soldiers who received Fansimef (MSP) 1 tab/week (group 1), 337 soldiers who received MSP 1 tab/2 week (group 2) and 165 soldiers who received chloroquine 300 mg base weekly plus Fansidar 1 tab/week (group 3). At the end of the study there were 9 and 13 falciparum malaria episodes in groups 1 and 2, respectively, with incidence rates of 0.8 and 1.8 cases/100 person-months (P-M). In group 3, the corresponding values were 30 episodes and an incidence of 7.2/100 P-M. For the second study which lasted from October 1987 - January 1988 in the same area, 498 soldiers were given Fansimef 1/2 tab/week (group 4), 499 soldiers were given Lariam 1/2 tab/week (group 5) and 247 soldiers were given chloroquine plus Fansidar (group 6). Thirty malaria episodes were found in group 4, for an incidence of 2.0/100 P-M. In group 5, 23 episodes were found, for an incidence of 1.6/100 P-M. In group 6, 74 episodes occurred, ie an incidence of 12.2/100 P-M. The incidence rates of malaria among Fansimef 1 tab weekly, Fansimef half dose weekly or Lariam half dose weekly were not significantly different but were different from chloroquine plus Fansidar groups. Adverse events in each group were mild.

Adult↗
PubMed1992

High-performance liquid chromatographic determination of dihydroorotate dehydrogenase of Plasmodium falciparum and effects of antimalarials on enzyme activity.

A reversed-phase high-performance liquid chromatographic technique for the determination of dihydroorotate dehydrogenase in Plasmodium falciparum was developed. The assay was applied to the evaluation of the effects of several antimalarial drugs on the enzyme. Treatment of both the asexual and gametocyte stages of P. falciparum in culture with menoctone, primaquine or the primaquine derivative WR 238605 led to depression of the enzyme activity, although the drugs did not appear to inhibit the enzyme directly.

Aminoquinolines↗
PubMed1992

Flow cytometric two-color staining technique for simultaneous determination of human erythrocyte membrane antigen and intracellular malarial DNA.

A novel fixative and permeabilization method is described which allows simultaneous flow cytometric detection of red blood cell membrane antigen and intracellular malaria parasites. To illustrate the method, red blood cells from patients with paroxysmal nocturnal hemoglobinuria were infected with Plasmodium falciparum and maintained in synchronous red blood cell culture. The infected red blood cells were immunolabeled with antibodies directed to the complement regulatory protein decay-accelerating factor (DAF) followed by subsequent fixations in paraformaldehyde and then glutaraldehyde in phosphate-buffered saline. Finally, DNA of the intraerythrocytic parasites was stained with propidium iodide. Using this technique, cellular morphology was well preserved, no cell aggregation was observed, and high-quality indirect immunofluorescence and parasite DNA staining were obtained with negligible nonspecific labelling. Simultaneous measurement of parasite DNA and red blood cell membrane determinants makes possible the investigation of alterations of red cell membrane proteins in association with development of intracellular malaria parasites.

Animals↗
PubMed1992

Presence of autoimmunity to pancreatic antigens in a patient with fibrocalculous pancreatic diabetes.

A case of fibrocalculous pancreatic diabetes (FCPD) is reported for which antibody and cellular immune characteristics were determined. The patient, a Thai woman, had serum islet cell antibodies (ICA) that were detected by both immunoperoxidase staining and an indirect enzyme-linked immunosorbent assay (ELISA). Serum anti-human insulin antibodies were negative by a displacement ELISA. Lymphoproliferation assay against pancreatic antigen prepared from a blood group O cadaveric donor was positive. Increased CD8+ lymphocytes were observed using direct immunofluorescence staining and flow cytometry. CD4+ T lymphocytes, B lymphocytes and NK cells were within normal levels. These findings provide evidence for autoimmunity to pancreatic antigens in a patient with fibrocalculous pancreatic diabetes.

Adult↗
PubMed1992

Detection of Plasmodium falciparum by polymerase chain reaction in a field study.

Detection of Plasmodium falciparum by polymerase chain reaction (PCR) was evaluated in 33 P. falciparum-infected patients with two different amplification systems over 5-7 days of curative treatment. In the K1-14 system, a P. falciparum DNA fragment of 206 bp was detected, and in the circumsporozoite (CS) system, a fragment of 800 bp was detected. The K1-14 and CS systems identified 95% and 93%, respectively, of 103 microscopically identified specimens; both systems detected as few as 11 parasites/microliters among these specimens. Specimens from 20 smear- and history-negative controls were all negative by both PCR systems. The K1-14 and CS systems detected P. falciparum DNA in 53% and 20%, respectively, of blood films collected on the first day and 3% and 0 of the blood films collected on the fourth day after reversion to microscopic negative. The simultaneous use of two independent PCR systems to monitor patients during curative treatment of P. falciparum infections convincingly demonstrated that P. falciparum DNA was present transiently in the blood of infected patients at a time when the parasite could no longer be detected microscopically.

Animals↗
PubMed1992

High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria.

The therapeutic efficacy and toxicity of a high-dose (25 mg/kg) mefloquine regimen (M25) and the currently recommended regimen of 15 mg/kg (M15) were compared in 199 patients with acute falciparum malaria in an area with deteriorating multidrug resistance on the Thai-Burmese border. The clinical and parasitologic responses were significantly more rapid with M25. The incidence of treatment failures by day 7-9 was 7% for M15 and 1% for M25 (P = .03) and had increased to 40% and 9%, respectively, by day 28 (P < .0001). Overall failure rates were highest in children (P = .02). Parasite clearance times were a good predictor of the therapeutic response; all patients with parasitemia persisting > 5 days after treatment experienced subsequent recrudescence. Side effects were dose-related and included dizziness, anorexia, nausea, vomiting, and fatigue. Although vomiting < 1 h after treatment was more likely in young children, children overall tolerated mefloquine better than adults, and men better than women. The optimum treatment dose of mefloquine in this area is 25 mg/kg.

Acute Disease↗
PubMed1992

Effect of orally active hydroxypyridinone iron chelators on human lymphocyte function.

Several iron chelators, 3-hydroxypyridin-4-ones (CP) and desferrioxamine (DF) were compared for their effect on DNA synthesis, cell viability and expression of cell proliferation markers. Short-term (4 h) exposure of human peripheral blood mononuclear cells to CP or DF inhibited the proliferative response of cells to concanavalin A (Con A). Inhibition by CP and DF showed a dose-dependent effect with CP compounds more active than DF. Increased inhibitory activity of CP over DF was partly due to the lipophilic properties of CP. Pre-saturation of CP and DF with exogenous ferric ion either diminished or prevented the inhibitory effect. At high chelator concentrations or prolonged (72 h) exposure of the cells to chelators, inhibition occurred but poor cell viability was observed. In contrast to their inhibition of DNA synthesis, these iron chelators showed little effect on protein synthesis and the expression of transferrin receptors and interleukin-2 (IL-2) receptors. These findings suggest that both DF and CP compounds exert their effect by chelation of ferric ion with subsequent inhibition of DNA synthesis.

Blood Proteins↗
PubMed1992

Cytoadherence characteristics of rosette-forming Plasmodium falciparum.

Sequestration of Plasmodium falciparum-infected erythrocytes to the capillary endothelium can cause obstruction and localized tissue damage. Occlusion of vessels in falciparum malaria infection has been related to two properties of the parasite: adhesion to endothelial cells and rosette formation. Our study on P. falciparum isolates from Thailand producing variable numbers of rosettes suggests the involvement of rosettes in capillary blockage caused by direct adhesion of the rosette-forming infected erythrocytes to various target cells, e.g., live human umbilical vein endothelial cells, monocytes, and platelets. These rosettes did not bind Formalin-fixed target cells, nor did they bind to live or fixed C32 or G361 melanoma cells. Classification of the receptors involved in cytoadherence of endothelial cells and monocytes by specific antibody blocking and flow cytometry indicated that CD36 was involved in the adherence of monocytes but that other receptors besides CD36 may be involved in parasite adherence to endothelial cells. The cytoadherence of infected erythrocytes to monocytes was also associated with CD54 (ICAM-1). Further, differentiation of adherent monocytes resulted in an inversion of CD36 and CD54 levels on the cell surface which correlated with a decrease in surface binding of infected erythrocytes. This observation suggests that the state of cell activation and differentiation may also contribute to sequestration of parasites and to the pathogenesis of malaria.

Animals↗
PubMed1992

Circumsporozoite genotyping of global isolates of Plasmodium vivax from dried blood specimens.

The prevalence and global distribution of two circumsporozoite (CS) genotypes of Plasmodium vivax (VK210 and VK247) were determined by genetic analysis of isolates from 234 malaria-infected patients. Whole blood specimens were collected on filter paper from patients infected with malaria in Thailand, Mexico, Papua New Guinea, Peru, Afghanistan (Pakistan), India, and western Africa and from 50 asymptomatic smear-negative controls. Following extraction of DNA from the filter paper samples, the CS gene was amplified by the polymerase chain reaction and genotyped by using oligoprobes specific for the VK210 and VK247 repeat epitopes. The sensitivity of genotyping from a single blood dot was 95.2%. The VK247 CS genotype was identified in the blood of patients from all seven study areas and was the predominant form present in samples from Thailand (83%) and Papua New Guinea (90%). In contrast, VK247 DNA was present in only 9% of isolates from Mexico. Individuals infected with both genotypes simultaneously were identified in all study areas except Mexico and were particularly common in Thailand (58%) and Papua New Guinea (60%). These findings indicate that the VK247 genotype of P. vivax is widely distributed but that its prevalence varies geographically. In addition, we conclude that use of samples of whole blood on filter paper is a practical and sensitive method for determining the genotypes of large numbers of malaria isolates collected in field settings.

Amino Acid Sequence↗
PubMed1992

Plasmodium coatneyi-infected rhesus monkeys: a primate model for human cerebral malaria.

Although several animal models for human cerebral malaria have been proposed in the past, none have shown pathological findings that are similar to those seen in humans. In order to develop an animal model for human cerebral malaria, we studied the pathology of brains of Plasmodium coatneyi (primate malaria parasite)-infected rhesus monkeys. Our study demonstrated parasitized erythrocyte (PRBC) sequestration and cytoadherence of knobs on PRBC to endothelial cells in cerebral microvessels of these monkeys. This is similar to the findings seen in human cerebral malaria. Cerebral microvessels with sequestered PRBC were shown by immunohistochemistry to possess CD36, TSP and ICAM-1. These proteins were not evident in cerebral microvessels of uninfected control monkeys. Our study indicates, for the first time, that rhesus monkeys infected with P. coatneyi can be used as a primate model to study human cerebral malaria.

Animals↗
PubMed1992

Malaria chemoprophylaxis using proguanil/dapsone combinations on the Thai-Cambodian border.

The Thai-Cambodian border is a difficult area in which to provide adequate malaria chemoprophylaxis because of multiple drug-resistant Plasmodium falciparum. In 1990-1991, Thai soldiers were randomly selected to receive proguanil (200 mg/day) combined with dapsone (4 mg or 12.5 mg/day) (n = 184) or pyrimethamine/dapsone (12.5 mg and 100 mg/week) (n = 177). Doxycycline (100 mg/day) was given to men with glucose-6-phosphate dehydrogenase deficiency (n = 77). Falciparum malaria attack rates were the same whether proguanil/dapsone (10.3%) or pyrimethamine/dapsone (11.3%) was used. However, proguanil/dapsone was more effective than pyrimethamine/dapsone in preventing vivax malaria (1.6% versus 12.4%). Men receiving doxycycline had falciparum malaria (3.9%) and vivax malaria (1.3%) at low rates. Adjusting the dapsone component from 4 mg to 12.5 mg did not improve the prophylactic effectiveness. Hematologic toxicity was not observed with the proguanil/dapsone combination. We conclude that proguanil/dapsone is not a useful alternative for malaria chemoprophylaxis on the Thai-Cambodian border.

Blood Cells↗
PubMed1992

Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand.

Reports of deteriorating quinine efficacy prompted us to investigate the ability of quinine-tetracycline to clear parasites and fever from patients with multiple drug-resistant Plasmodium falciparum infections. Past and present treatment results were compared at two study sites along the Thai-Cambodian border. In northeastern Thailand, quinine-tetracycline cleared parasites more quickly in 1990 than in 1987 (mean 3.4 and 4.0 days, respectively; P = 0.006). In southeastern Thailand, there were no significant differences between 1990 (n = 26) and 1981-1983 (n = 42) in the time taken to clear either parasites (median 96 and 93 hr, respectively; P = 0.35) or fever (mean 74 and 66 hr, respectively; P = 0.30). In vitro drug sensitivity testing revealed a two-fold decrease in susceptibility to quinine between 1983 and 1990 in isolates from the southeastern Thai-Cambodian border (mean inhibitory concentration 166 ng/ml and 320 ng/ml, respectively; P less than 0.001). We conclude that oral quinine-tetracycline continues to reliably clear parasites and fever from falciparum malaria patients infected in eastern Thailand. Periodic re-evaluations are warranted, however, since the decrease in vitro susceptibility to quinine may be followed by an in vivo decay in the treatment response.

Adult↗