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Search Results: 1 - 10 of 401257 matches for " Arjen M. Dondorp "
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Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.
Dondorp Arjen M,Desakorn Varunee,Pongtavornpinyo Wirichada,Sahassananda Duangjai
PLOS Medicine , 2005,
Abstract: BACKGROUND: In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. METHODS AND FINDINGS: We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 x 10(11) (95% confidence interval [CI] 5.8 x 10(11) to 8.5 x 10(11)) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 x 10(12), 95% CI 1.3 x 10(12) to 2.3 x 10(12)) than in patients hospitalised without signs of severity (geometric mean 2.8 x 10(11), 95% CI 2.3 x 10(11) to 3.5 x 10(11); p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 x 10(12), 95% CI 1.9 x 10(12) to 6.3 x 10(12); p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony-but in severe malaria is unrelated to stage of parasite development. CONCLUSION: Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.
Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies
Wirichada Pongtavornpinyo, Shunmay Yeung, Ian M Hastings, Arjen M Dondorp, Nicholas PJ Day, Nicholas J White
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-229
Abstract: A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment.The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures.This paper has demonstrated the use of a comprehensive mathematical model to describe malaria transmission and the spread of drug resistance. The model is strongly linked to the empirical evidence obtained from extensive data available from various sources. This model can be a useful tool to inform the design of treatment policies, particularly at a time when ACT has been endorsed by WHO as first-line treatment for falciparum malaria worldwide.For the past half-century, the malaria parasites of humans
Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum
Preeyaporn Monatrakul, Mathirut Mungthin, Arjen M Dondorp, Srivicha Krudsood, Rachanee Udomsangpetch, Polrat Wilairatana, Nicholas J White, Kesinee Chotivanich
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-326
Abstract: Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA]) were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90), of 3H-hypoxanthine uptake.Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm) (p= 0.001). As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range) IC50 6.4 (0.5 to 23.8) ng/ml versus 221.5 (174.4 to 250.4) ng/ml (p = 0.02), and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3) ng/ml versus 0.8 (0.2 to 2.3) ng/ml (p = 0.08). Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not significantly affected; median (range) IC90 448.0 (65 to > 500) ng/ml versus 368.8 (261 to 501) ng/ml for quinine (p > 0.05) and 17.0 (0.1 to 29.5) ng/ml versus 7.6 (2.3 to 19.5) ng/ml for artesunate (p = 0.4).'Immune' plasma containing anti-malarial antibodies inhibits parasite development and multiplication and increases apparent in vitro anti-malarial drug susceptibility of P. falciparum. The IC90 was much less affected than the IC50 measurement.Falciparum malaria remains the most important parasite infection in the tropical world. Develop
The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against Plasmodium falciparum
Kesinee Chotivanich, Mathirut Mungthin, Ronnatrai Ruengweerayuth, Rachanee Udomsangpetch, Arjen M Dondorp, Pratap Singhasivanon, Sasithon Pukrittayakamee, Nicholas J White
Malaria Journal , 2012, DOI: 10.1186/1475-2875-11-177
Abstract: Serum was obtained from non-immune volunteers under fasting conditions and after ingestion of a high fat meal and used in standard Plasmodium falciparum in-vitro susceptibility assays. Anti-malarial drugs, including lumefantrine, atovaquone and chloroquine in five-fold dilutions (range 0.05?ng/ml – 1?ug/mL) were diluted in culture medium supplemented with fasting or post-prandial 10% donor serum. The in-vitro drug susceptibility of parasite isolates was determined using the 3H-hypoxanthine uptake inhibition method and expressed as the concentration which gave 50% inhibition of hypoxanthine uptake (IC50).Doubling plasma triglyceride concentrations (from 160?mg/dL to 320?mg/dL), resulted in an approximate doubling of the IC50 for lumefantrine (191?ng/mL to 465?ng/mL, P?<?0.01) and a 20-fold increase in the IC50 for atovaquone (0.5?ng/mL to 12?ng/ml; P?<?0.01). In contrast, susceptibility to the hydrophilic anti-malarial chloroquine did not change in relation to triglyceride content of the medium.Lipidaemia reduces the anti-malarial activity of lipophilic anti-malarial drugs. This is an important confounder in laboratory in vitro testing and it could have therapeutic relevance.
Correction: Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2
Arjen M Dondorp,Varunee Desakorn,Wirichada Pongtavornpinyo,Duangjai Sahassananda,Kamolrat Silamut,Kesinee Chotivanich,Paul N Newton,Punnee Pitisuttithum,A. M Smithyman,Nicholas J White,Nicholas P. J Day
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020390
Abstract:
Estimation of the Total Parasite Biomass in Acute Falciparum Malaria from Plasma PfHRP2
Arjen M Dondorp,Varunee Desakorn,Wirichada Pongtavornpinyo,Duangjai Sahassananda,Kamolrat Silamut,Kesinee Chotivanich,Paul N Newton,Punnee Pitisuttithum,A. M Smithyman,Nicholas J White ,Nicholas P. J Day
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020204
Abstract: Background In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. Methods and Findings We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai–Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 × 1011 (95% confidence interval [CI] 5.8 × 1011 to 8.5 × 1011) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 × 1012, 95% CI 1.3 × 1012 to 2.3 × 1012) than in patients hospitalised without signs of severity (geometric mean 2.8 × 1011, 95% CI 2.3 × 1011 to 3.5 × 1011; p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 × 1012, 95% CI 1.9 × 1012 to 6.3 × 1012; p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony—but in severe malaria is unrelated to stage of parasite development. Conclusion Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.
Coma in fatal adult human malaria is not caused by cerebral oedema
Isabelle M Medana, Nicholas PJ Day, Navakanit Sachanonta, Nguyen TH Mai, Arjen M Dondorp, Emsri Pongponratn, Tran T Hien, Nicholas J White, Gareth DH Turner
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-267
Abstract: The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02).Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.Cerebral malaria (CM) is a diffuse but potentially reversible encephalopathy, caused by infection with the protozoan parasite Plasmodium falciparum. CM presents clinically with decreased consciousness, seizures and coma. The treated mortality rate is high (15-30%), and there may be long-term neurological and developmental sequelae in survivors, particularly young children. However, no major neurological deficit is detectable in the majority of survivors, suggesting that the processes leading to coma may be rapidly and potentially completely reversible [1,
Genotyping of Plasmodium vivax Reveals Both Short and Long Latency Relapse Patterns in Kolkata
Jung-Ryong Kim, Amitabha Nandy, Ardhendu Kumar Maji, Manjulika Addy, Arjen M. Dondorp, Nicholas P. J. Day, Sasithon Pukrittayakamee, Nicholas J. White, Mallika Imwong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039645
Abstract: Background The Plasmodium vivax that was once prevalent in temperate climatic zones typically had an interval between primary infection and first relapse of 7–10 months, whereas in tropical areas P.vivax infections relapse frequently at intervals of 3–6 weeks. Defining the epidemiology of these two phenotypes from temporal patterns of illness in endemic areas is difficult or impossible, particularly if they overlap. Methods A prospective open label comparison of chloroquine (CQ) alone versus CQ plus unobserved primaquine for either 5 days or 14 days was conducted in patients presenting with acute vivax malaria in Kolkata. Patients were followed for 15 months and primary and recurrent infections were genotyped using three polymorphic antigen and up to 8 microsatellite markers. Results 151 patients were enrolled of whom 47 (31%) had subsequent recurrent infections. Recurrence proportions were similar in the three treatment groups. Parasite genotyping revealed discrete temporal patterns of recurrence allowing differentiation of probable relapse from newly acquired infections. This suggested that 32 of the 47 recurrences were probable relapses of which 22 (69%) were genetically homologous. The majority (81%) of probable relapses occurred within three months (16 homologous, 10 heterologous) and six genetically homologous relapses (19%) were of the long latency (8–10 month interval) phenotype. Conclusions With long follow-up to assess temporal patterns of vivax malaria recurrence, genotyping of P.vivax can be used to assess relapse rates. A 14 day unobserved course of primaquine did not prevent relapse. Genotyping indicates that long latency P.vivax is prevalent in West Bengal, and that the first relapses after long latent periods are genetically homologous. Trial Registration Controlled-Trials.com ISRCTN14027467
Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance
Nicholas J White, Wirichada Pongtavornpinyo, Richard J Maude, Sompob Saralamba, Ricardo Aguas, Kasia Stepniewska, Sue J Lee, Arjen M Dondorp, Lisa J White, Nicholas PJ Day
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-253
Abstract: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed.Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission.Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.Resistance to anti-malarial drugs poses a major threat to mal
Modelling malaria elimination on the internet
Richard J Maude, Sompob Saralamba, Adrian Lewis, Dean Sherwood, Nicholas J White, Nicholas PJ Day, Arjen M Dondorp, Lisa J White
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-191
Abstract: An internet site is presented with a simple mathematical modelling platform for population level models of malaria elimination. It is freely accessible to all and designed to be flexible so both the platform and models can be developed through interaction with users. The site is an accessible introduction to modelling for a non-mathematical audience, and lessons learned from the project will help inform future development of mathematical models and improve communication of modelling results. Currently it hosts a simple model of strategies for malaria elimination and this will be developed, and more models added, over time. The iterative process of feedback and development will result in an educational and planning tool for non-modellers to assist with malaria elimination efforts worldwide.By collaboration with end users, iterative development of mathematical models of malaria elimination through this internet platform will maximize its potential as an educational and public health policy planning tool. It will also assist with preliminary optimisation of local malaria elimination strategies before commitment of valuable resources.Mathematical modelling has great potential as a tool to help guide efforts towards malaria elimination [1]. Different combinations of interventions are required for different epidemiological settings. However, there are limited data available to policymakers to inform their decisions on which strategies to employ. Mathematical modelling combines mechanistic understanding with available data from multiple sources to make predictions. It could potentially be used for preliminary evaluation of different strategies for malaria elimination in different epidemiological contexts much more rapidly and at lower cost than is possible through trial and error in the field [1]. Modelling is particularly useful where a field study cannot be done as is the case with large-scale elimination programmes for which it is desirable to get the strategy right fir
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