Management of malaria with acute renal failure

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Differences in genetic population structures of Plasmodium falciparum isolates from patients along Thai-Myanmar border with severe or uncomplicated malaria

<p>Abstract</p> <p>Background</p> <p>There have been many reports on the population genetic structures of <it>Plasmodium falciparum </it>from different endemic regions, but few studies have examined the characteristics of isolates from patients with different clinical outcomes. The population genetic structures of <it>P. falciparum </it>isolates from patients with either severe or uncomplicated malaria were examined.</p> <p>Methods</p> <p>Twelve microsatellite DNA loci from <it>P. falciparum </it>were used to assess the population genetic structures of 50 isolates (i.e., 25 isolates from patients with severe malaria and 25 from patients with uncomplicated malaria) collected in the Thai-Myanmar border area between 2002 and 2005.</p> <p>Results</p> <p>Genetic diversity and effective population sizes were greater in the uncomplicated malaria group than in the severe malaria group. Evidence of genetic bottlenecks was not observed in either group. Strong linkage disequilibrium was observed in the uncomplicated malaria group. The groups demonstrated significant genetic differentiation (<it>P </it>< 0.05), and allele frequencies for 3 of the 12 microsatellite loci differed significantly between the two groups.</p> <p>Conclusion</p> <p>These findings suggest that the genetic structure of <it>P. falciparum </it>populations in patients with severe malaria differs from that in patients with uncomplicated malaria. The microsatellite loci used in this study were presumably unrelated to antigenic features of the parasites, but, these findings suggest that some loci may influence the clinical outcome of malaria.</p

Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria

<p>Abstract</p> <p>Background</p> <p>This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria.</p> <p>Methods</p> <p>A total of 70 patients with acute uncomplicated <it>Plasmodium falciparum </it>malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows:</p> <p>Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54).</p> <p>Results</p> <p>Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent C_max: 3.74 <it>vs </it>2.41 μg/ml; C_max-ss: 2.80 <it>vs </it>2.08 μg/ml; C_max-min-ss: 2.03 <it>vs </it>0.71 μg/ml; AUC: 23.31 <it>vs </it>10.63 μg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, C_min-sswas lower in this group (0.80 <it>vs </it>1.37 μg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, V_z/F) and elimination half-life (t_1/2z, t_1/2e) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups.</p> <p>Conclusion</p> <p>The findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300–600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.</p

Increased fluidity and oxidation of malarial lipoproteins: relation with severity and induction of endothelial expression of adhesion molecules

INTRODUCTION: Oxidative stress has been demonstrated in malaria. The potential oxidative modification of lipoproteins derived from malaria patients was studied. These oxidized lipids may have role in pathogenesis of malaria. METHOD: The plasma lipid profile and existence of oxidized forms of very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) were investigated in malaria (17 mild and 24 severe patients) and 37 control subjects. Thiobarbituric acid reactive substances (TBARs), conjugated dienes, tryptophan fluorescence and fluidity of lipoproteins were determined as markers of oxidation. The biological effect of malarial lipoproteins was assessed by the expression of adhesion molecules on endothelial cells. RESULTS: Malarial lipoproteins had decreased cholesterol (except in VLDL) and phospholipid. The triglyceride levels were unchanged. The cholesterol/phospholipid ratio of LDL was decreased in malaria, but increased in VLDL and HDL. TBARs and conjugate dienes were increased in malarial lipoproteins, while the tryptophan fluorescence was decreased. The fluidity of lipoproteins was increased in malaria. These indicated the presence of oxidized lipoproteins in malaria by which the degree of oxidation was correlated with severity. Of three lipoproteins from malarial patients, LDL displayed the most pronounced oxidative modification. In addition, oxidized LDL from malaria patients increased endothelial expression of adhesion molecules. CONCLUSION: In malaria, the lipoproteins are oxidatively modified, and the degree of oxidation is related with severity. Oxidized LDL from malarial patients increases the endothelial expression of adhesion molecules. These suggest the role of oxidized lipoproteins, especially LDL, on the pathogenesis of disease

Suppression of Plasmodium falciparum by serum collected from a case of Plasmodium vivax infection.

BACKGROUND: It has frequently been reported that Plasmodium vivax suppressed Plasmodium falciparum and ameliorated disease severity in patients infected with these two species simultaneously. The authors investigate the hypothesis that immunological responses stimulated by P. vivax may play a role in suppressing co-infecting P. falciparum. METHODS: Sera, taken sequentially from one of the authors (YN) during experimental infection with P. vivax, were added to in vitro cultures of P. falciparum. Cross-reactive antibodies against P. falciparum antigens, and cytokines were measured in the sera. RESULTS: Significant growth inhibitory effects upon P. falciparum cultures (maximally 68% inhibition as compared to pre-illness average) were observed in the sera collected during an acute episode. Such inhibitory effects showed a strong positive temporal correlation with cross-reactive antibodies, especially IgM against P. falciparum schizont extract and, to a lesser degree, IgM against Merozoite Surface Protein (MSP)-119. Interleukin (IL)-12 showed the highest temporal correlation with P. vivax parasitaemia and with body temperatures in the volunteer. CONCLUSION: These results suggest the involvement by cross-reactive antibodies, especially IgM, in the interplay between plasmodial species. IL-12 may be one of direct mediators of fever induction by rupturing P. vivax schizonts, at least in some subjects. Future studies, preferably of epidemiological design, to reveal the association between cross-reactive IgM and cross-plasmodial interaction, are warranted

Lack of association between interleukin-10 gene promoter polymorphism

Abstract. Interleukin-10 (IL-10) is an important cytokine in the down -regulation of inflammatory responses, and it has been reported that a low plasma concentration of IL-10 is associated with severe anemia and cerebral malaria in Plasmodium falciparum infections. The IL-10 gene is located on chromosome 1q31-32, and a promoter polymorphism (-1082G/A) is known to affect IL-10 protein production. In order to examine the possible association of the -1082G/A polymorphism with the severity of malaria, we studied 203 mild malaria, 164 noncerebral severe malaria, and 109 cerebral malaria patients living in northwest Thailand. The genotyping was performed by a fluorescence resonance energy transfer (FRET) method. The frequencies of a major allele -1082A in mild malaria, in non-cerebral severe malaria, and in cerebral malaria patients were 92.6%, 92.1%, and 92.7% respectively. Our results showed no significant association of the -1082G/A polymorphism with the severity of malaria

Meteorological, environmental remote sensing and neural network analysis of the epidemiology of malaria transmission in Thailand

In many malarious regions malaria transmission roughly coincides with rainy seasons, which provide for more abundant larval habitats. In addition to precipitation, other meteorological and environmental factors may also influence malaria transmission. These factors can be remotely sensed using earth observing environmental satellites and estimated with seasonal climate forecasts. The use of remote sensing usage as an early warning tool for malaria epidemics have been broadly studied in recent years, especially for Africa, where the majority of the world’s malaria occurs. Although the Greater Mekong Subregion (GMS), which includes Thailand and the surrounding countries, is an epicenter of multidrug resistant falciparum malaria, the meteorological and environmental factors affecting malaria transmissions in the GMS have not been examined in detail. In this study, the parasitological data used consisted of the monthly malaria epidemiology data at the provincial level compiled by the Thai Ministry of Public Health. Precipitation, temperature, relative humidity, and vegetation index obtained from both climate time series and satellite measurements were used as independent variables to model malaria. We used neural network methods, an artificial-intelligence technique, to model the dependency of malaria transmission on these variables. The average training accuracy of the neural network analysis for three provinces (Kanchanaburi, Mae Hong Son, and Tak) which are among the provinces most endemic for malaria, is 72.8% and the average testing accuracy is 62.9% based on the 1994-1999 data. A more complex neural network architecture resulted in higher training accuracy but also lower testing accuracy. Taking into account of the uncertainty regarding reported malaria cases, we divided the malaria cases into bands (classes) to compute training accuracy. Using the same neural network architecture on the 19 most endemic provinces for years 1994 to 2000, the mean training accuracy weighted by provincial malaria cases was 73%. Prediction of malaria cases for 2001 using neural networks trained for 1994-2000 gave a weighted accuracy of 53%. Because there was a significant decrease (31%) in the number of malaria cases in the 19 provinces from 2000 to 2001, the networks overestimated malaria transmissions. The decrease in transmission was not due to climatic or environmental changes. Thailand is a country with long borders. Migrant populations from the neighboring countries enlarge the human malaria reservoir because these populations have more limited access to health care. This issue also confounds the complexity of modeling malaria based on meteorological and environmental variables alone. In spite of the relatively low resolution of the data and the impact of migrant populations, we have uncovered a reasonably clear dependency of malaria on meteorological and environmental remote sensing variables. When other contextual determinants do not vary significantly, using neural network analysis along with remote sensing variables to predict malaria endemicity should be feasible

Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1

BACKGROUND: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75 million people each year, mostly in South America and Asia. In addition to major morbidity this parasite is associated with relapses and a reduction in birthweight. The emergence and spread of drug resistance in Plasmodium falciparum is a major factor in the resurgence of this parasite. P. vivax resistance to drugs has more recently emerged and monitoring the situation would be helped, as for P. falciparum, by molecular methods that can be used to characterize parasites in field studies and drug efficacy trials. METHODS: Practical PCR genotyping protocols based on polymorphic loci present in two P. vivax genetic markers, Pvcs and Pvmsp1, were developed. The methodology was evaluated using 100 P. vivax isolates collected in Thailand. RESULTS AND DISCUSSION: Analysis revealed that P. vivax populations in Thailand are highly diverse genetically, with mixed genotype infections found in 26 % of the samples (average multiplicity of infection = 1.29). A large number of distinguishable alleles were found for the two markers, 23 for Pvcs and 36 for Pvmsp1. These were generally randomly distributed amongst the isolates. A total of 68 distinct genotypes could be enumerated in the 74 isolates with a multiplicity of infection of 1. CONCLUSION: These results indicate that the genotyping protocols presented can be useful in the assessment of in vivo drug efficacy clinical trials conducted in endemic areas and for epidemiological studies of P. vivax infections

RECRUDESCENCE IN ARTESUNATE-TREATED PATIENTS WITH FALCIPARUM MALARIA IS DEPENDENT ON PARASITE BURDEN NOT ON PARASITE FACTORS

Artemisinin derivatives are first-line antimalarial drugs in Thailand. No firm evidence of clinically relevant artemisinin resistance exists. When used as monotherapy, artesunate has been associated with a high treatment failure (recrudescence) rate, which could be due to low-level artemisinin resistance. To understand the causes of recrudescence, we retrospectively studied a cohort of 104 malaria patients treated with artesunate monotherapy, 32 of whom recrudesced. There was no difference in in vitro artesunate sensitivities between 6 nonrecrudescent isolates and 16 paired admission and recrudescent isolates. Paired admission and recrudescent isolates from 10 patients were genotyped; only 3 had pfmdr1 mutations. Patients with admission parasitemias >10,000 per µl had a 9-fold higher likelihood of recrudescence (adjusted odds ratio) compared with patients with lower parasitemias. This study suggests (1) recrudescence after treatment with artesunate is not the result of inherent parasite resistance, and (2) admission parasitemia may be useful in choosing therapeutic options