In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border

<p>Abstract</p> <p>Background</p> <p>On the borders of Thailand, <it>Plasmodium falciparum </it>has become resistant to nearly all available drugs, and there is an urgent need to find new antimalarial drugs or drug combinations. Ferroquine (SSR97193) is a new 4-aminoquinoline antimalarial active against chloroquine resistant and sensitive <it>P. falciparum </it>strains <it>in vivo </it>and <it>in vitro</it>. This antimalarial organic iron complex (a ferrocenyl group has been associated with chloroquine) is meant to use the affinity of <it>Plasmodium </it>for iron to increase the probability for encountering the anti-malarial molecule.</p> <p>The aim of the present study was to investigate the activity of ferroquine against <it>P. falciparum </it>isolates from an area with a known high multi-drug resistance rate.</p> <p>Methods</p> <p>Parasite isolates were obtained from patients with acute falciparum malaria attending the clinics of SMRU. In vitro cultures of these isolates were set-up in the SMRU-laboratory on pre-dosed drug plates, and grown in culture for 42 hours. Parasite growth was assessed by the double-site enzyme-linked pLDH immunodetection (DELI) assay.</p> <p>Results</p> <p>Sixty-five <it>P. falciparum </it>isolates were successfully grown in culture. The ferroquine mean IC₅₀(95% CI) was 9.3 nM (95% C.I.: 8.7 – 10.0). The mean IC50 value for the principal metabolite of ferroquin, SR97213A, was 37.0 nM (95% C.I.: 34.3 – 39.9), which is four times less active than ferroquine. The isolates in this study were highly multi-drug resistant but ferroquine was more active than chloroquine, quinine, mefloquine and piperaquine. Only artesunate was more active than ferroquine. Weak but significant correlations were found between ferroquine and its principal metabolite (r²= 0.4288), chloroquine (r²= 0.1107) and lumefantrine (r²= 0.2364).</p> <p>Conclusion</p> <p>The results presented in this study demonstrate that the new ferroquine compound SSR97193 has high anti-malarial activity in vitro against multi-drug resistant <it>P. falciparum</it>.</p

Spatio-temporal effects of estimated pollutants released from an industrial estate on the occurrence of respiratory disease in Maptaphut Municipality, Thailand

BACKGROUND: Maptaphut Industrial Estate (MIE) was established with a single factory in 1988, increasing to 50 by 1998. This development has resulted in undesirable impacts on the environment and the health of the people in the surrounding areas, evidenced by frequent complaints of bad odours making the people living there ill. In 1999, the Bureau of Environmental Health, Department of Health, Ministry of Public Health, conducted a study of the health status of people in Rayong Province and found a marked increase in respiratory diseases over the period 1993–1996, higher than the overall prevalence of such diseases in Thailand. However, the relationship between the pollutants and the respiratory diseases of the people in the surrounding area has still not been quantified. Therefore, this study aimed to determine the spatial distribution of respiratory disease, to estimate pollutants released from the industrial estates, and to quantify the relationship between estimated pollutants and respiratory disease in the Maptaphut Municipality. RESULTS: Disease mapping showed a much higher risk of respiratory disease in communities adjacent to the Maptaphut Industrial Estate. Disease occurrence formed significant clusters centred on communities near the estate, relative to the weighted mean centre of chimney stacks. Analysis of the rates of respiratory disease in the communities, categorized by different concentrations of estimated pollutants, found a dose-response effect. Spatial regression analysis found that the distance between community and health providers decreased the rate of respiratory disease (p < 0.05). However, after taking into account distance, total pollutant (p < 0.05), SO(2 )(p < 0.05) and NO(x )(p < 0.05) played a role in adverse health effects during the summer. Total pollutant (p < 0.05) and NO(x )(p < 0.05) played a role in adverse health effects during the rainy season after taking into account distance, but during winter there was no observed relationship between pollutants and rates of respiratory disease after taking into account distance. A 12-month time-series analysis of six communities selected from the disease clusters and the areas impacted most by pollutant dispersion, found significant effects for SO(2 )(p < 0.05), NO(x )(p < 0.05), and TSP (p < 0.05) after taking into account rainfall. CONCLUSION: This study employed disease mapping to present the spatial distribution of disease. Excessive risk of respiratory disease, and disease clusters, were found among communities near Maptaphut Industrial Estate. Study of the relationship between estimated pollutants and the occurrence of respiratory disease found significant relationships between estimated SO(2), NO(x), and TSP, and the rate of respiratory disease

Application of mobile-technology for disease and treatment monitoring of malaria in the "Better Border Healthcare Programme"

<p>Abstract</p> <p>Background</p> <p>The main objective of this study was to assess the effectiveness of integrating the use of cell-phones into a routine malaria prevention and control programme, to improve the management of malaria cases among an under-served population in a border area. The module for disease and treatment monitoring of malaria (DTMM) consisted of case investigation and case follow-up for treatment compliance and patients' symptoms.</p> <p>Methods</p> <p>The module combining web-based and mobile technologies was developed as a proof of concept, in an attempt to replace the existing manual, paper-based activities that malaria staff used in treating and caring for malaria patients in the villages for which they were responsible. After a patient was detected and registered onto the system, case-investigation and treatment details were recorded into the malaria database. A follow-up schedule was generated, and the patient's status was updated when the malaria staff conducted their routine home visits, using mobile phones loaded with the follow-up application module. The module also generated text and graph messages for a summary of malaria cases and basic statistics, and automatically fed to predetermined malaria personnel for situation analysis. Following standard public-health practices, access to the patient database was strictly limited to authorized personnel in charge of patient case management.</p> <p>Results</p> <p>The DTMM module was developed and implemented at the trial site in late November 2008, and was fully functioning in 2009. The system captured 534 malaria patients in 2009. Compared to paper-based data in 2004-2008, the mobile-phone-based case follow-up rates by malaria staff improved significantly. The follow-up rates for both Thai and migrant patients were about 94-99% on Day 7 <it>(Plasmodium falciparum) </it>and Day 14 <it>(Plasmodium vivax) </it>and maintained at 84-93% on Day 90. Adherence to anti-malarial drug therapy, based on self-reporting, showed high completion rate for <it>P. falciparum</it>-infected cases, but lower rate for <it>P. vivax </it>cases. Patients' symptoms were captured onto the mobile phone during each follow-up visit, either during the home visit or at Malaria Clinic; most patients had headache, muscle pain, and fatigue, and some had fever within the first follow-up day (day7/14) after the first anti-malarial drug dose.</p> <p>Conclusions</p> <p>The module was successfully integrated and functioned as part of the malaria prevention and control programme. Despite the bias inherent in sensitizing malaria workers to perform active case follow-up using the mobile device, the study proved for its feasibility and the extent to which community healthcare personnel in the low resource settings could potentially utilize it efficiently to perform routine duties, even in remote areas. The DTMM has been modified and is currently functioning in seven provinces in a project supported by the WHO and the Bill & Melinda Gates Foundation, to contain multi-drug resistant malaria on the Thai-Cambodian border.</p

Development of temporal modelling for forecasting and prediction of malaria infections using time-series and ARIMAX analyses: A case study in endemic districts of Bhutan

<p>Abstract</p> <p>Background</p> <p>Malaria still remains a public health problem in some districts of Bhutan despite marked reduction of cases in last few years. To strengthen the country's prevention and control measures, this study was carried out to develop forecasting and prediction models of malaria incidence in the endemic districts of Bhutan using time series and ARIMAX.</p> <p>Methods</p> <p>This study was carried out retrospectively using the monthly reported malaria cases from the health centres to Vector-borne Disease Control Programme (VDCP) and the meteorological data from Meteorological Unit, Department of Energy, Ministry of Economic Affairs. Time series analysis was performed on monthly malaria cases, from 1994 to 2008, in seven malaria endemic districts. The time series models derived from a multiplicative seasonal autoregressive integrated moving average (ARIMA) was deployed to identify the best model using data from 1994 to 2006. The best-fit model was selected for each individual district and for the overall endemic area was developed and the monthly cases from January to December 2009 and 2010 were forecasted. In developing the prediction model, the monthly reported malaria cases and the meteorological factors from 1996 to 2008 of the seven districts were analysed. The method of ARIMAX modelling was employed to determine predictors of malaria of the subsequent month.</p> <p>Results</p> <p>It was found that the ARIMA (p, d, q) (P, D, Q)^smodel (p and P representing the auto regressive and seasonal autoregressive; d and D representing the non-seasonal differences and seasonal differencing; and q and Q the moving average parameters and seasonal moving average parameters, respectively and s representing the length of the seasonal period) for the overall endemic districts was (2,1,1)(0,1,1)¹²; the modelling data from each district revealed two most common ARIMA models including (2,1,1)(0,1,1)¹²and (1,1,1)(0,1,1)¹². The forecasted monthly malaria cases from January to December 2009 and 2010 varied from 15 to 82 cases in 2009 and 67 to 149 cases in 2010, where population in 2009 was 285,375 and the expected population of 2010 to be 289,085. The ARIMAX model of monthly cases and climatic factors showed considerable variations among the different districts. In general, the mean maximum temperature lagged at one month was a strong positive predictor of an increased malaria cases for four districts. The monthly number of cases of the previous month was also a significant predictor in one district, whereas no variable could predict malaria cases for two districts.</p> <p>Conclusions</p> <p>The ARIMA models of time-series analysis were useful in forecasting the number of cases in the endemic areas of Bhutan. There was no consistency in the predictors of malaria cases when using ARIMAX model with selected lag times and climatic predictors. The ARIMA forecasting models could be employed for planning and managing malaria prevention and control programme in Bhutan.</p

Disease Surveillance Networks Initiative Asia: Final Evaluation

The DSN Initiative was launched in 2007 under the new strategy of the Rockefeller Foundation. The initiative intends:[1] To improve human resources for disease surveillance in developing countries, thus bolstering national capacity to monitor, report, and respond to outbreaks;[2] To support regional networks to promote collaboration in disease surveillance and response across countries; and[3] To build bridges between regional and global monitoring effortsThe purpose of the DSN evaluation in the Mekong region was twofold:[1]To inform the work and strategy of the Foundation, its grantees, and the broader field of disease surveillance, based on the experience of DSN investments in the Mekong region. More specifically, the evaluation will inform future directions and strategies for current areas of DSN Initiative work, particularly in Asia, and will highlight potential new areas of work and strategy; and[2] To provide accountability to the Rockefeller Foundation's board, staff, and stakeholders for the DSN funds spent in the Mekong region

A Comparison of Two Short-Course Primaquine Regimens for the Treatment and Radical Cure of Plasmodium vivax Malaria in Thailand

Thai adult males (N = 85) with acute Plasmodium vivax malaria and normal glucose-6-phosphate dehydrogenase screening were randomized to receive 30 mg or 60 mg primaquine daily for 7 days (N = 43 and 42, respectively). The regimens were well tolerated and all patients recovered fully. Median fever clearance (47 hours; range 4 to 130 hours), mean ± SD parasite clearance times (87.7 ± 25.3 hours), gametocyte clearance, and adverse effects were similar in the 2 groups. Two patients, 1 from each group, had a 30% reduction in hematocrit. The cumulative 28 day relapse rate (95% confidence interval) by Kaplan Meier survival analysis was 29% (16–49%) in the 30 mg group compared with 7% (2–24%) in the 60 mg group; P = 0.027. Comparison with previous data obtained at this same site suggests that the recurrences comprised approximately 17% recrudescences and 12% relapses in the 30 mg/day group compared with 3% recrudescences and 4% relapses in the 60 mg/day group. These data suggest that the dose-response relationships for primaquine's asexual stage and hypnozoitocidal activities in-vivo are different. A 1 week course of primaquine 60 mg daily is an effective treatment of vivax malaria in this region

Highly heterogeneous residual malaria risk in western Thailand

Over the past decades, the malaria burden in Thailand has substantially declined. Most infections now originate from the national border regions. In these areas, the prevalence of asymptomatic infections is still substantial and poses a challenge for the national malaria elimination program. To determine epidemiological parameters as well as risk factors for malaria infection in western Thailand, we carried out a cohort study in Kanchanaburi and Ratchaburi provinces on the Thailand-Myanmar border. Blood samples from 999 local participants were examined for malaria infection every 4 weeks between May 2013 and Jun 2014. Prevalence of Plasmodium falciparum and Plasmodium vivax was determined by quantitative PCR (qPCR) and showed a seasonal variation with values fluctuating from 1.7% to 4.2% for P. vivax and 0% to 1.3% for P. falciparum. Ninety percent of infections were asymptomatic. The annual molecular force of blood-stage infection (molFOB) was estimated by microsatellite genotyping to be 0.24 new infections per person-year for P. vivax and 0.02 new infections per person-year for P. falciparum. The distribution of infections was heterogenous, that is, the vast majority of infections (>80%) were found in a small number of individuals (<8% of the study population) who tested positive at multiple timepoints. Significant risk factors were detected for P. vivax infections, including previous clinical malaria, occupation in agriculture and travel to Myanmar. In contrast, indoor residual spraying was associated with a protection from infection. These findings provide a recent landscape of malaria epidemiology and emphasize the importance of novel strategies to target asymptomatic and imported infections

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

Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine-artesunate on the north-western border of Thailand

<p>Abstract</p> <p>Background</p> <p>The use of artemisinin derivatives has increased exponentially with the deployment of artemisinin combination therapy (ACT) in all malarious areas. They are highly effective and are considered safe, but in animal studies artemisinin derivatives produce neurotoxicity targeting mainly the auditory and vestibular pathways. The debate remains as to whether artemisinin derivatives induce similar toxicity in humans.</p> <p>Methods</p> <p>This prospective study assessed the effects on auditory function of a standard 3-day oral dose of artesunate (4 mg/kg/day) combined with mefloquine (25 mg/kg) in patients with acute uncomplicated falciparum malaria treated at the Shoklo Malaria Research Unit, on the Thai-Burmese border. A complete auditory evaluation with tympanometry, audiometry and auditory brainstem responses (ABR) was performed before the first dose and seven days after initiation of the antimalarial treatment.</p> <p>Results</p> <p>Complete auditory tests at day 0 (D0) and day 7 (D7) were obtained for 93 patients. Hearing loss (threshold > 25 dB) on admission was common (57%) and associated with age only. No patient had a threshold change exceeding 10 dB between D0 and D7 at any tested frequency. No patient showed a shift in Wave III peak latency of more than 0.30 msec between baseline and D7.</p> <p>Conclusion</p> <p>Neither audiometric or the ABR tests showed clinical evidence of auditory toxicity seven days after receiving oral artesunate and mefloquine.</p

Comparison of plasma, venous and capillary blood levels of piperaquine in patients with uncomplicated falciparum malaria

PURPOSE: Dihydroartemisinin-piperaquine (DP) is a fixed-dose artemisinin-based combination treatment. Field pharmacokinetic studies would be simplified and facilitated by being able to use small volume capillary assays rather than venous blood. The aim of this study was to describe the relationship between piperaquine concentrations measured in capillary blood, venous blood and venous plasma. METHODS: Samples of plasma, whole blood obtained by venesection and capillary blood were taken simultaneously from patients with uncomplicated Plasmodium falciparum malaria treated with DP between 0 and 9 weeks after treatment. Piperaquine concentrations in venous and capillary samples were measured using solid phase extraction and analysis by liquid chromatography with ultraviolet detection. RESULTS: A total of 161 sets of the three measures were obtained from 54 patients. Piperaquine concentrations in the venous blood samples were approximately twofold higher and those in the capillary blood samples were threefold higher than the corresponding venous plasma concentrations. Capillary blood piperaquine concentrations were approximately 1.7-fold higher than venous blood concentrations, and this difference also increased with time. CONCLUSION: Differences in whole blood and plasma levels of piperaquine suggest compartmentalisation of the drug within blood cells, as also occurs with the structurally related quinoline chloroquine. The relationship between piperaquine concentrations in the venous plasma, venous blood and capillary blood is variable and unpredictable at low concentrations. However, within the range of concentrations usually present in patients between 3 and 21 days after treatment with currently recommended doses, the relationship between capillary and venous whole blood is predictable; consequently, capillary blood sampling can be used in field assessments