Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010

<p>Abstract</p> <p>Background</p> <p>In Thailand, the proportion of <it>Plasmodium vivax </it>infection has become equal to <it>Plasmodium falciparum</it>. Reports of a trend of gradual decline of <it>in vitro </it>sensitivity of <it>P. vivax </it>to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance <it>P. vivax </it>in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with <it>in vitro </it>sensitivity of <it>P. vivax </it>isolates.</p> <p>Methods</p> <p>The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008 - August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females) with mono-infection of <it>P. vivax </it>malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days) and the anti-relapse drug primaquine (15 mg for 14 days). <it>In vitro </it>sensitivity of <it>P. vivax </it>isolates was evaluated by schizont maturation inhibition assay.</p> <p>Results</p> <p>All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of <it>P. vivax </it>parasitaemia nor appearance of <it>P. falciparum </it>occurred during the investigation period. <it>In vitro </it>data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI) values of IC₅₀for chloroquine were 100.1 and 134.7 (1.1-264.9) nM, respectively.</p> <p>Conclusion</p> <p><it>In vivo </it>results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with <it>P. vivax </it>in the Thai-Myanmar border area. <it>In vitro </it>sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of <it>P. vivax </it>is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to the drug policy.</p

Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border

<p>Abstract</p> <p>Background</p> <p>Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand. In the present study, the clinical efficacy of the three-day combination regimen of artesunate-mefloquine as first-line treatment for acute uncomplicated falciparum malaria in Thailand was monitored in an area along the western border (Thai-Myanmar) of the country.</p> <p>Methods</p> <p>A total of 150 Burmese patients (85 males and 65 females) aged between 16 and 50 years who were attending the Mae Tao clinic, Mae-Sot, Tak Province, and presenting with symptomatic acute uncomplicated <it>Plasmodium falciparum </it>malaria were included into the study. Patients were treated initially (day 0) with 4 mg/kg body weight artesunate and 15 mg/kg body weight mefloquine. The dose regimen on day 2 was 4 mg/kg body weight artesunate and 10 mg/kg body weight mefloquine. On day 3, artesunate at the dose of 4 mg/kg body weight was given with 0.6 mg/kg body weight primaquine. Whole blood mefloquine and plasma artesunate and dihydroartemisinin (active plasma metabolite of artesunate) concentrations following treatment were determined by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS), respectively.</p> <p>Results</p> <p>Thirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with <it>P. falciparum </it>and reappearance of <it>Plasmodium vivax </it>in their peripheral blood during follow-up. The Kaplan-Meier estimate of the 42-and 28-day efficacy rates of this combination regimen were 72.58% (95% CI: 63.20-79.07%) and 83.06 (95% CI 76.14-94.40%), respectively. Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) <it>vs </it>24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) <it>vs </it>26.0 (18.0-36.0) hr; <it>p </it>< 0.005]. Whole blood mefloquine concentrations on days 1, 7 and 14 in patients with sensitive and recrudescence response were comparable. Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) <it>vs </it>525 (452-599) ng/ml; <it>p </it>< 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.</p> <p>Conclusions</p> <p>Although pharmacokinetic (ethnic-related) factors including resistance of <it>P. falciparum </it>to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.</p

Preliminary investigation on the prevalence of malaria and HIV co-infection in Mae Sot District, Tak Province of Thailand

Objective: To preliminarily investigate the prevalence of HIV co-infection in patients with malaria in Mae Sot District, Tak Province of Thailand. Methods: The study was a retrospective study on blood samples collected from a total of 256 patients with malaria (all species and severity) who attended Mae Tao clinic for migrant workers, Tak Province during 2005–2007 (148 samples) and 2010–2012 (108 samples). Malaria diagnosis was performed based on microscopic examination of patients' blood smears. Chemiluminescent microparticle immunoassay and gel particle passive agglutination were employed for the detection of HIV antigen in patients' plasma. Results: Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax) are the two predominant malaria species with the ratio of about 1: 1 to 1.5:1. Most of the P. falciparum cases were presented with acute uncomplicated signs and symptoms with highest parasitemia of 1 045 000 asexual parasites/μL bloods. The prevalence of malaria and HIV co-infection during 2005-2007 was 1.35% (2/148 cases, 1 each for P. falciparum and P. vivax co-infection), but was increased to 2.78% (3/108 cases, 2 and 1 for P. falciparum and P. vivax co-infection, respectively) during 2010-2012. Conclusions: The increasing trend of prevalence of malaria and HIV co-infection in Mae Sot, Tak province was of a great concern on either pharmacodynamics or pharmacokinetics aspect. The study in a larger numbers of malaria patients in different endemic areas throughout the country with different time periods is underway

Expression of metallothionein isoforms in peripheral blood leukocytes from Thai population residing in cadmium-contaminated areas

Metallothionein (MT) is a group of proteins with high cadmium (Cd) affinity and with a potential role in Cd transportation and detoxification. The aim of the present study was to investigate the relationship between MT (MT-1A, MT-2A, and MT-3 isoforms) gene expression level in peripheral blood leukocytes and Cd-associated renal injury in non-occupational exposed Thai population. The study was conducted in adult subjects residing in Cd-contaminated areas of Mae Sot District, Thailand. The basal levels of MT-1A, MT-2A, and MT-3 mRNA expression were determined in leukocytes by quantitative RT-PCR. MT-1A and MT-2A expressions, particularly MT-1A, were found to be significantly increased with elevated levels of blood and urinary Cd levels. In subjects with high urinary Cd levels, negative correlations between MT-1A and microalbumin, and between MT-2A and β-MG, were observed. These results suggest that MT gene expression may reflect susceptibility of the exposed population to Cd-induced renal dysfunction. MT-1A mRNA expression in leukocytes might be developed as a potential biomarker of Cd exposure and Cd-induced renal dysfunction

Cadmium exposure in Thai populations from central, northern and northeastern Thailand and the effects of food consumption on cadmium levels

The aim of the present study was to investigate the association between cadmium body burden and the areas of exposure in Thailand, as well as blood pressure levels, the types and frequencies of foods, and alcohol consumption. A total of 182 healthy adult Thai subjects of both genders (89 males, 93 females) ages 18 to 57 years old weighing 40-95 kg were included in this study. Participants were residents from three main areas of Thailand: Pathum Thani Province (central Thailand; n=50), Khon Kaen Province (northeastern Thailand; n=43) and Mae Sot District, Tak Province (northern Thailand; n=89). The total amount of cadmium excreted in urine over 2 hours (μg/g creatinine) was used as an indicator of long-term cadmium exposure. Quantitation of cadmium was performed using electrothermal (graphite furnace) atomic absorption spectrometry (GFAAS). The urinary cadmium excreted displayed a normal frequency of distribution. Significantly higher mean cadmium levels were observed in subjects residing in Mae Sot, Tak Province (0.63 ± 1.41 μg/g creatinine) and Khon Kaen (0.51 ± 0.76 μg/g creatinine) compared to Pathum Thani Province (0.23 ± 0.35 μg/g creatinine). The proportion of subjects with elevated blood pressure was significantly higher in the group exposed to higher (n=39) as opposed to lower (n-5) levels of cadmium. There were no significant differences in the mean total amounts of cadmium excreted in the 2-hour urine samples from subjects who consumed different types of meat and offal, or from those who consumed them at different frequencies

Effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum infected erythrocytes.

In severe falciparum malaria cytoadherence of parasitised red blood cells (PRBCs) to vascular endothelium (causing sequestration) and to uninfected red cells (causing rosette formation) contribute to microcirculatory flow obstruction in vital organs. Heparin can reverse the underlying ligand-receptor interactions, but may increase the bleeding risks. As a heparin-derived polysaccharide, sevuparin has been designed to retain anti-adhesive properties, while the antithrombin-binding domains have been eliminated, substantially diminishing its anticoagulant activity. Sevuparin has been evaluated recently in patients with uncomplicated falciparum malaria, and is currently investigated in a clinical trial for sickle cell disease. The effects of sevuparin on rosette formation and cytoadherence of Plasmodium falciparum isolates from Thailand were investigated. Trophozoite stages of P. falciparum-infected RBCs (Pf-iRBCs) were cultured from 49 patients with malaria. Pf-iRBCs were treated with sevuparin at 37°C and assessed in rosetting and in cytoadhesion assays with human dermal microvascular endothelial cells (HDMECs) under static and flow conditions. The proportion of Pf-iRBCs forming rosettes ranged from 6.5% to 26.0% (median = 12.2%). Rosetting was dose dependently disrupted by sevuparin (50% disruption by 250 μg/mL). Overall 57% of P. falciparum isolates bound to HDMECs under static conditions; median (interquartile range) Pf-iRBC binding was 8.5 (3.0-38.0) Pf-iRBCs/1000 HDMECs. Sevuparin in concentrations ≥ 100 μg/mL inhibited cytoadherence. Sevuparin disrupts P. falciparum rosette formation in a dose dependent manner and inhibits cytoadherence to endothelial cells. The data support assessment of sevuparin as an adjunctive treatment to the standard therapy in severe falciparum malaria

The influence of iron stores on cadmium body burden in a Thai population

Cadmium is a toxin of increasing public health concern due to its presence in most human foodstuffs and in cigarette smoke. Exposure to cadmium leads to tissue bioaccumulation and, in particular, has nephrotoxic effects. The aim of the present study was to investigate the association between cadmium body burden and iron stores in a Thai population. A total of 182 healthy adult Thai subjects of both genders (89 males, 93 females) aged between 18 and 57 years and weighing 40-95 kg were included in this study. The total amounts of cadmium excreted in urine over 2 h (μg/g creatinine) were used as an index of long-term cadmium exposure. Quantitation of cadmium was performed using electrothermal (graphite furnace) atomic absorption spectrometry. The urinary cadmium excreted displayed a normal frequency distribution. The average urinary cadmium level did not exceed the WHO maximum tolerable internal dose for the non-exposed population (2 μg/g creatinine). Body iron stores reflected by serum ferritin levels did not show any correlation with cadmium burden in both males and females, although a relatively stronger influence of body iron store status on cadmium burden was shown in females. When the levels of serum ferritin were stratified into five levels (300 μg/l), a significant difference in total cadmium body burden was observed between females and males only in the group with a low level of serum ferritin o