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ABSTRACT: 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(2)-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.
Environmental toxicology and pharmacology. 09/2012;
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ABSTRACT: Human exposure to cadmium (Cd) produces a wide variety of toxic effects involving many organs and systems, but the kidney is the main organ affected among long-term Cd-exposed people. In the general population, the primary sources of Cd exposure are cigarette smoke and food (shellfish, offal and certain vegetables). The aims of the study were to investigate the association between urinary and blood Cd levels and personal habits relating to Cd intake (consumption of food stuff, water and tobacco smoking), levels of renal biomarkers in the urine or serum of 314 Thai subjects (85 males, 229 females) who resided in Cd-contaminated areas of Mae Sot District, Tak Province, Thailand. Based on the cut-off levels of 1 microg/g creatinine and 5 microg/l for urinary and blood Cd levels, respectively, nearly all subjects had urinary Cd levels lower than cut-off values for urine and blood (88.2 and 77.7%, respectively). Binary logistic backward stepwise regression analysis with five covariates (gender, residential areas, consumption of bamboo or chicken, and smoking status), and eight covariates (residential areas, consumption of beans, pork, fish or liver, types and sources of rice consumed and smoking status) best predicted urinary and blood Cd levels, respectively. For renal biomarkers, N-acetyl-beta-glucosaminidase (NAG) best predicted both urinary and blood Cd with good accuracy. A larger sample size with equal distribution of subjects with low (< 2 microg/g creatinine) and high (> 2 microg/g creatinine) urinary Cd levels should be studied to obtain the regression equation that would best predict Cd body burden.
The Southeast Asian journal of tropical medicine and public health 11/2011; 42(6):1521-30. · 0.60 Impact Factor
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ABSTRACT: The study objectives to investigate the distribution of the antimalarial drug mefloquine (MQ) in cellular and fluid blood compartments when given at therapeutic dosage with artesunate and to investigate an eventual association with the occurrence of treatment-related adverse events in Thai patients with acute uncomplicated falciparum malaria.
MQ distribution following administration of standard therapeutic doses (1,250 mg MQ in split dose) with artesunate to 20 Thai patients with acute uncomplicated falciparum malaria was assessed in whole blood, serum, plasma, red blood cells (RBC), white blood cells (WBC), and platelets using high -performance liquid chromatography.
All patients responded to treatment without reappearance of parasitemia during the 42-day follow-up period. There was no significant gender difference in MQ levels. The chronological change in MQ levels in all blood components, including ratios of plasma to serum, whole blood, RBC, platelets or WBC were similar and parallel in both genders. MQ concentrations at 14 and 168 h, in descending order, in both male and female patients were as follow: WBC > platelets > plasma > serum > whole blood > RBC. Gender-specific whole blood, serum, and RBC concentrations were similar at all time points, with median ratios of plasma:whole blood, plasma:serum, and plasma:RBC of 0.84:1.21, 1.09:1.64, and 1.59:3.79, respectively. Plasma vs whole blood and plasma vs RBC MQ concentrations showed a highly significant correlation, with r = 0.923 and 0.867, respectively. No association between occurrence of treatment-related adverse events and MQ concentrations in various blood components/fluids was observed in either gender.
Based on these observations, gender-specific therapeutic MQ dose adjustment is obviously not required.
European Journal of Clinical Pharmacology 07/2011; 67(7):687-91. · 2.85 Impact Factor
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ABSTRACT: The aims of the study were to investigate (i) the effects of environmental cadmium (Cd) on hypertension, biological markers of renal dysfunction and renal cytochrome P450-mediated arachidonate metabolism; and (ii) the association between genetic polymorphism of heme oxygenase-1 (HO-1) and hypertension and Cd-induced renal injury in the exposed Thai population. The study was conducted in adult subjects residing in Cd-contaminated malaria endemic areas of Mae Sot District, Thailand. All subjects were randomly selected and consistently distributed for sex, age and residential areas. Blood and urinary Cd levels were not significantly different between the case (hypertensive) and control (matched-pair normotensive) groups. While other renal dysfunction biomarkers were comparable between the two groups, urinary microalbumin, urinary 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) and serum creatinine were siginificantly higher in the hypertensive group. Only N-acetyl-β-glucosaminidase (NAG) showed positive correlation with Cd in hypertensive and normotensive group. With respect to heme oxygenase-1 (HO-1) polymorphism, the frequencies of (GT)(n) alleles were similar in both case and control groups. The frequency of SL genotype was significantly higher in the control group, whereas the frequency of ML genotype was significantly higher in the case group. Although no significant difference between 20-HETE and NAG levels in various HO-1 genotypes was found, a trend of increase in 20-HETE and NAG levels was observed in subjects carrying longer (GT)(n) repeats. Results from the present study provide no clear evidence on the direct effects of environmental Cd on high blood pressure development in the non-occupational exposed Thai population. Furthermore, the indirect effect of Cd through HO-1 (genetic polymorphism and prevalence of long GT(n) repeats) and 20-HETE was inconclusive. Based on the data obtained in the present investigation further studies should be performed which use a larger sample size and effectively control for confounding. This should provide more definitive evidence of the relationship between Cd exposure and high blood pressure.
Environmental toxicology and pharmacology. 05/2011; 31(3):416-26.
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ABSTRACT: In Thailand, the proportion of Plasmodium vivax infection has become equal to Plasmodium falciparum. Reports of a trend of gradual decline of in vitro sensitivity of P. vivax to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance P. vivax in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with in vitro sensitivity of P. vivax isolates.
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 P. vivax 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). In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition assay.
All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred during the investigation period. In vitro data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI) values of IC50 for chloroquine were 100.1 and 134.7 (1.1-264.9) nM, respectively.
In vivo results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with P. vivax in the Thai-Myanmar border area. In vitro sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of P. vivax is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to the drug policy.
Malaria Journal 02/2011; 10(1):44. · 3.19 Impact Factor
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ABSTRACT: To compare the applicability of the SYBR Green-I assay with the standard schizont maturation assay, for determination of sensitivity of Plasmodium vivax (P. vivax) to chloroquine and a new antifolate WR 99210.
The study was conducted at Mae Tao Clinic for migrant workers, Tak Province during April 2009 to July 2010. A total of 64 blood samples (1 mL blood collected into sodium heparinized plastic tube) were collected from patients with mono-infection with P. vivax malaria prior to treatment with standard regimen of a 3-day chloroquine. In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition and SYBR Green-I assays.
A total of 30 out of 64 blood samples collected from patients with P. vivax malaria were successfully analyzed using both the microscopic schizont maturation inhibition and SYBR Green-I assays. The failure rates of the schizont maturation inhibition assay (50%) and the SYBR Green-I assay (54%) were similar (P=0.51). The median IC10s, IC50s and IC90s of both chloroquine and WR99210 were not significantly different from the clinical isolates of P. vivax tested. Based on the cut-off of 100 nM, the prevalences of chloroquine resistance determined by schizont maturation inhibition and SYBR Green-I assays were 19 and 11 isolates, respectively. The strength of agreement between the two methods was very poor for both chloroquine and WR99210.
On the basis of this condition and its superior sensitivity, the microscopic method appears better than the SYBR Green-I Green assay for assessing in vitro sensitivity of fresh P. vivax isolates to antimalarial drugs.
Asian Pacific journal of tropical biomedicine. 01/2011; 1(1):49-53.
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ABSTRACT: 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.
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 Plasmodium falciparum 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.
Thirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with P. falciparum and reappearance of Plasmodium vivax 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) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 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) vs 525 (452-599) ng/ml; p < 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.
Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum 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.
Malaria Journal 10/2010; 9:273. · 3.19 Impact Factor
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ABSTRACT: 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 (microg/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 microg/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 (<20, 20-100, 101-200, 201-300, and >300 microg/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 of <20 microg/l. The cadmium body burden in females was about twice that in males in this group.
Environmental Geochemistry and Health 10/2009; 32(3):237-42. · 1.62 Impact Factor
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ABSTRACT: 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 (microg/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 microg/g creatinine) and Khon Kaen (0.51 +/- 0.76 microg/g creatinine) compared to Pathum Thani Province (0.23 +/- 0.35 microg/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.
The Southeast Asian journal of tropical medicine and public health 02/2009; 40(1):177-86. · 0.60 Impact Factor
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ABSTRACT: Fourteen (9 amino acids) peptides of Plasmodium falciparum pre-erythrocytic stage antigens, namely, TRAP, CTRP, LSA-1, STARP and MSP-1, restricted to HLA-A24 and specific to T-cell response were identified. The antigen-specific IFN-gamma responses of these synthetic peptides in malaria exposed and non-malaria exposed healthy adult volunteers were detected using the ex vivo ELISPOT assay. Five peptides from TRAP and CTRP antigens significantly increased IFN-y responses of 1/9 in malaria-exposed volunteers. There is no statistically significant difference in positive T-cell response induced by any peptides in malaria exposed volunteers when evaluated as a group. The frequency of expressed HLA-A24 in malaria-exposed and non-malaria-exposed healthy adults living in northwest and central Thailand was 90% (27/30) and 100% (12/12), respectively. Although no association between positive T-cell response and HLA-A24 was found, due to the low number of positive responders achieved, one positive responder in malaria- exposed group was presented as HLA-24.
The Southeast Asian journal of tropical medicine and public health 02/2009; 40(1):10-7. · 0.60 Impact Factor
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ABSTRACT: The study investigated the pharmacokinetics of fosmidomycin when given alone and in combination with clindamycin in patients with acute uncomplicated falciparum malaria.
A total of 15 and 18 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from out-patient department of Mae Sot Hospital, Tak Province, Thailand. Patients were treated with monotherapy with fosmidomycin at the dose of 1,200 mg every 8 hours for 7 days (n = 15) or combination therapy with fosmidomycin (900 mg every 12 hours for 7 days) and clindamycin (600 mg every 12 hours for 7 days) (n = 18). Blood samples were taken for pharmacokinetic investigations of clindamycin and/or fosmidomycin and 24-hour urine samples were collected during dosing period. Efficacy assessments included clinical and parasitological evaluation. Safety and tolerability were assessed based on clinical and laboratory investigations.
Both mono- and combination therapy regimens of fosmidomycin were well tolerated with no serious adverse events. Combination therapy with fosmidomycin and clindamycin was proven highly effective with 100% cure rate, whereas cure rate of monotherapy was 22% (28-day follow up). Pharmacokientics of fosmidomycin following mono- and combination therapy were similar except Vz/F and CL/F, which were significantly smaller in the combination regimen. Plasma concentration-time profiles of both fosmidomycin and clindamycin were best fit with a one-compartment open model with first-order absorption and elimination and with absorption lag time. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about the second or third dose. There was no evidence of dose accumulation during multiple dosing. Urinary recovery of fosmidomycin was 18.7 and 20% following mono- and combination therapy, respectively.
Pharmacokinetic dose optimization of fosmidomycin-clindamycin combination therapy with the course of treatment of not longer than three days is required to obtain a regimen which is safe and produced 100% cure for multidrug-resistant P. falciparum.
Malaria Journal 02/2007; 6:70. · 3.19 Impact Factor
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ABSTRACT: This study was conducted during 2002-2004 at Mae Sot District, on the Thai-Myanmar border, an area of multidrug-resistant Plasmodium falciparum malaria. Sixty-two patients with P. vivax malaria were included in the study. All were randomized into two groups to receive a 3-day regimen of chloroquine or a 3-day regimen of quinine. Primaquine was given to patients in both groups for the elimination of hepatic stages. Results from the present study suggest that the standard regimen of chloroquine and a 3-day course of quinine at the dose regimens under investigation were very effective and well tolerated for the treatment of P. vivax malaria in this area. All patients responded well to both drug regimens; the cure rates with chloroquine or quinine, when given concurrently with the tissue schizontocidal drug primaquine, were virtually 100% within 28 days of follow-up. No significant correlations between parasite clearance time (PCT) or fever clearance time (FCT) and inhibitory concentration 50 (IC50) were found. Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points.
Transactions of the Royal Society of Tropical Medicine and Hygiene 06/2006; 100(5):410-8. · 2.16 Impact Factor
