Sasithon Pukrittayakamee - Academia.edu (original) (raw)

Papers by Sasithon Pukrittayakamee

Research paper thumbnail of A hospital-based study of bloodstream infections in febrile patients in Dhulikhel Hospital Kathmandu University Teaching Hospital, Nepal

The Southeast Asian journal of tropical medicine and public health

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. ... more The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperature > or = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chl...

Research paper thumbnail of Contribution of humoral immunity to the therapeutic response in falciparum malaria

The American journal of tropical medicine and hygiene, 2001

The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was ... more The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was assessed in a case-control study. Forty adult Thai patients with acute falciparum malaria who had subsequent recrudescent infections and 40 patients matched for age, therapeutic regimen, and disease severity who were cured by Day 28 were studied. All cured patients had positive immunoglobulin (Ig) G to ring-infected erythrocyte surface antigen (RESA) in their admission plasma, compared with only 60% of patients who failed to respond to treatment (P < 0.001). The proportion of IgM-positive cases at admission was also higher in the successfully treated group than in the group with failure (70% versus 30%) (P < 0.001). The geometric mean (95% confidence interval) reciprocal IgG titer at admission was significantly higher in cured patients (187.0 [83.5-418.3]) compared with those who experienced treatment failure (11.6 [5.1-26.5]) (P < 0.001). The patients with uncomplicated malaria...

Research paper thumbnail of Identification of cryptic coinfection with Plasmodium falciparum in patients presenting with vivax malaria

The American journal of tropical medicine and hygiene, 2001

In Thailand, approximately 8% of patients treated for vivax malaria are found subsequently to hav... more In Thailand, approximately 8% of patients treated for vivax malaria are found subsequently to have coinfection with Plasmodium falciparum. A P. falciparum histidine rich protein 2 (PfHRP-2) dipstick test was evaluated as a predictor of mixed infections with subpatent P. falciparum in a prospective study of 238 patients admitted to the hospital with acute vivax malaria. Of these, 23 (10%) had subsequent development of falciparum malaria without reexposure. Patients with cryptic P. falciparum infection had a significantly lower mean (standard deviation) hematocrit than those with P. vivax alone: 29.6 (7.6%) versus 37.2 (6.4%) (P < 0.0001). Using microscopic appearance of P. falciparum after the start of treatment as the reference standard, the PfHRP-2 test was 74% sensitive and 99% specific in predicting mixed infections with subpatent P. falciparum parasitemia at presentation. The PfHRP-2 dipstick test may be a useful adjunct to microscopy in areas where mixed infections are common.

Research paper thumbnail of Studies of the neurotoxicity of oral artemisinin derivatives in mice

The American journal of tropical medicine and hygiene, 2000

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives ar... more Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an in...

Research paper thumbnail of Characteristics of Plasmodium vivax-infected erythrocyte rosettes

The American journal of tropical medicine and hygiene, 1998

To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 ad... more To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 adult Thai patients admitted with acute P. vivax malaria and a predominance of trophozoite and schizont stages in their peripheral blood smears. In each case, P. vivax-infected cells formed spontaneous rosettes with two or more uninfected red blood cells. Rosette formation of P. vivax was dependent on the divalent cations (Ca2+/Mg2+) and was highly sensitive to trypsin and heparin, but, unlike P. falciparum, rosettes of P. vivax did not reform after removal of heparin. Plasma taken from patients with either acute uncomplicated P. falciparum or P. vivax malaria reversed rosette formation of all P. vivax isolates whereas plasma from uninfected controls had no effect. There was a small but significant increase in rosette-reversing activity in plasma taken during the convalescent period (P < 0.001). The increment in reversal activity was significantly greater in plasma taken following recov...

Research paper thumbnail of A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria

Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatm... more Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. Methods The pharmacokinetic properties of oral artesunate and artemether (4 mg kg x1 ) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. Results Despite a 29% lower molar dose, oral artesunate administration resulted in signi®cantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (Pj0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40±76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the ®rst day of treatment, 31 (17±100)%, compared to the second day, 72 (44±118)% (P=0.018). In vivo parasite clearance and time above the in vitro IC 90 were similar for the two drugs, despite considerable differences in C max and AUC. Conclusions The oral antimalarial bioavailability following artemether was signi-®cantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.

Research paper thumbnail of Laboratory detection of artemisinin-resistant Plasmodium falciparum

Antimicrobial agents and chemotherapy, 2014

Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-r... more Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-resistant Plasmodium falciparum, defined phenotypically by low in vivo parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant P. falciparum is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC50) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-h WHO test (P = 0.001). TMI IC50s correlated significantly with the in vivo responses to artesunate (parasite clearance time [r = 0.44, P = 0.001] and parasite clearance half-life [r = 0.46, P = 0.001]), whereas the standard 48-h test value...

Research paper thumbnail of Effects of different antimalarial drugs on gametocyte carriage in P. vivax malaria

The American journal of tropical medicine and hygiene, 2008

The gametocytocidal and asexual stage activities of eight antimalarial and eight antibiotic-conta... more The gametocytocidal and asexual stage activities of eight antimalarial and eight antibiotic-containing regimens were evaluated in 349 adult patients with P. vivax malaria. Gametocytemia was found in 63% of patients (22% before and 41% after treatment). The median (range) gametocyte clearance time was 24 hours (range, 2-504 hours) and correlated with asexual parasite clearance time (r = 0.52, P < 0.001). Gametocytemia in vivax malaria was more common in patients with admission parasitemia > 10,000/microL and after treatment with drugs which have weak antimalarial activity, and was also associated with an increased rate of vivax reappearance (29.4% versus 14.1%, P = 0.002). Sexual stage activities corresponded with asexual stage activity for all tested regimens. Treatment with potent antimalarial drugs reduces the transmission potential of P. vivax.

Research paper thumbnail of Assessment of the neurotoxicity of oral dihydroartemisinin in mice

Transactions of the Royal Society of Tropical Medicine and Hygiene

High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, give... more High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of ...

Research paper thumbnail of In vitro efficacy of antimalarial drugs against Plasmodium vivax on the western border of Thailand

The American journal of tropical medicine and hygiene, 2004

The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven ant... more The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven antimalarial drugs was evaluated using the schizont maturation inhibition technique. The geometric mean 50% inhibition concentration (IC(50)) values were quinine = 308 ng/mL, amodiaquine =14 ng/mL, chloroquine =50 ng/mL, mefloquine = 127 ng/mL, sulfadoxine/pyrimethamine (80:1) = 800/10 ng/mL, pyrimethamine = 8 ng/mL, and artesunate = 0.5 ng/mL. Compared with P. falciparum in this area, P. vivax was more sensitive to chloroquine and artesunate, equally sensitive to quinine, and more resistant to mefloquine.

Research paper thumbnail of Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects

Antimicrobial agents and chemotherapy, 2015

Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may b... more Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540-180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesu...

Research paper thumbnail of Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

The Lancet Infectious Diseases, 2015

Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global contro... more Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Melinda Gates Foundation.

Research paper thumbnail of Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

Antimicrobial Agents and Chemotherapy, 2014

Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by... more Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (C max ), area under the concentration-time curve from 0 h to the end of the study (AUC 0 -last ), and area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.)

Research paper thumbnail of Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1

Malaria Journal, 2005

Background: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75... more 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.

Research paper thumbnail of Plasmodium vivax: restricted tropism and rapid remodelling of CD71 positive reticulocytes

Blood, 2014

• Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restric... more • Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restricted to the bone marrow.

Research paper thumbnail of Dichloroacetate for lactic acidosis in severe malaria: A pharmacokinetic and pharmacodynamic assessment

Metabolism, 1994

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We h... more Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Research paper thumbnail of Gestational diabetes mellitus prevalence in Maela refugee camp on the Thai–Myanmar Border: a clinical report

Global Health Action, 2014

Individuals in conflict-affected areas rarely get appropriate care for chronic or non-infectious ... more Individuals in conflict-affected areas rarely get appropriate care for chronic or non-infectious diseases. The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide, and new evidence shows conclusively that the negative effects of hyperglycemia occur even at mild glucose elevations and that these negative effects can be attenuated by treatment. Scientific literature on gestational diabetes in refugee camp settings is critically limited. A 75 g 2-hour glucose tolerance test was administered to 228 women attending the antenatal care (ANC) clinic in Maela refugee camp on the Thai-Myanmar border. Prevalence of GDM was determined using the HAPO trial cut-offs [≥92 mg/dL (fasting),≥180 (1 hour), and≥153 (2 hour)] and the WHO criteria [≥126 mg/dL (fasting), and 140 mg/dL (2 hour)]. From July 2011 to March 2012, the prevalence of GDM was 10.1% [95% confidence interval (CI): 6.2-14.0] when the cut-off determined by the HAPO trial was applied. Applying the older WHO criteria yielded a prevalence of 6.6% (95% CI 3.3-9.8). Age, parity, and BMI emerged as characteristics that may be significantly associated with GDM in this population. Other risk factors that are commonly used in screening guidelines were not applicable in this diabetes-naïve population. The prevalence of GDM is lower in this population compared with other populations, but still complicates 10% of pregnancies. New evidence regarding gestational diabetes raises new dilemmas for healthcare providers in resource-poor settings. Efforts to identify and treat patients at risk for adverse outcomes need to be balanced with awareness of the risks and burdens associated with over diagnosis and unnecessary interventions. Screening approaches based on risk factors or using higher cut-off values may help minimize this burden and identify those most likely to benefit from intervention.

Research paper thumbnail of Quantifying Low Birth Weight, Preterm Birth and Small-for-Gestational-Age Effects of Malaria in Pregnancy: A Population Cohort Study

PLoS ONE, 2014

Background: The association between malaria during pregnancy and low birth weight (LBW) is well d... more Background: The association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit.

Research paper thumbnail of Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

Science, 2014

Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate... more Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.

Research paper thumbnail of Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria

Malaria Journal, 2014

Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falcipa... more Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.

Research paper thumbnail of A hospital-based study of bloodstream infections in febrile patients in Dhulikhel Hospital Kathmandu University Teaching Hospital, Nepal

The Southeast Asian journal of tropical medicine and public health

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. ... more The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperature > or = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chl...

Research paper thumbnail of Contribution of humoral immunity to the therapeutic response in falciparum malaria

The American journal of tropical medicine and hygiene, 2001

The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was ... more The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was assessed in a case-control study. Forty adult Thai patients with acute falciparum malaria who had subsequent recrudescent infections and 40 patients matched for age, therapeutic regimen, and disease severity who were cured by Day 28 were studied. All cured patients had positive immunoglobulin (Ig) G to ring-infected erythrocyte surface antigen (RESA) in their admission plasma, compared with only 60% of patients who failed to respond to treatment (P < 0.001). The proportion of IgM-positive cases at admission was also higher in the successfully treated group than in the group with failure (70% versus 30%) (P < 0.001). The geometric mean (95% confidence interval) reciprocal IgG titer at admission was significantly higher in cured patients (187.0 [83.5-418.3]) compared with those who experienced treatment failure (11.6 [5.1-26.5]) (P < 0.001). The patients with uncomplicated malaria...

Research paper thumbnail of Identification of cryptic coinfection with Plasmodium falciparum in patients presenting with vivax malaria

The American journal of tropical medicine and hygiene, 2001

In Thailand, approximately 8% of patients treated for vivax malaria are found subsequently to hav... more In Thailand, approximately 8% of patients treated for vivax malaria are found subsequently to have coinfection with Plasmodium falciparum. A P. falciparum histidine rich protein 2 (PfHRP-2) dipstick test was evaluated as a predictor of mixed infections with subpatent P. falciparum in a prospective study of 238 patients admitted to the hospital with acute vivax malaria. Of these, 23 (10%) had subsequent development of falciparum malaria without reexposure. Patients with cryptic P. falciparum infection had a significantly lower mean (standard deviation) hematocrit than those with P. vivax alone: 29.6 (7.6%) versus 37.2 (6.4%) (P < 0.0001). Using microscopic appearance of P. falciparum after the start of treatment as the reference standard, the PfHRP-2 test was 74% sensitive and 99% specific in predicting mixed infections with subpatent P. falciparum parasitemia at presentation. The PfHRP-2 dipstick test may be a useful adjunct to microscopy in areas where mixed infections are common.

Research paper thumbnail of Studies of the neurotoxicity of oral artemisinin derivatives in mice

The American journal of tropical medicine and hygiene, 2000

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives ar... more Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an in...

Research paper thumbnail of Characteristics of Plasmodium vivax-infected erythrocyte rosettes

The American journal of tropical medicine and hygiene, 1998

To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 ad... more To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 adult Thai patients admitted with acute P. vivax malaria and a predominance of trophozoite and schizont stages in their peripheral blood smears. In each case, P. vivax-infected cells formed spontaneous rosettes with two or more uninfected red blood cells. Rosette formation of P. vivax was dependent on the divalent cations (Ca2+/Mg2+) and was highly sensitive to trypsin and heparin, but, unlike P. falciparum, rosettes of P. vivax did not reform after removal of heparin. Plasma taken from patients with either acute uncomplicated P. falciparum or P. vivax malaria reversed rosette formation of all P. vivax isolates whereas plasma from uninfected controls had no effect. There was a small but significant increase in rosette-reversing activity in plasma taken during the convalescent period (P < 0.001). The increment in reversal activity was significantly greater in plasma taken following recov...

Research paper thumbnail of A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria

Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatm... more Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. Methods The pharmacokinetic properties of oral artesunate and artemether (4 mg kg x1 ) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. Results Despite a 29% lower molar dose, oral artesunate administration resulted in signi®cantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (Pj0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40±76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the ®rst day of treatment, 31 (17±100)%, compared to the second day, 72 (44±118)% (P=0.018). In vivo parasite clearance and time above the in vitro IC 90 were similar for the two drugs, despite considerable differences in C max and AUC. Conclusions The oral antimalarial bioavailability following artemether was signi-®cantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.

Research paper thumbnail of Laboratory detection of artemisinin-resistant Plasmodium falciparum

Antimicrobial agents and chemotherapy, 2014

Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-r... more Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-resistant Plasmodium falciparum, defined phenotypically by low in vivo parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant P. falciparum is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC50) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-h WHO test (P = 0.001). TMI IC50s correlated significantly with the in vivo responses to artesunate (parasite clearance time [r = 0.44, P = 0.001] and parasite clearance half-life [r = 0.46, P = 0.001]), whereas the standard 48-h test value...

Research paper thumbnail of Effects of different antimalarial drugs on gametocyte carriage in P. vivax malaria

The American journal of tropical medicine and hygiene, 2008

The gametocytocidal and asexual stage activities of eight antimalarial and eight antibiotic-conta... more The gametocytocidal and asexual stage activities of eight antimalarial and eight antibiotic-containing regimens were evaluated in 349 adult patients with P. vivax malaria. Gametocytemia was found in 63% of patients (22% before and 41% after treatment). The median (range) gametocyte clearance time was 24 hours (range, 2-504 hours) and correlated with asexual parasite clearance time (r = 0.52, P < 0.001). Gametocytemia in vivax malaria was more common in patients with admission parasitemia > 10,000/microL and after treatment with drugs which have weak antimalarial activity, and was also associated with an increased rate of vivax reappearance (29.4% versus 14.1%, P = 0.002). Sexual stage activities corresponded with asexual stage activity for all tested regimens. Treatment with potent antimalarial drugs reduces the transmission potential of P. vivax.

Research paper thumbnail of Assessment of the neurotoxicity of oral dihydroartemisinin in mice

Transactions of the Royal Society of Tropical Medicine and Hygiene

High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, give... more High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of ...

Research paper thumbnail of In vitro efficacy of antimalarial drugs against Plasmodium vivax on the western border of Thailand

The American journal of tropical medicine and hygiene, 2004

The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven ant... more The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven antimalarial drugs was evaluated using the schizont maturation inhibition technique. The geometric mean 50% inhibition concentration (IC(50)) values were quinine = 308 ng/mL, amodiaquine =14 ng/mL, chloroquine =50 ng/mL, mefloquine = 127 ng/mL, sulfadoxine/pyrimethamine (80:1) = 800/10 ng/mL, pyrimethamine = 8 ng/mL, and artesunate = 0.5 ng/mL. Compared with P. falciparum in this area, P. vivax was more sensitive to chloroquine and artesunate, equally sensitive to quinine, and more resistant to mefloquine.

Research paper thumbnail of Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects

Antimicrobial agents and chemotherapy, 2015

Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may b... more Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540-180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesu...

Research paper thumbnail of Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

The Lancet Infectious Diseases, 2015

Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global contro... more Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; Melinda Gates Foundation.

Research paper thumbnail of Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

Antimicrobial Agents and Chemotherapy, 2014

Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by... more Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (C max ), area under the concentration-time curve from 0 h to the end of the study (AUC 0 -last ), and area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.)

Research paper thumbnail of Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1

Malaria Journal, 2005

Background: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75... more 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.

Research paper thumbnail of Plasmodium vivax: restricted tropism and rapid remodelling of CD71 positive reticulocytes

Blood, 2014

• Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restric... more • Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restricted to the bone marrow.

Research paper thumbnail of Dichloroacetate for lactic acidosis in severe malaria: A pharmacokinetic and pharmacodynamic assessment

Metabolism, 1994

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We h... more Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Research paper thumbnail of Gestational diabetes mellitus prevalence in Maela refugee camp on the Thai–Myanmar Border: a clinical report

Global Health Action, 2014

Individuals in conflict-affected areas rarely get appropriate care for chronic or non-infectious ... more Individuals in conflict-affected areas rarely get appropriate care for chronic or non-infectious diseases. The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide, and new evidence shows conclusively that the negative effects of hyperglycemia occur even at mild glucose elevations and that these negative effects can be attenuated by treatment. Scientific literature on gestational diabetes in refugee camp settings is critically limited. A 75 g 2-hour glucose tolerance test was administered to 228 women attending the antenatal care (ANC) clinic in Maela refugee camp on the Thai-Myanmar border. Prevalence of GDM was determined using the HAPO trial cut-offs [≥92 mg/dL (fasting),≥180 (1 hour), and≥153 (2 hour)] and the WHO criteria [≥126 mg/dL (fasting), and 140 mg/dL (2 hour)]. From July 2011 to March 2012, the prevalence of GDM was 10.1% [95% confidence interval (CI): 6.2-14.0] when the cut-off determined by the HAPO trial was applied. Applying the older WHO criteria yielded a prevalence of 6.6% (95% CI 3.3-9.8). Age, parity, and BMI emerged as characteristics that may be significantly associated with GDM in this population. Other risk factors that are commonly used in screening guidelines were not applicable in this diabetes-naïve population. The prevalence of GDM is lower in this population compared with other populations, but still complicates 10% of pregnancies. New evidence regarding gestational diabetes raises new dilemmas for healthcare providers in resource-poor settings. Efforts to identify and treat patients at risk for adverse outcomes need to be balanced with awareness of the risks and burdens associated with over diagnosis and unnecessary interventions. Screening approaches based on risk factors or using higher cut-off values may help minimize this burden and identify those most likely to benefit from intervention.

Research paper thumbnail of Quantifying Low Birth Weight, Preterm Birth and Small-for-Gestational-Age Effects of Malaria in Pregnancy: A Population Cohort Study

PLoS ONE, 2014

Background: The association between malaria during pregnancy and low birth weight (LBW) is well d... more Background: The association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit.

Research paper thumbnail of Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

Science, 2014

Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate... more Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.

Research paper thumbnail of Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria

Malaria Journal, 2014

Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falcipa... more Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.