Biomedical subjects
S Looareesuwan
Publications and source records attributed to S Looareesuwan.
Influence of hemoglobin E trait on the severity of Falciparum malaria.
To determine if hemoglobin E trait influences the course of acute malaria, adults hospitalized for the treatment of symptomatic infection with Plasmodium falciparum were studied retrospectively. Forty-two patients with hemoglobin E trait were compared with 175 reference subjects who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia. One patient (2.4%) with hemoglobin E trait had a severe complication of malaria by World Health Organization criteria (cerebral malaria), while 32 subjects in the reference group (18.3%) had one or more severe complications: cerebral malaria (n=18), hyperparasitemia (n=16), renal failure (n=10), and severe anemia (n=1) (P=.044 after adjustment for ethnic categories). The estimated odds of severe complications in the reference subjects were 6.9 times the odds in patients with hemoglobin E trait (95% confidence interval, 1.2-146. 4). These results suggest that hemoglobin E trait may ameliorate the course of acute falciparum malaria.
Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand.
Parasite genotyping by the polymerase chain reaction was used to distinguish recrudescent from newly acquired Plasmodium falciparum infections in a Karen population resident on the northwestern border of Thailand where malaria transmission is low (one infection/person/year). Plasmodium falciparum infections were genotyped for allelic variation in three polymorphic antigen loci, merozoite surface proteins-1 and -2 (MSP-1 and -2) and glutamaterich protein (GLURP), before and after antimalarial drug treatment. Population genotype frequencies were measured to provide the baseline information to calculate the probability of a new infection with a different or the same genotype to the initial pretreatment isolate. Overall, 38% of the infections detected following treatment had an identical genotype before and up to 121 days after treatment. These post-treatment genotypes were considered recrudescent because of the low (< 5%) probability of repeated occurrence by chance in the same patient. This approach allows studies of antimalarial drug treatment to be conducted in areas of low transmission since recrudescences can be distinguished confidently from newly acquired infections.
Treatment of malarial acute renal failure by hemodialysis.
We studied 112 patients with malarial acute renal failure (ARF) during the period 1991-1997 at Bangkok Hospital for Tropical Diseases (Mahidol University, Bangkok, Thailand). Hemodialysis was performed in 101 (90.2%) of these patients. The mean number of times the patients were hemodialyzed was 6.5 (range = 1-27). Ninety-three (83.0%) patients were oliguric and the remainder were nonoliguric. Patients who had oliguric renal failure required more hemodialyses and had more complications than the nonoliguric patients. The oliguric patients had an eight-fold higher risk of requiring six or more hemodialyses (95% confidence interval = 1.2-53.9, P = 0.0008). The overall mortality rate was 10.7% (12 of 112). Eleven of the patients who died were jaundiced and eight of them had cerebral malaria with a Glasgow Coma Score < or = 8. We conclude that hemodialysis is a useful treatment for oliguric and nonoliguric ARF from severe malaria, particularly when initiated early in the course of the illness.
A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand.
CGP 56697, a new oral fixed combination of artemether and benflumetol, was tested in a double-blinded, randomized trial in 252 adult patients treated either with CGP 56697 (4 x 4 tablets each containing 20 mg of artemether and 120 mg of benflumetol, given at 0, 8, 24, and 48 hr), or with mefloquine (three tablets of 250 mg at initial diagnosis, followed by two tablets of 250 mg at 8 hr). Baseline data of the two groups were comparable. The 28-day cure rate with CGP 56697 was lower than with mefloquine (69.3% versus 82.4%; P = 0.002). However, CGP 56697 was more effective than mefloquine in parasite clearance time (43 hr versus 66 hr; P < 0.001) fever clearance time (32 hr versus 54 hr; P < 0.005), and gametocyte clearance time (152 hr versus 331 hr; P < 0.001). This study revealed that CGP 56697 is effective against multidrug-resistant Plasmodium falciparum malaria in Thailand, but higher doses will probably be needed to improve the cure rate.
Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand.
The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.
Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.
The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was > 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.
Characterization of Plasmodium falciparum-infected erythrocyte and P-selectin interaction under flow conditions.
Plasmodium falciparum-infected erythrocytes (IRBC) roll on the adhesion molecule P-selectin in vitro under flow conditions that approximate the shear stress in capillary and postcapillary venules in which cytoadherence occurs in vivo. The pathological significance of this adhesive interaction is currently unknown. In this study, we further investigated the molecular interactions between IRBC and P-selectin by using a laminar flow system that allowed for the direct visualization of IRBC-substratum interactions. The results showed that the IRBC-P-selectin interaction was Ca2+-dependent and involved the lectin domain of P-selectin and a sialic acid residue on IRBC. The sialylated P-selectin ligand was trypsin-sensitive, which suggests that it could be part of the parasite antigen PfEMP1 that interacts with CD36 and intercellular adhesion molecule-1 (ICAM-1), but different from a trypsin-resistant IRBC ligand that adheres selectively to chondroitin sulfate A. Studies on the rolling and adhesion of IRBC on activated platelets that express both CD36 and P-selectin showed that inhibition of rolling on P-selectin reduced the adhesion of some clinical parasite isolates to CD36, whereas other parasite isolates appeared to interact directly with CD36. Thus, cytoadherence under physiological flow conditions may be mediated by multiple IRBC ligands that interact with different adhesion molecules in a cooperative fashion. These findings underscore the complexity of the interactions betweeen IRBC and vascular endothelium.
Measurement of serum nitrite/nitrate concentrations using high-performance liquid chromatography.
Previous studies have reported increased serum concentrations of nitrite/nitrate - the degradation products of nitric oxide - in Plasmodium vivax malaria and uncomplicated Plasmodium falciparum malaria. In all these studies, however, nitrite/nitrate has been measured spectrometrically using Griess reagent which carries major disadvantages in the determination of serum nitrite/nitrate. The method does not allow an exact differentiation of nitrite and biogenic amines that are physiologically present in plasma. In the present study we introduce high-performance liquid chromatography as a new, accurate and cost effective method for determination of serum nitrite/nitrate levels. Significantly increased nitrate concentrations were found in malaria patients and serum values remained above normal levels for at least 21 days. It could be shown that our HPLC method is a sensitive and cost-effective method for direct determination of nitrite/nitrate in serum samples, which is not influenced by the presence of biogenic amines.
A comparison of three different dihydroartemisinin formulations for the treatment of acute uncomplicated falciparum malaria in Thailand.
We compared the safety and efficacy of three formulations of dihydroartemisinin for the treatment of acute uncomplicated falciparum malaria in patients who received a total dose of 600 mg dihydroartemisinin over 5 days. The first group was treated by dihydroartemisinin produced and formulated in the People's Republic of China, the second group was treated by dihydroartemisinin produced in Vietnam but formulated by the Government Pharmaceutical Organization of Thailand and the third group was treated by dihydroartemisinin produced and formulated by the Government Pharmaceutical Organization of Thailand. All patients were admitted to hospital to evaluate safety and efficacy for a total of 28 days. By the third day of treatment, most patients were blood-smear negative for parasites and none had serious adverse effects. Minor symptoms such as nausea, dizziness and headache were similar in the three groups and disappeared after 3 days of treatment. One-hundred and thirty-three patients completed the 28-day follow-up period. The cure rates of groups I, II and III were 80%, 85% and 92%, respectively (P > 0.02). There were no significant differences in fever clearance or parasite clearance among the three groups. We conclude that the three formulations of dihydroartemisinin produced and formulated in different countries were safe and effective in treating uncomplicated falciparum malaria acquired in Thailand.
Immunogenicity of liposome-associated and refined antigen oral cholera vaccines in Thai volunteers.
A mixture of Vibrio cholerae antigens made up of crude fimbrial extract, lipopolysaccharide and procholeragenoid was administered orally to Thai volunteers either as free antigen or associated with liposomes. All vaccines and controls were administered in three doses given at 14 day intervals. Nine volunteers received liposome-associated vaccine and seven received free vaccine. Liposomes without antigens were given to eight volunteers and seven volunteers received 5% NaHCO3 solution alone. Both vaccines had 100% immunogenicity as determined by serum vibriocidal antibody responses. Liposomes were shown by indirect ELISA to localize the immune response against lipopolysaccharide and fimbriae to the intestinal mucosa. Vaccines given liposome-associated antigens had a higher rate of antigen-specific antibody response than did individuals who had received free antigens. The vaccines induced intestinal antibodies of IgM and/or IgA isotypes, but not IgG antibody.
Pustular eruption in a malaria patient treated with chloroquine.
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The course of anaemia after the treatment of acute, falciparum malaria.
To determine the course of anaemia following treatment for acute falciparum malaria, 72 adult Thai patients were followed for 4 weeks after starting effective therapy. Using the criteria of haemoglobin concentrations of < 13 g/dl in males and < 12 g/dl in females to define anaemia, all but two (97%) of the patients were anaemic at some point during the study period. At weekly observations, the erythropoietic response of each patient with anaemia was categorized clinically, on the basis of absolute reticulocyte counts (ARC) and indirect bilirubin concentrations (IBC). At 4 weeks, 40 (56%) of the patients were still anaemic. The results of tests on samples of peripheral blood from these 40 patients were consistent with hypoproliferative erythropoiesis (low-normal ARC and IBC; 33 patients), ineffective erythropoiesis (low-normal ARC but elevated IBC; five patients) or an appropriate response (elevated ARC and normal IBC; two patients). Of the variables measured at the time of enrolment into the study, only low serum albumin (P = 0.002) and elevated direct bilirubin (P = 0.009) were independently associated with persisting anaemia at 4 weeks. Anaemia may therefore persist in about one in every two Thai patients for up to 28 days after beginning effective treatment for acute Plasmodium falciparum malaria, hypoproliferative erythropoiesis appearing to be the most common mechanism of this anaemia. While it is likely that the malarial episode itself is somehow responsible for these persistent haematological changes, other, underlying, chronic processes might have a contributory role. Whatever the cause, the continuing anaemia appears to be related to the degree of hepatic dysfunction on admission.
Endogenous interleukin-10 modulates proinflammatory response in Plasmodium falciparum malaria.
Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 are implicated in the pathogenesis of severe Plasmodium falciparum malaria. In this study, the effect of IL-10 on their production by peripheral blood mononuclear cells (PBMC) from acutely infected patients was examined. Exogenous IL-10 inhibited malarial antigen-induced cytokine production by reducing mRNA accumulation. Maximal inhibition occurred when IL-10 was added in the first 2 h of stimulation. Conversely, the addition of anti-IL-10 markedly enhanced TNF-alpha, IL-1beta, and IL-6 production. The effect was significantly greater on PBMC from patients with uncomplicated infection than PBMC from patients with severe disease. Kinetics studies showed that TNF-alpha, IL-6, and IL-1beta were produced within 2-4 h of stimulation, while IL-10 was first detectable after 8 h. These findings suggest that IL-10 counter-regulates the proinflammatory response to P. falciparum. Severe falciparum malaria may be associated with an inadequate negative feedback response by IL-10.
Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria.
An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.
Effects of alpha-thalassemia on pharmacokinetics of the antimalarial agent artesunate.
Thalassemia is common in Southeast Asia, where artemisinin derivatives are frequently used in the treatment of malaria. It has been previously reported that artemisinin derivatives can be concentrated by uninfected thalassemic erythrocytes in vitro but not by normal erythrocytes. As a follow-up to this report, we studied the antimalarial kinetics of intravascular artesunate (2.4 mg/kg of body weight) in 10 persons with normal hemoglobins and in 10 patients with thalassemia (2 with alpha-thalassemia type 1-hemoglobin Constant Spring and 8 with alpha-thalassemia type 1-alpha-thalassemia type 2). Concentrations of artesunate and its active metabolites in plasma were measured by bioassay and expressed relative to those of dihydroartemisinin, the major biologically active metabolite. Concentrations of intravascular artesunate in plasma peaked in both the normal individuals and the thalassemic individuals 15 min after injection (the first time point). Plasma drug concentrations at all time intervals, except that at 1 h, were significantly higher in thalassemic subjects than in normal subjects (P < 0.05). The area under the concentration-time curve was 9-fold higher (P < 0.001) and the volume of distribution at steady state was 15-fold lower (P < 0.001) in thalassemic than in normal subjects. In light of the potential neurotoxicity of artemisinin derivatives, these results suggest that thalassemic subjects may need a drug administration regimen different from that of normal patients.
Effect of pentoxifylline on cytokine patterns in the therapy of complicated Plasmodium falciparum malaria.
The effect of pentoxifylline (PTX) was tested for its capacity to modulate cytokine responses during therapy of severe Plasmodium falciparum malaria in a placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand. The patients received standard antimalarial treatment with artesunate (120 mg intravenously given immediately, then 60 mg every 12 hr for a total dose of 600 mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the first three days of antimalarial treatment. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were markedly elevated in all patients prior to treatment. After 6 hr of high-dose PTX treatment, TNF and IL-6 levels significantly decreased while an increase in TNF and IL-6 levels was seen after 6 hr of low-dose PTX or placebo treatment (P < 0.01). After 12 and 24 hr of high-dose PTX infusion, TNF-receptor plasma concentrations were lower than in low-dose PTX- or placebo-treated patients (P < 0.01), whereas no differences between the groups with regard to IL-6 receptor levels were observed. We conclude that 40 mg/kg/day of PTX reduces plasma levels of TNF, IL-6, and TNF-receptor in patients with severe malaria. Whether this reduction improves clinical outcome remains to be determined.
Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand.
Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria. Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose pentoxifylline (1.67 mg/kg/hr). All 45 patients had one or more manifestations of severe malaria such as cerebral malaria (n = 18), renal failure requiring hemodialysis (n = 9), azotemia (n = 8), jaundice (n = 25), or hyperparasitemia (n = 30). The overall severity was comparable in the three groups. Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients. In addition, a number of subsidiary outcome variables were examined in specific subgroups, including the recovery time from coma for patients with cerebral malaria, the duration of intubation in patients with respiratory distress, the number of hemodialysis treatments needed for patients with acute renal failure, and the number of units of blood administered to patients requiring transfusion. Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment. No significant differences among the three treatment groups were found for any of the outcome variables examined. We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit.