RESUMEN
OBJECTIVE: To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. METHODS: We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose (n = 25) combination or loose tablets (n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24-25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. RESULTS: All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps ≤ 0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC(0-∞) was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable (P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. CONCLUSIONS: In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.
Asunto(s)
Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Malaria Falciparum/tratamiento farmacológico , Mefloquina/efectos adversos , Torsades de Pointes/inducido químicamente , Adolescente , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Artemisininas/administración & dosificación , Artemisininas/uso terapéutico , Artesunato , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Electrocardiografía/efectos de los fármacos , Femenino , Humanos , Masculino , Mefloquina/administración & dosificación , Mefloquina/uso terapéutico , Persona de Mediana Edad , Adulto JovenRESUMEN
A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P < or = 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P < or = 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.
Asunto(s)
Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Artemisininas/farmacocinética , Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Mefloquina/farmacocinética , Mefloquina/uso terapéutico , Adolescente , Adulto , Anciano , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacología , Artemisininas/administración & dosificación , Artemisininas/efectos adversos , Artemisininas/farmacología , Artesunato , Resistencia a Múltiples Medicamentos , Femenino , Humanos , Malaria Falciparum/metabolismo , Malaria Falciparum/patología , Masculino , Mefloquina/administración & dosificación , Mefloquina/efectos adversos , Mefloquina/farmacología , Persona de Mediana Edad , Plasmodium falciparum/efectos de los fármacos , Resultado del Tratamiento , Adulto JovenRESUMEN
Although cerebral malaria is a major life-threatening complication of Plasmodium falciparum infection, its pathophysiology is not well understood. Prolonged activation of the T helper type 1 (Th1) response characterized by the production of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha has been suggested to be responsible for immunopathological process leading to cerebral malaria unless they are downregulated by the anti-inflamatory cytokines produced by the Th2 response. The T cell immunoglobulin and mucin domain (TIM) family of proteins are cell surface proteins involved in regulating Th1 and Th2 immune responses. In this study, the possible association between the polymorphisms of TIM1, TIM3, and TIMD4 genes and the severity of malaria was examined in 478 adult Thai patients infected with P. falciparum malaria. The TIM1 promoter haplotype comprising three derived alleles, -1637A (rs7702919), -1549C (rs41297577) and -1454A (rs41297579), which were in complete linkage disequilibrium, was significantly associated with protection against cerebral malaria (OR = 0.41; 95% CI = 0.24-0.71; P= 0.0009). Allele-specific transcription quantification analysis revealed that the level of mRNA transcribed from TIM1 was higher for the protective promoter haplotype than for the other promoter haplotype (P= 0.004). Engagement with TIM1 in combination with T cell receptor stimulation induces anti-inflammatory Th2 cytokine production, which can protect the development of cerebral malaria caused by overproduction of pro-inflammatory Th1 cytokines. The present results suggest that the higher TIM1 expression associated with the protective TIM1 promoter haplotype confers protection against cerebral malaria.
Asunto(s)
Predisposición Genética a la Enfermedad , Malaria Cerebral/genética , Malaria Cerebral/prevención & control , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Receptores Virales/genética , Adulto , Alelos , Pueblo Asiatico/genética , Cromosomas Humanos Par 5/genética , Frecuencia de los Genes , Genoma Humano/genética , Haplotipos , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Desequilibrio de Ligamiento/genética , Proteínas de la Membrana/genética , Tailandia , Transcripción GenéticaRESUMEN
Pulmonary complication in severe Plasmodium falciparum malaria is manifested as a prolonged impairment of gas transfer or the more severe acute respiratory distress syndrome (ARDS). In either clinical presentation, vascular permeability is a major component of the pathologic process. In this report, we examined the effect of clinical P falciparum isolates on barrier function of primary dermal and lung microvascular endothelium in vitro. We showed that parasite sonicates but not intact infected erythrocytes disrupted endothelial barrier function in a Src-family kinase-dependent manner. The abnormalities were manifested both as discontinuous immunofluorescence staining of the junctional proteins ZO-1, claudin 5, and VE-cadherin and the formation of interendothelial gaps in monolayers. These changes were associated with a loss in total protein content of claudin 5 and redistribution of ZO-1 from the cytoskeleton to the membrane and the cytosolic and nuclear fractions. There was minimal evidence of a proinflammatory response or direct cellular cytotoxicity or cell death. The active component in sonicates appeared to be a merozoite-associated protein. Increased permeability was also induced by P falciparum glycophosphatidylinositols (GPIs) and food vacuoles. These results demonstrate that parasite components can alter endothelial barrier function and thus contribute to the pathogenesis of severe falciparum malaria.
Asunto(s)
Barrera Hematoacuosa/efectos de los fármacos , Barrera Hematoacuosa/fisiopatología , Permeabilidad Capilar/efectos de los fármacos , Plasmodium falciparum , Proteínas Protozoarias/farmacología , Familia-src Quinasas/fisiología , Uniones Adherentes/patología , Animales , Antimaláricos/farmacología , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Hemoproteínas/farmacología , Humanos , Pulmón/patología , Malaria Falciparum/fisiopatología , Merozoítos/química , Proteínas Protozoarias/metabolismo , Sonicación , Uniones Estrechas/patología , Familia-src Quinasas/metabolismoRESUMEN
The aim of this study was to assess the immunoglobulin (Ig)-subclass distribution of antimalarial antibody responses in 110 and 169 Thai patients with complicated and uncomplicated Plasmodium falciparum malaria, respectively. Antimalarial plasma IgG subclasses and IgE antibody levels against a crude malaria blood stages, and antigen preparation were determined using enzyme-linked immunosorbent assay (ELISA). On admission, the levels of anti-P. falciparum IgG1, IgG2 and IgG3 were significantly lower in patients with complicated malaria than uncomplicated malaria (IgG1, P < 0.0001; IgG2, P < 0.0001; IgG3, P < 0.0001). The levels of antimalarial IgE were slightly lower, but not statistically significant (P = 0.389) in the complicated malaria. After adjusting all antibody levels and age, anti-P. falciparum IgG3 levels remained significantly associated with complicated malaria. None of the other antibody concentrations showed statistically significant associations with complicated malaria. The anti-P. falciparum IgG3 levels were related to the IgG1 as well as IgG2 levels. A correlation between anti-P. falciparum IgG2 and IgE was observed in the complicated malaria group, and this may indicate their roles in the severity of disease. Our data suggest that anti-P. falciparum IgG3 is associated with a reduced risk of complicated malaria and that antimalarial Ig-subclasses are differently regulated in patients with complicated and uncomplicated malaria.
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Adolescente , Adulto , Anciano , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Femenino , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Malaria Cerebral/inmunología , Malaria Falciparum/parasitología , Masculino , Persona de Mediana Edad , TailandiaRESUMEN
We examined a possible association of three single nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF) promoter -1031T>C (rs1799964), -863C>A (rs1800630), and -857C>T (rs1799724) with severe malaria in 466 adult patients having Plasmodium falciparum malaria in northwest Thailand. Four TNF promoter alleles comprising these three SNPs were detected in the studied population. The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002). The association of U04 with susceptibility to cerebral malaria was not caused by linkage disequilibrium with any specific HLA-B and -DRB1 alleles.
Asunto(s)
Alelos , Malaria Cerebral/genética , Malaria Falciparum/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Pueblo Asiatico , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , TailandiaRESUMEN
OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. METHODS: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. RESULTS: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. CONCLUSION: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.
Asunto(s)
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Malaria Falciparum/tratamiento farmacológico , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Sesquiterpenos/farmacocinética , Enfermedad Aguda , Adolescente , Adulto , Análisis de Varianza , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Artemisininas/administración & dosificación , Artemisininas/uso terapéutico , Artesunato , Atovacuona/administración & dosificación , Atovacuona/farmacocinética , Atovacuona/uso terapéutico , Combinación de Medicamentos , Resistencia a Múltiples Medicamentos , Quimioterapia Combinada , Femenino , Semivida , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/metabolismo , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/metabolismo , Resultado del Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Proguanil/administración & dosificación , Proguanil/farmacocinética , Proguanil/uso terapéutico , Sesquiterpenos/administración & dosificación , Sesquiterpenos/uso terapéutico , TailandiaAsunto(s)
Ascariasis/parasitología , Ascaris lumbricoides , Malaria Vivax/parasitología , Animales , Temperatura Corporal , Eosinófilos , Heces/parasitología , Femenino , Fertilización , Fiebre/parasitología , Humanos , Recuento de Leucocitos , Masculino , Recuento de Huevos de Parásitos , Estudios RetrospectivosRESUMEN
The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance. We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg). However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects. Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.
Asunto(s)
Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Malaria Falciparum/tratamiento farmacológico , Mefloquina/administración & dosificación , Plasmodium falciparum/efectos de los fármacos , Sesquiterpenos/administración & dosificación , Adolescente , Adulto , Animales , Antimaláricos/efectos adversos , Antimaláricos/uso terapéutico , Artemisininas/efectos adversos , Artemisininas/uso terapéutico , Artesunato , Quimioterapia Combinada , Femenino , Humanos , Malaria Falciparum/parasitología , Masculino , Mefloquina/efectos adversos , Mefloquina/uso terapéutico , Persona de Mediana Edad , Sesquiterpenos/efectos adversos , Sesquiterpenos/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Preclinical studies have shown that curdlan sulphate (CRDS), a sulphated 1-->3-beta-D glucan, inhibits Plasmodium falciparum in vitro and down-modulates the immune response. A direct, non-specific effect on cytoadherence and rosetting may be predicted, as has been described with other sulphated polysaccharides, e.g. heparin. The anticoagulant effect of CRDS is 10-fold lower than heparin. Curdlan sulphate has, therefore, emerged as a candidate for adjunct medication in the treatment of severe/cerebral malaria. Two clinical studies were conducted using CRDS as adjunct medication to conventional therapy (artesunate) in patients with severe and severe/cerebral malaria. Both studies were double-blind and placebo-controlled to evaluate the efficacy and safety of the combination. Curdlan sulphate appeared to reduce the severity of the disease process, e.g. fever clearance time was shortened. Due to the small number of patients, there was no difference in mortality. The two treatment arms in both studies showed similar results for all laboratory parameters. The only adverse event recorded during CRDS treatment was an increase in activated partial thromboplastin time. This can be monitored easily. It seems that the patients who may benefit most are severe/cerebral cases with no organ damage on admission.
Asunto(s)
Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , beta-Glucanos/uso terapéutico , Adolescente , Adulto , Antimaláricos/efectos adversos , Artemisininas/uso terapéutico , Artesunato , Niño , Método Doble Ciego , Quimioterapia Combinada , Femenino , Fiebre/tratamiento farmacológico , Humanos , Malaria Cerebral/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Parasitemia/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Resultado del Tratamiento , beta-Glucanos/efectos adversosRESUMEN
Clinical presentation of Plasmodium falciparum malaria reflects a continuum from asymptomatic to multi-organ manifestation and death. Severe malaria is defined by the World Health Organization as a qualitative variable. We used the multi-organ dysfunction score (MODS) as a quantitative approach for severity in 29 patients with severe and complicated P. falciparum malaria to test its usefulness in discriminating different severity levels. The MODS on admission was highly correlated with the duration of symptoms after admission (r = 0.73, P < 0.001) and the serum level of tumor necrosis factor alpha (r = 0.41, P = 0.03). In addition, the simplified MODS, based mainly on clinical findings, was also correlated with liver and renal dysfunction during hospitalization (alanine transaminase, r = 0.42, P = 0.02; blood urea nitrogen, r = 0.45, P = 0.015). A score >or= 16 was associated with significantly longer disease duration (P = 0.018). Thus, this score might provide a predictive value for morbidity in P. falciparum malaria.
Asunto(s)
Malaria Falciparum/epidemiología , Malaria Falciparum/patología , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Animales , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/etiología , Malaria Falciparum/mortalidad , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/patología , Plasmodium falciparum , Valor Predictivo de las Pruebas , Tailandia/epidemiología , Factor de Necrosis Tumoral alfa/metabolismo , Organización Mundial de la SaludRESUMEN
Malaria remains a major cause of morbidity and mortality in tropical countries and subtropical regions in the world. Southeast Asia has the most resistant malaria parasites in the world, which has limited treatment options in this region. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The combination of dihydroartemisinin (DHA) and piperaquine (PQP) in the form of Artekin has been developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce treatment costs and toxicity. We conducted a study comparing a standard treatment for acute uncomplicated falciparum malaria (artesunate 4 mg/kg/day together with mefloquine 8 mg/kg/day oral route once a day for 3 days) (Group A) and a combination of dihydroartemisinin 40 mg and piperaquine 320 mg in the form of Artekin given once a day for 3 days (Group B) to determine safety, efficacy, and tolerability. One hundred and eighty patients were randomly enrolled at the ratio of 1:2 into groups A:B. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time or parasite clearance time between both groups. The 28-day cure rates were high, at 100% and 99%, in groups A and B, respectively. We conclude that Artekin was as effective and well-tolerated as artesunate-mefloquine, and can be used alternatively as the current treatment for multidrug-resistant P. falciparum malaria.
Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Mefloquina/uso terapéutico , Quinolinas/uso terapéutico , Sesquiterpenos/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Artesunato , Combinación de Medicamentos , Femenino , Humanos , Masculino , Mefloquina/administración & dosificación , Quinolinas/administración & dosificación , Sesquiterpenos/administración & dosificación , Tailandia , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. DESIGN: Cross-sectional survey. SETTING: Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. MAIN OUTCOME MEASURES: Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. RESULTS: Of the 188 tablet packs purchased which were labelled as 'artesunate' 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by 'Guilin Pharma', and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained <10% of the expected amount of active ingredient. CONCLUSIONS: An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999-2000. This is a serious threat to public health in the region.
Asunto(s)
Antimaláricos/provisión & distribución , Fraude/estadística & datos numéricos , Malaria/prevención & control , Automedicación/normas , Antimaláricos/química , Antimaláricos/normas , Artemisininas/análisis , Artemisininas/normas , Artesunato , Asia Sudoriental , Estudios Transversales , Etiquetado de Medicamentos/normas , Humanos , Mefloquina/análisis , Mefloquina/normas , Sesquiterpenos/análisis , Sesquiterpenos/normasRESUMEN
To study the influence of season on Plasmodium vivax gametocyte carriage, the relationship between monthly rainfall and the proportion of P. vivax patients with detectable gametocytaemia was analysed. Most of the data used came from 6807 aggregated observations collected, in a refugee camp on the Thai-Burmese border, between January 2000 and December 2002. There was a positive correlation between rainfall and the incidence of P. vivax infection (Spearman's rho=+0.42; P =0.01) but the prevalence of gametocyte carriage among those with P. vivax infection was negatively correlated with rainfall (Spearman's rho=-0.58; P <0.001). The latter, negative correlation remained significant after controlling for the proportion of visitors relative to camp residents (P =0.003). Migrations, changes in transmission patterns, seasonal haematological changes, and ultraviolet immunosuppression are discussed as potential explanations for these observations.
Asunto(s)
Malaria Vivax/transmisión , Estaciones del Año , Adolescente , Adulto , Distribución por Edad , Niño , Emigración e Inmigración , Humanos , Malaria Vivax/epidemiología , Prevalencia , Lluvia , Estudios Retrospectivos , Tailandia/epidemiologíaRESUMEN
Our previous study showed that in vitro susceptibility of Plasmodium vivax to chloroquine has significantly decreased in Thailand within the past two decades. Thus, the evaluation of alternative antimalarials for treatment of vivax malaria is needed. The aim of this study was to examine parasitological and clinical efficacy of an artemisinin derivative (artesunate) for the treatment of vivax malaria in patients who were admitted to the Bangkok Hospital for Tropical Diseases. We randomly allocated patients aged 12-56 years to receive 3.3mg/kg (adult dose 200 mg) on the first day, and for the next four days each patient was given 1.65 mg/kg orally (adult dose 100 mg), total dose = 600 mg. After the five-day course of artesunate, primaquine was given: a single oral dose of 15mg for 14 days. A total number of 42 patients received treatment. All participants were followed up for 28 days. In all the cases, both parasitemia and fever were resolved rapidly; the mean fever clearance time and parasite clearance time, 14.6 and 36.7 hours, respectively, showed that therapeutic response to artesunate was better than that of chloroquine. The 14-day cure rate was 100%, but reappearance of parasitemia was seen in two patients on days 21 and 25 following treatment, respectively. These two cases of failure rate should be considered as true relapse rather than recrudescence, since the relapse interval in Southeast Asian vivax malaria according to recent findings seems to be 3 weeks after start of treatment, if primaquine is not given or an inadequate amount is given. In conclusion, artesunate might be useful in treatment of vivax malaria, causing a good blood schizontocidal effect. However, to prevent emerging resistance it should never be used alone.
Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria Vivax/tratamiento farmacológico , Plasmodium vivax/efectos de los fármacos , Sesquiterpenos/uso terapéutico , Adolescente , Adulto , Animales , Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Artesunato , Niño , Cloroquina/farmacología , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Malaria Vivax/sangre , Masculino , Persona de Mediana Edad , Primaquina/uso terapéutico , Sesquiterpenos/administración & dosificación , Tailandia , Resultado del TratamientoRESUMEN
The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin (Twisinin, T-2 Program, Thailand) and 4 mg/kg body weight oral artesunate (AS; Guilin Pharmaceutical Works, Guangxi, China) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.h/ml, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) l/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) ml/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/ml was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.h/ml, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA.
Asunto(s)
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Sesquiterpenos/farmacocinética , Administración Oral , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/sangre , Área Bajo la Curva , Artemisininas/administración & dosificación , Artemisininas/sangre , Artesunato , Disponibilidad Biológica , Estudios Cruzados , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sesquiterpenos/administración & dosificación , Sesquiterpenos/sangre , TailandiaRESUMEN
The relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for > or = 28 days. All patients received a 7-day oral quinine regimen either alone (n = 22) or in combination with rifampin (n = 8). The median fever clearance time was 58.5 h, and the mean +/- standard deviation parasite clearance time was 73 +/- 24 h. After recovery, six patients had recrudescences of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 microg.day/ml had a relative risk of 5.3 (95% confidence interval = 1.6 to 17.7) of having a subsequent recrudescence of infection (P = 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 microg/ml and an MIC of 0.7 microg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).
Asunto(s)
Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Quinina/farmacocinética , Quinina/uso terapéutico , Adulto , Antibióticos Antituberculosos/uso terapéutico , Área Bajo la Curva , Quimioterapia Combinada , Semivida , Humanos , Malaria Falciparum/parasitología , Masculino , Estudios Prospectivos , Rifampin/uso terapéutico , Resultado del TratamientoRESUMEN
We examined a possible association of single-nucleotide polymorphisms (SNPs) in the promoters of IL-3, IL-4, and IL-13 genes on the 5q31-33, IL-3 -16T>C, IL-4 -590T>C, and IL-13 -1055C>T, with severity of malaria in 361 adult malaria patients in Thailand. The IL-13 -1055T allele showed a significant association with protection from severe malaria (OR 0.51, 95% CI 0.32-0.80; P=0.0032 by the chi(2) test), while allele frequencies of IL-3 -16T>C and IL-4 -590T>C were not statistically different between mild and severe malaria patients. An IL-13 -1055C>T has been reported to alter the regulation of IL-13 production. Thus, IL-13 -1055T may show resistance to severe malaria through the alteration of IL-13 production.
Asunto(s)
Interleucina-13/genética , Malaria Falciparum/prevención & control , Regiones Promotoras Genéticas , Adolescente , Adulto , Alelos , Sustitución de Aminoácidos , Animales , Frecuencia de los Genes , Humanos , Oportunidad Relativa , Plasmodium falciparum/patogenicidad , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Tailandia/epidemiologíaRESUMEN
In concurrent infections in vivo, the blood stages of Plasmodium vivax suppress those of Plasmodium falciparum. To see if the paroxysm (i.e. the periodic febrile episode) of P. vivax infection contributes to this suppression, sera from a P. vivax-infected volunteer were added to cultures of whole blood taken from cases of P. falciparum malaria. The crude 'rate' of schizont generation from the ring forms, measured as the percentage of all asexual parasites that were schizonts after incubation for 24 h, was similar whether the cultures contained serum samples collected during paroxysms or those collected, from the same volunteer, at other times (19.1% v. 18.9%; P=0.842). After a random-effect linear regression was used to adjust for disparities between the P. falciparum isolates, however, the degree of schizont maturation, measured as the mean number of nuclei per schizont, was significantly lower for the cultures with 'paroxysm serum' than for those with 'non-paroxysm serum' (4.8 v. 5.3; P=0.002). The proportion of schizonts considered mature was also significantly lower when 'paroxysm serum' was used (3.7% v. 6.3%: P=0.03). This appears to be the first in-vitro study in which sera collected during a paroxysm of P. vivax have been shown to inhibit the maturation of P. falciparum schizonts. The role of this mechanism in intra- and inter-specific competition is discussed.
Asunto(s)
Fiebre/parasitología , Malaria Vivax/sangre , Plasmodium falciparum/fisiología , Plasmodium vivax , Adolescente , Adulto , Animales , Femenino , Fiebre/sangre , Humanos , Modelos Lineales , Masculino , Parasitemia , Parasitología/métodosRESUMEN
Establishing the current status and distribution of soil-transmitted helminths is essential for developing and implementing parasite control. Although Southeast Asia is known to have a high prevalence of infection, a precise estimate of the total disease burden has not been fully described. Here, we use Geographical Information Systems (GIS) to collate and map recent published surveys on soil-transmitted helminth epidemiology and distribution for this region. Distinct geographical variation was observed, which is suggested to reflect climatic variation, as well as behavioral differences. However, for much of the region few data are available, and therefore it proved necessary to generate predictions of the distribution of soil-transmitted helminths using remotely sensed (RS) satellite sensor environmental variables. A significant finding was the importance of land surface temperature in influencing the distribution of Ascaris lumbricoides and Trichuris trichiura. Spatial analyses using RS satellite sensor data were then used to generate predictive maps of infection risk. This information provided the basis for an estimate of the population at risk of infection and the numbers requiring treatment. These applications of GIS and remote sensing provide a good basis for developing control of soil-transmitted helminths in the region.