Fiebre biliosa hemoglobinúrica como forma de presentación de la malaria aguda grave por Plasmodium falciparum / Hemoglobinuric bilious fever as a presentation of severe acute Plasmodium falciparum malaria

RESUMEN Introducción: La fiebre biliosa hemoglobinúrica es una de las complicaciones del paludismo grave, notificada con poca frecuencia, que se caracteriza por una hemólisis intravascular aguda en ocasiones masiva que conduce a hemoglobinuria y, finalmente, a una lesión renal aguda. Objetivo: Describir un caso de fiebre biliosa hemoglobinúrica como forma clínica de presentación de la malaria aguda grave. Caso clínico: Paciente masculino procedente de una zona endémica de paludismo con antecedentes de episodios recurrentes de malaria, quien, al tercer día de indicarle quimioprofilaxis antipalúdica con mefloquina, presentó un cuadro clínico de decaimiento, marcada astenia, fatiga, náuseas, vómitos, dolor abdominal difuso y emisión de orina oscura escasa, descritas por el paciente como "coca cola". Se diagnosticó fiebre biliosa hemoglobinúrica como forma clínica de presentación de una malaria aguda grave con baja parasitemia, constatado mediante examen de diagnóstico rápido y gota gruesa positivos a paludismo y hemoglobinuria masiva en el examen de orina con tira reactiva. La evolución del paciente fue favorable. Conclusiones: Este caso representa una forma no habitual de presentación de la enfermedad, que aunque no se sospecha usualmente, puede ocurrir. Este artículo es una alerta a los médicos que ejercen en áreas endémicas de malaria a permanecer atentos. Esta temible complicación puede ser la forma clínica de presentación de la malaria grave, particularmente en paciente expuestos crónicamente a infección por Plasmodium falciparum, que presenten una reacción hemolítica aguda masiva en ausencia de parasitemia elevada, cuando se administra quinina o mefloquina como tratamiento preventivo o curativo contra la malaria.

ABSTRACT Introduction: Hemoglobinuric bilious fever is one of the complications of severe malaria, infrequently notified, characterized by an acute intravascular hemolysis, massive in occasions, that leads to homoglobinuria and, finally to an acute renal lesion. Objective: To describe a case of hemoglobinuric bilious fever as clinical presentation of severe acute malaria. Clinical case: Male patient from a malaria-endemic area with a history of recurrent events of malaria, who, on the third day after receiving antimalarial chemoprophylaxis with mefloquine, presented with malaise, marked asthenia, fatigue, nausea, vomiting, diffuse abdominal pain, and scanty and dark urine emission, described by the patient as "Coca-Cola" like. Hemoglobinuric bilious fever was diagnosed as clinical presentation of severe acute malaria of low parasitemia, confirmed by malaria-positive quick diagnostic test and thick film, and massive homoglobinuria on urine dipstick test. Conclusions: This case represents an uncommon presentation of the disease, which is not usually suspected. This paper alerts physicians working in malaria-endemic areas to be attentive. This dread complication could be the clinical presentation of severe malaria, especially in patients chronically exposed to Plasmodium falciparum infection, who present with massive acute hemolytic reaction in the absence of high parasitemia when quinine or mefloquine is administered as preventive or curative treatment against malaria.

Alterações auditivas e vestibulares associadas ao uso da mefloquina: uma revisão integrativa / Auditory and vestibular changes associated with the use of mefloquine: an integrative review

RESUMO Objetivo descrever, por meio de revisão da literatura, alterações auditivas e/ou vestibulares relacionadas ao uso em curto ou em longo prazo da mefloquina. Estratégia de pesquisa trata-se de uma revisão integrativa, realizada nas seguintes bases de dados: PubMed, Web of Science, SciELO, LILACS, Scopus, ScienceDirect, Cochrane Library, Embase, OpenGrey, DissOnline e OAlster. Critérios de seleção foram incluídos estudos com participantes a partir de 18 anos de idade, que fizeram uso de mefloquina e que foram submetidos à avaliação auditiva e/ou questionário referente à função auditiva e vestibular. Foram excluídas revisões de literatura, capítulos de livros e estudos que utilizaram a mefloquina combinada a outros medicamentos. Resultados foram identificados 1.267 estudos nas bases de dados utilizadas, sendo selecionados 28 artigos para leitura completa. Destes, 12 foram incluídos na revisão, de acordo com os critérios de elegibilidade. Quatro artigos apontaram a presença de alterações vestibulares e auditivas, 2 indicaram apenas alterações auditivas e 6 apenas desordens vestibulares. No que se refere às manifestações auditivas, zumbido e perda auditiva foram os sintomas mais frequentes. Vertigem/tontura e desequilíbrio corresponderam às alterações vestibulares comumente apresentadas. Conclusão manifestações auditivas e vestibulares foram referidas em curto e longo prazo, após o tratamento com a droga. A descontinuação de seu uso possibilitou a reversão das manifestações, porém, em alguns casos, foi observada a permanência das afecções. Considera-se importante a realização de acompanhamento audiológico e vestibular durante a ingestão da mefloquina, visto o seu perfil de toxicidade e possíveis manifestações colaterais de caráter auditivo e vestibular.

ABSTRACT Objective To describe through a literature review auditory and/or vestibular alterations associated with the short or long-term use of mefloquine. Research strategy Integrative review performed on the following databases: Pubmed, Web of Science, Scielo, Lilacs, Scopus, Science Direct, Cochrane Library, Embase, Open Grey, DissOnline, OAlster. Selection Criteria The articles selected included studies with participants that were 18 years old or over, who used mefloquine and who were submitted to an auditory evaluation and/or a questionnaire regarding auditory and vestibular function. Literature reviews, book chapters, and studies using mefloquine associated with other drugs were excluded. Results 1,267 studies were identified in the databases used, 28 articles were selected for full reading, and out of these, twelve were included in the review according to the eligibility criteria. Four articles pointed out the presence of vestibular and auditory diseases, two indicated only auditory disorders, and six solely vestibular disorders. Regarding auditory manifestations, tinnitus and hearing loss (HL) were the most frequent symptoms. Vertigo/dizziness and imbalance matched to the vestibular changes were commonly observed. Conclusion Auditory and vestibular manifestations were referred to in the short and long-term after treatment with the drug. The discontinuation of its use made it possible to reverse the manifestations; however, in some cases, the permanence of the disorders was reported. Audiological and vestibular follow-up during mefloquine use is considered important, given its toxicity profile and possible side manifestations of an auditory and vestibular nature.

Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus (2019-nCoV) related coronavirus model / 中华医学杂志(英文版)

Background@#Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those without such facilities or 2019-novel coronavirus (2019-nCoV). This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV related coronavirus model.@*Methods@#A 2019-nCoV related pangolin coronavirus GX_P2V/pangolin/2017/ Guangxi was described. Whether GX_P2X uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA) -mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2X infection. The antiviral activities and antiviral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively.@*Results@#The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs-cepharanthine (CEP), selamectin and mefloquine hydrochloride exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48±0.02]×10-4 vs. 1.00±0.12, t=150.38, P<0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP has potent antiviral activities against both viral entry (1.00±0.37 vs. 0.46±0.12, t=2.42, P<0.05) and viral replication (1.00±0.43 vs. [6.18±0.95]×10-4, t=3.98, P<0.05).@*Conclusions@#Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and clinical trial of CEP for treatment of 2019-nCoV infection is warranted.

Adherence to malaria prophylaxis among travelers from a middle-income country

Abstract INTRODUCTION: Malaria is the main cause of death by infection among travelers and is preventable through a combination of chemoprophylaxis and personal protective measures. METHODS: Travelers were interviewed by phone 28-90 days after returning, to assess adherence to pre-travel advice for malaria prevention. RESULTS: A total 57 travelers were included. Adherence to chemoprophylaxis was significantly higher among participants prescribed mefloquine (n=18; 75%) than doxycycline (n=14; 45%). Adherence to mosquito repellent and bed net use was 65% and 67%, respectively. CONCLUSIONS: Adherence to malaria prophylaxis was lower than expected. Further studies testing innovative approaches to motivate travelers' compliance are required.

Patient age does not affect mefloquine concentrations in erythrocytes and plasma during the acute phase of falciparum malaria

Abstract Objective To evaluate whether patient age has a significant impact on mefloquine concentrations in the plasma and erythrocytes over the course of treatment for uncomplicated falciparum malaria. Methods A total of 20 children aged between 8 and 11 years and 20 adult males aged between 22 and 41 years with uncomplicated falciparum malaria were enrolled in the study. Mefloquine was administered to patients in both age groups at a dose of 20 mg kg−1. The steady-state drug concentrations were measured by reversed-phase high performance liquid chromatography. Results All patients had an undetectable mefloquine concentration on day 0. In adults, the plasma mefloquine concentrations ranged from 770 to 2930 ng mL−1 and the erythrocyte concentrations ranged from 2000 to 6030 ng mL−1. In children, plasma mefloquine concentrations ranged from 881 to 3300 ng mL−1 and erythrocyte concentrations ranged from 3000 to 4920 ng mL−1. There was no significant correlation between mefloquine concentrations in the plasma and erythrocytes in either adults or children. Conclusion In the present study, we observed no effect of patient age on the steady-state concentrations of mefloquine in the plasma and erythrocytes. We found that the mefloquine concentration in the erythrocytes was approximately 2.8-times higher than in the plasma. There were no significant correlations between mefloquine concentrations in the erythrocytes and plasma for either age group.

Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells

Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.

Effect of Mefloquine, a Gap Junction Blocker, on Circadian Period2 Gene Oscillation in the Mouse Suprachiasmatic Nucleus Ex Vivo

BACKGROUND: In mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions. METHODS: We examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2) gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC) knock-in mice using a real-time bioluminescence measurement system. RESULTS: Administration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms. CONCLUSION: These findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock.

Partial characterization of Plasmodium falciparum trophozoite proteome under treatment with quinine, mefloquine and the natural antiplasmodial diosgenone / Caracterización parcial del proteoma del trofozoíto de Plasmodium falciparum bajo tratamiento con quinina, mefloquina y el compuesto natural diosgenona

Introduction: Despite efforts to control malaria, around 10% of the world population is at risk of acquiring this disease. Plasmodium falciparum accounts for the majority of severe cases and deaths. Malaria control programs have failed due to the therapeutic failure of first-line antimalarials and to parasite resistance. Thus, new and better therapeutic alternatives are required. Proteomic analysis allows determination of protein expression levels under drug pressure, leading to the identification of new therapeutic drug targets and their mechanisms of action. Objective: The aim of this study was to analyze qualitatively the expression of P.falciparum trophozoite proteins (strain ITG2), after exposure to antimalarial drugs, through a proteomic approach. Materials and methods: In vitro cultured synchronized parasites were treated with quinine, mefloquine and the natural antiplasmodial diosgenone. Protein extracts were prepared and analyzed by two-dimensional electrophoresis. The differentially expressed proteins were selected and identified by MALDI-TOF mass spectrometry. Results: The following proteins were identified among those differentially expressed in the parasite in the presence of the drugs tested: enolase (PF10_0155), calcium-binding protein (PF11_0098), chaperonin (PFL0740c), the host cell invasion protein (PF10_0268) and proteins related to redox processes (MAL8P1.17). These findings are consistent with results of previous studies where the parasite was submitted to pressure with other antimalarial drugs. Conclusion: The observed changes in the P. falciparum trophozoite protein profile induced by antimalarial drugs involved proteins mainly related to the general stress response.

Introducción. A pesar de los esfuerzos para controlar la malaria, esta sigue siendo un problema de salud pública. Plasmodium falciparum es responsable de la mayoría de los casos graves y de las muertes. Los programas de control de la malaria han sido cuestionados debido al fracaso del tratamiento y a la resistencia del parásito a los antipalúdicos de primera línea, por lo que se requieren nuevas y mejores alternativas. El análisis proteómico permite identificar y determinar los niveles de expresión de las proteínas bajo la presión de los medicamentos, lo que posibilita la identificación de nuevos blancos terapéuticos y mecanismos de acción. Objetivo. Analizar cualitativamente la expresión diferencial de proteínas del citosol del trofozoíto de P. falciparum bajo tratamiento con quinina, mefloquina y el compuesto natural diosgenona mediante una aproximación proteómica. Materiales y métodos. Se trataron trofozoítos sincronizados y cultivados in vitro de P. falciparum (cepa ITG2) con quinina, mefloquina y el compuesto natural diosgenona. Los extractos proteicos se prepararon y analizaron por electroforesis bidimensional. Las proteínas con aparente expresión diferencial se seleccionaron e identificaron mediante espectrometría de masas MALDI-TOF. Resultados. Se encontraron las siguientes proteínas diferencialmente expresadas en el trofozoíto: la enolasa (PF10_0155), la proteína de unión a calcio (PF11_0098), la chaperonina (PFL0740c), la proteína de invasión a la célula del huésped (PF10_0268) y la proteína relacionada con procesos de reducción y oxidación (redox) (MAL8P1.17). Estos hallazgos son congruentes con resultados previos de estudios en los que el parásito fue presionado con otros medicamentos antipalúdicos. Conclusión. Los cambios observados en el perfil de proteínas del trofozoíto de P. falciparum tratado con antipalúdicos involucraron preferencialmente proteínas relacionadas con la respuesta al estrés general.

Eficacia terapéutica y eventos adversos de tratamientos para malaria vivax y malaria falciparum en gestantes en las regiones de Urabá y Alto San Jorge, Colombia, 2008-2011 / Therapeutic efficacy and adverse events of treatments for vivax and falciparum malaria in pregnant women in the regions of Uraba and Alto San Jorge, Colombia, 2008-2011

Objetivo: evaluar, con el protocolo de la Organización Mundial de la Salud (OMS) de 1998, la respuesta terapéutica antimalárica (RTA) y los eventos adversos (EA) en cuatro esquemas de tratamiento antiplasmodial en gestantes colombianas, con diagnóstico de malaria no complicada por P. vivax o por P. falciparum, según gota gruesa.Materiales y métodos: experimento controlado aleatorizado en paralelo. Se calculó un tamaño muestral de 60 pacientes con P. vivax y 30 con P. falciparum. Se evaluaron cuatro tratamientos: malaria vivax en cualquier trimestre de gestación tratada con cloroquina o con amodiaquina; malaria falciparum en trimestres 2 y 3, terapia tratada con artesunato-mefloquina o arteméter-lumefantrina. Se hizo seguimiento por 28 días. Se midió la proporción de falla terapéutica y de eventos adversos. Los grupos se comparan mediante análisis univariado. El protocolo del estudio fue registrado en el sitio: ClinicalTrials. gov bajo el registro: MGP-02. Resultados: se trataron 90 pacientes. La RTA fue adecuada en 97-100% de los casos de malaria vivax (variación del método de análisis) y en 100% de los casos con malaria falciparum. Los EA más comunes fueron dolor epigástrico, mareo, tinitus y visión borrosa. No hubo eventos adversos graves.Conclusiones: la cloroquina y la amodiaquina tienen igual respuesta terapéutica adecuada. Las combinaciones artesunato-mefloquina y arteméterlumefantrina no mostraron fallas terapéuticas. Se requieren estudios en otros lugares del país con los esquemas evaluados y con otros.

Objective: To assess, using the 1998 WHO protocol, adequate clinical and parasitological response (ACPR) and adverse events (AEs) to 4 antiplasmodial treatment regimens in pregnant Colombian women diagnosed with uncomplicated P. vivax or P. falciparum malaria on the basis of thick blood smear.Materials and methods: Parallel randomized controlled trial. The estimated sample size was 60 patients with P. vivax and 30 with P. falciparum. Four treatments were assessed: vivax malaria in any trimester treated with chloroquine or amodiaquine; falciparum malaria in second and third trimesters treated with artesunate-mefloquine or artemether-lumefantrine. Patients were followed for 28 days. Measurements included the proportion of therapeutic failures and of adverse events. Groups were compared using univariate analysis. The study protocol was registered in ClinicalTrials.gov under the Protocol Record MGP-02. Results: Overall, 90 patients were treated. ACPR was adequate in 97-100% of vivax cases (analytical method variation) and in 100% of falciparum cases. The most common AEs were epigastric pain, dizziness, tinnitus and blurred vision. There were no serious adverse events. Conclusions: Both chloroquine as well as amodiquine have similar adequate responses. No therapeutic failures were found for the combinations of artesunate-mefloquine and artemether-lumefantrine. Studies need to be done in other places of the country using the regimens assessed as well as others.

A Case of Mefloquine-Induced Psychosis / 대한정신약물학회지

Mefloquine is a common anti-malarial agent used for the treatment and prophylaxis of malaria. Here we report a case of a 39-year-old, otherwise healthy woman from South Korea, who had developed visual and auditory hallucination with sleep disturbance after oral administration of mefloquine before traveling to an endemic region. To our knowledge, this would be the first reported case of mefloquine-induced psychosis in South Korea to date. This report underlines the importance of awareness and detection of neuropsychiatric side effects of mefloquine.

Development and validation of an HPLC method for the simultaneous determination of artesunate and mefloquine hydrochloride in fixed-dose combination tablets

The present study developed and validated an HPLC method for the simultaneous determination of artesunate (AS) and mefloquine hydrochloride (MQ) in fixed-dose combination tablets, according to ICH guidelines. The chromatographic separation was carried out on an XBridge C18 (250 x 4.6 mm i.d., 5 µm particle size, Waters) analytical column. The mobile phase included a 0.05 M monobasic potassium phosphate buffer (pH adjusted to 3.0 with phosphoric acid) and acetonitrile (50 + 50, v/v). The flow rate was 1.0 mL/min, and the run time was 13 minutes. A dual-wavelength approach was employed: AS detection was performed at 210 nm and MQ was detected at 283 nm, using a diode array detector. Stability of sample solutions was evaluated for 8 hours after preparation, during which time the solutions remained stable. Youden's test was employed to evaluate robustness. The method proved to be linear (r²>0.99), precise (RSD<2.0%), accurate, selective, and robust, proving to be appropriate for routine drug quality control analysis.

Um método por cromatografia a líquido de alta eficiência para a determinação simultânea de artesunato (AS) e cloridrato de mefloquina (MQ) em comprimidos em dose fixa combinada foi desenvolvido e validado, de acordo com as normas do ICH. A separação cromatográfica foi realizada com uma coluna analítica XBridge C18 (250 x 4,6 mm d.i., partículas de 5 µm, Waters). A fase móvel foi constituída de tampão fosfato monobásico de potássio 0,05 M (pH ajustado para 3,0 com ácido fosfórico) e acetonitrila (50 + 50, v/v). O fluxo da fase móvel foi de 1,0 mL/min e o tempo de corrida foi de 13 minutos. Utilizaram-se dois comprimentos de onda: a detecção do AS foi realizada em 210 nm e a de MQ foi realizada em 283 nm, utilizando-se um detector de arranjo de diodos. A estabilidade das soluções padrão e amostra foi avaliada por 8 horas após sua preparação e as soluções permaneceram estáveis nesse período. O teste de Youden foi empregado para a avaliação da robustez do método. O método se mostrou linear (r²>0,99), preciso (DPR<2,0%), exato, seletivo e robusto, sendo adequado para análises rotineiras de controle de qualidade dos medicamentos.

Pharmacodynamics of mefloquine and praziquantel combination therapy in mice harbouring juvenile and adult Schistosoma mansoni

Praziquantel (PZQ) is currently the only drug widely used for the treatment of schistosomiasis, but the antimalarial drug mefloquine (Mef) possesses interesting antischistosomal properties. Combination therapy with these two drugs has been suggested as a strategy for transmission control, as PZQ is active against adult worms and Mef is active against schistosomula. To examine the efficacy of combination therapy, Schistosoma mansoni-reinfected mice were separated into seven groups: untreated (I), treated with PZQ in doses of 200 mg/kg (II) or 1,000 mg/kg (III), treated with Mef in doses of 200 mg/kg (IV) or 400 mg/kg (V); each dose was divided equally and given on two consecutive days. Group VI was treated with doses of PZQ + Mef as in groups II and IV, respectively, while group VII was treated with PZQ + Mef as in groups III and V, respectively. PZQ + Mef at the reduced doses of 200 mg/kg each enhanced the therapeutic efficacy over the reduced PZQ dose alone as shown by a very high reduction in the total numbers of mature worms (95 percent vs. 49 percent), immature worms (96 percent vs. 29 percent) and the complete eradication of immature females, mature females and immature eggs. The reduction in worm burden was associated with the healing of hepatic granulomatous lesions and the normalisation of all liver enzymes. Therefore, the use of Mef with PZQ is more effective than PZQ alone and should be considered for clinical trials in humans as a potential treatment regimen to prevent treatment failures in areas with high rates of schistosomiasis.

Efficacy of a 3-day artesunate-mefloquine combination in the treatment of uncomplicated falciparum malaria in Kanchanaburi province of Thailand

Background: In Kanchanaburi province located on the Thai-Myanmar border, Plasmodium falciparum parasites have developed significant resistance to commonly-used anti-malarials. For use against falciparum malaria, 2-day artesunate-mefloquine combination (MAS2) has recently been replaced by a 3-day artesunate-mefloquine combination (MAS3) that is an artemisinin-based combination therapy regimen recommended by the WHO. Objective: Investigate the efficacy and safety of MAS3 in the treatment of uncomplicated falciparum malaria in patients of Kanchaburi province. Methods: The study was conducted at Bongtee sub-district, Sai Yok district, Kanchanaburi province between June and November 2009. Fifty-one uncomplicated falciparum malaria patients were enrolled. Inclusion, exclusion and study method followed the WHO protocol for assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Patients received a MAS3 and were followed for 42 days. Results: All patients clinically recovered, but four patients were again parasitaemic on day 21, (1 patient) 28 (2 patients) and 42 (1 patient), respectively. Molecular analyses suggested that all recurrences were caused by recrudescence. There were no severe adverse events, but complaints of headache, gastrointestinal upset, nausea, and vomiting. Delay in parasite clearance was found. Proportion of parasite clearance on day 1, 2, 3 and 7 were 17.7%, 62.7%, 80.4%, and 100%, respectively. Conclusion: MAS3 is comparable to MAS2, and meet the WHO efficacy criteria for use against falciparum malaria, but the effect on parasite clearance was inferior to that of MAS2. Close monitoring evaluation is required.

Mefloquine chemoprophylaxis against malaria in Japanese travelers: results of a study on adverse effects

Although Mefloquine is commonly used as a prophylactic drug for travelers to malaria endemic areas, there are only limited reports about its adverse effects in Japanese travelers. We carried out a prospective observation study of 107 travelers who were prescribed mefloquine as chemoprophylaxis against malaria prior to their departure from November 2004 to October 2006. We carefully sought the appropriate prescription for each client according to the guidelines for Japanese overseas travelers. The clients consisted of 71 men and 36 women of whom we were able to follow 65 travelers until the end of their prophylactic procedure. Of the 65, 47 travelers completed their full course of chemoprophylaxis. Different adverse effects were reported in 19 travelers of them such as fatigue (n=9), dizziness (n=6), headache (n=3), nausea (n=3), drowsiness (n=2), strange dreams (n=2), anxiety (n=2), fever (n=1) and skin rash (n=1). Three travelers were incapable of continuing chemoprophylaxis due to the adverse effects, but no serious events were noted. Through our study, mefloquine chemoprophylaxis seemed tolerable for Japanese travelers. We believe that our detailed consultation and careful monitoring reduced the incidence of severe adverse effects and maintained the high rate of adherence to chemoprophylaxis.

In vitro effect of current antimalarial drugs on the survival of paired Schistosoma mansoni adult worms and their egg production

Some field trials have already demonstrated the high antischistosomal potential of combination therapies using Artesunate (ART) and current antimalarial drugs (Boulanger <I>et al.,</I> 2007; Mohamed <I>et al.,</I> 2009; Sissoko <I>et al.,</I> 2009). The antischistosomal effects of these drugs are noteworthy, especially when they are used for the treatment of malaria in schistosomiasis endemic areas. However, the antischistosomal effects of Amodiaquine (AQ), Primaquine (PQ), Chloroquine (CQ) and Pyrimethamine (Py) have never been assessed by <I>in vitro</I> incubation. The objective of the present study is to assess the <I>in vitro</I> effects of current antimalarial drugs on the egg productivity of adult worm pairs of <I>S. mansoni</I> and their survival times. The effect of the current antimalarial drugs Mefloquine (MQ), quinine (QN), AQ, PQ, CQ, Sulfadiazine (Sf) and Py on the egg output of adult worm pairs of <I>Schistosoma mansoni</I> and their survival times during <I>in vitro</I> culture were assessed at a concentration of 10 Μg⁄ml. AQ, PQ, CQ and Py significantly inhibited the daily egg output of paired female worms at a concentration of 10 Μg⁄ml during the 1 or 2-day <I>in vitro</I> cultivation. However, QN and Sf did not significantly affect the daily egg output during the 8-day incubation. One-day exposure to MQ killed all paired male and female adult worms. AQ and PQ significantly decreased the survival of both paired male and female worms during the 14-day incubation, but QN, CQ, Py and Sf did not exert any similar effect. The present result is consistent with an assessment of the antischistosomal effects of artemisinin-based combination therapy in malaria and schistosomiasis co-endemic areas.

Respuesta terapéutica a mefloquina, estado nutricional y variantes alélicas del gen CYP3A4 en pacientes con malaria falciparum no complicada; Antioquia (Colombia) / Malaria: efficacy of mefloquine according to nutritional status and alellic variations of the CYP3A4 gen

Introducción: hay poca información sobre las relaciones entre la falla de la terapia antimalárica y algunos factores del hospedero (estado nutricional, fenotipo y genotipo del citocromo CYP450 que metaboliza el medicamento antipalúdico). Objetivo: explorar si la falla terapéutica de la mefloquina dada a pacientes con malaria falciparum no complicada se puede explicar por la influencia del estado nutricional del enfermo y del fenotipo y genotipo de su citocromo CYP3A4. Materiales y métodos: estudio de casos y controles no pareado. Pacientes: hombres y mujeres adultos, de Turbo y El Bagre (Antioquia, Colombia). Resultados: se evaluó la respuesta terapéutica en 46 enfermos; hubo solo tres fallas (6,5%); por la muy baja ocurrencia de falla terapéutica (n = 3/46), los resultados se presentan en forma descriptiva para los 46 pacientes. La relación dextrometorfano/3-metoximorfinano fue 0,39 (mediana); 20% fueron metabolizadores lentos. Las concentraciones sanguíneas medianas de mefloquina a las 24 horas (C24h) y al día 14 (Cd14) fueron 1.363 + 397 ng/mL y 978 + 106 ng/mL, respectivamente. Los 46 pacientes presentaron el alelo CYP3A4*2 (silvestre). Conclusión: no se pudo evaluar con profundidad la relación entre la respuesta a la terapia antimalárica, por una parte y, por otra, la actividad del CYP450 y el estado nutricional, pero hubo hallazgos que justifican la evaluación y control de las características del hospedero en estudios posteriores de farmacocinética antimalárica.

Introduction: Information on the relationship between treatment failure in malaria and factors of the host (nutritional status, phenotype and genotype of cytochrome CYP450) involved in the metabolism of antimalarials is scarce. Objective: To explore whether treatment failure of mefloquine administered to patients with noncomplicated falciparum malaria can be explained in terms of the patient’s nutritional status and the CYP3A4 phenotype and genotype. Materials and methods: Non-matched case-control study. Patients were adult males and females, inhabitants of Turbo and El Bagre (Antioquia, Colombia). Results: The therapeutic response was assessed in 46 patients, and there were only three failures (6.5%); due to the rare occurrence of therapeutic failure (n = 3/46), results are presented in a descriptive way for the 46 patients. The dextrometorphan/3-methoxymorphinan ratio was 0.39 (median); 20% of the patients were slow metabolizers. The blood concentrations of mefloquine at 24 hours (C24h) and at day 14 (Cd14) were (median) 1.363 ± 397 ng/mL and 978 ± 106 ng/mL, respectively. All 46 patients had the wild CYP3A4*2 allele. Conclusion: We were unable to assess in depth the relationship between the response to mefloquine, on the one hand and, on the other, CYP450 activity and nutritional status. However, there were findings that justify the assessment and control of the characteristics of the host in subsequent studies of antimalarial pharmacokinetics.

Imported Malaria in Korea: a 13-Year Experience in a Single Center

The incidence of imported malaria has been increasing in Korea. We reviewed data retrospectively to evaluate the epidemiology, clinical features, and outcomes of imported malaria from 1995 to 2007 in a university hospital. All patients diagnosed with imported malaria were included. Imported malaria was defined as a positive smear for malaria that was acquired in a foreign country. A total of 49 patients (mean age, 35.7 year; M : F = 38 : 11) were enrolled. The predominant malarial species was Plasmodium falciparum (73.5%), and the most frequent area of acquisition was Africa (55.1%), followed by Southeast Asia (22.4%) and South Asia (18.4%). Fourteen-patients (30.6%) suffered from severe malaria caused by P. falciparum and 1 patient (2.0%) died of multiorgan failure. Most of the patients were treated with mefloquine (79.2%) or quinine (10.2%); other antimalarial agents had to be given in 13.2% treated with mefloquine and 44.4% with quinine due to adverse drug events (ADEs). P. falciparum was the most common cause of imported malaria, with the majority of cases acquired from Africa, and a significant number of patients had severe malaria. Alternative antimalarial agents with lower rates of ADEs might be considered for effective treatment instead of mefloquine and quinine.

Malaria y embarazo: un caso importado de África / Malaria and pregnancy: an imported case from Africa

La malaria es un importante problema de saluden el mundo y es la principal causa de enfermedad ymuerte en muchas zonas tropicales y subtropicales, principalmente en África subsahariana donde las infecciones por Plasmodium falciparum son las másfrecuentes, situación particularmente importante, porque esta especie puede provocar malariagrave e incluso la muerte. Según la OrganizaciónMundial de la Salud se presentan entre 350 a 500millones de casos por año, la gran mayoría enÁfrica subsahariana, donde se registran el 60...

A Clinical Study of Adverse Reactions after Taking Mefloquine / 감염과화학요법

BACKGROUND: Mefloquine is widely used for a chemoprophylactic agent against malaria, however, there is a tendency to avoid mefloquine as preventive medicine due to its side effects. Therefore, we carried out this study to provide travelers with safety information regarding consumption of mefloquine through a prospective research for adverse reactions. MATERIALS AND METHODS: The study had been estimated for the relationship between administration of mefloquine and symptoms of which person had been prescribed of mefloquine at the International Clinic of National Medical Center from May 1, 2006 to October 30, 2006 by phone interviews every three days prior to departure and 4 times every week following a return from the travel. RESULTS: Adverse reactions had been reported in 73 (18.6%) persons among 393 travelers who had taken mefloquine with the figure of 38 (52.1%) males, 35 (47.9%) females and 98 (24.9%) occurrences of adverse reactions. The most common adverse reaction was febrile sensation. Most (96%) of adverse reactions had been detected in 3 weeks after being taken mefloquine and there was no difference between sex and age. Most of travelers who had complained the symptoms got better spontaneously or through the symptomatic treatment. Some travelers had taken other medicines and had gotten several vaccinations concurrently. Only 3 cases that took medicine for hypothyroidism were related to adverse reactions of mefloquine (P<0.05). CONCLUSION: There were adverse reactions which were reported in 18.6% of travelers after taking mefloquine and malraria hasn't occurred. So mefloquine is considered as a primary preventive agent against malaria.