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.

Chloroquine and mefloquine resistance profiles are not related to the circumsporozoite protein (CSP) VK210 subtypes in field isolates of Plasmodium vivax from Manaus, Brazilian Amazon

BACKGROUND The central repetitive region (CRR) of the Plasmodium vivax circumsporozoite surface protein (CSP) is composed of a repetitive sequence that is characterised by three variants: VK210, VK247 and P. vivax-like. The most important challenge in the treatment of P. vivax infection is the possibility of differential response based on the parasite genotype. OBJECTIVES To characterise the CSP variants in P. vivax isolates from individuals residing in a malaria-endemic region in Brazil and to profile these variants based on sensitivity to chloroquine and mefloquine. METHODS The CSP variants were determined by sequencing and the sensitivity of the P. vivax isolates to chloroquine and mefloquine was determined by Deli-test. FINDINGS Although five different allele sizes were amplified, the sequencing results showed that all of the isolates belonged to the VK210 variant. However, we observed substantial genetic diversity in the CRR, resulting in the identification of 10 different VK210 subtypes. The frequency of isolates that were resistant to chloroquine and mefloquine was 11.8 and 23.8%, respectively. However, we did not observe any difference in the frequency of the resistant isolates belonging to the VK210 subtypes. MAIN CONCLUSION The VK210 variant is the most frequently observed in the studied region and there is significant genetic variability in the CRR of the P. vivax CSP. Moreover, the antimalarial drug sensitivity profiles of the isolates does not seem to be related to the VK210 subtypes.

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.

Malaria por Plasmodium vivax y falla al tratamiento radical / Failure to radical cure in Plasmodium vivax malaria

Relapsing Plasmodium vivax malaria is due to activation of dormant intrahepatic parasitic forms known as hypnozoits. Primaquine is the only available drug effective against hypnozoits and, alongside a schizonticidal drug, constitutes the radical treatment of malaria. Failure of radical treatment is frequently attributed to inadequate dosing, poor adherence, or reinfection. However, several cases of radical treatment failure without these factors have been reported, inferring that metabolic properties of the host or tolerance mechanisms of the parasite may be implied. A case of malaria due to Plasmodium vivax acquired in the Amazonic region, treated outside endemic area, with multiple relapses despite adequate radical treatment is described.

La infección por Plasmodium vivax se caracteriza por la formación de hipnozoítos que permanecen quiescentes en los hepatocitos del hospedero y son responsables de las recaídas de la malaria. Primaquina es el único fármaco en uso para la erradicación de los hipnozoítos y asociado a un agente esquizonticida, constituye el tratamiento radical. Las fallas al tratamiento radical están relacionados con una dosificación subóptima, adherencia inadecuada y reinfección. Sin embargo, cuando estos factores están ausentes, se han postulado mecanismos propios del metabolismo del hospedero y de tolerancia del parásito. Se describe un caso de malaria por P. vivax adquirido en la región amazónica asistido fuera de la zona endémica, con múltiples recaídas a pesar del tratamiento radical adecuado.

Highly active ozonides selected against drug resistant malaria

Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.

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.

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.

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.

A Case of Mixed Malaria Infection with Severe Hemolytic Anemia after Travel to Angola / 감염과화학요법

In Korea, Plasmodium vivax (P. vivax) is the most common agent of malaria infection. However, as travel to regions where malaria is endemic increases, so do the numbers of Plasmodium falciparum and mixed infections. P. falciparum predominates, while P. vivax is rare in west-central Africa. We report on a case of mixed malaria infection with severe hemolytic anemia caused by P. falciparum and P. vivax in a 38-year-old man after traveling to Angola. A diagnosis of P. falciparum malaria was made by microscopic examination. However, both P. vivax and P. falciparum were detected by the polymerase chain reaction (PCR). As a radical cure P. vivax, the patient was treated with mefloquine, artemether, and primaquine. Both P. falciparum and P. vivax had disappeared from peripheral blood by admission day 4, however, low grade fever and headache persisted, and his hemoglobin and hematocrit levels were depleted. A peripheral blood smear was negative for both P. vivax and P. falciparum; however, a direct anti-globulin test and anti-nuclear antibody test were positive, suggesting immune hemolytic anemia. After conservative treatment, which included a transfusion with packed red blood cells (RBC), his symptoms and signs showed improvement and laboratory findings were normalized.

A Case of Imported Plasmodium malariae Malaria

Malaria, the most common vector-borne parasite infection worldwide, results from infection by Plasmodium species. Approximately 80% of malaria cases are caused by P. vivax, which is broadly distributed from tropical to temperate regions; P. falciparum is the second most common infectious species. P. malariae and P. ovale are responsible for a relatively small proportion of malaria cases. Here, we report the case of a 23-yr-old Korean woman who acquired a P. malariae infection while visiting the Republic of Ghana in West Africa for business. She was diagnosed with P. malariae malaria on the basis of peripheral blood smear (PBS) and species-specific conventional and real-time PCR assays for 18S rRNA. She was treated with hydroxychloroquine, and the resulting PBS examination on day 2 suggested that negative conversion occurred. At her 1-month follow-up, however, both the PBS examination and molecular test for malaria demonstrated recurrent parasitemia. We started rescue therapy with mefloquine, and the patient recovered successfully. This is an important finding suggesting possible late recrudescence of a chloroquine-resistant P. malariae strain identified not only by its morphological features, but also by molecular tests.

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.

Quality of essential drugs in tropical countries: evaluation of antimalarial drugs in the Brazilian Health System / Qualidade de medicamentos essenciais em países tropicais: avaliação de medicamentos antimaláricos no Sistema de Saúde do Brasil

INTRODUCTION: The emergence of drug resistance is one of the main problems concerning malaria treatment. The use of counterfeit and/or substandard antimalarial drugs can contribute to the development of parasite resistance. Thus, the aim of this study was to evaluate the quality of antimalarial drugs distributed in Brazil. METHODS: Samples containing chloroquine phosphate, mefloquine hydrochloride, primaquine phosphate, and quinine sulfate tablets were delivered to the Rio de Janeiro central storeroom (CENADI), state storerooms (SS), and Basic Health Units (BHUs) in the north region of Brazil - a total of 10 sample sets. After 5 months of storage, the samples were collected, and in vitro quality control analyses according to official and published methods were performed. RESULTS: Inadequate drug storage conditions were found in two SS and in all BHUs evaluated. There were no quality deviations found in the chloroquine samples. The quinine samples exhibited weight variation above the allowed limits. The primaquine samples were found to have packaging deficiency. The release of mefloquine in samples from some regions showed a statistically significant difference when compared with the CENADI samples. CONCLUSIONS: It is important to periodically evaluate the quality and storage conditions of essential drugs. The quality deviations found with the primaquine and quinine samples are not related to storage conditions and must be addressed urgently. The decreased mefloquine release from tablets is related to formulation problems or influenced by inadequate storage conditions, prompting further investigation. Even with the mentioned problems, the samples would probably not contribute to resistant parasite selection.

INTRODUÇÃO: O aparecimento de resistência aos medicamentos é um dos maiores problemas do tratamento da malária. O uso de medicamentos falsos e/ou de má qualidade pode contribuir para o desenvolvimento de resistência no parasita. Este estudo tem por objetivo avaliar a qualidade dos medicamentos antimaláricos distribuídos no Brasil. MÉTODOS: Amostras contendo comprimidos de difosfato de cloroquina, cloridrato de mefloquina, difosfato de primaquina e sulfato de quinina foram enviadas ao almoxarifado central na Cidade do Rio de Janeiro (CENADI), almoxarifados estaduais (SS) e Unidades Básicas de Saúde (UBS) nos estados da região norte do Brasil, totalizando dez amostras. Após cinco meses de armazenamento, as amostras foram coletadas e analisadas segundo métodos oficiais e da literatura. RESULTADOS: Foram encontradas condições inadequadas de armazenamento de medicamentos em duas SS e em todas as UBS avaliadas. Não foram encontrados problemas de qualidade com as amostras de cloroquina. As amostras de quinina apresentaram variação de peso acima dos limites permitidos. Amostras de primaquina foram encontradas com problemas na embalagem. A cedência de mefloquina de comprimidos, em algumas regiões, apresentou diferença estatisticamente significativa quando comparada com a amostra do CENADI. CONCLUSÕES: É importante avaliar, periodicamente, a qualidade e as condições de armazenamento de medicamentos essenciais. Desvios de qualidade encontrados com as amostras de primaquina e quinina não estão relacionados às condições de armazenamento e devem ser corrigidos urgentemente. O decréscimo na cedência de mefloquina dos comprimidos está relacionado com a formulação ou foi influenciada por condições de armazenamento inadequadas, necessitando de uma investigação posterior. Apesar dos problemas mencionados, as amostras provavelmente não contribuiriam para a seleção de parasitas resistentes.

Case of Malarial Hepatitis by Plasmodium Vivax / 대한소화기학회지

Malarial infection is one of the most important tropical diseases, but also increasing in the temperate regions. Severe malaria with organ dysfunction is commonly associated with Plasmodium falciparum, but rarely with Plasmodium vivax. Malarial hepatitis is also unusual in P. falciparum and very rare in P. vivax. Only 3 cases of malarial hepatitis caused by P. vivax have been reported in the world. Because the presence of hepatitis in malaria indicates a more severe illness with higher incidence of other complications and poor prognosis, malarial patients should be meticulously monitored for hepatic dysfunction with or without jaundice. We report here a case of malarial hepatitis caused by P. vivax that was presented by fever, general ache, nausea, fatigue, and significant elevation of aminotransferase and bilirubin.

Analysis of the direct and indirect costs of treatment of imported malaria in the Slovak Republic / Análise dos custos diretos e indiretos do tratamento da malária importada na República Eslovaca

This study analyzed the approximate cost of treatment of patients hospitalized with a diagnosis of imported malaria in Slovakia. Between 2003 and 2007, 15 patients with imported malaria were hospitalized. The mean direct cost of the treatment was 970.75 euros and the mean indirect cost was 53.15 euros. For the patient with the highest cost of treatment, the use of mefloquine prophylaxis would have represented only 0.5 percent of the total direct cost of treating the disease. Despite the partial resistance of plasmodia, malaria chemoprophylaxis is unequivocally a cheaper choice than subsequent treatment of malaria.

Análise do custo aproximado do tratamento dos doentes hospitalizados na Eslováquia com malária importada. Entre 2003 a 2007, foram internados 15 doentes com malária importada. Os custos médios diretos do tratamento foram avaliados em 920,75 euros e indireto em 53,15 euros. No doente com o custo mais elevado de tratamento, a utilização da profilaxia com mefloquina representaria somente 0,5 por cento do total dos custos diretos do tratamento da doença. Apesar da resistência parcial do plasmódio, a quimioprofilaxia da malária é inequivocamente uma opção mais econômica do que o tratamento posterior da malária.

Estudio piloto de la eficacia y de los efectos sobre los gametocitos del esquema artesunato-mefloquina-primaquina para la malaria por Plasmodium falciparum / Therapeutic efficacy of a regimen of artesunate-mefloquine-primaquine treatment for Plasmodium falciparum malaria and treatment effects on gametocytic development

Introducción. El tratamiento de la malaria por P. falciparum requiere de un esquema seguro, eficaz y de impacto en la transmisión. En 2006, se implementó en Antioquia el esquema artesunato-mefloquina y se adicionó primaquina para eliminar los gametocitos. Objetivo. Evaluar la eficacia y acción gametocida de los esquemas artesunato-mefloquina-primaquina y artesunato-mefloquina en pacientes con malaria no complicada por P. falciparum de Turbo, Antioquia. Materiales y métodos. Ensayo clínico aleatorio; los tratamientos se suministraron de forma supervisada y se realizó seguimiento clínico-parasitológico en los días 1, 2, 3, 7, 14, 21, 28, 35, y 42, para evaluar la respuesta según el protocolo OMS-2003 modificado. Resultados. Entre abril de 2007 y febrero de 2008, 50 pacientes fueron reclutados; los resultados mostraron una eficacia de 100% (IC95% 86,3%-100%) para el esquema artesunato-mefloquina (con/sin primaquina); la parasitemia y la fiebre fueron eliminadas completamente al tercer día de tratamiento en todos los pacientes. La eliminación de gametocitos fue mayor con el uso de primaquina; al tercer día de seguimiento, el 92% (IC95% 74%-99%) de los pacientes que recibieron primaquina no tuvieron gametocitos, en comparación con 78,3% (IC95% 59%-93%) de pacientes del grupo artesunato-mefloquina. Además, el esquema artesunato-mefloquina-primaquina eliminó la gametocitemia una semana antes que el esquema sin primaquina. Conclusión. Se recomienda el uso del esquema artesunato-mefloquina para la malaria por P. falciparum por su alta eficacia y se sugieren futuras evaluaciones del beneficio de la PQ en la reducción de la densidad y prevalencia de gametocitos.

Introduction. The treatment of Plasmodium falciparum malaria requires a safe and effective therapeutic treatment regimen, which in turn has high impact on the transmission. In 2006, an artesunate (AS)-mefloquine (MQ) treatment program was implemented in Antioquia. In addition, primaquine (PQ) was added to eliminate malaria gametocytes in the bloodstream. Objective. The efficacy and gametocytocidal activity was evaluated for two treatment regimens, AS-MQ-PQ and AS-MQ, in patients with uncomplicated P. falciparum malaria. Materials and methods. Between April 2007 and February 2008, 50 patients were recruited for the trial in Turbo, Antioquia. A randomized clinical trial was conducted. Treatment compliance was supervised, with a clinical and parasitological assessment on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 to evaluate response rate according to the WHO 2003 protocol. Results. Clinical response and parasite elimination efficacy of AS-MQ (with or without PQ) was 100% (95% CI 86.3%-100%), and parasitemia and fever were absent on day 3 of treatment in all patients. Gametocyte elimination was superior when PQ was used--92% (95% CI: 74%-99%) of patients who received PQ had no gametocytes on day 3, compared to 78.3% (95% CI: 59%-93%) of patients who only received AS-MQ. Furthermore, circulating gametocytes were eliminated on average one week faster when the AS-MQ-PQ treatment scheme was used compared to the scheme without PQ. Conclusion. These studies recommend the use of AS-MQ to treat P. falciparum malaria given its good therapeutic efficacy. However, further assessment is suggested concerning the benefit of adding PQ to this treatment scheme.

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.