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.

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.

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.

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.

El citocromo P-450 y la respuesta terapéutica a los antimaláricos / Cytochrome P-450 and the response to antimalarial drugs

OBJETIVOS: Evaluar la relación entre los factores genéticos y fenotípicos del sistema enzimático del citocromo P-450 y la respuesta terapéutica antimalárica a la cloroquina, la amodiaquina, la mefloquina y el proguanil, así como determinar la influencia de algunos factores biológicos y sociales del hospedero en el comportamiento de este complejo enzimático. MÉTODOS: Revisión sistemática de las bases de literatura biomédica PubMed, Excerpta Medica, LILACS y SciELO mediante descriptores en español e inglés. Se usaron los siguientes descriptores: "CYP-450" y "citocromo P-450" y sus combinaciones con "proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "farmacocinética de proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "resistencia a proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "metabolismo", "farmacogenética", "enfermedad", "inflamación", "infección", "enfermedad hepática", "malaria", "nutrición" y "desnutrición". Estos mismos términos se usaron en inglés. La búsqueda se limitó a los artículos publicados en español, inglés y portugués hasta el 30 de junio de 2005 y a cuatro medicamentos antimaláricos: amodiaquina, cloroquina, mefloquina y proguanil. RESULTADOS: Algunos factores genéticos del citocromo P-450 humano (principalmente su polimorfismo), así como otros de tipo biológico y social (la propia presencia de enfermedad, inflamación o infección, la administración de medicamentos antimaláricos y su combinación, y el estado nutricional del paciente), influyen en la actividad de ese complejo enzimático. Solo en la última década se ha abordado el estudio de las bases genéticas de los citocromos y se han podido dilucidar los mecanismos de algunas interacciones entre fármacos y del metabolismo de estos, lo que ha permitido caracterizar el proceso de biotransformación de la amodiaquina y de la cloroquina. Se espera que nuevas investigaciones permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos...

A comparative clinical trial of combinations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria.

With the deteriorating situation of multidrug resistant falciparum malaria, a new drug or drugs in combinations are urgently needed. We conducted a study comparing a combination of dihydroartemisinin 240 mg and mefloquine 1,250 mg given over 3 days (Group 1) and a combination of dihydroartemisinin 240 mg and azithromycin 1,500 mg given over 3 days (Group 2), to determine safety, efficacy and tolerability. All of the patients stayed in a non-malaria endemic area during the study. By the third day after drug administration, most patients were free of parasites and none had serious adverse events. The cure rates at day 28 were 100% and 69.7% in Group 1 and Group 2, respectively (p<0.01). We conclude that a combination of dihydroartemisnin and azithromycin was safe and effective and may be another interesting regimen of the treatment of uncomplicated multidrug resistant Plasmodium falciparum malaria in Thailand.

An open randomized clinical trial of Artecom vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

The efficacy and safety of Artecom were assessed in an open randomized trial in adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand. Three hundred and fifty-two patients were randomly enroled at the ratio of 2:1 into group A:B and received Artecom (group A) and the standard combination of artesunate and mefloquine (group B) respectively. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time and parasite clearance time between the two groups. The 28-day cure rates were high as 97% in both groups. Artecom was effective and well-tolerated as artesunate-mefloquine, the current treatment in this area of multidrug-resistant P. falciparum malaria.

Treatment of uncomplicated Plasmodium falciparum malaria in Myanmar: a clinical decision analysis.

This study was undertaken to compare cost-effectiveness of three drug regimes for treatment of uncomplicated falciparum malaria in Myanmar. The alternative regimens in this study were chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and mefloquine (MFQ) along with their therapeutic efficacy in Myanmar. The study was performed by modeling a clinical decision tree based on a hypothetical 1,000 adult uncomplicated falciparum malaria cases. Key variables were (i) three drug regimes: CQ, SP and MFQ, (ii) three categories of therapeutic efficacy of each drug: adequate clinical response (ACR), early treatment failure (ETF) and late treatment failure (LTF) according to the 1996 WHO protocol, and (iii) compliance with each drug. In structuring the model, necessary assumptions were made. The cost effectiveness was measured as cost per case cured and cost per case prevented death related to the provided drug, from the provider's perspective. According to the present price and therapeutic efficacy, SP is the most cost effective drug for a case cured in all three categories of efficacy (US$ 0.12 per case cured in ACR, US$ 0.38 per case cured in ETF and US$ 0.54 per case cured in LTF). For a case prevented death, CQ is most cost effective in all three categories (US$ 0.58 per case prevented death in the ACR, US$ 2.14 per case prevented death in the ETF and US$ 2.51 per case prevented death in the LTF). The lowest cost effective regimen is MFQ for both indicators of effectiveness at the present price and therapeutic efficacy. A sensitivity analysis was performed for sensitive values.

Resistência à mefloquina do tipo RIII em crianças com malária falciparum em Manaus, AM, Brasil / RIII mefloquine resistance in children with falciparum malaria in Manaus, AM, Brazil

Relata-se a ocorrência de resistência à mefloquina administrada na dose de 20mg/kg em 51 crianças com malária falciparum atendidas em centro de referência em Manaus, Brasil, no período de outubro a novembro de 1997. Todas as crianças foram avaliadas nos dias 3, 5, 7, 14, 21, 28 e 35 do tratamento, segundo critérios clínico e parasitológico. Foi encontrada uma incidência de resistência RIII de 5,9 por cento (IC 95 por cento variando de 1,5 a 17,2), a razäo cura/resistência calculada foi 20:1 e cura/gravidade 62:1. Os dados chamam a atençäo para a importância da resistência à mefloquina nesse grupo de crianças

Mefloquina no tratamento da leishmaniose cutânea em uma área endêmica de Leishmania (Viannia) braziliensis / Efficacy of mefloquine in the treatment of skin leishmaniasis in an endemic area of Leishmania (Viannia) braziliensis

O objetivo deste trabalho foi avaliara eficácia da mefloquina numa regiäo endêmica de leishmaniose cutânea por Leishmania (Viannia) braziliensis, considerando que esta droga de administraçäo oral, eficaz no tratamento da malária, com meia vida prolongada e efeitos colaterais pouco freqüentes poderia ser menos tóxica e de mais fácil administraçäo, quando comparadas com os antimoniais pentavalentes. Em Corte de Pedra, no litoral sul do Estado da Bahia, foram tratados, aleatoriamente, dez pacientes portadores de lesöes leishmanióticas, subdivididos em dois grupos. O primeiro grupo recebeu mefloquina pela via oral, dose de 250mg/dia, durante seis dias, repetindo-se o mesmo esquema após intervalo de três semanas. O segundo grupo recebeu antimoniato de meglumina (Glucantime©) diariamente, pela via endovenosa, na dose de 20mg/kg por20 dias. Do grupo da mefloquina só um paciente apresentou cicatrizaçäo depois do segundo ciclo. Um desses, com quatro lesöes apresentou nova lesöo durante o primeiro ciclo de tratamento. A evoluçäo dos outros três foi lenta sendo que em nove semanas nenhum deles tinha cicatrizado as úlceras que permaneciam com grande infiltraçäo e sinais evidentes de atividade. O grupo tratado com Glucantime© apresentou evidente melhora

Mefloquine in treatment of cutaneous leishmaniasis

Três casos de leishmaniose tegumentar em pacientes internados no Hospital Escola da Faculdade de Medicina do Triângulo Mineiro, Uberaba, MG, foram tratados com mefloquina, na dose de 4,2mg/kg/dia por via oral, durante seis dias. Nova série foi repetida três semanas após. Nenhum dos três pacientes foi curado

Plasmodium vivax resistance to chloroquine (R2) and mefloquine (R3) in Brazilian Amazon region

Estamos relatando pela primeira vez um paciente com malária por Plasmodium vivax que mostrou resistência R2 à cloroquina e resistência R3 à mefloquina na Amazônia brasileira, de acordo com os critérios clínicos da OMS para resistência da malária. A falha foi observada com cloroquina oral, näo supervisionada, cloroquina oral administrada sob rigorosa supervisäo e com mefloquina no mesmo esquema. A paciente curou com o artesunato oral

Malaria congénita / Congenital malaria

La malaria congénita tiene una incidencia variable, se describe en promedio en el 8 por ciento de los embarazos de mujeres con malaria, con cifra máxima de 25 por ciento. La transmisión transplacentaria depende de varios factores, entre ellos la paridad e inmunidad materna. La infección placentaria es necesaria para la transmisión al feto de los merozoitos que en la circulación fetal, parasitan a los glóbulos rojos sin efectuar el ciclo pre eritrocitico. La edad de aparición de los síntomas es variable, generalmente después de la segunda semana de vida y a diferencia de la malaria de adquisición horizontal, se caracteriza principalmente por fiebre, hepato-esplenomegalia, distress respiratorio y diarrea. El diagnóstico se hace mediante un frontis sanguíneo y gota gruesa. El tratamiento dependerá del tipo de plasmodio causal y de la zona en la cual fue adquirido. Es un diagnóstico que debe ser considerado en un neonato febril, cuya madre haya estado en zonas de riesgo para adquirir malaria, incluso años antes

A clinical trial of combination of artesunate and mefloquine in the treatment of acute uncomplicated falciparum malaria: a short and practical regimen.

The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant fall in patient compliance not only lowers cure rates but also predisposes to the further spread of drug-resistance. Sequential treatment with artesunate given over 5 days followed by mefloquine produced 100% cure rates in previous study, but might not be a suitable regimen for field treatment. We conducted a clinical trial of a combination of artesunate and mefloquine given twice daily for 2 days in 150 patients with acute uncomplicated falciparum malaria. The dose of artesunate (200 mg) and mefloquine (312.5 mg) were given simultaneously in a separate package. All patients were admitted to a hospital in Bangkok for 28 days to exclude re-infection and monitor the possible adverse effects. One hundred and thirty patients completed the study with 28 days follow up. Twenty patients (13%) left the hospital prior to completion of follow-up for reasons unrelated to their treatment. Cure rate was 97% (126/130). There were no RII or RIII failures and all four patients with treatment failures were of the RI type. The mean parasite clearance time and fever clearance time were 46.4 and 42.5 hours, respectively. All patients were tolerated the combination drugs well and there were no serious toxic adverse reactions. The results indicate that combination of artesunate and mefloquine given twice daily for 2 days is effective and well tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug resistant falciparum malaria.

Pulmonary edema in cerebral malaria patients in Thailand.

Pulmonary edema is a serious complication of falciparum malaria that usually occurs in association with cerebral malaria, acute renal failure, high parasitemias, or delayed antimalarial treatment. From 1993 to 1996, 120 adult patients admitted to the intensive care unit of the Bangkok Hospital for Tropical Diseases were enrolled in a prospective study to assess the combination of artesunate and mefloquine for the treatment of cerebral malaria. Twenty-five patients (21%) presented with pulmonary edema and a majority developed complications in other organs as well, especially acute renal failure. In most patients (19 of 25), pulmonary edema was noted on the first day of admission and was associated with higher parasitemias and levels of acidemia, than in patients without pulmonary edema. Ten of the 25 patients diagnosed with pulmonary edema developed signs consistent with adult respiratory distress syndrome (ARDS). The mean central venous pressure when pulmonary edema was diagnosed was markedly lower in ARDS than in non-ARDS patients, supporting the argument that fluid imbalance is not essential for malaria-induced lung injury. Seven of 10 patients with ARDS died, 5 within 24 hours of admission, but there were no deaths in the 15 pulmonary edema patients without ARDS. Early diagnosis and prompt treatment remain important principles to reduce the morbidity and mortality associated with complicated falciparum malaria. This report emphasizes that ARDS, when concurrently occurs, is a poor prognostic clinical indicator in cerebral malaria.

A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand.

Plasmodium falciparum in Thailand is highly resistant to chloroquine, sulfadoxine-pyrimethamine and there is increasing resistance to quinine and mefloquine. The use of qinghaosu derivatives alone or in combination with mefloquine has been shown successfully effective against multidrug resistant P. falciparum in many clinical trials. However their applications with ambulatory treatment should be assessed. 394 uncomplicated falciparum malaria cases studied at Trat and Chanthaburi malaria clinics, eastern Thailand, were allocated at random to receive either one of the seven following regimens: A) artesunate 600 mg over 2 days and mefloquine 1,250 mg in divided doses. B) artemether 640 mg over 2 days and mefloquine 1,250 mg in divided doses. C) artesunate alone 700 mg over 5 days period. D) artemether alone 800 mg over 5 days period. E) quinine plus tetracycline for 7 days. F) mefloquine 1,250 mg in divided doses and G) artesunate 600 mg over 2 days period and mefloquine 750 mg. The follow-up was on Days 1, 2, 7, 14, 21 and 28. Patients tolerated all regimens very well and there was no serious side effects. The adverse effects did not differ among the seven regimens. The cure rates were 98.7, 97.1, 97.9, 96.7, 92.3, 100 and 95.2%, respectively. There was no significant difference of cure rates among various regimens. A total of 16 P. vivax and 1 P. malariae reinfections were reported among the study groups during the second half of the follow-up period, 14 of which were from the groups administered short action drugs (artesunate, artemether or quinine). The results suggested that either artesunate 600 mg or artemether 640 mg in combination with mefloquine 1,250 mg over a period of two days should be considered as alternative regimens for treating uncomplicated multi-drug resistant falciparum malaria.