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.

La quinina y sus congéneres. Interacciones y reacciones adversas de importancia clínica / Quinine and its congenerous. Clinically important interactions and adverse drug reactions

Muy a pesar de la existencia de variados grupos de fármacos antimaláricos, en muchas partes del mundo continúan siendo fármacos de primera línea para el tratamiento de la malaria o paludismo la Quinina y sus congéneres. Dado que esta patología es capaz de afectar al ser humano expuesto en cualquier etapa de la vida, la posibilidad de interacción de los fármacos antimaláricos conjuntamente con cualquier otro tipo de medicación, ya por la presencia en el paciente afecto de malaria, de alguna otra patología, sea esta de carácter agudo o crónico, nos motivaron a la ejecución de la presente revisión, sumándole a ello además variadas reacciones adversas de importancia clínica. En lo que respecta al embarazo y lactancia podemos considerar que, en general, la mayoría de estos antimaláricos son seguros y eficaces durante el embarazo, no constituyendo este estado fisiológico una contraindicación absoluta para su empleo, sin embargo, debe valorarse en cada caso la relación riesgo/beneficio.

An in vivo test to assess mefloquine 25 mg/kg for the treatment of uncomplicated falciparum malaria in Rondônia, Brazil

Drug-resistant Plasmodium falciparum is undermining malaria control efforts worldwide. In Brazil, mefloquine (MQ) at a dose of 15 mg/kg body weight is used to treat P. falciparum. At this dose, MQ resistance developed rapidly in Thailand. Use of a higher MQ dose may retard the development of resistance. We treated 50 patients aged one to 67 years who had acute, uncomplicated P falciparum malaria using MQ 25 mg/kg. There were no serious adverse events. Two patients complained of dizziness and insomnia. Assessing evaluable patients, the day 42 cure rate was 40/42 [95.2 percent (95 percent confidence interval 83.8 to 99.4 percent)]. Mefloquine was efficacious and well tolerated in this small cohort from the state of Rôndonia.

Chemoprophylaxis according to the guidelines on malaria prevention for Japanese overseas travelers.

Mefloquine has been licensed and registered in Japan for chemoprophylaxis against malaria since 2001. Guidelines for the prevention of malaria for Japanese overseas travelers were published by a group of malaria specialists under the auspices of the Japanese Society of Tropical Medicine and the Ministry of Health, Labor and Welfare, but not until March 2005. We implemented these guidelines in our clinic at the International Medical Center of Japan in Tokyo and, to better understand whether these guidelines are optimally useful, we conducted a study of Japanese travelers who visited our clinic seeking pertinent information and prophylaxis against malaria. The study group comprised 52 individuals who visited our clinic during the period October 2004 through June 2005 prior to travel abroad. On the basis of the above-mentioned guidelines, mefloquine was given to 27 of these individuals, 22 of whom were judged to need regular chemoprophylaxis. Mefloquine was not recommended to the other 25 individuals because their stays abroad would have been too long to avoid possible side effects or too short for symptoms to appear. In fact, some were traveling to malaria-free areas. Of the 27 individuals given mefloquine, 7 (26%) reported side effects, such as headache, vertigo, and nausea, 17 (63%) reported no side-effects, and the other 3 (11%) were unable to be followed. The diversity of destinations and accompanying malaria risks makes it very difficult for us to administer chemoprophylaxis to overseas travelers appropriately. The guidelines proved to be somewhat useful, but further experience in malaria chemoprophylaxis is needed for physicians to provide reliable pre-travel consultation.

Comparative activities of chloroquine mefloquine and sulphadoxine-pyrimethamine on in vivo and ex vivo male reproductive functions in mammalian models

Comparative reproductive activities of chloroquine, mefloquine and sulphadoxine-pyrimethamine were explored in albino Wistar rats and semen from West African Dwarf Buck [WADB] with a view to elucidating the mechanism of action of these drugs on malereproduction. Five adult male rats were administered 0.5 mL distilled water and served as the control. Five rats each were administered orally chloroquine [10 mg kg -1 b.w.], mefloquine [10 mg kg -1 b.w.] and sulphadoxine-pyrimethamine [5 mg kg -1 b.w.] orally, for four weeks. Each group had it's own recovery group. Sperm counts, motility and morphology were reduced in rats treated with these drugs in the order mefloquine [p<0.05]> chloroquine > sulphadoxine-pyrimethamine. There was an appreciable recovery in the motility of sperms in all recovery groups. Semen samples from WADB were extended separately with chloroquine, mefloquine and sulphadoxine-pyrimethamine. Extender 1 [first control] had no PENSTRIP [Penicillin and Streptomycin combination] while extender 2 [standard extender; second control] had PENSTRIP. Semen in extenders 3, 4 and 5 were treated with chloroquine, mefloquine and sulphadoxine-pyrimethamine, respectively. Spermatozoa progressive motility in these extenders examined under the microscope at 24 h for 5 days significantly reduced in mefloquine [p<0.01], slightly with chloroquine and unchanged with sulphadoxine-pyrimethamine. The pH of the extenders was significantly reduced in duration dependent manner in mefloquine while it remained unchanged with chloroquine and sulphadoxine-pyrimethamine. The results suggest the safety of sulphadoxine-pyrimethamine and chloroquine in preservation of semen ex vivo while the negative impact of mefloquine could reside within the testis or epididymis

Mefloquine--its 20 years in the Thai Malaria Control Program.

Due to the deteriorating efficacy of sulfadoxine-pyrimethamine (SP or Fansidar), from the mid-1970s the Thai Malaria Control Program was actively involved in testing potential replacement drugs to be used as the primary therapy for falciparum malaria in Thailand. In 1983, a large-scale field trial of mefloquine, a long-acting antimalarial drug known for its efficacy against chloroquine- and SP-resistant Plasmodium falciparum, was initiated on the Thai-Cambodian border. The study enrolled over 60,000 patients and eventually led to the formal establishment of mefloquine as the first line drug for the treatment of uncomplicated falciparum malaria in the country. Mefloquine has played a significant role in the control of malaria in Thailand for the past two decades, initially in combination with SP, then by itself, and currently in selected areas as a partner drug in the combination therapy with artesunate. Thailand is the country with the most experience in the use of this drug in a malaria control program. We present here a review of mefloquine's pharmacology and usage in Thailand.

Six-years monitoring the efficacy of the combination of artesunate and mefloquine for the treatment of uncomplicated falciparum malaria.

Plasmodium falciparum in Thailand is multi-drug resistant. In a previous study it was shown that artesunate and mefloquine were effective, as follow up, we monitored the efficacy of this regimen for six years. During 1997-2002, 516 adult male volunteer patients in Chanthaburi Province were enrolled (50 patients in the first year, 400 patients in 1998-2001 and 66 patients in 2002). The symptom complex and parasite count (thick blood film) were monitored on days 0, 1, 2, 7, 14, 21, 28, 35 and 42. The dosages used were artesunate (ATS) 150 mg and mefloquine (M) 750 mg at hour 0 and ATS 100 mg and M 500 mg at hour 24. Their ages ranged from 30-35 years and their mean body weights were 54-56 kg. The presenting symptoms were fever 100%, headache 97-100%, anorexia 78-90%, and nausea 28-40%. The geometric mean of parasitemia ranged from 7,357-12,750/mm3. Defervescence in one day was found in 42-76% of patients and 85-100% in 2 days. The sensitivity (S) ranged from 87-94% and RI resistance (recrudescence) ranged from 6-13%. Forty patients demonstrated RI type of response, 37 were cured after being retreated with the same dosage and another 3 patients were cured after the third course of treatment. The aggravated adverse effects included vomiting (8-20%), anorexia (1-41%) and diarrhea (0-16%). These side effects were mild and transient. The efficacy of the artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria was high. The RI type of response was possibly due to re-infection or multiple broods and not to drug resistance. The adverse effects of anorexia, nausea, vomiting and diarrhea were mild and transient for mefloquine. The combination can be used as stand by treatment in areas of multi-drug resistant falciparum malaria.

Estudo da eficácia e tolerância do artesunato oral isolado e em associaçäo com mefloquina, no tratamento da malária falciparum näo complicada em área endêmica do Pará, Brasil / An efficacy and tolerant study of oral artesunate alone and in combination with mefloquine in the treatment of uncomplicated falciparum malaria in an endemic area of Pará, Brazil

Com o objetivo de avaliar a eficácia e tolerância do artesunato no tratamento da malária falciparum nao complicada em área endêmica do Estado do Pará, 153 pacientes foram randomizados e estudados em três grupos, distribuídos por esquema terapêutico (I recebeu mefloquina l000mg; II utilizou artesunato l000mg; III usou a combinaçao de 600mg de artesunato seguida de 500 de mefloquina). A avaliaçao constou de exame clínico e parasitológico diariamente nos primeiros 7 dias e semanalmente até o 35§ dia do acompanhamento e de análise bioquímica e hematológica realizada antes e no 7§ dia, visando o controle de cura e a identificaçao de possíveis efeitos associados à administraçao das drogas. Os grupos estudados foram homogêneos quanto ao sexo, parasitemia e presença de febre. O tempo para desaparecimento da parasitemia foi mais curto nos grupos II e III, respectivamente, cujos esquemas terapêuticos empregaram artesunato. O desaparecimento da febre foi mais rápido no grupo tratado com a combinaçao das drogas. Alteraçoes clínicas e bioquímicas associadas a administraçao das drogas nao mostraram diferenças significativas entre os grupos estudados. O desaparecimento precoce da febre e parasitemia, e a ausência de importantes efeitos indesejáveis, sugerem que artesunato administrado isoladamente ou em combinaçao com mefloquina constituem medidas terapêuticas capazes de contribuir para o controle da doença na regiao.

Quimioprofilaxia da malária com mefloquina na amazônia brasileira / Mefloquine chemoprophylaxis of malaria in the Brazilian Amazonia

Em estudo randômico duplo-cego, 122 voluntários morando em área endêmica de malária na Regiäo Amazônica de Rondônia) foram divididos em quatro grupos para estudo da supressäo malárica. O grupo I recebeu 500 mg de mefloquina a cada quatro semanas; o grupo II 250 mg de mefloquina a cada duas semanas; o grupo III um comprimido de Fansidar (500 mg de sulfadoxina + 25 mg de pirimetamina) por semana e o grupo IV, recebeu apenas placebo. Um ataque agudo de malária ocorreu em um indivíduo do grupo I, em dois indivíduos do grupo II e em seis indivíduos dos grupos III e IV. A proteçäo verificada nos grupos em uso de mefloquina foi significantemente superior comparada ao grupo placebo. A mefloquina, em ambas as dosagens usadas, mostrou-se efetiva na supressäo malárica em uma área onde o Plasmodium falciparum plurirresistente é altamente prevalente

Fansimef for prophylaxis of malaria: a double-blind randomized placebo controlled trial.

At a time when Fansimef, the fixed combination of mefloquine, sulfadoxine and pyrimethamine was considered for prophylaxis of falciparum malaria, a randomized double-blind study comparing the efficacy and tolerability of Fansimef with that of Lariam (mefloquine), Fansidar, chloroquine and placebo in malaria prophylaxis was performed in Thailand from July 1987 to January 1988. The study population of 602 adult males was recruited in Pak Tongchai District, some 360 km North-East of Bangkok, where multiresistant P. falciparum is endemic. All active treatments and placebo were given once weekly for 24 weeks with doses as follows: Fansimef: 125 mg mefloquine + 250 mg sulfadoxine + 12.5 mg pyrimethamine (1 half-strength tablet); Lariam: 125 mg mefloquine (1 half-strength tablet); Fansidar: 500 mg sulfadoxine + 25 mg pyrimethamine; chloroquine; 300 mg. A loading dose of 2 half-strength tablets was given in the Fansimef group in weeks 1 and 2 and in the Lariam group in weeks 1 to 4. The incidence of acute episodes of P. falciparum per 100 person months of prophylaxis was 0.17 each in the Fansimef and the Lariam groups, 1.18 in the Fansidar group, 0.69 in the chloroquine group and 0.64 in the placebo group (differences statistically not significant). Clinically adverse events were reported by 170 subjects (Fansimef 28, Lariam 29, Fansidar 41, choroquine 43, placebo 29; differences statistically not significant). The most frequent adverse events in all groups were headache, sleepiness, dizziness and weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials of mefloquine with tetracycline.

A comparative trial of the combination of mefloquine or MSP with tetracycline was carried out in fifty-one adult Thai male patients with acute falciparum malaria. The patients were randomized to receive either the combination of tetracycline (250 mg qid for 7 days) with mefloquine 4 tablets (1,000 mg) or with MSP 4 tablets (one tablet contains 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimethamine). Fifty patients had a complete 28-day follow-up period. Both regimens produced similar efficacy with no difference in adverse effects. In the mefloquine plus tetracycline group, the cure rate was 72% (18/25). One patient had an RIII response, the others showed initial response to the treatment with FCT and PCT of 40.7 +/- 27.4 and 76.2 +/- 34.2 hours (mean +/- SD) respectively. However, 6 patients developed recrudescence between days 17 and 29 (RI), 3 of these had vomiting. In the MSP plus tetracycline group, the cure rate was 76% (19/25). The means (+/- SD) of FCT and PCT were 44.7 +/- 38.0 and 80.6 +/- 25.0 hours, respectively. Six patients had recrudescence between days 17 and 31 (RI), 2 of these had vomiting. Although the addition of tetracycline improved the cure rate of mefloquine when compared with standard dose of mefloquine alone (3 tablets), these combinations seem to be useful in areas where alternative drugs are not available.

Tratamento de 75 pacientes portadores de malária pelo P. Falciparum, em Porto Velho (RO), com mefloquina / Treatment of 75 patients with malaria caused by Plasmodium falciparum, in Porto Velho (Rondonia), with mefloquine

Foi avaliada a resposta terapêutica em 75 doentes com malária pelo P. falciparum, em Porto Velho - Rondônia, tratados com mefloquina nas doses de 1250, 1000 e 750 mg. Näo houve diferença significante nos resultados obtidos nos três grupos. Até o terceiro dia de tratamento, a febre desapareceu em 76,0% dos casos. A parasitemia negativou-se em 68,0% dos pacientes nos 3 primeiros dias após o início do tratamento, em 24,0% no quarto dia e em 5,3% no quinto. Havia um doente positivo no sexto dia e outro no sétimo. Nenhum paciente apresentou trofozoíto no período de seguimento de 7 a 28 dias. Näo houve modificaçöes do quadro hematológico, exceto por um incremento da taxa de reticulócitos em 76,0%. As alteraçöes bioquímicas registradas no seguimento dos doentes constaram de elevaçäo da desidrogenase lática (28,0%) e, da fosfatase alcalina (41,3%). As reaçöes colaterais foram discretas e infreqüentes; em 72,0% dos tratados näo se constatou nenhum efeito secundário. Näo se verificou nenhum caso de recidiva. A mefloquina revelou-se eficaz e bem tolerada no tratamento da malária no Estado de Rondônia