Mefloquine Prophylaxis Research Articles

Malaria antibodies and mefloquine levels among United Nations troops in Angola.

The United Nations deployed about 8,000 soldiers in a peacekeeping mission in Angola. Malaria is the most common disease there and consequently it was the major risk to the UN troops. Most of them are from malaria free areas. As a result of improper prophylactic measures there were many cases of malaria, including some deaths in 1995. In February-March 1996, an Israeli team was sent to Angola to evaluate the malaria situation among UN soldiers. This paper deals specifically with some aspects of chemoprophylaxis and diagnosis. The efforts were concentrated in one particular area where malaria incidence had been reported as the highest. Blood samples were collected from nonimmune soldiers who were using mefloquine as a prophylactic drug and were exposed to malaria. The mefloquine and the antimalarial antibody plasma levels were monitored. While the local laboratory indicated that about 80% had a malaria episode, the serological results revealed that only 5 soldiers of the 56 (9%) examined had antimalarial antibodies, of which 3 were Angolans. Despite a controlled prophylactic regimen there was considerable variability in mefloquine plasma levels: 46% of the samples were below the required prophylactic level and 26% above it. All patients who were proven positive with malaria by both microscopic and serologic observation had a low level of mefloquine. In field conditions, a kit which identifies plasmodial antigens, is preferable, to a microscopic diagnostic method. Controlled mefloquine prophylaxis may not prevent malaria, especially when blood levels are low. The reason for the low mefloquine blood levels is not clear and needs further evaluation.

Do Travelers Really Take Their Mefloquine Malaria Chemoprophylaxis? Estimation of Adherence by an Electronic Pillbox

Nonadherence to chemoprophylaxis could explain why some travelers get malaria. Adherence is notoriously difficult to assess, and most studies have been conducted using questionnaires. This study aims at assessing continuous adherence more accurately with the help of an electronic pillbox. Adult travelers to sub-Saharan Africa had to fill a questionnaire on demographic and travel data, drug intake, and adverse events. They received oral and written information about malaria and mefloquine prophylaxis and a Medication Event Monitoring System (MEMS, Aardex, Zug, Switzerland), ie, a bottle closed with a cap containing a microprocessor recording date and time of all openings, filled with the exact number of mefloquine 250 mg tablets (Lariam, Roche Reinach, Switzerland). The MEMS) was returned with the questionnaire after completion of chemoprophylaxis. According to the MEMS, only 26 of 81 travelers (32.1%) took all the doses at the expected date, another 8 (9.9%) did so but starting late with the first dose, and 19 others (23.5%) took all the pills but with intervals of +/-1 day from the right date. Another eight (9.9%) took all the pills but in a random way. The remaining 20 travelers (24.7%) missed some doses, mainly after return. Strict adherence as assessed by electronic monitoring was therefore lower than adherence measured by questionnaire (32.1% vs 48% in taking all the tablets on the right day). There was no difference between the two methods when a broader definition of adherence was applied [taking all the tablets on the right day (+/-1 day); 53/81 (65.4%)], but the MEMS showed that some answers to the questionnaire were not reliable. The use of electronic pillboxes confirms the low adherence of travelers to mefloquine chemoprophylaxis in spite of extensive information about the disease and its prevention. Electronic assessment of pill taking, for the first time applied to malaria chemoprophylaxis, gives new insights into the real adherence of travelers.

Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor

To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline. Open-label, prospective study and cross-sectional questionnaire and interview. Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001-October 2001 and October 2001-May 2002). Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment. Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again. Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.

Absence of nucleotide polymorphism in a Plasmodium vivax multidrug resistance gene after failure of mefloquine prophylaxis in French Guyana

Vivax malaria is widespread and resistance has been described for chloroquine and sulfadoxine-pyrimethamine. We report on evidence of failure of mefloquine prophylaxis in a French soldier who contracted Plasmodium vivax in French Guyana, South America. Despite regular weekly mefloquine prophylaxis (250 mg/d), the patient presented with a first episode of vivax malaria, which was treated by chloroquine alone, then experienced a second crisis in France. The reappearance of the parasites occurred one day after the end of prophylaxis, confirming parasitological and clinical resistance in a non-immune patient. Mefloquine was detected by a liquid chromatography assay in plasma at a level of 1062 ng/ml, which was higher than the expected concentration after five months of weekly prophylaxis. This isolate had no single nucleotide polymorphisms of the pvmdr1 gene at seven allele positions: pvmdr1 N91, Y189, Y976, S1071, F1076, N1079 and D1291, corresponding to codons 86, 184, 939, 1034, 1039, 1042 and 1246 in P. falciparum. This observation of failure of mefloquine prophylaxis against P. vivax, when added to previously reported chloroquine and atovaquone-proguanil failure, strengthens the case for re-evaluating drug policies for vivax malaria and the need for continuous research on molecular markers of drug resistance.

The relationship between body weight and tolerance to mefloquine prophylaxis in non-immune adults: results of a questionnaire-based study.

The relationship between body weight and tolerance to mefloquine prophylaxis in non-immune adults: results of a questionnaire-based study.

Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine.

We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas. We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine prophylaxis during the period between 1 May 1999 and 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after starting weekly intake of 250 mg mefloquine. We compared the intraindividual change in scores between baseline and follow-up visit on the Dutch shortened Profile of Mood States, and on the Continuous Performance Test (CPT) which measures sustained attention. The final cohort consisted of 151 subjects with a mean age of 38 years. In this population, a significant impairment of mood state was observed in those with a body mass index (BMI) < or = 20 kg m(-2). Stratification for gender showed that the total mood disturbance in females in the lowest BMI category significantly increased by 8.42 points [95% confidence interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males. Stratification for history of use of mefloquine showed that the risks were highest in first-time users. Analyses of the CPT showed that reaction time in women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95% CI 7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant decrease. Risk factors for mefloquine-associated neuropsychiatric adverse events and concentration impairment are female gender, low BMI, and first-time use. The frequency of neuropsychiatric effects is highest in women with a BMI < or = 20 kg m(-2).

Prophylaxis failure due to probable mefloquine resistant P. falciparum from Tanzania

Failures of mefloquine prophylaxis in travellers returning from Africa have been reported repeatedly. Non-compliance to chemoprophylaxis is considered to be a major factor for failure. Only few reports on mefloquine prophylaxis failure in sub-Saharan Africa were able to report blood levels of the drug that were sufficient for prophylactic effectiveness. We report the case of a 44-year-old German female who travelled to Tanzania for 3 weeks. The patient reported that she never missed a dose of mefloquine during her weekly prophylaxis schedule. Four weeks after returning from Tanzania, the patient presented with fever, headache and myalgia. Only a few trophozoites of Plasmodium falciparum were found in a thick film. Blood levels of mefloquine at that stage were at 1400 ng/ml, thus largely excluding non-compliance and malabsorption. To our knowledge, this is the first case of confirmed prophylaxis failure due to mefloquine resistance in East Africa.

Neuropsychiatric events during prophylactic use of mefloquine before travelling.

It has been suggested that neuropsychiatric events during use of mefloquine are more common in females than in males and are partly explained by the psychological stress of travelling. Therefore, we investigated neuropsychiatric events in females and males on mefloquine in the 3-week prophylactic period that precedes travelling. Furthermore, we investigated whether first-time users had a higher risk of neuropsychiatric adverse events than subjects with a history of mefloquine use. We enrolled all patients who visited a Travel Clinic for mefloquine prophylaxis during the period 1 May 1999 to 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after the start of mefloquine but before travelling. We asked patients to register any adverse event in a diary and measured the intra-individual change in scores on the Dutch Shortened Profile Of Mood States (POMS) at baseline and at the end of follow-up. The final cohort consisted of 179 subjects with a mean age of 3 years. Females reported adverse events more frequently than males ( P=0.005). Overall, we observed a small but significant increase in the score on the domain fatigue [0.74 points, 95% confidence interval (CI) 0.18, 1.30]. The effect was exclusively present in females and not in males. First-time users of mefloquine increased 2.81 points (95% CI 0.70, 4.92) on the total score of the POMS, and among those, women showed the largest increase of 4.58 points (95% CI 0.74, 8.43). The use of mefloquine was associated with neuropsychiatric adverse effects. Females encountered neuropsychiatric effects more frequently than males, which could be confirmed by validated psychological tests. Neuropsychiatric effects were more common in first-time users than in individuals who had used mefloquine before.

Mefloquine Prophylaxis and Neuropsychiatric Side Effects: A Review of Randomized Controlled Trials

Mefloquine Prophylaxis and Neuropsychiatric Side Effects: A Review of Randomized Controlled Trials

Mefloquine for malaria chemoprophylaxis 1992-1998: a review.

Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food increases the bioavailability of mefloquine. Steady-state pharmacokinetics of weekly prophylaxis in long term travelers have shown that toxic accumulation does not occur and that weekly dosing is associated with protective levels of the drug. The pharmacokinetics of mefloquine are highly stereospecific and all pharmacokinetic parameters, except tmax are significantly different for the (+) and (-) enantiomers. Mefloquine and its metabolite are not appreciably removed by hemodialysis. Steady-state levels of mefloquine can be attained in a reduced time frame of 4 days compared to 7-9 weeks using a loading dose strategy of 250 mg mefloquine daily for 3 days followed thereafter by weekly mefloquine dosage. This strategy, is however, associated with a higher incidence of an adverse event (AE). Cumulative evidence suggests a high protective efficacy of mefloquine (>91%) in nonimmune travelers to areas of chloroquine resistant Plasmodium falciparum (CRPF) except for clearly defined regions of multi-drug resistance. Reports from sub-Saharan Africa indicate a low but increasing level of resistance to this drug. Mefloquine resistance is associated with halofantrine and quinine resistance but not with chloroquine resistance. Penfluridol has been shown to reverse P. falciparum mefloquine resistance in vitro. There is some controversy regarding the tolerabilty of mefloquine for malaria chemoprophylaxis. A review of the studies conducted during 1992-1998 shows that in the reporting of any AE the incidence lies in the range (12-90%) and where there is a comparator, is equivalent to the incidence reported for almost all alternative regimens. When some measure of subjective severity is applied to the rating of AE, it appears that 11-17% of travelers are, to some extent, incapacitated by AE. Major studies and worldwide monitoring have shown that serious events are rare. A recent meta-analysis showed that rates of withdrawal and overall incidence of AE with mefloquine were not significantly higher than those observed with comparator regimens except that mefloquine was more likely to cause insomnia and fatigue. Withdrawals in mefloquine arms were higher than in placebo arms. No performance deficit or functional impairment was observed in five clinical toxicity studies of mefloquine prophylaxis, including a study of driving performance. There is limited data regarding use of mefloquine in pregnancy. Early animal studies have documented teratogenic and embryotoxic effects associated with the use of high dose mefloquine. Two studies have shown a relatively high incidence of spontaneous abortions in mefloquine users. Cumulative evidence, however, is reassuring and has led the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to sanction the use of mefloquine in pregnant women during the second and third trimesters. In conclusion, mefloquine prophylaxis is recommended for travelers to high risk areas of chloroquine resistant Plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug associated adverse events.

Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers' health.

The effectiveness of mefloquine to prevent malaria caused by Plasmodium falciparum is influenced by the sensitivity of the malaria parasites to this drug. Concern has been raised that resistance to mefloquine may develop in sub-Saharan Africa as has been observed in Southeast Asia. Case reports, along with blood smears to confirm the diagnosis and blood samples to determine the mefloquine concentration, were provided on any Peace Corps volunteer serving in sub-Saharan Africa who was diagnosed with malaria. We defined prophylaxis failures probably due to mefloquine resistance as patients with P. falciparum malaria confirmed at the Centers for Disease Control and Prevention, reported compliance with prophylaxis, no ingestion of mefloquine between date of illness onset and date of blood drawing, and a mefloquine level > or = 620 ng/ml in blood drawn within five days of onset of illness. Between January 1, 1991 and September 6, 1996, 44 (31%) of 140 volunteers with confirmed P. falciparum had blood drawn within five days of onset of illness. Twenty-nine (66%) had not fully complied with prophylaxis. Five of 15 prophylaxis failures in four countries had mefloquine levels > or = 620 ng/ml. Failure of mefloquine prophylaxis is primarily due to noncompliance. Evidence of probable resistance to mefloquine among strains of P. falciparum was found in five Peace Corps volunteers in sub-Saharan Africa. Clusters of well-documented prophylaxis failures need to be followed-up by therapeutic in vivo studies to document parasite resistance to mefloquine. Reduced sensitivity to mefloquine does not (yet) appear to be a significant problem in sub-Saharan Africa.

Malaria anticircumsporozoite antibodies in Dutch soldiers returning from sub-Saharan Africa.

One hundred and twenty-five Dutch servicemen returning from central Africa after a short deployment were enrolled in a study aimed at assessing the effectiveness of malaria prevention measures. None of the persons developed an episode of clinically overt malaria during or after deployment, and no antibodies against blood stages of Plasmodium falciparum could be found. However, antibodies against the circumsporozoite protein (CS) of P. falciparum were demonstrable in 14 persons (11.2% of the study population) by an ELISA test using the recombinant CS-antigen R32tet32, while one person only was positive in an IFA test based on schizonts of P. fieldi as antigen. We concluded that the anti-CS-positive servicemen were probably bitten by mosquitoes carrying P. falciparum parasites while the IFA-positive person was possibly infected by P. vivax, P. ovale or P. malariae parasites. There was no significant association between the different antimalaria preventive measures and the development of anti-CS antibodies. Therefore mefloquine prophylaxis as the single most widely used preventive measure in this group of servicemen was possibly a major contributing factor in averting development of overt malaria.

Review of trials confirms toxicity of mefloquine prophylaxis

Review of trials confirms toxicity of mefloquine prophylaxis

Mefloquine to prevent malaria: a systematic review of trials

Objective: To evaluate the research evidence on the efficacy and tolerability of mefloquine chemoprophylaxis.Search strategy: Any potentially relevant trial from the Cochrane Infectious Disease Group's register of controlled trials; systematic...

People in the UK are to be advised to begin mefloquine prophylaxis 2???3 weeks prior to travel

People in the UK are to be advised to begin mefloquine prophylaxis 2???3 weeks prior to travel

Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial

A prospective randomized double-‘blind’ trial was undertaken during a military exercise in East Africa to determine whether there was a significant difference in the incidence of side effects experienced by soldiers taking mefloquine 250 mg weekly compared with those taking chloroquine 300 mg weekly and proguanil 200 mg daily as chemoprophylaxis for malaria. Subject to their informed voluntary consent, male soldiers who were not aviators were included in the study. Identical questionnaires were completed voluntarily at the end of 2 and 8 weeks. Symptoms were classified by nature into ‘all’, ‘neuropsychological’, ‘enteric’ and ‘other’, and by severity into ‘severe’ and ‘very severe’. The proportions of respondents experiencing side effects were compared to seek statistically significant differences between the chemoprophylactic groups. Quesionnaire 1 was completed after 2 weeks by 183 of 317 subjects (58%) randomly assigned mefloquine and by 176 of 307 subjects (57%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was not significantly different between the groups (71/183 vs. 70/176), odds ratio 0·96 (95% confidence interval [CI] 0·63 to 1·47). Questionnaire 2 was completed after 8 weeks by 145 of 317 subjects (46%) randomly assigned mefloquine and by 142 of 307 subjects (46%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was still not significantly different between the groups (95/145 vs. 103/142), odds ratio 0·72 (95% CI 0·43 to 1·19). None of the subjects developed a serious neuropsychological reaction. Among respondents, 12·8% and 38% admitted lack of full compliance at 2 and 8 weeks, respectively. Exclusion of these subjects during a secondary analysis did not affect the results. None of the subjects developed malaria in the 12 months following return to the UK. Subject to the limitations of a response rate that was smaller than desired and the fact that the study was conducted in fit male military personnel, these results support evidence which indicates that mefloquine is no more toxic than chloroquine-proguanil.

Tolerance of mefloquine chemoprophylaxis in Dutch military personnel.

From June until October 1993, a battalion of Dutch marines was stationed in Cambodia for a United Nations deployment. In 73 volunteers who used mefloquine as malaria chemoprophylaxis, possible mefloquine-related adverse events were monitored with special emphasis on QT prolongation. All participants started mefloquine chemoprophylaxis with a loading dose (250 mg a day for three days) one week before departure, followed by a weekly dose (250 mg) for approximately 25 weeks. One month before (t - 1) and one (t + 1) and three (t + 3) months after mefloquine prophylaxis was started, an at rest electrocardiogram was made. Frequency, PR-, and QT-intervals were measured; blood samples for liver transaminases, total white blood cell count, and mefloquine concentration were obtained after one and three months. Adverse events such as dizziness, headache, coordination problems, and nausea were spontaneously reported in one (1.4%) and three (4.1%) persons at t + 1 and t + 3, respectively, while specific questioning revealed adverse events in nine (12.3%) and five (6.9%) persons, respectively, at the same time point. Three months after starting chemoprophylaxis, the heart rate at rest and total white blood cell count were lower (P < 0.05), while the QTc-interval was longer and levels of liver transaminases increased (P < 0.05), although both were still within the normal range. There was no extreme prolongation of the QTc-interval or increased levels of liver transaminases that resulted in a need to stop the chemoprophylaxis. No accumulation of mefloquine in the serum occurred, and no relationship was observed between the incidence of adverse events and serum mefloquine concentrations. The incidence of self reported mefloquine-related adverse events was low. In conclusion, mefloquine chemoprophylaxis was safe and well-tolerated in this group.

Mefloquine Prophylaxis and Hearing, Postural Control, and Vestibular Functions.

Background: Mefloquine (MQ) is an important antimalarial drug. Dizziness and other adverse neuropsychiatric reactions have however restricted its use. Method: Ten healthy adult volunteers were given MQ (Lariam) 250 mg once weekly for 16 weeks. Measurement of postural sway (posturography), nystagmus recording, determinations of hearing thresholds (Bekesy audiometry), and determinations of drug concentrations were done before, after 4, 32, and 109 days of weekly MQ intake and 3 months after the last dose. Results: All volunteers were able to continue their professional work and normal daily activities. Several mild symptoms were reported. In at least one of the volunteers, these symptoms were probably caused by the MQ intake. Hearing thresholds remained normal. No significant changes were noted in the nystagmus tests. The recorded values of sway index were within the normal range (99% confidence interval) in all volunteers in all test situations, and no differences were seen at the time of maximal drug concentrations (day 109) compared to before or after the study. There was no correlation between the plasma concentrations of MQ, the two MQ enantiomers (RS and SR), or the main mefloquine metabolite and the sway index. Conclusion: Although no effect was seen on the vestibular system in the present study, further tests in a flight simulator will be needed before MQ can be recommended for pilots. (J Travel Med 2:66-69, 1995)

CNS adverse events associated with antimalarial agents. Fact or fiction?

CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too toxic for humans, has been the antimalarial of choice for 40 years. While a range of serious CNS effects have been documented during chloroquine therapy, the incidence is unclear (extrapyramidal symptoms occur with an incidence of 1 in 5000). Amodiaquine has a higher incidence of mild CNS effects than chloroquine. Mefloquine therapy causes dose-related transient dizziness. Serious CNS events during mefloquine therapy occur in 1:1200 Asians and 1:200 Caucasians/Africans. Risk factors include dosage, concomitant drug use/interactions, previous history of a CNS event and disease severity. Retreatment (within a month) increases the risk in Asians 7-fold. Studies indicate that the frequency of serious CNS events with mefloquine prophylaxis (1:10,000) is similar to that with chloroquine (1:13,600). Quinine causes cinchonism at standard therapeutic doses. High-tone hearing loss occurs, but irreversible auditory or ocular effects are very rare. The artemisinin derivatives are associated with dose-dependent brain lesions in rodent, canine and nonhuman primates. At low doses, histological injury has been demonstrated, without clinical neurological signs. No significant toxicity has been reported in humans. Other antimalarial drugs are seldom associated with CNS adverse events. Data do not suggest a need to diminish the correct use of the quinoline derivatives. Irreversible effects are extremely rare and usually associated with overdosing or prior history of a serious CNS event. Concomitant therapeutic use of 2 drugs from the same family, or retreatment with the same drug, should be avoided. Onset of drug-associated serious CNS events requires drug discontinuation and future avoidance of the drug.

Mefloquine Prophylaxis Prevents Malaria during Pregnancy: A Double-Blind, Placebo-Controlled Study

A double-blind, placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy (> 20 weeks of gestation) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border. Mefloquine gave > or = 86% (95% confidence interval [CI], 59%-94%) protection against Plasmodium falciparum and complete protection against Plasmodium vivax infections. Mefloquine prophylaxis was well tolerated; use of an initial loading dose (10 mg/kg) was associated with transient dizziness, but there were no other significant adverse effects on the mother, the pregnancy, or infant survival or development (followed for 2 years). Falciparum malaria was associated with maternal anemia and a mean reduction in birth weight in gravidae I, II, and III of 225 g (95% CI, 26-423). Maternal anemia at delivery (hematocrit < 30%) was associated with increased infant mortality: 26% versus 15% (relative risk, 1.9; 95% CI, 1.1-3.2). Mefloquine is safe and effective for antimalarial prophylaxis in the second half of pregnancy.