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Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe

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... Only the female Anopheles mosquitoes are able to transmit the parasite because they require regular blood meals to develop their eggs; the males only feed on sugary fluids instead. The Anopheles genus has about 430 known species of which [30][31][32][33][34][35][36][37][38][39][40] transmit malaria. To put these figures into perspective, there are 41 mosquito genera grouping 3500 species. ...
... Mefloquine is both a prophylactic and therapeutic for uncomplicated malaria (35). It is a drug of choice for travellers to malaria endemic regions but because of serious toxicities patients must be screened before administration (36)(37)(38)(39). It causes psychological and neurological side effects. ...
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Malaria is one of the oldest infectious diseases that afflict humans and its history extends back for millennia. It was once prevalent throughout the globe but today it is mainly endemic to tropical regions like sub-Saharan Africa and South-east Asia. Ironically, treatment for malaria has existed for centuries yet it still exerts an enormous death toll. This contradiction is attributed in part to the rapid development of resistance by the malaria parasite to chemotherapeutic drugs. In turn, resistance has been fuelled by poor patient compliance to the relatively toxic antimalarial drugs. While drug toxicity and poor pharmacological potentials have been addressed or ameliorated with various nanomedicine drug delivery systems in diseases like cancer, no clinically significant success story has been reported for malaria. There have been several reviews on the application of nanomedicine technologies, especially drug encapsulation, to malaria treatment. Here we extend the scope of the collation of the nanomedicine research literature to polymer therapeutics technology. We first discuss the history of the disease and how a flurry of scientific breakthroughs in the latter part of the nineteenth century provided scientific understanding of the disease. This is followed by a review of the disease biology and the major antimalarial chemotherapy. The achievements of nanomedicine in cancer and other infectious diseases are discussed to draw parallels with malaria. A review of the current state of the research into malaria nanomedicines, both encapsulation and polymer therapeutics polymer-drug conjugation technologies, is covered and we conclude with a consideration of the opportunities and challenges offered by both technologies. Please find the paper it is available online using the DOI: https://doi.org/10.1007/s11095-018-2517-z
... In addition, it was stipulated that only travelers without a contraindication to the medication receive a prescription and that the traveler carry an alert card at all times. 52 The risk of developing severe or disabling neuropsychiatric side effects ranges from 1/607 to 1/20,000 compared with a rate for chloroquine of 1/1181 to 1/13,600. 50 Mefloquine is contraindicated in the setting of allergy to the medication or related compounds (e.g. ...
... Active or recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, convulsions, cardiac conduction abnormalities and treatment with halofantrine or ketoconazole are also contraindications. 52 Mefloquine is an ideal chemoprophylactic agent for long-term travelers, children, and pregnant women, but due to the potential toxicities, it should be reserved when other agents are contraindicated and for areas with high malaria risk such as sub-Saharan African and parts of Oceania. ...
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Malaria, a parasitic disease caused by protozoa belonging to the genus Plasmodium, continues to represent a formidable public health challenge. Despite being a preventable disease, cases reported among travelers have continued to increase in recent decades. Protection of travelers against malaria, a potentially life-threatening disease, is of paramount importance, and it is therefore necessary for healthcare professionals to be up to date with the most recent recommendations. The present review provides an update of the existent measures for malaria prevention among travelers.
... The Eastern Virginia Medical School (EVMS) critical care COVID-19 management protocols of Eastern do not recommend hydroxychloroquine prophylaxis. 6,7 ...
... Mefloquine is recommended for pregnant travelers at significant risk of malaria as prophylaxis by CDC and WHO. Recent strengthened warnings on mefloquine use from both the FDA and the European Medicines Agency may negatively affect prescribers' willingness to recommend mefloquine [91], but there are few alternatives. Atovaquone-proguanil, marketed as Malarone ™ is the most widely prescribed antimalarial for prophylaxis in the UK, but is contraindicated in pregnancy [92,93], although there is little or no data on its safety. ...
Article
Introduction: Over 100 million women and their babies are at risk of malaria in pregnancy each year. Malaria prevention in pregnancy relies on long-lasting insecticidal nets (LLINs), and, in Africa, intermittent preventive treatment in pregnancy (IPTp). Increasing resistance of malaria parasites to sulfadoxine-pyrimethamine, the only drug endorsed for IPTp, and increasing mosquito resistance to pyrethroids used in LLINs, threaten the efficacy of these proven strategies, while operational challenges restrict their implementation in areas of great need. Areas covered: This review summarizes strategies for malaria prevention in pregnancy (both currently used and those undergoing preclinical and clinical evaluation), primarily drawing on publications and study protocols from the last decade. Challenges associated with each strategy are discussed, including the particular problem of HIV and malaria in pregnancy, and areas of further research are highlighted. Expert commentary: Alternative drugs for IPTp are needed. Dihydroartemisinin-piperaquine is particularly promising, but requires further evaluation, and might contribute to artemisinin resistance. Intermittent screening and treatment in pregnancy (ISTp) is an alternative to IPTp that could reduce unnecessary antenatal drug exposure and resistance risk, but it is not recommended with current, insensitive screening tests. Optimal strategies for areas of low or declining malaria transmission remain to be determined.
... It would also provide travel medicine practitioners the option of being able to prescribe a chemoprophylactic agent with a weekly dosing regimen, but without the neuropsychiatric adverse event profile associated with mefloquine [3]. In some jurisdictions, concerns regarding the neuropsychiatric effects of mefloquine have resulted in very restrictive prescribing rules and there is concern that in the future this drug may not be available for special populations [4]. ...
Article
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Background: Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. Methods: The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. Results: At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). Conclusions: As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future.
... Currently, atovaquone/proguanil is the number one choice for malaria prevention in short duration travel. Doxycycline is also widely used while mefloquine use has become more restricted [8]. There is a need for a broader palette of anti-malarials due to the challenges in the choice of the right drug for individual travellers who may have co-morbidities, co-medications, complicated itineraries and exposures, adherence issues, financial limitations and varying duration of travel. ...
... In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. A commentary has discussed the implications of these changes and the possible outcome that mefloquine will be displaced as a firstline anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children may be deprived of an anti-malarial that has been used for these niche groups and for whom no alternative is currently available [7]. ...
Article
Introduction: Malaria prevention can be complex due to the individual characteristics of the traveller, travel destination, duration of stay and type of travel. Our aim in this study was to document malaria chemoprophylaxis recommendations provided by travel-medicine experts in Europe for specific risk groups of travellers visiting malaria-endemic areas of sub-Saharan Africa. Methods: Travel medicine experts in Europe were asked to complete an online questionnaire, a 28-item Survey Monkey survey, on 11 malaria prevention scenarios. We also reviewed the recommendations of the UK, U.S. CDC, Germany, Switzerland, WHO and the electronic Medicines Compendium (eMC) for malaria prevention in risk groups. Results: The questionnaire was sent to 110 travel medicine experts in 19 countries. The response rate was 44.55%. The experts would recommend, as first choice, malaria chemoprophylaxis atovaquone/proguanil for an adult traveller with no co-morbidities travelling for 2 weeks (91.67% of experts) and for 2 months (51.06%), for a healthy tourist child travelling for two weeks (68.09%) and for an adult traveller with liver cirrhosis (57.78%). Mefloquine was the first choice for a healthy tourist child travelling for 2 months (59.57%), for a tourist infant (8 kg) travelling for 2 weeks (59.57%) and for 2 months (68.09%), for a pregnant VFR (74.47%), for a breast-feeding mother with her 5 kg infant (72.34%) and for a VFR family with limited budget (63.83%). For an adult traveller with renal impairment the experts recommended mefloquine (42.22%) or doxycycline (37.78%). All experts (100%) recommended mosquito repellents. Mosquito nets were recommended routinely by 95.35% of the experts, air-conditioning by 83.72% and impregnated clothing by 81.40%. Conclusion: The European experts differ in pre-travel anti-malarial recommendations for risk groups visiting malaria endemic areas of sub-Saharan Africa. Contraindications are not always observed and there are no uniform recommendations for high-risk groups. 9 experts would recommend atovaquone/proguanil to a traveller with severe renal impairment although most reviewed national recommendations consider this a contraindication. Discordance in recommendations, a lack of key data and few chemoprophylaxis options limit choices for pre-travel health advisors.
... In 2013, the US Food and Drug Administration (FDA) issued a "boxed warning" about mefloquine and risk of neurological or psychiatric events, with special warnings to be given to users. However, there remains a lack of clarity over the evidence base for this, and concerns these developments limit the use of an important drug in preventing malaria in travellers [6]. Nevertheless, recently the UK Defence Committee concluded that mefloquine should only be used as a "drug of last resort" [7]. ...
Article
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Background: Mefloquine is recommended in international health guidelines for preventing malaria in travellers. Reports of psychosis and suicide are often alluded to but are not clearly established. Methods: We carried out a systematic review to identify and critically appraise any death or parasuicide associated with mefloquine prophylaxis. We developed a comprehensive search that included publications up to 11 July 2017. We included case studies but excluded newspaper reports. Two authors independently appraised each death or parasuicide against a standardised causality assessment tool. The protocol was registered on PROSPERO (CRD42016041988). Results: We identified 527 articles that required full-text retrieval; of these 17 were unique publications that reported deaths or parasuicide. Eight unique publications had sufficient detail to be included in causality assessment. We identified 2 deaths with a probable association that appeared to be idiosyncratic drug reactions; we categorised the remaining 8 deaths as "unlikely" to be related to mefloquine, or "unclassifiable". There was one parasuicide with a possible causal association. There were 9 additional publications that searched spontaneous drug reporting databases; none provided sufficient detail to perform a causality assessment. Conclusions: Overall, the number of deaths that we could reliably attribute to the prophylactic use of mefloquine is very low.
... Mefloquine's safety profile yet in particular its subsequent association with neurologic or psychiatric adverse events including psychosis and suicide have since raised great concerns among many prescribers and patients alike, and have received significant media attention [3]. As in 2013 the U.S. Food and Drug Administration, and the European Medicines Agency attached special warnings to the use of mefloquine, the access to an important first-line antimalarial for certain group of travelers at high risk for malaria including pediatric, pregnant, or long-term travelers, and travelers visiting friends and relatives (VFR) to malaria holo-endemic regions, had all of a sudden seemed to be at risk, and the quality of evidence underpinning those actions was indeed questioned by some [4]. We, hence, applaud Tickell-Painter et al. to have investigated once again with Cochrane review methodology the efficacy and safety of mefloquine [5], and in particular its alleged associations with deaths and attempted suicides as published in this issue of the journal [6]. ...
... In most areas with malaria, atovaquone-proguanil, doxycycline, and mefloquine are equally effective (>95%) in preventing malaria, but disadvantages (e.g., more reports of adverse events in persons taking doxycycline or mefloquine, as well as resistance to mefloquine) may hamper their use (Table S2 in the Supplementary Appendix). 60 Chemoprophylaxis may be started well before departure (3 to 4 weeks for mefloquine) if there is concern about possible side effects of any drug. Weekly administration of mefloquine, if side effects are not an issue, is preferable for long-term travel because of lower cost and convenience. ...
Article
The scope of illnesses that may befall international travelers is broad. A guide to preparing for the preventable causes of illness is provided. Physicians may find it useful in counseling their patients who travel internationally.
... In addition, doxycycline is contraindicated in pregnant women and younger children, and it is also associated with phototoxicity (10,11). Mefloquine is not recommended in some Southeast Asian countries where mefloquine resistance has emerged, and it is not recommended for pregnant women, infants, and persons with neuropsychiatric disorders (12). For areas where malaria is hyperendemic in Africa, chemoprevention is deployed in the form of intermittent preventive therapy (IPT) and seasonal malaria chemoprevention (SMC) to target high-risk populations, such as children and pregnant women. ...
Article
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New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single-doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for two months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated without any serious adverse events. Four adverse events (transient and slight elevation of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale . These trials showed that NQAZ had a good safety profile and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.
... Malaria prevention in travellers can be complex and requires consideration of a number of factors including the individual characteristics of the traveller, travel destination, duration of stay and type of travel. It is further complicated by differing international guidelines [8] and prescribing restrictions [9]. Committee on Malaria Prevention (ACMP) guidelines for malaria prevention in travellers from the UK and WHO guidance adhere with the 'ABCD' approach to malaria prevention. ...
Article
Background: Malaria prevention in travellers can be complex and requires consideration of a number of factors. UK healthcare professionals providing pre-travel malaria advice can access specialist support from the National Travel Health Network and Centre (NaTHNaC) telephone advice line. The aim of this study is to characterise queries to the NaTHNaC telephone advice line regarding pre-travel malaria advice. Method: Telephone calls received to NaTHNaC's advice line are recorded using an online data capture form. All calls relating to malaria advice during 2016 were selected and data extracted. Analysis was undertaken using Microsoft Excel and STATA. Results: During 2016, 1803 malaria-related calls were received; the majority from general practice and calls were from across the UK. The most common type of pre-travel malaria query was country-specific followed by travellers with special health needs. Many queries related to pregnant and breastfeeding travellers, children under 5 years and travellers over 60 years. Conclusions: This review presents a large and exceptional dataset and reflects the ambiguity amongst some healthcare professionals regarding malaria advice. We have identified potential knowledge gaps, and as a result will strengthen future guidance, enhance existing malaria maps, and inform the development of future clinical educational activity.
... Tafenoquine is the only once-weekly prophylaxis that can be used in areas with chloroquine-and mefloquineresistant parasites. Tafenoquine can also provide an alternative weekly prophylaxis regimen to mefloquine, but potentially without the concerns regarding NPAEs that restrict mefloquine use [4,8]. Thus, the NPAE profile of tafenoquine is of great clinical interest. ...
Article
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Background: Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers' prophylaxis. The development of tafenoquine has been conducted over many years, using various dosing regimens in diverse populations. Methods: This review brings together all the preclinical and clinical data concerning tafenoquine central nervous system safety. Data were assembled from published sources. The risk of neuropsychiatric adverse events (NPAEs) with single-dose tafenoquine (300 mg) in combination with chloroquine to achieve P. vivax relapse prevention is particularly examined. Results: There was no evidence of neurotoxicity with tafenoquine in preclinical animal models. In clinical studies in P. vivax relapse prevention, nervous system adverse events, mainly headache and dizziness, occurred in 11.4% (36/317) of patients with tafenoquine (300 mg)/chloroquine versus 10.2% (19/187) with placebo/chloroquine; and in 15.5% (75/483) of patients with tafenoquine/chloroquine versus 13.3% (35/264) with primaquine (15 mg/day for 14 days)/chloroquine. Psychiatric adverse events, mainly insomnia, occurred in 3.8% (12/317) of patients with tafenoquine/chloroquine versus 2.7% (5/187) with placebo/chloroquine; and in 2.9% (14/483) of patients with tafenoquine/chloroquine versus 3.4% (9/264) for primaquine/chloroquine. There were no serious or severe NPAEs observed with tafenoquine (300 mg)/chloroquine in these studies. Conclusions: The risk:benefit of single-dose tafenoquine/chloroquine in P. vivax relapse prevention is favourable in the presence of malaria, with a low risk of NPAEs, similar to that seen with chloroquine alone or primaquine/chloroquine.
... This oral medication has a half-life of about three weeks and appears to be active against SARS-CoV-2 in vitro, which makes it suitable for weekly antiviral prophylaxis. 59,60 The troubling neuropsychiatric side effects of mefloquine make the drug a less attractive option for PrEP. ...
Article
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To date, more than 35 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), and more than one million have died in the COVID-19 pandemic. International economies are stalled and social isolation based on palpable fear of death remains the order of the day. The United States and other countries are moving toward resuming work activities and social interaction to boost economic recovery. While this makes financial sense, from a medical perspective our population has already suffered and will continue to suffer severe losses in the absence of a viable aggressive prophylaxis strategy for SARS-CoV-2. Herein, we present a plan to address this problem.
Article
Background: There are several possible malaria prevention strategies for travellers. In Switzerland, chemoprophylaxis (CP) is recommended for persons visiting areas highly endemic for malaria and stand-by emergency treatment (SBET) for areas with moderate to low risk. Objective: To describe the type of malaria prevention prescribed to travel clinic attendees with a specific focus on changes over time following adaptation of recommendations. Methods: All pre-travel first consultation data recorded between November 2002 and December 2012 were included. Country-specific malaria preventive recommendations provided and medicines prescribed over time were analysed. Results: In total, 64 858 client-trips were recorded. 91% of travellers planned to visit a malaria endemic country. Among those clients, 42% were prescribed an antimalarial medicine as CP only, 36% as SBET only, and 3% both. Between 2002 and 2012, there was a 16% drop of CP prescription ( P < 0.001) and a 21% increase of SBET prescription ( P < 0.001). Among travellers receiving CP, the proportion of those prescribed mefloquine dropped from 82% in 2002 to 46% in 2012 while those prescribed atovaquone-proguanil (AP) increased from 7% to 39%. For those prescribed SBET, the proportion dropped from 46% to 30% for AP and increased from 2% to 61% for artemether-lumefantrine. CP prescription for travellers to India fell from 62% to 5% and SBET prescription increased from 40% to 88% after the change of recommendation from CP to SBET in 2005 for this country. Comparatively, CP prescription for travellers to Senegal, for which no change of recommendation occurred, remained relatively stable between 88% in 2002 and 89% in 2012. Conclusion: This study shows the considerable decline of antimalarial prescription for chemoprophylaxis that occurred over the 10-year period in favour of SBET.
Article
Introduction: Malaria in pregnancy continues to be a significant public health burden globally, with over 100 million women at risk each year. Sulfadoxine-pyrimethamine (SP) is the only antimalarial recommended for intermittent preventive therapy in pregnancy (IPTp) but increasing parasite resistance threatens its viability. There are few other available antimalarial therapies that currently have sufficient evidence of tolerability, safety, and efficacy to replace SP. Areas covered: Novel antimalarial combinations are under investigation for potential use as chemoprophylaxis and in IPTp regimens. The present review summarizes currently available therapies, emerging candidate combination therapies, and the potential challenges to integrating these into mainstream policy. Expert opinion: Alternative drugs or combination therapies to SP for IPTp are desperately required. Dihydroartemisinin-piperaquine and azithromycin-based combinations are showing great promise as potential candidates for IPTp but pharmacokinetic data suggest that dose modification may be required to ensure adequate prophylactic efficacy. If a suitable candidate regimen is not identified in the near future, the success of chemopreventive strategies such as IPTp may be in jeopardy.
Article
La quimioprofilaxis antipalúdica es esencial para la protección frente al paludismo durante un viaje, como complemento de la protección contra los vectores. Sus modalidades varían en función del riesgo de cada viaje. Los Plasmodium sólo son sensibles a la cloroquina en algunas regiones del Caribe y América Latina, donde es factible prescribir este fármaco (dosis de 1,7 mg/kg al día, durante la estancia y 4 semanas tras el retorno). En cualquier otro lugar, es preciso elegir entre atovacuona-proguanil, mefloquina y doxiciclina. Atovacuona-proguanil dispone de una presentación pediátrica en comprimidos, utilizable a partir de los 5 kg de peso (sin autorización de comercialización en Francia, en niños de 5-10 kg de peso; luego un comprimido pediátrico al día por cada 10 kg de peso hasta los 40 kg). Tras el regreso, solamente debe continuarse durante 1 semana. La mefloquina no tiene presentación pediátrica (5 mg/kg a la semana desde los 15 kg de peso y, sin autorización de comercialización en Francia, con 5-15 kg de peso). Se administra una vez por semana, pero debe continuarse durante 3 semanas tras el regreso (tres tomas). Su tolerabilidad debe probarse antes de la partida, pero parece buena en los niños. La doxiciclina (50 mg/día para un peso inferior a 40 g y 100 mg/día por encima de ese peso) se reserva para los niños mayores de 8 años. La quimioprofilaxis es indispensable en toda el África subsahariana, donde el riesgo de paludismo por Plasmodium falciparum es importante. Se valora con el viajero para las demás áreas, donde el riesgo es bajo o variable, y en función del tipo de viaje. La elección entre los diferentes fármacos depende de las contraindicaciones, el cumplimiento previsible y el coste.
Article
Background: A primary reason for non-adherence to malaria chemoprophylaxis is fear of latent side effects. We examined latent effects of malaria chemoprophylaxis among Returned Peace Corps Volunteers (RPCVs). Methods: During July 18-September 16, 2016, RPCVs who served during 1995-2014 with an e-mail address in Peace Corps' RPCV database were invited to take an internet-based survey on malaria prophylaxis and medical diagnoses. "Good adherence" meant taking prophylaxis "as prescribed" or "most of the time." Prevalence of diseases diagnosed after Peace Corps service was compared between users and nonusers of each antimalarial using log-binomial regression. Results: Of 8931 participants (11% response rate), 5055 (57%) took chemoprophylaxis. Initial chemoprophylaxis was mefloquine 59%, chloroquine 13%, doxycycline 16%, atovaquone-proguanil 4%, and "other" 8%. Sixty percent reported good adherence. Mefloquine users had the best adherence (67% good adherence). Prevalences of most diseases were similar between exposed and unexposed groups. Certain psychiatric diagnoses were slightly more likely among mefloquine users (PR 1.14, 95% CI [1.04-1.25], P = 0.0048). When excluding those with prior psychiatric illness, there were no differences in psychiatric diagnosis rates. Conclusion: Malaria chemoprophylaxis use by Peace Corps Volunteers is safe. Avoiding mefloquine use in those with prior psychiatric illness can reduce psychiatric side effects.
Article
Background: The UK deployed a task force to Sierra Leone to assist in ending the 2014/15 Ebola outbreak. Malaria protection was based on existing Defence Policy which saw a wide range of bite prevention measures deployed. Atovaquone/Proguanil ("A/P"), Doxycycline ("D") and Mefloquine ("M") were the chemoprophylactic medications that were prescribed. A survey was undertaken to audit the Adverse Effect (AE) burden experienced by the population. Method: A questionnaire based survey was administered that sought information on individuals' experiences with malaria chemoprophylaxis. Results: 337 personnel were eligible to take part and 151 (46.3%) individuals returned questionnaires. The reported AE rates for the three drugs were "A/P" 28% of the respondents, "D" 25% and "M" 23.1%. 24 individuals (15.9%) reported 1 AE while 34 (22.5%) reported multiple AEs. Eight (5.3%) individuals changed medication (Five "A/P", two "M" and one "D" because of unacceptable AE but no significant neuro/psychological conditions were reported. The malaria attack rate for the deployed population was 0.4 cases per thousand person weeks which is very low when compared to other military deployments to the West African Area. Conclusion: UK Defence policy is effective in the way it balances the risk of malaria with that of AE due to chemoprophylaxis. "M" remains an acceptable chemoprophylactic agent for a section of the population.
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Die Mobilität ist in den letzten Jahrzehnten in allen Bevölkerungsschichten massiv angestiegen. Mehr Freizeit bzw. Urlaub, Billigflüge, ein zunehmendes Angebot an Kreuzfahrten, wohl aber auch die Sehnsucht, andere Länder und Kulturen kennenzulernen, führen immer mehr Menschen nicht nur in europäische Urlaubsdestinationen, sondern auch in entfernte Regionen mit oft nur eingeschränkter medizinischer Versorgung. Häufig werden dabei die Kinder mit auf die Reise genommen. Interessanterweise ist das Thema „Reisemedizin“ im Erwachsenbereich gut besetzt, im Kinder- und Jugendbereich gibt es dazu aber relativ wenig Literatur und kaum Forschung. In diesem Beitrag werden einige Aspekte der pädiatrischen Reisemedizin beleuchtet. Angesprochen werden u. a. Fragen der Hygiene, der Versorgung mit Nahrung und Wasser, der Infektionsprophylaxe, des Sonnenschutzes und der medizinischen Versorgung im Krankheitsfall. Beschrieben werden auch Möglichkeiten, die das „Wohlfühlen“ von Kindern auf Reisen gewährleisten können. Des Weiteren werden die Themen Flugtauglichkeit und Höhenaufenthalt behandelt. Schließlich wird dargestellt, welche Gegenstände und Medikamente sich in einer Reiseapotheke für Kinder befinden sollen. Gemeinsam mit den anderen 3 Arbeiten dieses Themenhefts sollen Kinder- und Jugendärzte ausreichend Information erhalten, um Eltern für Reisen mit Kindern kompetent beraten zu können.
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Background Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. Methods We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. Results Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%–13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%–0.1% among other antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%–15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%–1.4% among users of other antimalarials). Conclusions The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women.
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Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (-)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (K i = 0.71-341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine's effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [(3)H]5-HT uptake by the 5-HT transporter. Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines.
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Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but its prescribing requires careful attention to rule out contraindications to its use, including a history of certain psychiatric and neurological disorders. The prevalence of these disorders has not been defined in cohorts of U.S. military personnel deployed to areas where long-term malaria chemoprophylaxis is indicated. Military medical surveillance and pharmacosurveillance databases were utilized to identify contraindications to mefloquine use among a cohort of 11,725 active duty U.S. military personnel recently deployed to Afghanistan. A total of 9.6% of the cohort had evidence of a contraindication. Females were more than twice as likely as males to have a contraindication (OR = 2.48, P < 0.001). These findings underscore the importance of proper systematic screening prior to prescribing and dispensing mefloquine, and the need to provide alternatives to mefloquine suitable for long-term administration among deployed U.S. military personnel.
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Mefloquine is a 4-methanolquinoline anti-malarial that in recent years has fallen out of favor for use as chemoprophylaxis against infection with chloroquine-resistant Plasmodium falciparum malaria owing in part to growing concerns of side effects and potential neurotoxicity. Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine's neuropsychiatric and physical side effects and the clinical significance of the drug's neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. It is posited that these effects represent an idiosyncratic neurotoxic syndrome of progressive limbic encephalopathy and multifocal brainstem injury caused by the drug. This case provides insights into the clinical significance of mefloquine neuronal gap junction blockade and neurotoxicity demonstrated in animal models, points to recommendations for the management of affected patients including diagnostic considerations and appropriate referrals, and highlights critical implications for the continued safe use of the medication.
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Malaria infects 10,000 to 30,000 international travellers each year. It can be prevented through anti-mosquito measures and drug prophylaxis. However, antimalaria drugs have adverse effects which are sometimes serious. To compare the effects of currently used antimalaria drugs when given as prophylaxis to non-immune adult and child travellers who are travelling to regions with Plasmodium falciparum resistance to chloroquine. Specifically, to assess the efficacy, safety, and tolerability of atovaquone-proguanil, doxycycline, and mefloquine compared to each other, and also when compared to chloroquine-proguanil and to primaquine. In August 2009 we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, LILACS, BIOSIS, mRCT, and reference lists. We handsearched conference proceedings and one specialist journal, and contacted researchers and drug companies. We searched PubMed for drug-related deaths. Randomized and quasi-randomized controlled trials of any antimalaria drug regimen currently used by non-immune international travellers. We independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We resolved any disagreement through discussion. We combined dichotomous outcomes using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI). Eight trials (4240 participants) met the inclusion criteria. Evidence on comparative efficacy from head-to-head comparisons was limited. Atovaquone-proguanil compared to doxycycline had similar adverse events reported. Compared to mefloquine, atovaquone-proguanil users had fewer reports of any adverse effect (RR 0.72, 95% CI 0.6 to 0.85), gastrointestinal adverse effects (RR 0.54, 95% CI 0.42 to 0.7), neuropsychiatric adverse events (RR 0.86, 95% CI 0.75 to 0.99), and neuropsychiatric adverse effects (RR 0.49, 95% CI 0.38 to 0.63), besides a better total mood disturbance score (MD -7.20, 95% CI -10.79 to -3.61). Similarly, doxycycline users had fewer reported neuropsychiatric events than mefloquine users (RR 0.84, 95% CI 0.73 to 0.96). We also examined these three regimens against chloroquine-proguanil; this latter regimen had more reports of any adverse effect (RR 0.84, 95% CI 0.73 to 0.96) and of gastrointestinal adverse effects (RR 0.71, 95% CI 0.6 to 0.85). Atovaquone-proguanil and doxycycline are the best tolerated regimens, and mefloquine is associated with adverse neuropsychiatric outcomes.
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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).
Malaria chemoprophylaxis regimens: a descriptive drug utilisation study
  • M Bloechliger
  • P Schlagenhauf
  • S Toovey
  • G Schnetzler
  • I Tatt
  • D Tomjanovic
Bloechliger M, Schlagenhauf P, Toovey S, Schnetzler G, Tatt I, Tomjanovic D, et al. Malaria chemoprophylaxis regimens: a descriptive drug utilisation study. Travel Med Infect Dis 2014; 12(6PtB):718e25.