Use Of Mefloquine Research Articles

Malaria in long-term travelers: Infection risks and adherence to preventive measures – A prospective cohort study

BackgroundChemoprophylaxis and anti-mosquito measures are key to preventing malaria in travelers. Long-term travelers are at higher risk than short-term travelers, but their adherence to preventive measures is lower. Our aim was to determine malaria exposure risks and predictors for adherence to malaria-preventive measures in long-term travelers. MethodsLong-term travelers (>12 weeks) completed a weekly questionnaire about preventive measures, symptoms, and malaria treatment abroad. Blood samples were tested for seroconversion to Plasmodium falciparum anti-circumsporozoite (PfCSP) antibody. Adherence to preventive measures was defined as number of weeks of their usage divided by number of weeks in malaria-endemic areas. ResultsOf 561 travelers, the median travel time was 20 weeks (IQR 16–25). Eighteen were treated for malaria, all in sub-Saharan Africa. Sixteen PfCSP seroconversions were found, of whom only 3 had traveled to high-endemic areas. Of the 18 travelers treated for malaria, only one seroconverted. No associations were found between covariates and seroconversion. Neither treatment abroad nor seroconversion were reliable predictors for exposure. ‘Full adherence’ to chemoprophylaxis was reported by 52% (218/417) and was associated with travel to Africa, use of mefloquine, lack of prior travel history, shorter duration of travel, and use of DEET. ConclusionsThe risk of malaria in this long-term travelers cohort was low. Our data confirm that anti-PfCSP seroconversion is not a reliable method to retrospectively identify incident infection, or probably exposure. Prevention efforts should focus on more experienced travellers and longer travel duration, for whom mefloquine should be considered as the first-choice chemoprophylaxis.

A Cross-sectional Cohort Study to Assess Long-term Neurocognitive and Psychiatric Symptoms of Mefloquine Use in Veterans.

To evaluate the associations between neurocognitive and psychiatric health outcomes with mefloquine or any antimalarial exposure. Medical records were systematically reviewed to identify veterans that indicated antimalarial medication use. Linear regression was performed to examine associations between mefloquine/antimalarial exposure and health outcomes. The mefloquine-exposed group was further compared with normative populations for the same health outcomes. In the adjusted models, no significant differences were noted between the two exposure groups and the unexposed group for any of the health measures (P-value > 0.05). When compared to normative population samples, the mefloquine-exposed group had poorer health and greater neurobehavioral symptom severity or cognitive complaints. This study suggests that mefloquine use by veterans referred for intensive evaluation of their military deployment exposures and health was not associated with increased, long-term, neurocognitive/psychiatric symptoms compared to unexposed veterans.

Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins.

Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of Plasmodium falciparum (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate the differences of stabilities of mefloquine–PfACBP749 and mefloquine–hACBP complexes. The stability of mefloquine in the binding cavity of PfACBP749 is less than its stability in the binding pocket of hACBP. Although the essential tyrosine residues (tyrosine-30 and tyrosine-33 of PfACBP749 and tyrosine-29 and tyrosine-32 of hACBP) mediate the initial binding of mefloquine to the proteins by π-stacking interactions, additional temporally longer interactions between mefloquine and aspartate-22 and methionine-25 of hACBP result in stronger binding of mefloquine to hACBP. The higher fluctuation of mefloquine-binding residues of PfACBP749 contributes to the instability of mefloquine in the binding cavity of the protein. On the contrary, in the mefloquine-bound state, the stability of hACBP protein is less than the stability of PfACBP749. The helix-to-coil transition of the N-terminal hydrophobic region of hACBP has a destabilizing effect upon the protein’s structure. This causes the induction of aggregation properties in the hACBP in the mefloquine-bound state. Taken together, we describe the mechanistic features that affect the differential dynamic stabilities of mefloquine-bound PfACBP749 and hACBP proteins.

Ex vivo susceptibility of Plasmodium falciparum to antimalarial drugs in Northern Uganda

In Uganda, artemether-lumefantrine was introduced as an artemisinin-based combination therapy (ACT) for malaria in 2006. We have previously reported a moderate decrease in ex vivo efficacy of lumefantrine in Northern Uganda, where we also detected ex vivo artemisinin-resistant Plasmodium falciparum. Therefore, it is necessary to search for candidate partner alternatives for ACT. Here, we investigated ex vivo susceptibility to four ACT partner drugs as well as quinine and chloroquine, in 321 cases between 2013 and 2018. Drug-resistant mutations in pfcrt and pfmdr1 were also determined. Ex vivo susceptibility to amodiaquine, quinine, and chloroquine was well preserved, whereas resistance to mefloquine was found in 45.8%. There were few cases of multi-drug resistance. Reduced sensitivity to mefloquine and lumefantrine was significantly associated with the pfcrt K76 wild-type allele, in contrast to the association between chloroquine resistance and the K76T allele. Pfmdr1 duplication was not detected in any of the cases. Amodiaquine, a widely used partner drug for ACT in African countries, may be the first promising alternative in case lumefantrine resistance emerges. Therapeutic use of mefloquine may not be recommended in this area. This study also emphasizes the need for sustained monitoring of antimalarial susceptibility in Northern Uganda to develop proper treatment strategies.

Rationale for use mefloquine for COVID-19 treatment

Currently, the use of mefloquine in patients with COVID-19 does not have sufficient scientific justification and, given the unfavorable efficacy and safety profile, cannot be considered for routine use in clinical practice.

Evidence for linkage of pfmdr1, pfcrt, and pfk13 polymorphisms to lumefantrine and mefloquine susceptibilities in a Plasmodium falciparum cross

BackgroundLumefantrine and mefloquine are used worldwide in artemisinin-based combination therapy (ACT) of malaria. Better understanding of drug susceptibility and resistance is needed and can be obtained from studies of genetic crosses. MethodsDrug response phenotypes of a cross between Plasmodium falciparum lines 803 (Cambodia) and GB4 (Ghana) were obtained as half-maximal effective concentrations (EC50s) and days to recovery (DTR) after 24 h exposure to 500 nM lumefantrine. EC50s of mefloquine, halofantrine, chloroquine, and dihydroartemisinin were also determined. Quantitative trait loci (QTL) analysis and statistical tests with candidate genes were used to identify polymorphisms associated with response phenotypes. ResultsLumefantrine EC50s averaged 5.8-fold higher for the 803 than GB4 parent, and DTR results were 3–5 and 16–18 days, respectively. In 803 × GB4 progeny, outcomes of these two lumefantrine assays showed strong inverse correlation; these phenotypes also correlated strongly with mefloquine and halofantrine EC50s. By QTL analysis, lumefantrine and mefloquine phenotypes mapped to a chromosome 5 region containing codon polymorphisms N86Y and Y184F in the P. falciparum multidrug resistance 1 protein (PfMDR1). Statistical tests of candidate genes identified correlations between inheritance of PfK13 Kelch protein polymorphism C580Y (and possibly K189T) and lumefantrine and mefloquine susceptibilities. Correlations were detected between lumefantrine and chloroquine EC50s and polymorphisms N326S and I356T in the CVIET-type P. falciparum chloroquine resistance transporter (PfCRT) common to 803 and GB4. ConclusionsCorrelations in this study suggest common mechanisms of action in lumefantrine, mefloquine, and halofantrine responses. PfK13 as well as PfMDR1 and PfCRT polymorphisms may affect access and/or action of these arylaminoalcohol drugs at locations of hemoglobin digestion and heme metabolism. In endemic regions, pressure from use of lumefantrine or mefloquine in ACTs may drive selection of PfK13 polymorphisms along with versions of PfMDR1 and PfCRT associated with lower susceptibility to these drugs.

Comparative study of mefloquine and sulphadoxine-pyrimethamine for malaria prevention among pregnant women with HIV in southwest Nigeria

To compare the effectiveness of mefloquine and sulphadoxine-pyrimethamine as intermittent preventive therapy for malaria among pregnant women with HIV. The present randomized, controlled, prospective, open-label study enrolled women with HIV who had reached at least 16weeks of pregnancy attending prenatal clinics at secondary and tertiary health facilities in South West Nigeria between January 1 and August 31, 2016. Block randomization was used to assign patients to treatment with mefloquine or sulphadoxine-pyrimethamine for malaria prophylaxis. The primary outcome was malaria parasitemia at delivery. Data were compared with the χ2 and t tests on a per-protocol basis. Of 142 women enrolled and randomized equally to each group, 131 (92.3%) completed the study (64 in the mefloquine group and 67 in the sulphadoxine-pyrimethamine group). Blood-sample malaria parasites were isolated from 6 (9%) and 5 (7%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at enrolment, and 6 (9%) and 9 (13%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at delivery; the differences between the groups was not significant at enrolment (P=0.693) or delivery (P=0.466). Outcomes following prophylactic use of mefloquine for intermittent preventive therapy for malaria among pregnant women with HIV were comparable to sulphadoxine-pyrimethamine treatment; mefloquine is a feasible alternative therapy. ClinicalTrials.gov: NCT02524444.

Deaths and parasuicides associated with mefloquine chemoprophylaxis: A systematic review.

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. We carried out a systematic review of the literature to identify and critically appraise any reported 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). 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. Overall, the number of deaths that we could reliably attribute to the prophylactic use of mefloquine is very low.

Anti-proliferative and anti-angiogenic activities of ion-channel modulators: In-ovo, in-vitro and in-vivo study

ObjectiveAngiogenesis is the development of new blood vessels. The ion channels on endothelium play a vital action in cell proliferation and so in the related angiogenesis. We aimed to investigate the anti-angiogenic effects of Mefloquine (Cl− channel blocker) and 4-Aminopyridine (K+ channel blocker). MethodsThe anti-angiogenic activities of Mefloquine and 4-Aminopyridine (4-AP) were investigated by in-vivo (sponge implantation method), in-vitro (aortic ring assay) and in-ovo (CAM, Chick Chorioallantoic membrane) methods. The standard antiangiogenic drug used was Bevacizumab. ResultsIn the CAM assay, both the ion channel blockers exhibited noticeable antiangiogenic activity at the concentrations of 10−5 M and 10−4 M where they significantly exhibited ant proliferative activity by inhibiting the new blood vessel formation. For the further confirmation anti-angiogenic activity was evaluated in vitro and in vivo. In Rat aortic ring assay reduction in the area of sprouts were observed with 40 μM of 4-AP and 7 μM of Mefloquine. A significant reduction in weight of sponges, number of blood vessels formed and hemoglobin content were observed at 4.2 mg/kg of 4-AP and 20 mg/kg and 30 mg/kg of Mefloquine. ConclusionsThese scientific findings indicate the use of Mefloquine and 4-Aminopyridine in pathological situations involving excessive angiogenesis. Negative regulation of cell volume, cell migration and proliferation of blood vessels may be the underlying molecular mechanisms.

Long term health outcomes among Returned Peace Corps Volunteers after malaria prophylaxis, 1995-2014.

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). 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. 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. Malaria chemoprophylaxis use by Peace Corps Volunteers is safe. Avoiding mefloquine use in those with prior psychiatric illness can reduce psychiatric side effects.

Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: A pooled analysis of 19, 850 individual patients.

Mefloquine (MQ) has been used for the treatment of malaria since the mid-1980s, first as monotherapy or as fixed combination with sulfadoxine-pyrimethamine (MSP) and since the mid-1990s in combination with artesunate. There is a renewed interested in MQ as part of a triple therapy for the treatment of multi-drug resistance P. falciparum malaria. The widespread use of MQ beyond south-East Asia has been constrained by reports of poor tolerability. Here we present the side effect profile of MQ for the treatment of uncomplicated malaria on the Thai-Myanmar/Cambodia borders. In total 19,850 patients received seven different regimens containing either 15 or 24–25 mg/kg of MQ, the latter given either as a single dose, or split over two or three days. The analysis focused on (predominantly) gastrointestinal and neuropsychiatric events as compared to the new fixed dose combination of MQ plus artesunate given as equal doses of 8 mg/kg MQ per day over three days. Gastrointestinal side effects were dose-dependent and associated with the severity of malaria symptoms. Serious neuropsychiatric side effects associated with MQ use were rare: for a single 25 mg/kg dose it was 11.9 per 10,000 treatments (95% confidence interval, CI, 4–285) vs. 7.8 (3–15) for the 15 mg/kg dose. The risk with 25 mg/kg was much higher when it was given as repeat dosing in patients who had failed treatment with 15 mg/kg MQ in the preceding month; (RR 6.57 (95% CI 1.33 to 32.4), p = 0.0077). MQ was best tolerated as 15 mg/kg or as 24 mg/kg when given over three days in combination with artesunate. We conclude that the tolerance of a single dose of MQ in the treatment of uncomplicated malaria is moderate, but can be improved by administering it as a split dose over three days.

Identification of a Syndrome Class of Neuropsychiatric Adverse Reactions to Mefloquine from Latent Class Modeling of FDA Adverse Event Reporting System Data.

IntroductionAlthough mefloquine use is known to be associated with a risk of severe neuropsychiatric adverse reactions that are often preceded by prodromal symptoms, specific combinations of neurologic or psychiatric reactions associated with mefloquine use are not well described in the literature. This study sought to identify a distinct neuropsychiatric syndrome class associated with mefloquine use in reports of adverse events.MethodsLatent class modeling of US Food and Drug Administration Adverse Event Reporting System (FAERS) data was performed using indicators defined by the Medical Dictionary for Regulatory Activities neurologic and psychiatric high-level group terms, in a study dataset of FAERS reports (n = 5332) of reactions to common antimalarial drugs.ResultsA distinct neuropsychiatric syndrome class was identified that was strongly and significantly associated with reports of mefloquine use (odds ratio = 3.92, 95% confidence interval 2.91–5.28), defined by a very high probability of symptoms of deliria (82.7%) including confusion and disorientation, and a moderate probability of other severe psychiatric and neurologic symptoms including dementia and amnesia (18.6%) and seizures (18.1%). The syndrome class was also associated with symptoms that are considered prodromal including anxiety, depression, sleep disturbance, and abnormal dreams, and neurological symptoms such as dizziness, vertigo, and paresthesias.ConclusionsThis study confirms in FAERS reports the existence of a severe mefloquine neuropsychiatric syndrome class associated with common symptoms that may be considered prodromal. Clinical identification of the characteristic symptoms of this syndrome class may aid in improving case finding in pharmacovigilance studies of more serious adverse reactions to the drug.

Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection

Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5–8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.

Pattern of Antimalarial Drug Use in Malaysia

This work aims to identify the pattern of antimalarial use in Malaysia as a baseline data on common drugs used in the local setting. Data on malaria prevalence and drug use pattern over the past 10-years was collected retrospectively from Vector Borne Disease Sector and Pharmaceutical Services Division, Ministry of Health. The defined daily dose/inhabitant/years is used to describe the antimalarial utilization pattern. We observed a decline of 42% malaria cases within a span of 10 years despite a steady increase in the number of P. knowlesi cases noted in Malaysia. Infections caused by the P. falciparum and P. vivax species demonstrated a reduction in cases within the span of 10 years. Between 2005 and 2013 both chloroquine and primaquine were noted to be the most common antimalarial drugs used, followed by pyrimethamine-combination and quinine. Artemisinin in particularly artesunate and mefloquine use were found to be limited during the study period. Despite being one of the oldest drugs, the quinolines were found to be the most common antimalarials used. The use of primaquine is highlighted due to the gradual increase in the use of the drug in recent years. Indeed, the general decrease in antimalarial use is attributed to the distinct reduction in malaria cases in the country.

Opportunities missed to review mefloquine use in the UK military

Opportunities missed to review mefloquine use in the UK military

Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria.

Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane-mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.

Use of mefloquine (Lariam) in UK military under scrutiny

Use of mefloquine (Lariam) in UK military under scrutiny

Eye disorders reported with the use of mefloquine (Lariam(®)) chemoprophylaxis--A drug safety database analysis.

Between 80 and 90 million travellers visit malaria endemic areas annually and many require malaria chemoprophylaxis. The characterization of the risk and nature of eye disorders occurring during the use of malaria chemoprophylaxis is relevant for travel medicine advisors. We did a database analysis on eye disorder adverse events reported for mefloquine (as Lariam®) using the F. Hoffmann-La Roche global drug safety database for the time frame February 1984 to January 18th, 2011. These adverse event reports were reviewed by a trained ophthalmologist. The analysis focused on 3 categories of eye disorders--Category 1: visual acuity; Category 2: anatomical parts of the eye and Category 3: neuro-ophthalmic events. To put our analysis in context, an extensive literature search on "mefloquine" and "eye disorders" was conducted. A total of 591 cases with 695 events assigned to the "Eye disorder" SOC in individuals exposed to mefloquine chemoprophylaxis were reported. The highest proportion of events (n = 493, 70.9%) was in Category 1: visual acuity (mainly visual impairment and blurred vision), followed by Category 3: neuro-ophthalmic events (n = 124, 17.8%). The majority of visual adverse events were non-serious but 37.7% (n = 223) of cases were classified as serious. Nine events of maculopathy were reported and 48 cases with 53 events described symptoms of optic neuropathy. Mefloquine, like other anti-malarials, may be associated with eye disorders. Prescribers of anti-malarials should inform travellers regarding the risk of potential ocular side effects. Users of chemoprophylaxis who experience visual disorders should be referred to an ophthalmologist.

Guantanamo: America's Battle Lab

Guantanamo: America's Battle Lab

Assessment of mefloquine in-vivo efficacy on juvenile and adult stages of Schistosoma haematobium (Egyptian strain)

Background The large-scale use of praziquantel might result in selection of drug-resistant parasites. Hence, there is an important need to develop new antischistosomal compounds. Objective This study aimed for assessment of antischistosomal properties of an antimalarial drug, mefloquine (MFQ), on juvenile and adult Schistosoma haematobium worms. Materials and methods Infected hamsters were divided into two main groups, I and II, each subdivided into (a) and (b) subgroups. Groups Ia and IIa received 200 mg/kg MFQ as single oral dose, 49 and 82 days postinfection, respectively. Groups Ib and IIb served as untreated controls, respectively. Ten days later, animals were killed. Parasitological assessment (worm burden, tissue egg load, and oogram pattern), histopathological examination, and scanning electron microscopy were performed to evaluate MFQ efficacy. Results MFQ treatment of the juvenile group Ia resulted in considerable worm burden reductions of 75.9, 69.6, and 88.6% for male, female, and coupled worms, respectively. In the treated adult group IIa, the corresponding results were 24.8 and 95% for male and coupled worms, respectively. Separate female worms were detected only in the treated groups. In group IIa treated animals, MFQ also had an observed but statistically insignificant effect on tissue egg load and oogram pattern. Schistosomal granuloma area, diameters, and numbers were insignificantly decreased. Tegumental changes of treated worms in the form of shrunken deformed tegument, loss or flattening of tubercles, furrows, and blebbing were observed. Conclusion Results concluded by this study elucidate promising MFQ antischistosomal efficacy on both juvenile and adult stages of S. haematobium with more evident effect on juvenile forms, which enforces the potential use of MFQ as an effective antischistosomal drug.