Effects Of Mefloquine Research Articles

Blockade by mefloquine of intercellular electrical coupling between vascular endothelial cells in the guinea-pig mesenteric arteries

Mefloquine, an antimalarial drug, has been reported to block exogenously transfected gap junctions composed of either C x 36 or C x 50 more potently than those composed of other connexins. Using the conventional whole-cell clamp technique, we investigated the effects of mefloquine on intercellular electrical coupling in vascular endothelial cells of guinea-pig mesenteric arteries, where expressions of C x 40 and C x 43 have been identified. Mefloquine (50 microM) almost abolished the current required to impose a 10 mV command step, leaving only rapid capacitive currents and some sustained currents after about 3 min. The relaxation of the capacitive current could be well fitted with a single exponential function. The effect of mefloquine was reversible and the time course of the current induced by the voltage step gradually changed back after mefloquine was removed. The mean input resistance and capacitance in the presence of mefloquine were 323 MOmega and 10.1 pF, respectively. While intercellular electrical coupling was well blocked by mefloquine (50 microM), the membrane hyperpolarized from -24.0 to -32.5 mV. The results indicate that mefloquine effectively blocks gap junctions without producing major side effects in vascular endothelial cells and that this compound is a useful tool in the investigation of gap junctions.

Dr. Mefloquine‐Induced Eosinophilic Pneumonia

Mefloquine has been widely used for prophylaxis and treatment of patients with chloroquine-resistant malaria; the drug is usually well tolerated. Rarely, adverse effects may be severe, including gastrointestinal disturbances, neuropsychiatric reactions, cardiovascular manifestations, skin lesions, musculoskeletal symptoms, and bone marrow toxicity. We describe a 67-year-old woman with fever, dyspnea on exertion, peripheral blood eosinophilia, and diffuse pulmonary infiltrates on chest radiography. She had taken mefloquine for malaria prophylaxis for an 8-week trip to South Africa. A thorough work-up led to the diagnosis of eosinophilic pneumonia caused by the mefloquine. Her condition improved after the drug was discontinued. To our knowledge, this is the first report of mefloquine-induced eosinophilic pneumonia. Clinicians should be aware of this rare, potential adverse effect of mefloquine.

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-d-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited dose-related and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.

Controversies and Misconceptions in Malaria Chemoprophylaxis for Travelers

Controversies in malaria prevention arise from the absence of data, conflicting data between different studies, conflicting recommendations, deviation of local practice from scientific data, and varying risk thresholds. Misconceptions about the seriousness of malaria, the tolerability of chemoprophylaxis drugs, and the efficacy and safety of repellents contribute to the controversies. To compare several national guidelines on malaria chemoprophylaxis to identify variations in recommendations. We reviewed studies on tolerability of mefloquine with particular focus on its neuropsychiatric adverse effects and influence on performance. We also describe why most recommended chemoprophylactic regimens fail to prevent relapses of Plasmodium vivax malaria and review available options. We searched scientific publications in MEDLINE via PubMED for relevant articles with a cutoff date of December 2006 using the search terms malaria, chemoprophylaxis, travel, mefloquine, neuropsychiatric adverse events, tolerability, vivax malaria, and primaquine. Additional references were obtained from bibliographies of the selected articles. There were no language restrictions. Gaps and conflicts exist among current guidelines. Health authorities vary in the chemoprophylaxis drugs they recommend, the indications for continuous prophylaxis vs no prophylaxis, and the use of standby emergency treatment. Despite widespread reports on the adverse effects of mefloquine, controlled studies found that serious neuropsychiatric adverse events occur at rates comparable with or lower than other chemoprophylaxis drugs. Moreover, mefloquine does not appear to impair performance while driving, flying, or diving. Vivax malaria causes significant illness in travelers, but current first-line chemoprophylaxis agents do not prevent relapses of vivax malaria. Although not licensed in most countries as primary prophylaxis, primaquine effectively prevents relapses of vivax malaria. Prevention of malaria in travelers requires detailed knowledge of malaria epidemiology and host-vector-parasite interactions. Decisions are complicated by a lack of standardized recommendations, controversies, and misconceptions. Improved international consensus is indicated to minimize conflicting guidelines, clarify controversies, and promote adherence to preventive measures.

Maculopathy associated with mefloquine (Lariam) therapy for malaria prophylaxis

Case report: We report maculopathy occurring in a patient after 18 months of weekly mefloquine for malaria prophylaxis. Macular retinal pigment epithelium changes bilaterally were visually insignificant, with the patient demonstrating 20/20 corrected visual acuity bilaterally.Comments: Retinal change as an adverse effect of mefloquine has not previously been reported.

Assessment of the Effect of Mefloquine on Artesunate Pharmacokinetics in Healthy Male Volunteers

The effect of mefloquine on artesunate pharmacokinetics was assessed in 20 volunteers given artesunate for 3 days, followed > or =21 days later by combination therapy for 3 days. The areas under the concentration-time curve from 0 h to infinity for dihydroartemisinin, the active metabolite of artesunate, were similar on day 3 of the two dosing periods (P = 0.12), implying no interaction.

MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine

Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein. The association between MDR1 C1236T, G2677T, and C3435T single-nucleotide polymorphisms and the occurrence of neuropsychiatric adverse effects was examined in a prospective cohort study of 89 healthy white travelers taking mefloquine. Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T, and C3435T polymorphisms were similar to those found in other white populations, and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, women with the 1236TT, 2677TT, and 3435TT genotypes had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes, with odds ratios of 6.3 (95% confidence interval [CI], 1.1-36.9), 10.5 (95% CI, 1.1-100.6), and 5.4 (95% CI, 1.1-30.0), respectively. The association for women homozygous for the 1236-2677-3435 TTT haplotype was even stronger (P = .004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed. In this study the MDR1 1236TT, 2677TT, and 3435TT genotypes, along with the 1236-2677-3435 TTT haplotype, were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travelers.

Mefloquine Effects on the Lens Suggest Cooperative Gating of Gap Junction Channels

Mefloquine (MFQ) selectively blocks exogenously expressed gap junction channels composed of Cx50 but not Cx46. The purpose of the current study was to evaluate MFQ effects on wild-type (WT) mouse lenses that express both Cx50 and Cx46 in their outer shell of differentiating fibers (DFs). Lenses in which Cx46 was knocked into both Cx50 alleles (KI) were used as controls; MFQ had no effect on coupling in these lenses. When WT lenses were exposed to MFQ, the DF coupling conductance decreased significantly, suggesting that Cx50 contributes about 57% of the coupling conductance in DF and Cx46 contributes 43%. Remarkably, in the presence of MFQ, the 43% of the channels that remained open did not gate closed in response to a reduction in pH, whereas in the absence of MFQ, the same pH change caused all the DF channels to gate closed. Since MFQ is a selective blocker of Cx50 channels, it appears that Cx46 channels lack pH-mediated gating in the absence of functional Cx50 channels but are pH-sensitive in the presence of Cx50 channels. These results suggest the two types of channels interact and gate cooperatively.

Mefloquine‐Induced Pneumonitis

Mefloquine is indicated as oral treatment and as prophylaxis for malaria in areas where chloroquine-resistant malaria is present. Gastrointestinal and neuropsychiatric side effects of mefloquine are well known. More severe neuropsychiatric disorders such as psychosis, depression, hallucinations, and seizures are also reported in the literature. We are reporting a case of drug-induced pneumonia due to mefloquine. This diagnosis was confirmed 4 months after the adverse event, after restarting the same malaria prophylaxis, which could be considered as an unintentional provocation test. This is the third case report in the literature of acute lung injury caused by mefloquine.

Mefloquine Enhances Nigral γ-Aminobutyric Acid Release via Inhibition of Cholinesterase

Mefloquine, a widely used antimalarial drug, has many neuropsychiatric effects. Although the mechanisms underlying these side effects remain unclear, recent studies show that mefloquine enhances spontaneous transmitter release and inhibits cholinesterases. In this study, we examined the effect of mefloquine on GABA receptor-mediated, spontaneous inhibitory postsynaptic currents (sIPSCs) of dopaminergic neurons, mechanically dissociated from the substantia nigra pars compacta of rats aged 6 to 17 postnatal days. Mefloquine (0.1-10 microM) robustly and reversibly increased the frequency of sIPSCs with an EC50 of 1.3 microM. Mefloquine also enhanced the frequency of miniature inhibitory postsynaptic currents in the presence of tetrodotoxin but without changing their mean amplitude. This suggests that mefloquine acts presynaptically to increase GABA release. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in medium containing low Ca2+ (0.5 mM) or following pretreatment with 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester (30 microM), a membrane-permeable Ca2+ chelator. In contrast, 100 microM Cd2+ did not alter the action of mefloquine. This suggests that mefloquine-induced facilitation of GABA release depends on extracellular and intraterminal Ca2+ but not on voltage-gated Ca2+ channels. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in the presence of the anticholinesterase agent physostigmine or blockers of non-alpha7 nicotinic acetylcholine receptors. Taken together, these data suggest that mefloquine enhances GABA release through its inhibition of cholinesterase. This allows accumulation of endogenously released acetylcholine, which activates neuronal nicotinic receptors on GABAergic nerve terminals. The resultant increase of Ca2+ entry into these terminals enhances vesicular release of GABA. This action may contribute to the neurobehavioral effects of mefloquine.

Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals

Effectiveness against chloroquine-resistant Plasmodia makes mefloquine a widely used antimalarial drug. However, mefloquine's neurologic effects offset this therapeutic advantage. Cellular actions which might contribute to the neurologic effects of mefloquine are not understood. Structural similarity to tacrine suggested that mefloquine might alter cholinergic synaptic transmission. Therefore, we examined mefloquine's effects at a model cholinergic synapse. Triangularis sterni nerve–muscle preparations were isolated from adult mice and examined with sharp electrode current clamp technique. Within 30 min of exposure to 10 μM mefloquine, miniature endplate potentials (mepps) occurred in summating bursts and their mean frequency increased 10-fold. The threshold concentration for the increase of mean mepp frequency was 0.6 μM mefloquine. Mefloquine continued to increase mean mepp frequency for preparations bathed in extracellular solution lacking Ca 2+. In contrast, mefloquine no longer increased mean mepp frequency for preparations pre-treated with the intracellular Ca 2+ buffer BAPTA-AM. Although mefloquine disrupts a thapsigargin-sensitive neuronal Ca 2+ store, pre-treatment with thapsigargin did not alter the mefloquine-induced alterations of mepps. Since mefloquine, like oligomycin, inhibits mitochondrial F OF 1H +ATP synthase we tested the interaction between these two chemicals. Like mefloquine, oligomycin induced bursts and increased mean frequency of mepps. Furthermore, pre-treatment with oligomycin precluded the mefloquine-induced alterations of asynchronous transmsitter release. These data suggest that mefloquine inhibits ATP production which increases the concentration of Ca 2+ within the cytosol of nerve terminals. This elevation of Ca 2+ concentration selectively increases asynchronous transmitter release since 10 μM mefloquine did not alter stimulus-evoked transmsitter release.

Mefloquine inhibits cholinesterases at the mouse neuromuscular junction

Mefloquine is effective against drug-resistant Plasmodium falciparum. This property, along with its unique pharmacokinetic profile, makes mefloquine a widely prescribed antimalarial drug. However, mefloquine has neurologic effects which offset its therapeutic advantages. Cellular actions underlying mefloquine's neurologic effects are poorly understood. Here, we demonstrate that mefloquine inhibits human recombinant acetylcholinesterase. To explore the consequences of this action, we investigated mefloquine's actions at a model cholinergic synapse, the mouse neuromuscular junction. Sharp electrode recording was used to record miniature endplate potentials (mepps) in the Triangularis sterni muscle. Within 30 min of exposure to 10 μM mefloquine, mepps were altered in three ways: 10–90% rise time, 90–10% decay time and amplitude significantly increased. Mepp decay time increased linearly with mefloquine concentration. Pretreatment of muscles with the cholinesterase inhibitor physostigmine (3 μM) precluded the mefloquine-induced prolongation of mepp decay. Mefloquine also prolonged mepps at endplates of acetylcholinesterase knock-out mice. Since the selective butyrylcholinesterase inhibitor iso-OMPA (100 μM) also prolonged mepp decay at the neuromuscular junction of acetylcholinesterase knock-out mice, mefloquine inhibition of this enzyme is physiologically relevant. The non-selective anti-cholinesterase action can contribute to the neurologic effects of mefloquine.

Gamma-aminobutyric acid and mefloquine-induced seizures in mice

The role of GABAergic mechanism in the convulsant effect of mefloquine was investigated in mice. Mefloquine dose dependently induced tonic seizures in mice. Aminooxyacetic acid, diaminobutyric acid and muscimol significantly protected mice against mefloquine-induced seizures by significantly delaying the onset and decreasing the incidence of the seizures. Bicuculline and picrotoxin significantly enhanced the seizure producing effect of mefloquine and also significantly antagonised the protective effect of muscimol against the seizures. Phenobarbitone and diazepam effectively protected mice against mefloquine-induced seizures. Phenytoin did not alter mefloquine-induced seizures. These data indicate that GABA mechanisms might be involved in seizures produced by mefloquine in mice.

Clinical Pharmacology Of Malaria

Effective chemotherapy of malaria relies on an accurate diagnosis and an appropriate affordable choice of drugs bearing in mind likely adverse effects, patterns of drug resistance, and the degree of host immunity. Choice of Antimalarial Drug: Treatment of multidrug-resistant Plasmodium falciparum malaria prevalent in our environment relies increasingly on combination chemotherapy using blood schizonticides. Chloroquine and Sulfodoxine/Pyremethamine have been cheap and safe options. However widespread resistance to these drugs (and the problem of chloroquine-related pruritus) means that these agents are often ineffective. Quinine has been relied on for multidrug-resistant malaria. However its marked toxicity potential (e.g. cinchonism and ventricular tachyarrhythmias) means that other drugs such as mefloquine, doxycycline, chlorproguanil-dapsone and proguanil-atovaquone are preferred. Halofantrine is not recommended because of its cardiotoxic potential. Increasing problems with drug resistance have led to current recommendations for the use of artemisinin-based combination therapy such as co-artemether (artemether plus lumefantrine). Plasmodium vivax, P. ovale and P. malariae remain sensitive to chloroquine, and likewise the emergent parasite P. knowlesi. Primaquine is used to eradicate hypnozoites of P. vivax and P. ovale. Treatment of malaria: Prompt treatment is of vital importance, especially in patients who lack innate or acquired immunity. Delaying effective treatment increases morbidity and mortality. Circumstances such as pregnancy and infancy should be taken into account, for example to avoid possible teratogenic effects of mefloquine, artemisinins or halofantrine during the first trimester, and to avoid primaquine and halofantrine while breastfeeding. Supportive treatment is important in severe malaria. Fever is part of the host defence against infection and so should not be entirely suppressed. Careful attention should be paid to fluid balance, to postural hypotension and hypoglycemia (which are exacerbated by quinoline antimalarials), to accompanying bacterial infections, renal impairment and the need for anticonvulsants or blood transfusion. Therapeutic failure may be due to a wrong diagnosis, or an additional cause for the febrile illness apart from malaria. Parasite resistance to antimalarials, poor patient compliance, and the use of fake or substandard drugs are alternative explanations. Key Words: Malaria, Drug treatment of Malaria, Clinical Pharmacology Orient Journal of Medicine Vol.16(2) 2004: 59-69

Resistance reversal action of ketoconazole against mefloquine resistance of Plasmodium yoelii nigeriensis

Ketoconazole at 200 mg/kg dose has been found to exert marginal antimalarial action against multidrug resistant (MDR) Plasmodium yoelii nigeriensis ( P. yoelii nigeriensis) in Swiss mice with 25% protection (2/8 mice) while at lower Ketoconazole dose i.e., 75–100 mg/kg, 14.28% mice were protected. Mefloquine (MFQ) (at 8 and 16 mg/kg) exerted suppressive action against MDR P. yoelii nigeriensis resulting in 25 and 14.28% protection of mice respectively. Combined treatment with Ketoconazole and mefloquine resulted in protection of 5/6 mice (83.33%) at MFQ 4 mg/kg + Ketoconazole 100 mg/kg dose, 7/8 (87.5%) mice at MFQ 8 mg/kg + Ketoconazole 20 mg/kg dose and 5/7 (71.42%) mice at MFQ 16 mg/kg + Ketoconazole 25 mg/kg dose and 5/6 (83.33%) mice at MFQ 16 mg/kg + Ketoconazole 100 mg/kg dose. Ketoconazole has been found to enhance the protective effect of mefloquine against MFQ resistant P. yoelii nigeriensis resulting in 66–88% protection of the mice treated with the appropriate combinations. The combination also increased suppression of parasitaemia at different times. The Ketoconazole combination with MFQ significantly increased the mean survival time of the treated mice compared to individual drugs alone. The study shows that Ketoconazole when administered with MFQ exerts bio-enhancing action against mefloquine resistance of MDR P. yoelii nigeriensis.

The effect of mefloquine and volume-regulated anion channel inhibitors on induced transport in Plasmodium falciparum-infected human red blood cells

The malaria parasite Plasmodium falciparum activates new permeation pathways (NPP) in the host cell membrane of infected human red blood cells (RBCs), which are permeable to anions, cations and a range of organic solutes. It has been suggested from inhibitor and substrate selectivity studies that the NPP may be identical to the volume-activated anion channel (VRAC) present in many mammalian cell types. Here we have tested several known inhibitors of VRAC on the transport of choline and lactate in malaria-infected human RBCs and on parasite growth. Mefloquine, tamoxifen and clomiphene were all without effect on malaria-induced transport at concentrations up to 10 μM and only mefloquine (IC 50 = 24 nM) and, to a lesser degree, clomiphene (IC 50 = 6.2 μM) inhibited parasite growth below this level. It is concluded that the antimalarial effect of mefloquine does not involve the inhibition of malaria-induced transport via the NPP and there is no evidence at present for VRAC and the NPP being identical.

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).

Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement?

BackgroundMefloquine is a clinically important antimalaria drug, which is often not well tolerated. We critically reviewed 516 published case reports of mefloquine adverse effects, to clarify the phenomenology of the harms associated with mefloquine, and to make recommendations for safer prescribing.PresentationWe postulate that many of the adverse effects of mefloquine are a post-hepatic syndrome caused by primary liver damage. In some users we believe that symptomatic thyroid disturbance occurs, either independently or as a secondary consequence of the hepatocellular injury. The mefloquine syndrome presents in a variety of ways including headache, gastrointestinal disturbances, nervousness, fatigue, disorders of sleep, mood, memory and concentration, and occasionally frank psychosis. Previous liver or thyroid disease, and concurrent insults to the liver (such as from alcohol, dehydration, an oral contraceptive pill, recreational drugs, and other liver-damaging drugs) may be related to the development of severe or prolonged adverse reactions to mefloquine.ImplicationsWe believe that people with active liver or thyroid disease should not take mefloquine, whereas those with fully resolved neuropsychiatric illness may do so safely. Mefloquine users should avoid alcohol, recreational drugs, hormonal contraception and co-medications known to cause liver damage or thyroid damage. With these caveats, we believe that mefloquine may be safely prescribed in pregnancy, and also to occupational groups who carry out safety-critical tasks.TestingMefloquine's adverse effects need to be investigated through a multicentre cohort study, with small controlled studies testing specific elements of the hypothesis.

Serious adverse events of mefloquine in relation to blood level and gender.

Mefloquine is widely used for prophylaxis in areas with chloroquine-resistant falciparum malaria. As the use of mefloquine has increased, so have the reports on its adverse effects. We sought to evaluate the possible association between serum levels of mefloquine and serious side effects caused by this drug by means of a case-control design study. The study population included 17 patients who presented to emergency rooms or travel clinics with symptoms suggesting serious adverse effects of mefloquine and 28 controls (healthy people, still taking mefloquine after travel). The mean age of the patients and the controls was 31.5 +/- 11.6 years and 34 +/- 12.2 years, respectively. The percentage of women among the patients was higher than in the control population (76% versus 40%, respectively; P = 0.03). Most of the complaints were related to the central nervous system (13 of 17); 5 patients interrupted their trip and 2 others were hospitalized. No difference in the level of mefloquine in the blood was found between the patients and the control groups. Also, no significant difference was found between mefloquine levels in the blood of men and women. These results suggest that blood levels of mefloquine do not correlate with its severe adverse events. Women tended to be more susceptible than men, despite having similar blood levels of the drug.

Cognitive and Neuropsychiatric Side Effects of Mefloquine

Back to table of contents Previous article Next article LetterFull AccessCognitive and Neuropsychiatric Side Effects of MefloquineDebbie J. Javorsky, Ph.D., Geoffrey Tremont, Ph.D., Gabor I. Keitner, M.D., and A. Hilton Parmentier, M.D., Debbie J. JavorskySearch for more papers by this author, Ph.D., Geoffrey TremontSearch for more papers by this author, Ph.D., Gabor I. KeitnerSearch for more papers by this author, M.D., and A. Hilton ParmentierSearch for more papers by this author, M.D., Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RIPublished Online:1 May 2001AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Mefloquine hydrochloride is often used as a prophylaxis for malaria. Rare cases of neuropsychiatric side effects have been reported with its use.1–3Case ReportWe document the neuropsychological functioning of a 52-year-old master's-educated woman with no psychiatric history who used mefloquine prophylactically once a week for 3 weeks (250 mg) prior to and during a trip to Africa and who acutely developed anxiety, paranoia, visual hallucinations, confusion, and depressive symptoms during her return flight. She was initially treated as an outpatient with olanzapine, lorazepam, fluoxetine, and trazodone. When she continued to show suicidal ideation, other neuropsychiatric symptoms, and cognitive disturbances 3 months after her last dose of mefloquine, she was hospitalized for inpatient psychiatric treatment. Laboratory and infectious disease workup showed mildly elevated TSH (7.04 μU/ml) with normal free T3 and T4, and was positive for past exposure to hepatitis A. Brain MRI showed no abnormalities. Medical history was noncontributory. She had previously used mefloquine as a prophylaxis intermittently for about 4 years with no adverse reactions. While hospitalized, she was treated with risperidone and paroxetine and showed improvement in mood symptoms and cognition over 4 days. After initially living with her daughter following discharge, she has returned to independent functioning.During a brief neuropsychological evaluation on day 2 of her admission, she was alert and partially oriented, misstating her age and the city, time, date, and day of the week. Her affect was sad. She reported feeling depressed, afraid, confused, and tense. Test results revealed impaired attention and mental control difficulties, with slowed performance on overlearned tasks, inaccuracies in mentally manipulating information, and inability to alternate between counting by sixes and reciting the days of the week. Psychomotor speed was slowed. Performance on several tasks of executive functioning indicated difficulty with response set maintenance, verbal fluency, and judgment/problem solving. Her copy of a complex design showed significantly impaired visuospatial and constructional skills. On a verbal list learning test, she learned 10 of 12 words, but recalled only 3 of them after a 20-minute delay. Although she correctly endorsed 11 of the words with a recognition format, she made 7 false-positive errors.CommentThis case is the first to carefully document the neuropsychological functioning of an individual with severe mefloquine side effects and demonstrates that mefloquine may produce deficits in orientation, attention, psychomotor speed, and executive, visuospatial, and verbal memory functioning, as well as mood and psychotic symptoms. The potential mechanism of the drug in causing these deficits is not entirely clear, although there is evidence that the neuropsychiatric side effects of mefloquine are a result of a central cholinergic syndrome,3 which may also explain cognitive changes seen in the present case. Our patient's cognitive impairments were well beyond what would be expected based solely on her psychiatric symptoms and possible subclinical hypothyroidism. Although multiple factors may have contributed to her cognitive impairment, the temporal relationship between onset of her symptoms and mefloquine use suggests a high likelihood that mefloquine was the causal factor.References1 Sturchler D, Handschin J, Kaiser D, et al: Neuropsychiatric side effects of mefloquine. N Engl J Med 1990; 322:1752-1753Google Scholar2 Weinke T, Trautmann M, Held T, et al: Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991; 45:86-91Crossref, Medline, Google Scholar3 Speich R, Haller A: Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med 1994; 331:57-58Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byA Cross-sectional Cohort Study to Assess Long-term Neurocognitive and Psychiatric Symptoms of Mefloquine Use in Veterans21 April 2022 | Military Medicine, Vol. 41The American Journal of Tropical Medicine and Hygiene, Vol. 99, No. 3Antimicrobial-induced cognitive side effectsMental Health Clinician, Vol. 6, No. 4SpringerPlus, Vol. 4, No. 1Hallucinations and Persecutory Delusions in Mefloquine-Associated SuicideAmerican Journal of Forensic Medicine & Pathology, Vol. 33, No. 2Biological Psychiatry, Vol. 71, No. 1Keeping Score on Psychiatric Drug Effects: Is Mefloquine Safe for Malaria Chemoprophylaxis?3 August 2016 | Journal of Pharmacy Technology, Vol. 22, No. 1Clinical Pharmacokinetics, Vol. 42, No. 15Pharmacoepidemiology and Drug Safety, Vol. 10, No. 6 Volume 13Issue 2 May 2001Pages 302-302 Metrics PDF download History Published online 1 May 2001 Published in print 1 May 2001