Signal detection to identify serious adverse events (neuropsychiatric events) in travelers taking mefloquine for chemoprophylaxis of malaria

Naing, Cho; Aung, Kyan; Ahmed, Syed Imran; Mak, Joon Wah

doi:10.2147/dhps.s34493

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…[5][6][7] Studies evaluating the occurrence of neuropsychiatric outcomes (NPOs) after mefloquine use report mixed results, but a large proportion of these studies found an association between mefloquine and NPOs. [7][8][9][10][11][12][13][14][15][16][17] Due to the extensive use of mefloquine for malaria prevention among service members before 2009 and its continued, limited use, after that point, the need to evaluate adverse events in service members who took the drug is evident. Therefore, a retrospective population-based cohort study was conducted among service members.…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members

Eick-Cost

Rohrbeck

et al. 2017

The American Society of Tropical Medicine and Hygiene

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Abstract. Mefloquine was widely prescribed to U.S. military service members until 2009 when use was limited to personnel with contraindications to doxycycline and no contraindications to mefloquine. The need to estimate the occurrence of neuropsychiatric outcomes (NPOs) in service members prescribed mefloquine warranted a comprehensive evaluation of this issue. Active component service members filling a prescription for mefloquine, doxycycline, or atovaquone/proguanil (A/P) between January 1, 2008 and June 30, 2013, were included in the analysis. The risk of developing incident NPOs and the risk of subsequent NPOs among subjects with a history of the condition were assessed. A total of 367,840 individuals were evaluated (36,538 received mefloquine, 318,421 received doxycycline, and 12,881 received A/P). Among deployed individuals prescribed mefloquine, an increased risk of incident anxiety was seen when compared with doxycycline recipients (incidence rate ratio [IRR] = 1.12 [1.01-1.24]). Among nondeployed mefloquine recipients, an increased risk of posttraumatic stress disorder (PTSD) was seen when compared with A/P recipients (IRR = 1.83 [1. 07-3.14]). An increased risk of tinnitus was seen for both deployed and nondeployed mefloquine recipients compared with A/P recipients (IRR = 1.81 [1.18-2.79]), 1.51 (1.13-2.03), respectively). Six percent of the mefloquine cohort had an NPO in the year before receiving mefloquine. When comparing individuals with a prior neuropsychiatric history to those without, the ratio of relative risks for adjustment disorder, anxiety, insomnia, and PTSD were higher (not statistically significant) for mefloquine compared with doxycycline. These findings emphasize the continued need for physicians prescribing mefloquine to conduct contraindication screening.

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Section: Introductionmentioning

confidence: 99%

Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members

Eick-Cost

Rohrbeck

et al. 2017

The American Society of Tropical Medicine and Hygiene

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“…Greater importance should be placed on ROR signals with a lower 95% CI limit of 2 or higher. 12) The overall ROR of each SMQ exceeded 2 in both databases, excluding liver damage in JADER, demonstrating that these SMQ are representative adverse reactions of ganciclovir.…”

Section: Discussionmentioning

confidence: 87%

“…The range of the 95% CI of the ROR increases and signal detection becomes unlikely when the num- ber of reported cases is small. 11) The total number of reported cases in FAERS was approximately 18-times that in JADER ( Table 1), suggesting that the range of the 95% CI of ROR was higher in JADER because of a smaller total number of reported cases, resulting in no signal detection. It is possible that signals will be detected as the number of reported cases increases in the future.…”

Section: Discussionmentioning

confidence: 97%

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS

Ando

Taguchi

Enoki

et al. 2019

Biological & Pharmaceutical Bulletin

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Investigation of the occurrence time of adverse drug reactions helps to prevent the development and aggravation of adverse reactions, but the expression time of ganciclovir-induced adverse events has not been elucidated. In this study, using databases of spontaneous adverse event reports, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), the incidence of adverse reactions due to ganciclovir and their expression time were analyzed. As a result of calculation of the reporting odds ratio (ROR) and 95% confidence interval for individual main adverse reactions of ganciclovir (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure), a signal was detected for all adverse reactions in both databases, except for liver damage in JADER. Furthermore, the Weibull distribution was performed for the analysis of onset time of each ganciclovir-induced adverse event. The results of Weibull parameter α and β values of each adverse event in both JADER and FAERS suggested that most adverse events occurred within 30 d and classified into the early failure type, except that thrombocytopenia and acute renal failure in JADER classified into the random failure type. Based on these findings, it concluded that the paying attention to signs of each ganciclovirinduced adverse event is required from the early phase after ganciclovir administration. However, in FAERS, development after a long-term course also accounted for 11%, suggesting that long-term periodic monitoring of adverse reactions would be also required.

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“…The use is limited by various side effects [4] including neuropsychiatric disorders [10,11,12,13,14], skin reactions [15] as well as risk of miscarriage and stillbirth [16]. Mefloquine triggers apoptosis [17,18,19,20,21] and may sensitize tumor cells for cytostatic treatment [20].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

Bissinger

Barking

Alzoubi

et al. 2015

Cell Physiol Biochem

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Background: The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), and ceramide. Methods: Phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS) from 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca²⁺]_i from Fluo3-fluorescence, and ceramide abundance from specific antibody binding. Results: A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 µg/ml), significantly decreased forward scatter (≥5 µg/ml), significantly increased ROS abundance (5 µg/ml), significantly increased [Ca²⁺]_i (7.5 µg/ml) and significantly increased ceramide abundance (10 µg/ml). The up-regulation of annexin-V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca²⁺. Even in the absence of extracellular Ca²⁺, mefloquine significantly increased annexin-V-binding. Conclusions: Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca²⁺]_i and up-regulation of ceramide abundance.

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Signal detection to identify serious adverse events (neuropsychiatric events) in travelers taking mefloquine for chemoprophylaxis of malaria

Cited by 6 publications

References 30 publications

Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members

Neuropsychiatric Outcomes After Mefloquine Exposure Among U.S. Military Service Members

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS

Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

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