Central Anticholinergic Syndrome with the Antimalarial Drug Mefloquine

Speich, Rudolf; Haller, Alois

doi:10.1056/nejm199407073310120

Cited by 47 publications

(20 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, the neurotoxicity associated with mefloquine is such that some have questioned its clinical utility as a prophylactic drug (7). There are several approaches to the amelioration of this problem, including (i) administration of neuroprotective drugs such as physostigmine (26), (ii) reformulation of mefloquine as a pure isomer (24), and (iii) reengineering of the mefloquine molecule to yield derivatives that are less neurotoxic but retain their antimalarial activity. Bhattacharjee and Karle (3) earlier showed that the in vivo potency of 4-quinolinecarbinolamines was correlated with key stereoelectronic features, including electrostatic potential and lipophilicity.…”

mentioning

confidence: 99%

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

Dow¹,

Koenig

Wolf

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The clinical potential of mefloquine has been compromised by reports of adverse neurological effects. A series of 4-quinolinecarbinolamines were compared in terms of neurotoxicity and antimalarial activity in an attempt to identify replacement drugs. Neurotoxicity (MTT [thiazolyl blue reduction] assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC 50 ) of mefloquine was 25 M, while those of the analogs were 19 to 200 M. The relative (to mefloquine) therapeutic indices of the analogs were determined after using the tritiated hypoxanthine assay for assessment of the antimalarial activity of the analogs against mefloquine-sensitive (W2) and -resistant (D6 and TM91C235) Plasmodium falciparum strains. Five analogs, WR157801, WR073892, WR007930, WR007333, and WR226253, were less neurotoxic than mefloquine and exhibited higher relative therapeutic indices (RTIs) against TM91C235 (2.9 to 12.2). Conventional quinoline antimalarials were generally less neurotoxic (IC 50 s of 400, 600, and 900 for amodiaquine, chloroquine, and quinine) or had higher RTIs (e.g., 30 for halofantrine against TM91C235). The neurotoxicity data for the 4-quinolinecarbinolamines were used to develop a three-dimensional (3D), function-based pharmacophore. The crucial molecular features correlated with neurotoxicity were a hydrogen bond acceptor (lipid) function, an aliphatic hydrophobic function, and a ring aromatic function specifically distributed in the 3D surface of the molecule. Mapping of the 3D structures of a series of structurally diverse quinolines to the pharmacophore allowed accurate qualitative predictions of neurotoxicity (or not) to be made. Extension of this in silico screening approach may aid in the identification of less-neurotoxic quinoline analogs.

show abstract

mentioning

confidence: 99%

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

Dow¹,

Koenig

Wolf

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…It has been suggested that it may be related to primary liver damage with secondary thyroid damage [31]. Severe mefloquine-induced neuropsychiatric side effects have also been attributed to a central anticholinergic syndrome [32]. It has been suggested that adverse reactions to mefloquine, including neuropsychiatric reactions, can be potentiated by concomitant ethanol ingestion [33] and by conditions that can lead to mild dehydration such as prolonged air travel, hot or dry conditions, and strenuous physical activity [31].…”

Section: Discussionmentioning

confidence: 99%

Severe Neuropsychiatric Reaction in a Deployed Military Member after Prophylactic Mefloquine

Peterson

Seegmiller²,

Schindler³

2011

Case Reports in Psychiatry

View full text Add to dashboard Cite

Recent studies of military personnel who have deployed to Iraq and Afghanistan have reported a number of combat-related psychiatric disorders such as posttraumatic stress disorder, depression, and traumatic brain injury. This case report involves a 27-year-old male active-duty US military service member who developed severe depression, psychotic hallucinations, and neuropsychological sequelae following the prophylactic use of the antimalarial medication mefloquine hydrochloride. The patient had a recent history of depression and was taking antidepressant medications at the time of his deployment to the Middle East. Psychiatrists and other health care providers should be aware of the possible neuropsychiatric side effects of mefloquine in deployed military personnel and should consider the use of other medications for malaria prophylaxis in those individuals who may be at increased risk for side effects.

show abstract

“…headache, dizziness, sleeplessness or abnormal dreams), we found 44 published cases of moderate to serious neuropsychiatric adverse events after mefloquine treatment in 18 papers, of which only three (Ekue et al 1983;Harinasuta et al 1983;Bernard et al 1987) were published before 1989, the remainder after 1989 (Bernard et al 1989;Patchen et al 1989;Rouviex et al 1989;Stuiver et al 1989;Luxemburger et al 1991;Weinke et al 1991;Caillon et al 1992;De Gennes et al 1992;Marsepoil et al 1993;Sowunmi et al 1993;Hennequin et al 1994;Rønn and Bygbjerg 1994;Sowunmi 1994;Speich & Haller 1994;Sowunmi et al 1995). …”

Section: Literature Reviewmentioning

confidence: 98%

Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

Rønn

Rønne-Rasmussen

et al. 1998

Tropical Med Int Health

View full text Add to dashboard Cite

Mefloquine has been increasingly used for treatment of chloroquine‐resistant malaria since its introduction in the late 1970s. In 1987 the first case of toxic encephalopathy was published, and in 1989 the WHO initiated reporting and investigation of neuropsychiatric adverse reactions of mefloquine. Neuropsychiatric adverse drug reactions are now well documented. We compared an open prospective 3 year study including all patients with P. falciparum treated with mefloquine with an earlier published, retrospective study on a comparable population from our department covering the period up to 1989.dollar;>In the retrospective study neuropsychiatric adverse effects were not specifically asked for, while in the prospective study possible adverse reactions were registered daily according to a specified questionnaire. No case of neuropsychiatric adverse reaction was registered in the retrospective study. In the prospective study, 28% had one or more neuropsychiatric adverse reactions, although severity was mostly mild to moderate. Other adverse reactions occurred in 96% in the retrospective study compared to 81% in the prospective study. In conclusion: one often finds only what one looks for, e.g adverse events may be overlooked for a decade, if relatively uncommon. This report also shows that retro‐ and prospective studies may give very different results.

show abstract

Central Anticholinergic Syndrome with the Antimalarial Drug Mefloquine

Cited by 47 publications

References 4 publications

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

Severe Neuropsychiatric Reaction in a Deployed Military Member after Prophylactic Mefloquine

Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

Contact Info

Product

Resources

About