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Antimicrobial Agents and Chemotherapy, March 2006, p. 1045-1053, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.1045-1053.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

G. Dow,1* R. Bauman,2 D. Caridha,1 M. Cabezas,3 F. Du,4 R. Gomez-Lobo,3 M. Park,2 K. Smith,1 and K. Cannard1

Divisions of Experimental Therapeutics,1 Military Casualty Research,2 Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland, 20910,3 FD Neurotechnologies, Inc., P.O. Box 785, Ellicott City, Maryland 210414

Received 5 August 2005/ Returned for modification 22 August 2005/ Accepted 18 November 2005

Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.

* Corresponding author. Mailing address: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910. Phone: (301) 319-9009. Fax: (301) 319-9954. E-mail: geoffrey.dow{at}na.amedd.army.mil.

Antimicrobial Agents and Chemotherapy, March 2006, p. 1045-1053, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.1045-1053.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Caridha, D., Yourick, D., Cabezas, M., Wolf, L., Hudson, T. H., Dow, G. S. (2008). Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin. Antimicrob. Agents Chemother. 52: 684-693 [Abstract] [Full Text]  
  • Croft, A. M (2007). A lesson learnt: the rise and fall of Lariam and Halfan. JRSM 100: 170-174 [Full Text]  
  • Dow, G. S., Heady, T. N., Bhattacharjee, A. K., Caridha, D., Gerena, L., Gettayacamin, M., Lanteri, C. A., Obaldia, N. III, Roncal, N., Shearer, T., Smith, P. L., Tungtaeng, A., Wolf, L., Cabezas, M., Yourick, D., Smith, K. S. (2006). Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs. Antimicrob. Agents Chemother. 50: 4132-4143 [Abstract] [Full Text]  


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