Research

“Despite the public outcry about [mefloquine], it is extraordinary that no real attempt [was] made to properly explore the adverse effects of [this drug] in terms of what causes these effects, who is likely to experience them, how long the effects typically last, how the effects can be mitigated, and how they should be managed if they do occur.”

Dr Ashley Croft, A lesson learnt: the rise and fall of Lariam and Halfan, 2007

Ashley Croft

Dr Ashley Croft

Featured Research

J. Livezey, T. Oliver and L. cantilever, Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine, Drug Safety: Case Reports, vol. 3, no. 7., 2016.

“A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.”

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Walter Reed Army Institute of Research

Published Papers – Mefloquine

A. M. Croft, Mefloquine, madness and the Ministry of Defence, The Pharmaceutical Journal, 12 November 2015.

R. L. Nevin, Rational Risk-Benefit Decision-Making in the Setting of Military Mefloquine PolicyJournal of Parasitology Research, vol. 2015 , Article ID 260106, 2015.

S. McCarthy, Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence ForceJournal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

J. C. Quinn, Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

R. L. Nevin, Organic depersonalization as a chronic sequela of mefloquine intoxication, Psychosomatics, vol. 56, no. 1, 2015.

Åsa Ringqvist, Per Bech, Birte Glenthøj, Eskild Petersen, Acute and long-term psychiatric side effects of mefloquine: A follow-up on Danish adverse event reportsTravel Medicine and Infectious Disease, vol. 13, no. 1, pp. 80-88, 2014.

R. L. Nevin, Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine, International Journal for Parasitology: Drugs and Drug Resistance, vol. 4, no. 2, pp. 118-125, 2014.

R. L. Nevin, Mefloquine and post-traumatic stress disorder, in Elspeth C. Ritchie (ed.), Forensic and Ethical Issues in Military Behavioural Health, Borden Institute, Surgeon General U.S. Army, Falls Church, 2014.

E. C. Ritchie, J. Block and R. L. Nevin, Psychiatric side effects of mefloquine: applications to forensic psychiatry, Journal of the American Academy of Psychiatry and the Law, vol. 41, no. 2, pp. 224-235, 2013.

R. L. Nevin, Mass administration of the antimalarial drug mefloquine to Guantánamo detainees: a critical analysisTropical Medicine and International Health, vol. 17, no. 10, pp. 1281-1288, 2012.

R. L. Nevin, Mefloquine blockade of connexin 36 and connexin 43 gap junctions and risk of suicideBiological Psychiatry, vol. 71:e1-2, 2012.

S. Toovey, Mefloquine neurotoxicity: A literature review, Travel Medicine and Infectious Disease, vol. 7, no. 1, pp. 2-6, 2009.

A. M. Croft, A lesson learnt: the rise and fall of lariam and halfan, Journal of the Royal Society of Medicine, vol. 100, no. 4, pp. 170-174, 2007.


Published Case Reports – Mefloquine

R. L. Nevin and E. C. Ritchie, FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine, Federal Practitioner, in press, 2016.

J. Livezey, T. Oliver and L. cantilever, Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine, Drug Safety: Case Reports, vol. 3, no. 7., 2016.

K. McEvoy, B. and M. S. Chisolm, Depersonalization/derealisation disorder after exposure to mefloquine, Psychosomatics, vol. 56, no. 1, 2015.

R. L. Nevin, Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report, Travel Medicine and Infectious Disease, vol. 10, no. 3, pp. 144-151, 2012.

A. C. Chester and P. Sandroni, Case report: peripheral polyneuropathy and mefloquine prophylaxis, American Journal of Tropical Medicine and Hygiene, vol. 85, no. 6, pp. 1008-1009, 2011.

A. Bhanji and C. Atkins and M. Karim, Postural orthostatic tachycardia syndrome: a case report of palpitations and dizziness following prophylactic mefloquine use, International Journal of Clinical Pharmacology and Therapeutics, vol. 48, no. 9, pp. 577-581, 2010.

N. Jousset, M. Guilleux, L. de Gentile et al., [Spectacular suicide associated with mefloquine] [Article in French], Presse Medicale, vol. 35, no. 5, pp. 789-92, 2006.

S. Jha, R. Kumar and R. Kumar, Mefloquine toxicity presenting with polyneuropathy – a report of two cases in India, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 100, no. 6, pp. 594-596, 2006.

A. B. Whitworth and W. Aichhorn, First-time diagnosis of severe depression: induced by mefloquine?, Journal of Clinical Psychopharmacology, vol. 25, no. 4, pp. 399-400, 2005.

C. Even, S. Friedman, and K. Lanouar, Bipolar disorder after mefloquine treatment, Journal of Psychiatry & Neuroscience, vol. 26, no. 3, pp. 252-253, 2001.

S. Watt-Smith, K. Mehta and C. Scully, Mefloquine-induced trigeminal sensory neuropathy, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, vol. 9, no. 2, pp. 163-165, 2001.

P. Lebain, C. Juliard, J. P. Davy et al., Neuropsychiatric symptoms in preventive antimalarial treatment with mefloquine: apropos of 2 cases, L’Encéphale, vol. 26, no. 4, pp. 67-70, 2000.

M. Fusetti, A. Eibenstein, V. Corridore et al., [Mefloquine and ototoxicity: a report of 3 cases] [Article in Italian], La Clinica Terapeutica, vol. 150, no. 5, pp. 379-382, 1999.

J. T. Lysack and C. L. Lysack, A severe adverse reaction to mefloquine and chloroquine prophylaxis, Australian Family Physician, vol. 27, no. 12, pp.1119-1120, 1998.

R. Speich and A. Haller, Central anticholinergic syndrome with the antimalarial drug mefloquine, New England Journal of Medicine, vol. 331, pp. 57-58, 1994.

T. Marsepoil et al., [Encephalopathy and memory disorders during treatments with mefloquine] [in French], La Revue de Medecine Interne, vol. 14, no. 8, pp. 788-791, 1993.

B. Rouveix, Mefloquine and an acute brain syndrome, Annals of Internal Medicine, vol. 110, no. 7, pp. 577-578, 1989.

J. Bernard, J. Le Camus, J. Sarrouy et al., Toxic encephalopathy caused by mefloquine?, Presse Médicale, vol. 16, no. 33, pp. 1654-1655, 1987.


Published Neuropharmacology Studies – Mefloquine

A. Janowsky, A. J. Eshleman, R. A. Johnson, Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro, Psychopharmacology (Berlin), vol. 231, no. 14, pp. 2771-2783, 2014.

J. H. Shin, S. J. Park, Y. K. Jo et al., Suppression of autophagy exacerbates mefloquine-mediated cell death, Neuroscience Letters, vol. 515, no. 2, pp. 162–67, 2012.

V. K. Lall, M. Dutschmann, J. Deuchars and S.A. Deuchars, The anti-malarial drug Mefloquine disrupts central autonomic and respiratory control in the working heart brainstem preparation of the rat, Journal of Biomedical Science, vol. 19, no. 103, 2012.

D. Milatovic, J. W. Jenkins, J. E. Hood et al., Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase, NeuroToxicology, vol. 32, no. 5, pp. 578-585, 2011.

J. E. Hood, J. W. Jenkins, D. Milatovic et al., Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons, NeuroToxicology, vol. 31, no. 5, pp. 518-523, 2010.

Y. Geng, L. Kohli, B. J. Klocke and K.A. Roth, Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent, Neuro-Oncology, vol. 12, no. 5, pp. 473-481, 2010.

G. Dow, R. Bauman, D. Caridha et al., Mefloquine induces dose-related neurological effects in a rat model, Antimicrobial Agents and Chemotherapy, vol. 50, no. 3, pp. 1045-1053, 2006.

G. S. Dow, D. Caridha, M. Goldberg et al., Transcriptional profiling of mefloquine-induced disruption of calcium homeostasis in neurons in vitro, Genomics, vol. 86, no. 5, pp. 539-550, 2005.

G. S. Dow, M. L. Koenig, L. Wolf et al., The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-Resistant Plasmodium falciparum Strains, Antimicrobial Agents and Chemotherapy, vol. 48, no. 7, pp. 2624-2632, 2004.

S. Barraud de Lagerie, E. Comets, C. Gautrand et al., Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice, British Journal of Pharmacology, vol. 141, no. 7, pp. 1214-1222, 2004.

Y. T. Pham, F. Nosten, R. Farinotti et al., Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria, International Journal of Clinical Pharmacology and Therapeutics, vol. 37, no. 1, pp. 58-61, 1999.

S. Baudry, Y. T. Pham, B. Baune et al., Stereoselective passage of mefloquine through the blood-brain barrier in the rat, Journal of Pharmacology and Pharmacotherapeutics, vol. 49, no. 11, pp. 1086-1090, 1997.

R. Chevli and C. D. Fitch, The antimalarial drug mefloquine binds to membrane phospholipidsAntimicrobial Agents & Chemotherapy, vol. 21, no. 4, pp. 581-586, 1982.


Published Papers – Tafenoquine and Other 8-Aminoquinolines

R. L. Nevin, Unexpected pharmacological and toxicological effects of tafenoquineOccupational Medicine, vol. 65, no. 417, 2015.

C. Vuong, L. H. Xie, B. M. J. Potter et al., Differential cytochrome P450 2D metabolism alters tafenoquine pharmacokinetics, Antimicrobial Agents and Chemotherapy, vol. 59, no. 7, pp. 3864–3869, 2015.

P. S. Fasinu, B. L. Tekwani, N. P. Dhammika Nanayakkara et al., Enantioselective metabolism of primaquine by human CYP2D6, Malaria Journal, vol. 13, no. 507, 2014.

S. R. Marcsisin, J. C. Sousa, G. A. Reichard et al., Tafenoquine and NPC-1161B require CYP 2D metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds, Malaria Journal, vol. 13, no. 2, 2014.

B. S. Pybus, J. C. Sousa, X. Jin et al., CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquineMalaria Journal, vol. 11, no. 259, 2012.

P. E. Nasveld, Tafenoquine in the prophylaxis and treatment of malaria in Australian Defence Force personnel, PhD thesis, James Cook University, 2011.

P. E. Nasveld, M. D. Edstein, M. Reid et al., Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects, Antimicrobial Agents and Chemotherapy, vol. 54, no. 2, pp. 792–798, 2010.

S. Kitchener, P. Nasveld and M. Edstein, Tafenoquine for the treatment of recurrent Plasmodium vivax malaria, American Journal of Tropical Medicine & Hygiene, vol. 76, no. 3, pp. 494-6, 2007.

N.J. Elmes, S.J. Bennett and P.E. Nasveld, Malaria in the Australian Defence Force: the Bougainville experience, ADF Health, vol. 5, no. 2, 2004.

P. Nasveld, S. Kitchener, M. Edstein and K. Rieckmann, Comparison of tafenpquine (WR238605) and primaquine in the post-exposure (terminal) prophylaxis of vivax malaria in Australian Defence Force personnel, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 96, no. 6, pp. 683-684, 2002.


Presentations

Dr Remington Nevin, Mefloquine: A Psychotropic Medication, 12 April 2013

Dr Remington Nevin, Presentation to the U.S. Food and Drug Administration on Mefloquine Neurotoxicity, 11 January 2013

Dr Remington Nevin, Neuropsychiatric Events Associated with Mefloquine, 27 November 2012


Current Projects

Ethics of mefloquine and tafenoquine drug trials using military personnel as subjects. Contact us.

Implications of mefloquine and tafenoquine neurotoxicity for research into post-traumatic stress disorder and traumatic brain injury. Contact us.


Research Proposals

Mefloquine neurotoxicity and moral injury among veterans. Contact us.

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