Mefloquine symptoms and conditions

Antimicrobial Agents and Chemotherapy, July 2004, p. 2624-2632, Vol. 48, No. 7
0066-4804/04/$08.00+0 DOI: 10.1128/AAC.48.7.2624-2632.2004

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-Resistant Plasmodium falciparum Strains
Geoffrey S. Dow,1* Michael L. Koenig,2 Lesley Wolf,2 Lucia Gerena,1 Miriam Lopez-Sanchez,1 Thomas H. Hudson,1 and Apurba K. Bhattacharjee1
Divisions of Experimental Therapeutics,1 Neurosciences, Walter Reed Army Institute of Research, Silver Spring, Maryland 209102

Received 16 September 2003/ Returned for modification 25 November 2003/ Accepted 3 March 2004

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 assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC50) of mefloquine was 25 µM, while those of the analogs were 19 to 200 µM. 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 (IC50s 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.

Singulair, montelukast, contains a chloroquine in it's molecular structure. I am praying that the FDA takes this investigation seriously. Other countries are concerned about the neuro-psychiatric side effects of these categories of drugs for some very good reasons.

"In summary, we have used a combination of electrophysiology, ligand binding, homology modelling and simulated docking to define the mechanisms by which quinine, chloroquine and mefloquine inhibit the 5-HT3 receptor response. Our observations further extend the number of receptors known to be affected by these compounds and the growing diversity of targets may account for the broad spectrum of side effects that have been reported by patients receiving them (Luzzi and Peto, 1993; Palmer et al., 1993; Taylor and White, 2004). Inhibition of the 5-HT3-mediated current could have wide-ranging effects in the nervous system, as 5-HT3 receptors can modulate a variety of neurotransmitter responses such as those to GABA, dopamine and cholecystokinin (Thompson et al., 2006b)."

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