A small-fish model for behavioral-toxicological screening of new antimalarial drugs: a comparison between erythro- and threo-mefloquine

BMC Research Notes

Wei Weng¹  Liqun Zhu¹  Hans Maaswinkel¹ 

[1] Research and Development, xyZfish, 2200 Smithtown Ave, Ronkonkoma 11779-7329, NY, USA

关键词: 3D tracking;    Antimalarial drugs;    Zebrafish;    Goldfish;    Behavioral toxicology;    Threo-mefloquine;    Erythro-mefloquine;   

Others  :  1164305
DOI  :  10.1186/s13104-015-1088-x

 received in 2014-09-15, accepted in 2015-03-24,  发布年份 2015

【 摘 要 】

Background

New antimalarial drugs need to be developed because over time resistance against the existing drugs develops. Furthermore, some of the drugs have severe side effects. Here we describe a behavioral small-fish model for early detection of neurotoxic effects of new drugs. As case example we compare the effects of two mefloquine diastereomers on the behavior of goldfish using an automated 3D tracking system.

Findings

In a preliminary experiment, the overall toxic effects in terms of motor and respiratory impairments were determined during a 3-hour exposure to the drugs at relatively high doses (21.5 and 43 mgL). In the second experiment, behavioral testing was performed 24 h after a 3.5-h drug exposure to a low dose (14.25 mgL) of either drug. For the two high doses, erythro-mefloquine resulted in severe motor problems and respiratory problems occurred. In goldfish treated with threo-mefloquine, at 43 mgL the motor/respiratory impairments were less severe and at 21.5 mgL no such problems were observed. For the lower dose (14.25 mgL), erythro-mefloquine reduced locomotion. There was also a tendency for increased freezing, and the preference for quadrant two of the observation container was increased. No behavioral effects of threo-mefloquine were found.

Conclusions

The results demonstrate that in goldfish exposed to the drugs dissolved in the water, threo-mefloquine has less severe toxic effects as compared to erythro-mefloquine. These findings are consistent with other studies and support the usefulness of the small-fish model for predicting adverse effects of new antimalarial drugs during the initial phases of drug development.

【 授权许可】

   
2015 Maaswinkel et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]WHO: World Malaria Report. World Health Organization Press, Geneva; 2013.
• [2]Dow GS, McCarthy WF, Reid M, Smith B, Tang D, Shanks GD: A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area. Malar J 2014, 13:49. BioMed Central Full Text
• [3]Croft AM: A lesson learnt: the rise and fall of Lariam and Halfan. J R Soc Med 2007, 100:170-4.
• [4]Barrett PJ, Emmins PD, Clarke PD, Bradley DJ: Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travelers. BMJ 1996, 313:525-8.
• [5]Kitchener SJ, Nasveld PE, Gregory RM, Edstein MD: Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor. Med J Aust 2005, 182:168-71.
• [6]Korhonen C, Peterson K, Bruder C, Jung P: Self-reported adverse events associated with antimalarial chemoprophylaxis in peace corps volunteers. Am J Prev Med 2007, 33:194-9.
• [7]Petersen E, Ronne T, Ronn A, Bygbjerg I, Larsen SO: Reported side effects of chloquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers. J Travel Med 2000, 7:79-84.
• [8]Philips-Howard PA, ter Kuile FO: CNS adverse events associated with antimalarial agents. Fact or fiction? Drug Saf 1995, 12:370-83.
• [9]Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K: Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991, 45:86-91.
• [10]Dow G, Bauman R, Caridha D, Cabezas M, Du F, Gomez-Lobo R, et al.: Mefloquine induces dose-related neurological effects in a rat model. Antimicrob Agents Chemother 2006, 50:1045-53.
• [11]van Essen TA, van der Giessen RS, Koekkoek SK, Vanderwerf F, Zeeuw CI, van Genderen PJ, et al.: Anti-malaria drug mefloquine induces motor learning deficits in humans. Front Neurosci 2010, 19:191.
• [12]Rendi-Wagner P, Noedl H, Wernsdorfer WH, Wiedermann G, Mikolasek A, Kollaritsch H: Unexpected frequency, duration and spectrum of adverse events after therapeutic dose of mefloquine in healthy adults. Acta Trop 2002, 81:167-73.
• [13]Dow GS, Hudson TH, Vahey M, Koenig ML: The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro. Malar J 2003, 2:14. BioMed Central Full Text
• [14]Caridha D, Yourick D, Cabezas M, Wolf L, Hudson TH, Dow GS: Mefloquine disruption of calcium homeostasis in mammalian cells is similar to that induced in ionomycin. Antimicrob Agents Chemother 2008, 52:684-93.
• [15]Hood JE, Jenkins JW, Milatovic D, Rongzhu L, Aschner M: Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons. Neurotoxicology 2010, 31:518-23.
• [16]Milatovic D, Jenkins JW, Hood JE, Yu Y, Rongzhu L, Aschner M: Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase. Neurotoxicology 2011, 32:578-85.
• [17]Milner E, McCalmont W, Bhonsle J, Caridha D, Carroll D, Gardner S, et al.: Structure-activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of plasmodium falciparum. Med Chem Lett 2010, 20:1347-51.
• [18]Milner E, Sousa J, Pybus B, Melendez V, Gardner S, Grauer K, et al.: Characterization of in vivo metabolites of WR319691, a novel compound with activity against plasmodium falsiparum. Eur J Drug Metab Pharmacokinet 2011, 36:151-8.
• [19]Wipf P, Mo T, Geib SJ, Caridha D, Dow GS, Gerena L, et al.: Synthesis and biological evaluation of the first pentafluorosulfanyl analogs of mefloquine. Org Biomol Chem 2009, 7:4163-5.
• [20]Iglesias R, Spray DC, Scemes E: Mefloquine blockade of pannexin 1 currents: resolution of a conflict. Cell Commun Adhes 2009, 16:131-7.
• [21]Zhu L, Weng W: Catadioptric stereo-vision system for the real-time monitoring of 3D behavior in aquatic animals. Physiol Behav 2007, 91:106-19.
• [22]Maaswinkel H, Zhu L, Weng W: Using an automated 3D-tracking system to record individual and shoals of adult zebrafish. J Vis Exp 2013, 82:e50681.
• [23]Kim L, He L, Maaswinkel H, Zhu L, Sirotkin H, Weng W: Anxiety, hyperactivity and stereotypy in a zebrafish model of fragile X syndrome and autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 2014, 55:41-9.
• [24]Prochnow N, Abdulazim A, Kurtenbach S, Wildförster V, Dvoriantchikova G, Hanske J, et al.: Pannexin1 stabilizes synaptic plasticity and is needed for learning. PLoS One 2012, 7:e51767.
• [25]Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, et al.: Antagonists of the human adenosine A2A receptor. Part 1: discovery and syntheis of thieno [3,2-d] pyrimidine-4-methanone derivatives. Bioorganic Med Chem Letters 2008, 18:2916-9.
• [26]Fletcher A, Shepherd R: Administering to subject effective dose of (+)-mefloquine or pharmaceutically acceptable salt thereof substantially free of (−)-enantiomer; reduced side effects. US Patent 2003, 6664397:B1.
• [27]Karle JM, Olmeda R, Gerena L, Milhous WK: Plasmodium falciparum: role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents. Exp Parasitol 1993, 76:345-51.
• [28]Chaparro MJ, Vidal J, Angulo-Barturen I, Bueno JM, Burrows J, Cammack N, et al.: Case study of small molecules as antimalarials: 2-amino-1-phenylethanol (APE) derivatives. ACS Med Chem Lett 2014, 5:657-61.
• [29]Basco LK, Gillotin C, Gimenez F, Farinotti R, Le Bras J: In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against plasmodium falciparum. Br J Clin Pharmacol 1992, 33:517-20.
• [30]Gimenez F, Farinotti R, Thuillier A, Hazebroucq G, Wainer IW: Determination of the enantiomers of mefloquine in plasma and whole blood using a coupled achiral-chiral high-performance liquid chromatographic system. J Chromatogr 1990, 529:339-46.
• [31]Schmidt LH, Crosby R, Rasco J, Vaughan D: Antimalarial activities of various 4-quinolonemethanols with special attention to WR-142,490 (mefloquine). Antimicrob Agents Chemother 1978, 13:1011-30.
• [32]Carroll FI, Blackwell JT: Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, optical purity, and absolute stereochemistry. J Med Chem 1974, 17:210-9.