Electroencephalographic and behavioral convulsant effects of hydrobromide and hydrochloride salts of bupropion in conscious rodents

Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. ORIGINAL RESEARCH Electroencephalographic and behavioral convulsant effects of hydrobromide and hydrochloride salts of bupropion in conscious rodents David C Henshall 1 Nick Dürmüller 2 H Steve White 3 Robert Williams 4 Paul Moser 2 Mark Dunleavy 1 Peter H Silverstone 5 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; 2 Porsolt and Partners Pharmacology, Le Genest-Saint-Isle, France; 3 NeuroAdjuvants, Inc., Salt Lake City, UT, USA; 4 Biovail Technologies, Ltd., Dublin, Ireland; 5 Biovail Corporation, Mississauga, ON, Canada 1 Abstract: A novel bromide salt of the antidepressant bupropion (bupropion HBr) has recently been developed and approved for use in the United States. Given previous use of bromides to treat seizures, and that the existing chloride salt of bupropion (HCl) can cause seizures, it is important to determine if the HBr salt may be less likely to cause seizures than the HCl salt. In the present animal studies this was evaluated by means of quantified electroencephalogram (EEG), observation, and the rotarod test in mice and rats. Both bupropion salts were tested at increasing equimolar doses administered intraperitoneally. The results in mice showed that bupropion HCl 125 mg/kg induced a significantly higher ten-fold increase in the mean number of cortical EEG seizures compared to bupropion HBr (7.50 ± 2.56 vs 0.75 ± 0.96; p = 0.045), but neither drug caused any brain injuries. In rats bupropion HBr 100 mg/kg induced single EEG seizure activity in the cortical and hippocampal (depth) electrodes and in significantly (p ⬍ 0.05) fewer rats (44%) compared to bupropion HCl, which induced 1 to 4 convulsions per rat in all rats (100%) dosed. The total duration of cortical seizures in bupropion HCl-treated rats was significantly longer than the corresponding values obtained in bupropion HBr-treated rats (424.6 seconds vs 124.5 seconds respectively, p ⬍ 0.05). Bupropion HCl consistently induced more severe convulsions at each dose level compared to bupropion HBr. Both treatments demonstrated a similar dose-dependent impairment of rotarod performance in mice. In conclusion, these findings suggest that bupropion HBr may have a significantly lower potential to induce seizures in mice and rats, particularly at higher doses, compared to bupropion HCl. Determination of this potential clinical advantage will require human studies. If confirmed by such studies, it is likely that this potential beneficial clinical benefit would be due to the presence of the bromide salt given the long history of the use of bromide to treat seizure disorders. Keywords: bupropion hydrobromide, bupropion hydrochloride, EEG, seizures, mice, rats, motor impairment Introduction Correspondence: Peter Silverstone Departments of Neuroscience and Psychiatry, University of Alberta, 8440-112 Street, Edmonton, Canada, T6R 2A1 Tel +1 780 407 6576 Fax +1 780 407 6672 Email Bupropion hydrochloride (HCl), a widely used antidepressant, is associated with a dose-dependent risk of seizures when given at therapeutic doses or following overdose in humans,1–6 and in animals.7,8 The precise mechanism of bupropion-induced seizures remains unknown. Recently, Biovail (Biovail Laboratories International SRL, St. Michael, Barbados) has developed a new extended-release tablet formulation of bupropion hydrobromide (HBr) for once-daily administration. The administration of bupropion HBr to steady-state levels was safe and well tolerated for up to five weeks in healthy nonsmoking adult volunteers.9 The bromide salt was chosen for stability reasons. However, once developed there arose the possibility that this formulation had a reduced seizure risk compared to bupropion HCl. This is because high-dose bromide is associated with treatment of seizures. Bromides were first introduced in the treatment of seizures in 1857 by Sir Charles Locock10,11 and gained wide usage until Neuropsychiatric Disease and Treatment 2009:5 189–206 189 © 2009 Henshall et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Henshall et al the introduction of phenobarbital in 1912. When phenytoin was introduced in 1937, it heralded the demise of bromides as antiepileptic drugs in the modern age of antiepileptics.12 Although the mechanism of action of bromide as an antiseizure agent is not known, developing a hydrobromide salt of bupropion may therefore potentially reduce the seizure risk associated with the use of bupropion. The objectives of these studies were to: (i) assess the electroencephalographic and behavioral convulsant, and central nervous system effects of bupropion HBr in comparison to the effects of equimolar doses of bupropion HCl in conscious mice and rats, and (ii) show a difference, if any, in the sensitivity of the rodents to the two salts of bupropion. Materials and methods Mice electroencephalogram study The objectives of this study were to: (a) determine the comparative cortical electroencephalogram (EEG) proconvulsant effects of equimolar doses of bupropion HCl and bupropion HBr in mice, and (b) determine if the bupropion-induced seizures were associated with any histopathological brain injury, and if so, determine any differences between the two salts in the magnitude of the injury. The study was conducted at the In vivo Neuroscience Laboratory, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland. All experimental and operational procedures were performed in accordance with the current standard operating procedures of the Biomedical Research Facility at the Royal College of Surgeons in Ireland and the research study was undertaken under the remit of current Research Ethics Committee approval for the study of seizure effects in mouse models (REC 098). Animals Thirty (30) female CD-1 mice (Charles River laboratories, Margate, Kent, UK) weighing 25–29 g were housed in groups of five to six per cage in standard polypropylene cages for mice with stainless steel lids in the Biomedical Research Facility. They were acclimatized for a minimum period of four days with standard laboratory rodent processed sawdust used as bedding material in the cages in an environmentally controlled animal room (temperature 22 ± 3 °C; relative humidity 50% ± 20%) with a 12-hour light/dark cycle. Each cage was identified using cage cards with information on the researcher/principal investigator, study number, cage number, animal number, number of animals, species, strain, sex, signature of technician and start date. After allocation to gr (...truncated)