University of Birmingham Topiramate is more effective than acetazolamide at lowering intracranial pressure Scotton, William J; Botfield, Hannah F; Westgate, Connar Sj; Mitchell, James L; Yiangou, Andreas; Uldall, Maria S; Jensen, Rigmor H; Sinclair, Alex J DOI: 10.1177/0333102418776455 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Scotton, WJ, Botfield, HF, Westgate, CS, Mitchell, JL, Yiangou, A, Uldall, MS, Jensen, RH & Sinclair, AJ 2018, 'Topiramate is more effective than acetazolamide at lowering intracranial pressure', Cephalalgia. https://doi.org/10.1177/0333102418776455 Link to publication on Research at Birmingham portal Publisher Rights Statement: William J Scotton, Hannah F Botfield, Connar SJ Westgate, James L Mitchell, Andreas Yiangou, Maria S Uldall, Rigmor H Jensen, and Alex J Sinclair, Topiramate is more effective than acetazolamide at lowering intracranial pressure, Cephalalgia, First Published June 13, 2018; https://doi.org/10.1177/0333102418776455. 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International Headache Society 2018 than acetazolamide at lowering Reprints and permissions: sagepub.co.uk/journalsPermissions.nav intracranial pressure DOI: 10.1177/0333102418776455 journals.sagepub.com/home/cep William J Scotton1,2,3,*, Hannah F Botfield4,* , Connar SJ Westgate1,2 , James L Mitchell1,2,3, Andreas Yiangou1,2,3, Maria S Uldall5, Rigmor H Jensen5 and Alex J Sinclair1,2,3 Abstract Background: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. Methods: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazo- lamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. Results: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% (p ¼ 0.0009) and 21% (p ¼ 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% (p ¼ 0.018), compared to 5% reduction with acetazolamide (p ¼ >0.999). Conclusion: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intra- cranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest. Keywords Cerebrospinal fluid, idiopathic intracranial hypertension, headache, choroid plexus Date received: 18 December 2017; revised: 14 February 2018; 23 March 2018; accepted: 9 April 2018 Introduction 1Metabolic Neurology, Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK Idiopathic intracranial hypertension (IIH) typically 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health affects obese woman of childbearing age and is charac- Partners, Birmingham, UK 3 terised by raised intracranial pressure (ICP). Morbidity Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK results from chronic disabling headaches and papilloe- 4Institute of Inflammation and Ageing, University of Birmingham, dema, with the potential for severe visual loss (perman- Edgbaston, Birmingham, UK ent in up to 25%) (1). IIH affects 1–2 per 100,000 of the 5Danish Headache Center, Clinic of Neurology, Rigshospitalet-Glostrup, general population and 20 per 100,000 of the obese University of Copenhagen, Glostrup, Denmark female population with numbers expected to rise over *These authors contributed equally to this work. the forthcoming decade in line with escalating obesity Corresponding author: figures (2). Management strategies focus on disease Alexandra Sinclair, Metabolic Neurology, Institute of Metabolism and modification through weight loss, although this is Systems Research, University of Birmingham, Edgbaston, B15 2TT, UK. notoriously difficult to achieve (3). Therefore, the Email: [email protected] 2 Cephalalgia 0(0) majority of patients receive pharmacological therapy After treatments and surgical procedures, the rats were with the aim of reducing cerebrospinal fluid (CSF) monitored daily for any adverse effects. secretion and consequently ICP. For those with fulmin- ant IIH and rapidly declining vision, CSF diversion Drugs surgery may be necessary (4). Acetazolamide is the most commonly used drug in The dose of the drug was determined using the 2005 IIH. Class 1 evidence has demonstrated modest improve- FDA guidance for industry, which describes how to ment in visual EeldfunctioninpatientswithIIHwith estimate the maximum safe starting dose in healthy vol- mild visual loss (5,6). However, the 2015 Cochrane unteers (8): Human equivalent dose (mg/kg) ¼ rat drug review (7) has summarised that there is currently insuffi- concentration (mg/kg)/6.2. Therefore, to convert the cient evidence to recommend or reject the efficacy of human dose to an equivalent rat dose we used the equa- acetazolamide for treating IIH. Between 19–48% of tion: rat drug concentration (mg/kg) ¼ 6.2 Â human patients will not tolerate acetazolamide due to side effects dose (mg/kg based on a 60 kg human). The rat clinical (5,6) and consequently alternative drugs maybe pre- dose was calculated using the human single dose, and scribed such as topiramate, furosemide, amiloride and the rat high dose was equivalent to the human daily octreotide. However, there is extremely limited mechan- dose (Table 1). istic and clinical data to support their use. The purpose of Previous studies investigating the effects of drugs on this study was to determine which drug currently used to ICP administered them via various routes; however, in treat IIH has the greatest effect at lowering ICP in rats to this study we standardised the delivery route to sub- provide pre-clinical evidence for its use in IIH. cutaneous injection before going on to assess the most promising drugs via their usual route of administration (oral). Acetazolamide (A6011, Sigma-Aldrich), fur- Materials and methods osemide (F4381, Sigma-Aldrich) and topiramate Experimental animals (13623, Cayman Chemical) were initially dissolved in NaOH and then the pH lowered to 8.7, 7.7 and 7.8 Female Sprague-Dawley (SD) rats (Taconic, Denmark) respectively, with hydrochloric acid (HCl). Amiloride weighing 150–250 g were used in this study. The rats HCl (129876-100, Merck Millipore) and Octreotide were maintained in cages kept under a 12-hour light/ acetate salt (H-5972, Bachem) were dissolved in sterile dark cycle with free access to food and water. All experi- water. The stock solutions were further diluted in 0.9% mental procedures were approved by the Danish Animal sodium chloride (NaCl) to their final concentrations for Experiments Inspectorate (license number 2014-15-0201- subcutaneous injection. Hyperosmolar solutions are 00256) and comply with the ARRIVE guidelines. known to have ICP lowering effects (9), therefore we Table 1. Human and rat equivalent doses*. Human single Human daily Rat clinical Rat high Rat Tmax Drug (clinical) dose (high) dose dose dose (T½) hours Reference Subcutaneous Topiramate 50 mg 200 mg 5.2 mg/kg 20.6 mg/kg 0.7 Æ 0.5 (2.5) (11) 20 mg/kg oral Acetazolamide 1 g 4 g 103.3 mg/kg 413.4 mg/kg 1–3 (6) (12) oral Amiloride 5 mg 20 mg 516.7 mg/kg 2.0 mg/kg 4 (21.7)** (13) 10 mg/kg oral Octreotide 350 mg 2 mg 36.2 mg/kg 206.6 mg/kg 1 (0.7 Æ 0.1) (14) 500 mg/kg SC Furosemide 40 mg 240 mg 4.1 mg/kg 24.8 mg/kg 1 (0.5) (15) 40 mg/kg oral Oral Topiramate – 200 mg – 6.25 mg/rat Acetazolamide – 4 g – 125 mg/rat *Rat drug concentration (mg/kg) ¼ 6.2 Â human dose (mg/kg based on a 60 kg human). **Tmax for subcutaneous amiloride is not known but is expected to be less than the oral Tmax. Scotton et al. 3 measured the sodium and chloride concentrations of plasma concentration (Tmax) for the majority of the each drug in solution. The osmolarity of the clinical drugs; Table 1 (11–15)).