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European Review for Medical and Pharmacological Sciences 2011; 15: 1187-1195 induces weight loss and improves insulin sensitivity in dietary obese rats: comparison to sibutramine

D.M. ABO-ELMATTY, S.A. ZAITONE*

Department of and *Department of Pharmacology and Toxicology; Faculty of Pharmacy, Suez Canal University, Ismailia (Egypt)

Abstract. – Background and Objectives: BP = Topiramate is newly approved as DBP = Diastolic blood pressure that seems to promote body weight loss in hu- FAs = Fatty acids mans. The present study was designed to evalu- FDA = and Administration ate the weight-controlling properties of topiramate in dietary obese female rats in comparison with HDL-C = High sibutramine. HFD = High diet Materials and Methods: Fifty rats were as- HOMA-IR index = model assess- signed as normal, high fat diet (HFD), HFD + sibu- ment insulin resistance in- tramine (7.5 mg/kg, p.o.), HFD + topiramate (25 dex mg/kg, p.o.) and HFD + topiramate (50 mg/kg, LDL-C = Low density lipoprotein cholesterol p.o.). Body weight was registered, was NPD = Normal palatable diet tested in Vogel’s test and blood pressure (BP) was measured. In addition, index, adipose tissue R-QUICKI = Revised quantitative insulin sen- index, blood and pro- sitivity check index file were measured in all groups. Further, serum SBP = Systolic blood pressure insulin, leptin and adiponectin were determined. TAG = Triacylglycerol Results: Feeding with HFD induced a significant TC = Total cholesterol increase in body weight of rats as well as insulin resistance and serum as compared to nor- mal group (p<0.05). These measurements were suppressed by sibutramine treatment. However, a significant elevation in BP and anxiety behavior Introduction were detected as compared with HFD group (p<0.05). Topiramate (50 mg/kg, p.o.) group The current obesity pandemic imposes a major showed weight loss, improved insulin resistance, global disease burden. The rise in obesity will be lessened anxiety behavior without influence on BP. accompanied by increases in related disorders Discussion: Our data ensures the findings that topiramate has a weight controlling properties such as , and 1 with no anxiogenic or hypertensive effects. Fur- diseases . Obesity has been traditionally chal- ther investigations are needed to determine the lenged with diets, exercise and behavioral modi- utility of topiramate in the clinical management of fication. These techniques have still so far failed obesity. to halt the obesity pandemic. Given the enormity of the obesity problem, adjunctive pharmacother- Key Words: apy provides an attractive solution2. However, Obesity, Topiramate, Weight control, Anxiety, Blood very few drugs have been developed for obesity Pressure. treatment and those that are approved have only limited success1. When sibutramine was received approval from Abbreviations the American Food and Drugs Administration (FDA) in November of 1997, it represented the AMPA = α-amino-3-hydroxy-5-methyl-4- first unique agent of a new class of isoxazolepropionic acid for the treatment of obesity. Sibutramine is a

Corresponding Author: Sawsan A. Zaitone, Ph.D; e-mail: [email protected] 1187 D.M. Abo-Elmatty, S.A. Zaitone pharmacological agent with selective norepi- NPD for five months; the remaining rats received nephrine, serotonin and a lesser extent, HFD for three months to establish diet-induced dopamine, reuptake inhibitor3. Cardiovascular obesity. Table I illustrates the formula of the diet: side effects include an increase in systolic and di- it provides 17% energy as carbohydrates, 25% as astolic BP, and an increase in heart rate, tachy- , and 58% as fat as a percentage of total cardia and palpitations. These adrenergic side ef- kcal/g10. Rats receiving HFD were divided equal- fects are a particular concern for patients with ly into four groups. One group returned to nor- hypertension. Additionally, an increase appear- mal diet and the other groups returned to normal ance of mood-related disorders has been reported diet and treated with sibutramine (7.5 mg/kg/day, during sibutramine treatment such as insomnia4 p.o.)11 or topiramate (25 mg/kg/day, p.o.) or topi- and generalized anxiety and panic disorders5. ramate (50 mg/kg/day, p.o.)12 for additional two However, in October of 2010, sibutramine was months. The changes in body weight were moni- removed from the US market due to an evident tored every week. The were cared for in increased risk of heart attack and . After accordance with the principles and guidelines of withdrawal of sibutramine, only one - the Canadian Council on care and use of experi- orlistat-has been approved by the FDA for long- mental animals. All experimental procedures fol- term use in the treatment of obesity6. Reported lowed were in accordance with guidelines of the side effects of orlistat include flatus with dis- Institutional Care and Use Committee. charge and oily stool. Severe problems such as fecal urgency, incontinence and abdominal pain Drugs can also occur2. The adverse effects of these Sibutramine hydrochloride (Medical Union agents highlighted a continued need for safe and Pharmaceuticals, Ismailia, Egypt) was dissolved effective medications for the treatment of obesity in distilled and administered orally. Topira- with a positive impact on health related quality mate (Delta Pharm, 10th of Ramadan City, Egypt) of life. was dissolved in 2% tween-80 solution. Topiramate is a structurally novel therapeutic agent currently approved for marketing as an Testing Anxiety in Vogel’s Proconflict antiepileptic . Topiramate has been reported Situation Test to exert multiple pharmacological effects that Briefly, after 24 hrs of water deprivation, each may determine its broad range of activities in- rat was placed in the cage of the anxiometer. The cluding anticonvulsant, analgesic, and mood-sta- cage is a Plexiglas box (25×25×25 cm) equipped bilizing properties7. Topiramate has been report- with a grid floor of stainless steel bars and a ed to cause a decrease in body weight in some drinking bottle containing water (Anxiometer epileptic patients during clinical evaluation8. Model, LE 3206, Panlab s.l., Barcelona, Spain) These observations prompted studies to elucidate was used for training and testing for animals the mechanistic basis of topiramate induced where it was given an opportunity to consume weight loss in animals9. Therefore, the present study was designed for evaluation of the weight controlling properties of Table I. Composition of the high fat diet. topiramate in dietary obese rats in comparison with sibutramine. Further, we aimed to explore Amount the role of improving insulin resistance or regula- Ingredients (g/kg)e tion of adipokines in this pharmacological effect. Powdered NPD1 365 Lard2 310 Casein3 250 4 Materials and Methods Cholesterol 10 Vitamin and mineral mix5 60 DL-Methionine6 03 Animals and Experimental Design Yeast powder7 01 Fifty female albino rats were housed in stan- 8 dard cages and maintained under controlled room chloride 01 temperature (25 ± 3) and normal light-dark cycle 1,2,7,8Purchased from the market; 3Difco (Becton Dickinson, with free access to food and water. Rats had ini- France), 4Oxford Lab, Mumbai, India; 5,6Sigma-Aldrich, tial body weight 150-180 g. Ten rats received MO, USA; 8ADWIC Co., Cairo, Egypt.

1188 Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats water from a drinking bottle. A sharp decrease high HOMA index denotes low insulin sensitivi- of the number of drinking episodes testifies to ty23. To assess insulin sensitivity, another derived the existence of anxiety and increased fear in an- index was suggested, i.e., the revised quantitative imal13,14. insulin sensitivity check index (R-QUICKI) = [1/log fasting insulin (μU/ml) + log fasting glu- Measuring Systemic Arterial cose (mg/dl)]24. Blood Pressure Rats were deeply anaesthetized with thiopental Statistical Analysis sodium (40 mg/kg, i.p.)15 and placed on a temper- The results are expressed as mean ± SEM. The ature-controlled panel. A laparotomy was per- data was analyzed using Statistical Package of formed and a non-occlusive, polyvinyl catheter Social Sciences (SPSS) program version 16, was implanted in the abdominal aorta, caudal to Chicago, IL, USA. One-way analysis of vari- the kidneys, through a puncture wound in the ance, ANOVA, followed by Bonferroni’s multi- aortic wall made with the tip of an L-shaped 18- ple comparisons test were employed for statisti- gauge needle. The catheter was fixed by tying a cal analysis. A value of p≤0.05 was considered to ligature. The arterial catheter was filled with he- be statistically significant. parin solution (1.000 USP U/ml)16 and connected to digital BP monitor (Columbus Instruments, OHIO, 43204, USA) for BP recording. Mean systolic BP (SBP) and diastolic BP (DBP) were Results measured for each group. Body Weight Gain, Liver Index and Blood Sampling and Adipose Tissue Index Biochemical Analysis In the current study, HFD group showed a sig- After measuring the BP, blood samples were nificant increase in the percentage body weight collected by cardiac puncture. Serum was sepa- gain as compared to NPD group (53 ± 6 vs. 17 ± rated and kept at –80°C until performing the bio- 2 g, respectively, p≤0.05, Table II). Treatment chemical measurements. Serum insulin was de- with sibutramine (7.5 mg/kg/day, p.o.) for two termined using ultra sensitive rat insulin ELISA months significantly reduced percentage body kit (Crystal Chem Inc., Downers Grove, IL weight gain to 31 ± 3 g (p≤0.05). Similarly, treat- 60515, USA)17. Serum leptin was measured by ment with the high dose of topiramate (50 rat leptin ELISA kit (Crystal Chem Inc., USA)18. mg/kg/day, p.o.) reduced the percentage weight Serum adiponectin was detected by rat gain value significantly to 36 ± 5 g as compared adiponectin ELISA kit (AdipoGen Inc. Korea) to HFD group (p≤0.05, Table II). according to the manufactures’ instructions19. Moreover, liver and adipose tissue indices Serum glucose level was estimated enzymati- were significantly higher in HFD group as com- cally according to the method of Trinder20 using pared to NPD group (p≤0.05). Sibutramine (7.5 Spinreact diagnostics kits (Girona, Spain). Total mg/kg/day, p.o.) and topiramate (50 mg/kg, p.o.) cholesterol (TC), triacyl glycerol (TAG), low den- could reduce the high liver index value. Howev- sity lipoprotein cholesterol (LDL-C) and high den- er, only sibutramine could reduce the high adi- sity lipoprotein cholesterol (HDL-C) were mea- pose tissue index (p≤0.05, Table II). sured colorimetrically using commercial kits from (Stanbio, Boerne, TX, USA)21. Additionally, liver Serum and index was calculated by the formula: liver index = Atherogenic Index (liver weight/body weight) × 100, adipose tissue Serum lipid profile was significantly increased index = (retroperitoneal adipose tissue by feeding HFD. Table II shows that a significant weight/body weight) × 100 and in- increase in TC, TG and LDL-C and a decrease in dex was calculated by the formula: atherosclerosis HDL-C were detected in HFD group as com- index = (serum TC − HDL-C) / HDL-C22. pared to NPD group. Sibutramine or topiramate Finally, two indirect indices were calculated. could reduce the serum level of TAG as com- First, homeostasis model assessment of insulin pared to HFD group. Additionally, the difference resistance (HOMA-IR) index was calculated by in the calculated atherogenic index between the the following formula: [fasting serum insulin HFD group and the treated groups was not sig- (μU/ml)×fasting serum glucose (mM/L)]/22.5. A nificant (p≤0.05, Table II).

1189 D.M. Abo-Elmatty, S.A. Zaitone

Table II. Body weight, liver index, lipid index, serum lipid profile and atherogenic index in the experimental groups.

NPD HFD Sibutramine Topiramate Topiramate Groups group group (7.5 mg/kg) (25 mg/kg) (50 mg/kg)

Body Weight (baseline) 163.8 ± 3.5 165.7 ± 2.5 165.7 ± 3.5 165.8 ± 5 166 ± 4 Body Weight (final) 192 ± 4.4 250 ± 0.2 216 ± 0.3 238 ± 0.7 224 ± 0.2 % Δ wt (g) 17 ± 2 53 ± 6* 31 ± 3# 42 ± 6* 36 ± 5*# Liver index 4 ± 0.1 5.8 ± 0.2* 4.7 ± 0.1*# 5.1 ± 0.3* 5 ± 0.2*# Adipose tissue index 0.7 ± 0.06 1.7 ± 0.1* 1 ± 0.06*# 1.5 ± 0.2*a 1.5 ± 0.1*a TC (mg/dl) 80 ± 4 122 ± 3* 112 ± 4* 120 ± 5* 119 ± 4* TAG (mg/dl) 92 ± 4 161 ± 4* 118 ± 4*# 128 ± 5*# 126 ± 5*# LDL-C (mg/dl) 49 ± 2 60 ± 2* 53 ± 3 61 ± 3* 60 ± 2.5* HDL-C (mg/dl) 39 ± 2 30 ± 1* 34 ± 2 31 ± 3* 32 ± 2 Atherogenic index 1 ± 0.1 3.2 ± 0.2* 2.4 ± 0.2* 2.8 ± 0.2* 2.8 ± 0.2*

NPD: normal palatable diet, HFD: high fat diet, TC: total cholesterol, TAG: triacyl glycerol, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol. Results are expressed as mean ± SEM (n=10). *Significantly differ- ent from NPD group at p≤0.05. #Significantly different from HFD group at p≤0.05. aSignificantly different from sibutramine group at p<0.05.

Fasting Blood Glucose, Serum Insulin, group. The lessened insulin sensitivity was im- HOMA-IR index and R-QUICKI proved after treatment with sibutramine or the Table III reveals that feeding with HFD result- two dose levels of topiramate (p≤0.05, Table III). ed in significant and hyperinsu- linemia in rats as compared to rats fed with NPD Serum Leptin and Adiponectin (p≤0.05). Sibutramine and topiramate groups HFD group showed a significant decrease in showed significant reductions in serum glucose serum leptin and adiponectin levels as compared and insulin levels as compared to HFD group to NPD group (p≤0.05). Treatment with sibu- (p≤0.05, Table III). tramine could increase serum leptin without in- HOMA-IR index was significantly increased fluence on serum adiponectin level. In contrast, in HFD group by 302% times as compared with topiramate group showed a significant increase NPD group. Treatment with sibutramine or topi- in serum adiponectin without influence on leptin ramate could decrease the calculate HOMA-IR as compared to HFD group (p≤0.05, Table III). index (p≤0.05, Table III). On the other hand, R- Moreover, serum adiponectin level in the topira- QUICKI calculated in HFD group was signifi- mate (50 mg/kg) group was significantly higher cantly lower than the calculated value for NPD than the observed level in sibutramine group.

Table III. Fasting serum levels of glucose, insulin, HOMA-IR index, R-QUICKI, leptin and adiponectin in the experimental groups.

NPD HFD Sibutramine Topiramate Topiramate Groups group group (7.5 mg/kg) (25 mg/kg) (50 mg/kg)

Serum glucose (mg/dl) 80.6 ± 2.9 134 ± 3* 113 ± 4.2*# 111 ± 5*# 111 ± 4*# Insulin (ng/ml) 0.95 ± 0.04 2.3 ± 0.12* 1.6 ± 0.1*# 1.4 ± 0.1*# 1.6 ± 0.1*# HOMA-IR index 4.7 ± 0.2 18.9 ± 0.83* 11.3 ± 0.8*# 10.8 ± 1*# 11 ± 0.8*# R-QUICKI 0.3 ± 2 × 10-3 0.26 ± 1 × 10-3* 0.27 ± 2 × 10-3*# 0.29 ± 2 ×10-3*# 0.28 ± 2 × 10-3*# Leptin (ng/ml) 4.2 ± 0.14 3.6 ± 0.06* 4.17 ± 0.12# 3.7 ± 0.2 3.9 ± 0.1 Adiponectin (ng/ml) 5.9 ± 0.2 3.5 ± 0.1* 3.8 ± 0.2* 4.1 ± 0.5*# 4.3 ± 0.4*#a

NPD: normal palatable diet, HFD: high fat diet, HOMA-IR index: homeostasis model assessment- insulin resistance in- dex, R-QUICKI: revised quantitative insulin sensitivity check index. Results are expressed as mean ± SEM (n=10). *Sig- nificantly different from NPD group at p≤0.05. #Significantly different from HFD group at p≤0.05. aSignificantly different from sibutramine group at p≤0.05.

1190 Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats

Vogel’s Proconflict Situation Test blood glucose regulation were observed as com- In the current study, HFD-fed rats showed the pared to NPD group. Consistent with our results, same drinking behavior in Vogel test as the HFD has been shown to produce rapid weight NPD-fed rats. Licking is suppressed in sibu- gain in rodents, mild hyperglycemia, hyper- tramine-treated rats in comparison to HFD-fed triglyceridemia, and com- rats. However, treatment with topiramate (25 pensatory hyperinsulinemia together with re- mg/kg) and (50 mg/kg) increased the drinking duced glucose disappearance rate25,26. behavior and the number of shocks received by In the current study, serum leptin level was the animal as compared to HFD group (p≤0.05, decreased in rats fed HFD compared to those Figure 1a and b). under NPD. In agreement, fat feeding has been shown to impair leptin expression and to alter hypothalamic peptide expression in a way that Arterial Blood Pressure Measurement promotes food ingestion and fat accumula- Figure 2 illustrates that sibutramine group had tion27,28. The important physiologic function of a significant elevation in both SBP and DBP as leptin is to regulate in nonadipocytes the intra- compared with HFD group. Whereas, rats treated cellular homeostasis of FAs and TAG so as to with topiramate showed normal BP values maintain a sufficient supply of FAs for essential (p≤0.05). functions while avoiding TAG overload29. Thus, prevention of obesity is not the primary function of leptin. Leptin also reduces food intake and body Discussion weight through interactions with the central neur- al network, particularly in the hypothalamus30,31. The results of the current study showed that In addition, central leptin administration sup- over a period of three months, exposure of rats to pressed daily food intake in rats32. Leptin resis- HFD led to increased weight gain, liver index tance has been shown to exist in obese human and adipose tissue index. In addition, hyperlipi- patients, who are hyperphagic but have very high demia, hyperinsulinemia and impairment in serum leptin levels. It was suggested that there is

A B Number of licks Number of shocks

NPD HFD SibutramineTopiramate Topiramate NPD HFD SibutramineTopiramate Topiramate (25 mg/kg) (50 mg/kg) (25 mg/kg) (50 mg/kg)

Figure 1. Number of licks and number of shocks received by rats in Vogel test. Rats were fasted overnight and placed indi- vidually in the cage of the anxiometer. 20 drinking episodes were allowed (unpunished response) before the timer started fol- lowed by a 10 min punished drinking component, during which an electric shock (0.3 mA during 2 sec) was delivered upon every 20 drinking episodes. Number of drinking episodes (A) and number of shocks (B) were decreased in sibutramine group (7.5 mg/kg) as compared to HFD group. Topiramate (25 mg/kg) and (50 mg/kg) increased the number of licks and shocks sig- nificantly as compared to HFD group or sibutramine group. NPD: normal palatable diet, HFD: high fat diet. Results are ex- pressed as mean ± SEM (n=10). *Significantly different from NPD group at p≤0.05. #Significantly different from HFD group at p≤0.05. aSignificantly different from sibutramine group at p≤0.05.

1191 D.M. Abo-Elmatty, S.A. Zaitone

Systolic BP

Diastolic BP Blood pressure (mmHg) Blood pressure

NPD HFD SibutramineTopiramate Topiramate (25 mg/kg) (50 mg/kg)

Figure 2. Systolic and diastolic BP of rats. Rats were deeply anaesthetized and BP was measured from the renal . Sibu- tramine group (7.5 mg/kg) showed a significant increase in both systolic and diastolic BP values as compared to HFD group. Topiramate group (25 mg/kg) or (50 mg/kg) showed normal BP values. NPD: normal palatable diet, HFD: high fat diet. Re- sults are expressed as mean ± SEM (n=10). *Significantly different from NPD group at p≤0.05. #Significantly different from HFD group at p≤0.05. aSignificantly different from sibutramine group at p≤0.05.

a leptin-sensitive pathway and a leptin-insensi- has positive effects on the lipid profile (mainly tive (or less sensitive) pathway in the regulation TAG and HDL-C) and glycemic control in stud- of feeding33. ies for up to one year39. A recent hypothesis argued that there is disso- In the current investigation, sibutramine ciation between the increase in both leptin store group showed high SBP and DBP values as and adipose tissue weight, and the decrease in compared to NPD group. Many studies revealed plasma leptin levels initially begin after six an increase in SBP, DBP and pulse rate in obese weeks after sucrose feeding in rats34. Similar to patients after sibutramine treatment compared leptin results, the current study revealed that to placebo treatment40-42. The Authors highlight- serum adiponectin level was decreased in rats fed ed that sibutramine induced more weight loss HFD compared to those under NPD. In agree- than placebo which is coupled with a significant ment, adiponectin is downregulated in two mod- tachycardia. These adrenergic side effects are of els of HFD feeding35,36. a particular concern for patients with hyperten- The current results showed that sibutramine sion. The cardiostimulatory effect represents the mediated body weight loss in obese rats along most common of sibutramine. with favorable effects on biochemical parameters This may be done by inhibition of dopamine re- and insulin sensitivity. In accordance, many stud- uptake and of sibutramine’s in vivo efficacy to ies reported that treatment with sibutramine sup- increase extracellular levels of dopamine in nu- pressed food intake and weight gain in rats1,25,37,38 cleus accumbens43. Consistently, some Authors and our findings are compatible with these obser- suggest that the use of sibutramine could raise vations. Additionally, sibutramine administration BP and induce arrhythmias in some patients44, enhances sympathetic nervous system activation, may be because of paradoxical effect on the au- which in turn reduces plasma adiponectin level25. tonomic system45,46. This observation may further support our find- Furthermore, our study revealed an apparent ings since serum adiponectin level in sibutramine interplay between sibutramine medication and group did not increase in comparison with the behavior; treatment with sibutramine increased HFD group. Clinically, sibutramine reduces food the expression of anxiety-related behaviors in the intake and body weight more than placebo and rats submitted to Vogel’s proconflict situation

1192 Topiramate induces weight loss and improves insulin sensitivity in dietary obese rats test. In previous reports, sibutramine has been as- properties may explain the effect of sociated with psychosis47, hypomania and ma- topiramate that was observed in the Vogel pro- nia48,49, exacerbations of panic attacks, depres- conflict test. sion, and suicidal tendencies50. In conclusion, our data ensures the findings Our findings demonstrate that chronic treat- that topiramate possess weight controlling and ment with topiramate (50 mg/kg) produced a sig- insulin sensitizing properties with no anxiogenic nificant weight loss in obese rats. Moreover, IR or hypertensive effects. Therefore, it may be used was diminished significantly as indicated by safely in obese hypertensive patients. Further in- HOMA-IR and R-QUICKI indices. These results vestigations are needed to confirm our findings seem to be compatible with those obtained by and to determine the utility of topiramate in the Wilkes et al.51. The Authors emphasized that top- clinical . iramate treatment in obese rats led to a decrease in plasma glucose and an increase in insulin sen- sitivity. More recently, Jing et al12 concluded that topiramate decreased serum insulin levels in –––––––––––––––––––– young and adult rats. Studies with obese (fa/fa) Acknowledgements female Zucker rats demonstrated that topiramate We wish to acknowledge Delta Pharm Company (10th treatment led to a reduction in blood glucose and of Ramadan City, Egypt) for providing topiramate TAG levels52. Clinically, some Authors conclud- and Medical Union Pharmaceuticals Company (Is- ed that topiramate can significantly reduce body mailia, Egypt) for kindly providing sibutramine hy- weight and BP in obese people, with mild to drochloride. moderate adverse effects53. The precise mechanism by which topiramate induces weight loss remains under investigation but appears not to involve noradrenergic or serotonergic mechanism. Topiramate has con- References sistently decreased the efficacy of energy uti- lization in animal models, and effects on food 1) JEWETT DC, HAHN TW, SMITH TR, FIKSDAL BL, consumption have varied with the model. These WIEBELHAUS JM, DUNBAR AR, et al. Effects of sibu- tramine and rimonabant in rats trained to dis- effects on energy efficiency may be mediated criminate between 22- and 2-h food deprivation. by stimulation of lipoprotein in brown Psychopharmacol 2009; 203: 453-459. adipose tissue and , thus increas- 2) HALFORD JCG. Pharmacotherapy for obesity. Ap- ing thermogenesis9,52. Topiramate also increases petite 2006; 46: 6-10. 1,54 the expression of uncoupling 2 and 3 , 3) MCNEELY W, G OA KL. Sibutramine: a review of its thus directly decreasing the efficiency of energy contribution to the management of obesity. utilization53. Another possible mechanism is that Drugs 1998; 56: 1093-1124. topiramate might directly induce weight loss in 4) NISOLI E, CARRUBA MO. A benefit-risk assessment rodent by stimulation of energy expenditure as of sibutramine in the management of obesity. well as reduction of energy intake55. Drug Safety 2003; 26: 1027-1048. Additionally, animal studies have shown that 5) BINKLEY K, KNOWLES SR. Sibutramine and panic at- tacks. Am J Psychiatr 2002; 159: 1793-1794. stimulation of the lateral hypothalamus by gluta- α 6) CHAPUT JP, ST-PIERRE S, TREMBLAY A. Currently avail- mate and glutamate , including kainite/ - able drugs for treatment of obesity: sibutramine amino-3-hydroxy-5-methyl-4-isoxazole propi- and orlistat. Med Chem 2007; 7: 3-10. onic acid (AMPA) agonist, causes an intense, 7) M ARCOTTE D. Use of Topiramate: a new rapid, dose dependent increase in food intake. antiepileptic drug as a mood stabilizer. J Aff Topiramate is an antagonist at kainite/AMPA Disord 1998; 50: 245-251. 56 glutamate receptors . Furthermore, diverse 8) REIFE R, PLEDGER G, WU SC. Topiramate as add- pharmacological properties of topiramate have on therapy: pooled analysis of randomized con- been identified including the following: a posi- trolled trials in adults. Epilepsia 2000; 41: S66- S71. tive modulatory effect on the activity of GABA at GABA-A receptors, a negative modulatory ef- 9) RICHARD D, PICARD F, L EMIEUX C, LALONDE C, SAM- SON P, D ESHAIES Y. The effect of topiramate and fect on voltage-dependent sodium channels, and sex hormones on energy balance of male and some negative effect on high voltage-activated femal rats. Int J Obes Relat Metab Disord 2002; calcium channels55. These pharmacological 3: 344-353.

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