Topiramate chemical structure
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Topiramate

Topiramate (brand name: Topamax®) is an anticonvulsant drug produced by Ortho-McNeil, a division of Johnson & Johnson. It is used to treat epilepsy in both children and adults. In children it is also indicated for treatment of Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays). It is also FDA approved for, and now most frequently prescribed for, the prevention of migraines. It has been used by psychiatrists to treat bipolar disorder, although it is not FDA approved for this purpose and such use is somewhat controversial. more...

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This drug has been investigated for use in treatment of obesity, especially to aid in the reduction of binge eating, and also as a possible treatment for alcoholism. However, these uses are not actively promoted by the manufacturer, and like its use for bipolar disorder, are "off-label" uses. The drug is also used in clinical trials to treat Post Traumatic Stress Disorder. A pilot study suggests that Topiramate is possibly effective against infantile spasm.

Pharmacodynamics

Chemically, Topiramate is a sulfamate-substituted monosaccharide, related to fructose, a rather unusual chemical structure for an anticonvulsant. Topiramate is quickly absorbed after oral use. Most of the drug (70%) is excreted in the urine as unchanged drug. The remainder is extensively metabolized by hydroxylation, hydrolysis, and glucuronidation. Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. Topiramate enhances GABA-activated chloride channels. In addition, Topiramate inhibits excitatory neurotransmission, through actions on kainate and AMPA receptors. There is evidence that Topiramate has a specific effect on GluR5 kainate receptors. It is also an inhibitor of carbonic anhydrase, particular subtypes II and IV, but this action is weak and unlikely to be related to its anticonvulsant actions, but may account for the bad taste and the development of renal stones seen during treatment. Its possible effect as a mood stabilizer seems to occur before anticonvulsant qualities at lower dosages. Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secundarily generalized tonic-clonic seizures in the kindling model, findings predective of a broad spectrum of antiseizure activities clinically.

Side effects

The most common side effects include a change in taste (carbonated beverages, especially diet sodas and beer, taste particularly bad) and feelings of pins and needles in the head and extremities. Less common side effects include cognitive deficiency (particularly word-finding difficulty); grogginess; lethargy; renal stones, impairment of fine motor skills; vision abnormality and transient or permanent vision loss (see below for FDA warning); weight loss; breast pain; abdominal pain; menstrual disorder; taste changes; pharyngitis; sinusitis; diplopia; rash; leukopenia; fatigue; dizziness; insomnia; anxiety; depression; paresthesia; diarrhea; nausea; dyspepsia; constipation; dry-mouth; dysmenorrhea.

Rarely, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.

The side-effects most frequently leading to discontinuation of therapy with topiramate were :

Read more at Wikipedia.org


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Topiramate for weight loss in obesity - Treatments for Obesity - Author Abstract
From Nutrition Research Newsletter, 7/1/03

The prevalence of obesity has been rising steadily throughout the world for more than 15 years. The rise in obesity will undoubtedly be accompanied by increases in related disorders such as diabetes, hypertension, gall bladder disease, and heart disease. The associated health care costs will be high. Diet and physical activity remain the cornerstones of therapy for obesity, although results have been disappointing. The difficulty in maintaining long-term weight loss through diet and behavior modification has led to an increasing interest in other avenues for treatment, particularly pharmacotherapy. To date, only two medications--sibutramine and orlistat--have been approved for long-term use in the treatment of obesity, and additional effective pharmacological treatments are needed. Topiramate (TPM) is a novel broad-spectrum neurotherapeutic agent approved by the FDA and more than 75 countries around the world for selected seizure disorders. A retrospective analysis of data from trials of TPM in epilepsy revealed that patients treated with TPM experienced a progressive weight loss for 18 months, which was maintained until the end of the 24-month observation period. Further evidence for the association of weight loss with TPM therapy is found in open-label clinical trials in patients with epilepsy, bipolar disorder, and binge eating disorder.

To evaluate the efficacy and safety of TPM in the treatment of obesity, the present study was the first to conduct a controlled clinical trial in healthy obese subjects. Reported here are the results of this 24-week, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial in obese subjects. The first clinical trial was limited to healthy obese subjects who were between 18 and 75 years of age with a BMI e>30 to <50 kg/[m.sup.2] or a BMI of e>27 to <50 kg/[m.sup.2] if the subject also had controlled hypertension and/or dyslipidemia. More than 80% of the subjects were premenopausal women. Only 2% of the subjects were more than 65 years old. During an initial 1-week screening period, volunteers were assessed with a complete medical examination, and eligible subjects were randomized to receive either placebo or 64 mg, 96 mg, 192 mg, or 384 mg of TPM daily. To allow differentiation from those doses approved for the treatment of seizure disorders (200 mg/d to 400 mg/d), a different dose range of 64 mg/d to 384 mg/d was selected for clinical assessment in obesity. A 12-week drug titration schedule was used.

All subjects also participated in a standardized, commercially available, behavioral modification weight management program called Pathways to Change. This program, which focuses on lifestyle and self-management in areas related to weight loss and obesity, was administered by trained clinic staff. Starting at the second visit and at each subsequent visit, each counselor introduced a unique lifestyle topic that was consistent for that particular visit across all sites. An individualized diet that was 600 kcal/d less than maintenance needs was calculated and presented to each subject at the second visit.

At this visit, subjects were given a Food and Activity Tracker so subjects could keep a record of their food and physical activity for 3 days before the next clinic visit. At the end of the maintenance, subjects were tapered off the medication.

TPM produced significantly greater weight loss than placebo at all doses. The weight loss was the same with the two higher doses, which produced more weight loss than the lower doses. Weight loss continued throughout the trial and did not plateau at 24 weeks. At 24 weeks, weight loss was -2.6% for placebo and -0.5%,-4.8%, -6.3%, and -6.3%, respectively, for groups treated with 64 mg/d, 96 mg/d 192 mg/d, and 384 mg/d TPM. Among the completers, those receiving placebo experienced -3.6% weight loss compared with losses of -5.8%, -6.5%, -8.2%, and -8.5%, respectively, for those receiving 64 mg/d, 96 mg/d, 192 mg/d, and 384 mg/d TPM. Although most patients had normal BP measurements at baseline, significant deceases were observed in SBP for each of the four TPM treatment groups and significant decreases in DBP for the three higher dosages. As expected, in those subjects who lost more than 5% or 10% of body weight, there were greater reductions in BP and modest changes in total cholesterol, LDLs, and triglycerides.

Adverse events occurred in more than 5% of TPM-treated subjects across the four treatment groups. Most of these events involved the central nervous system (CNS) or peripheral nervous systems and were mild to moderate in severity. In general, most subjects developed the adverse events early, within the first 8 weeks of therapy. By week 8, 50% of the placebo group and 60% to 80% of the TPM-treatment patients had experienced a CNS-related adverse event. Nearly all CNS-related events had resolved before the end of the trial. Adverse events were the cause of discontinuation in 11% of the placebo-treated patients and in 21% of the TPM-treated patients. The most common side effects leading to discontinuation were difficultly with memory, paresthesia, difficulty with concentration or attention, and mood problems. The adverse events generally showed a pattern of increasing incidence with increasing dose.

In this trial, TPM produced significantly greater weight loss than placebo at all doses. The two lower doses produced similar weight loss, which was less than that produced by the two higher doses. However, because subjects tolerated the lower doses of 64 mg/d and 96 mg/d better than the higher doses and because these lower doses were clinically effective in producing weight loss, it would seem that the lower doses warrant further clinical evaluation for the long-term treatment of obesity.

G Bray, P Hollander, S Klein, R Kushner, B Levy, M Fitchet, B Perry. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 11(6): 722-733 (June 2003) [Correspondence: George A. Bray, MD, Division of Obesity, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: brayga@pbrc.edu]

COPYRIGHT 2003 Frost & Sullivan
COPYRIGHT 2003 Gale Group

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