Launched as Topamax in the late 1990s, topiramate came from the research benches of epilepsy laboratories. All major pharmaceutical companies have complex laboratories, where scientists and biochemists spend their time trying to discover new chemical compounds, or new clinical applications of already available substances. Depakene was discovered by accident, when a chemical used as a diluent, valproic acid, was found to be a potent antiepileptic in the 1970s.

The topiramate molecule was planned to fit a well defined part of the GABA receptor. Barbiturates, alcohol and the benzodiazepines, all worked at this major central nervous system receptor. What researchers were looking for was a drug that was antiepileptic as the barbiturates and the benzodiazepines, but did not make people drunk, sleepy, or addicted.

When it began to be tested in animals, topiramate showed great efficacy, in rats, cats, eventually dogs and monkeys. These animals are bred with genetic disorders or brain lesions that cause epilepsy of one kind or another, the so-called disease models. Results began to be shown in congresses, and expectations were high. Experiments in normal volunteers clarified the clinical pharmacology and the best manner of making the tablets.

The next step was patients with with seizures uncontrolled even on a combination of 2 or 3 potent drugs.  And, along with a few other drugs of many that were tested in the 1980s and 90s, as oxcarbazepine, felbamate, gabapentin, lamotrigine and vigabatrin, topiramate came out quite well. Already in the market with the brand name Topamax, it was initially used in very severe cases, along with other medications, in complex clinical situations, with multiple drug interactions.

Topiramate has efficacy against different kinds of seizures, generalized and localized. It has a long half-life. This detail of clinical pharmacology makes life for patients significantly easier, and coping with unexpected events as small surgeries, trauma, dental emergencies, gastric and intestinal disorders, cancer treatment, all much easier and safer. Topiramate does not lose effect with time and it does not create chemical addiction, as benzodiazepines, such as alpazolam, clonazepam.

Topiramate does have effects on liver enzymes, which need to be well known by physicians, and make its use along with other medications and alcohol complex and dangerous.  Another characteristic is its lipophilia, or friendship with fat, it likes adipose tissue. So, as people lose fat tissue, topiramate gains effect. The effetcs on appetite, tremor, headache, neuropathic pain and mood were discovered early on, and topiramate ends up perhaps being the only sedative drug that also decreases appetite. But clinical use is complex, and small dose adjustments are necessary every few weeks or at most every few months. That may sound preposterous to many patients, who would prefer to look after their own doses and medications.

There are other details of the use of topiramate, as its effect on intestinal function, somewhat akin to Xenical, another  weight-loss drug that has non nervous effects only. Furthermore, as with many other drugs, there is an age problem. The younger people are, the more medication they need to have the same effect. So, as people grow older, lose weight and add new drugs to their regimen, they need constant attention to the drugs they are already on. Although the cost of topiramate may be not much nowadays, and it is generally available in generic and personalized pharmacies, the risk of accidents and self-medication is high.

 

Dr Paulo Rogério Mudrovitsch de Bittencourt, FAAN

PhD in Medicine (Clinical Pharmacology of Antiepileptic Drugs and Benzodiazepines)

Former President of Liga Brasileira de Epilepsia and 1st Vice President and member of various executive commissions, International League Against Epilepsy

www.dimpna.com

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