Topiramate

Topiramate reduces glutamate release from neurons and antagonizes acdvadon of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, a glu-tamatergic excitatory amino acid receptor. A double-blind, placebo-con drolled dial conducted in 296 ALS pa dents over 12 months showed a faster rate of decline in arm sdrength and no effect on survival from topiramate (Cudkowicz et al., 2003). This dial had a large dropout rate and proceeded to a phase HI dial without first exploring the effects of topiramate in the SOD model. 

Topiramate w as recently studied in the marmoset model of PD (Silverdale et al., 2005). Overacdve AMPA receptor-mecUated dansmission may be involved in the pathogenesis of levodopa-induced dyskinesias. Topiramate significantly reduced levodopa-induced dyskinesias without affecdng the andparkinsonian acdon of levodopa. Further studies are needed to better elucidate the potendal benefits of topiramate in PD. 

Lamodigine is another glutamate release inhibitor that has been stucUedinneurodegeneradve diseases. In ALS, 300 mg of lamodigine per day had no effect w hen compared to placebo in a small number of padents (Ryberg et al., 2003). Lamodigine also failed to show symptomadc benefit in padents with PD (Shinotoh et al., 1997), but neither study had adequate pow er to duly assess efficacy. 

Molecular formula C12H21NO8S Molecular weight 339.36 CAS Registry No 97240-79-4 Merck Index 13, 9625 

Sample preparation Vortex 200 (xL plasma or CSF with 25 xL 20 p,g/mL IS in MeCNiwater 50 50 and 400 p,L MeCN, centrifuge at lODOOrpm for 5 min. Mix a 250 xL aliquot of the supernatant with 100 p.L 0.1% formic acid, inject a 10 xL aliquot. 

Mobile phase MeOH 200 XM ammonium acetateiformic acid 40 60 0.1 

Detector MS, PE Sciex API 3000, nebulizer 375°, nebulizer gas nitrogen at 75 psi, corona needle - 3 mA, auxiliary gas nitrogen at 10 units, curtain gas nitrogen at 8 units, negative ion mode, collision gas nitrogen at 5 units, collision energy 60 eV, m/z 338.2-78.1 

Internal standard l,2 3,4-bis-0-(l-methylethyhdene-a -D-galactopyranose sulfamate) (collision energy 30 eV, m/z 338.2—96.1) (3.50) 

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Scheme 9.36 Application of ipso/ortho dihydroxylation in the synthesis of a topiramate analog.

Johnson BA, Ait-Daoud N, Bowden CL, et al Oral topiramate for rrearment of alcohol dependence a randomised conrrolled trial. Lancet 361 1677—1685, 2003 June HL, Foster KL, McKay PF, er al The reinforcing properties of alcohol are mediared hy GABAj j receptors in rhe venrral pallidum. Neuropsychopharmacology... 

Anticonvulsants Carbamazepine, valproic acid, gabapentin, topiramate... 

Other anticonvulsants, such as gabapentin and topiramate, are also being used by some clinicians, but controlled trials are lacking. 

Vigabatrin (not marketed in United States), tiagabine, topiramate, gabapentin, carbamazepine, lamotrigine... 

Yang Y, Li Q, Shuaib A. Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology 2000 39 881-888. 

The last few years has seen an explosion in AEDs. Some of those mentioned above may fall by the wayside and others appear. At the time of writing, we could include felbamate, zonisamide oxcarbazepine and topiramate. They all appear to have a phenytoin-like action on sodium channels, although topiramate appears to also potentiate the action of GABA on GABAa receptors like the benzodiazepines but through a different site. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Xiang, X., Ko, C. Y., and Guh, H. Y., Ion-exchange chromatography/ electrospray mass spectrometry for the identification of organic and inorganic species in topiramate tablets, Anal. Chem., 68, 3726, 1996. 

Allopurinol, indinavir, sulfadiazine, topiramate, triamterene, and zonisamide... 

Complication of carbonic anhydrase inhibitor or topiramate pharmacotherapy... 

Myoclonic Not mentioned Lamotrigine Valproate Valproate Topiramate (children with severe myoclonic epilepsy of infancy) Second-line Clobazam6 Clonazepam Lamotrigine Levetiracetam Piracetam6 Topiramate... 

Phenobarbital Phenytoin Topiramate Valproate Oxcarbazepine Topiramate Second-line Clobazam6 Gabapentin Levetiracetam Phenytoin Tiagabine... 

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