Abstracts

We and others have shown that [italic]in vitro[/italic], the antiepileptic drugs (AEDs) zonisamide (ZNS) and topiramate (TPM) inhibit the zinc metalloenzyme carbonic anhydrase (CA), an enzyme involved in gluconeogenesis, ion transport, and provision of HCO[sub]3[/sub]^-. Hippocampal neuronal GABAergic depolarization is reported to be dependent on HCO[sub]3[/sub]^- and thus on intracellular CA activity. We studied some aspects of cognitive impairment among patients exposed to TPM and other AEDs., We examined the incidence of treatment-emergent cognitive adverse events in placebo (PBO)-controlled studies of AEDs that are CA inhibitors (CAIs) (TPM, ZNS) vs. newer AEDs that are not known CAIs (tiagabine, TB; gabapentin, GP; lamotrigine, LG; and levetiracetam, LTA). We used data available from clinical PBO-controlled randomized add-on trials for each of the AEDs, because head-to-head comparisons of these drugs in premarketing clinical trials were lacking. Two cognitive variables examined were psychomotor slowing and concentration/memory impairment., The incidence of [underline]psychomotor slowing[/underline] was: (n = 414) vs. (n = 291), 21% vs. 2%; (n = 289) vs. (n = 230), 4% vs. 2%; (n = 494) vs. (n = 275), 10% vs. 5%; (n = 543) vs. (n = 378), [lt]1% vs. [lt]1%; (n = 711) vs. (n = 419), 2% vs. [lt]1%; and (n = 769) vs. (n = 439), [lt]1% vs. [lt]1%. The incidence of [underline]impaired concentration/memory[/underline] were: vs. 28% vs. 5%; vs. 12% vs. 4%; and [lt]1% for the remainder., From the clinically significant increase in the incidence of impaired concentration/memory in patients exposed to the CAIs TPM and ZNS vs. PBO and no observed effect of non-CAI AEDs relative to PBO, we hypothesized that CA and provision of HCO[sub]3[/sub]^- are important in neuronal homeostasis. CA acts as a molecular switch in the development of synchronous gamma-frequency firing of hippocampal pyramidal cells. [Ruusuvuori E., [italic]et al[/italic]. [italic]J[/italic].[italic]Neurosci[/italic] 2004;24:2699-2707]. GABAergic excitation and associated gamma oscillations seem dependent on CA activity, HCO[sub]3[/sub]^- availability, membrane pH gradients and provision for ionized calcium (adding H⁺ to a solution of HCO[sub]3[/sub]^- will generate more carbonic, CO[sub]2[/sub] and H[sub]2[/sub]O). CAI may medicate some aspects of cognition as demonstrated by our report.,