Atagabalin

Excessive excitability or hyperexcitability of glutamate-containing neurons in the brain has been proposed as a possible explanation for anxiety, stress-induced disorders, epilepsy, and some neurodegenerative diseases. However, direct measurement of glutamate on a rapid time scale has proven to be difficult. Here we adapted enzyme-based microelectrode arrays (MEA) capable of detecting glutamate in vivo, to assess the effectiveness of hyperexcitability modulators on glutamate release in brain slices of the rat neocortex. Using glutamate oxidase coated ceramic MEAs coupled with constant voltage amperometry, we measured resting glutamate levels and synaptic overflow of glutamate after K(+) stimulation in brain slices. MEAs reproducibly detected glutamate on a second-by-second time scale in the brain slice preparation after depolarization with high K(+) to evoke glutamate release. This stimulus-evoked glutamate release was robust, reproducible, and calcium dependent. The K(+)-evoked glutamate release was modulated by ligands to the α(2)δ subunit of voltage sensitive calcium channels (PD-0332334 and PD-0200390). Meanwhile, agonists to Group II metabotropic glutamate (mGlu) receptors (LY379268 and LY354740), which are known to alter hyperexcitability of glutamate neurons, attenuated K(+)-evoked glutamate release but did not alter resting glutamate levels. This new MEA technology provides a means of directly measuring the chemical messengers involved in glutamate neurotransmission and thereby helping to reveal the role multiple glutamatergic system components have on glutamate signaling.

To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr).

In this open‐label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min−1; n= 6); mild RI (CLcr 51 to ≤80 ml min−1; n= 6); moderate RI (CLcr >30 to 50 ml min−1; n= 6); and severe RI (CLcr ≤30 ml min−1; n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration–time data.

PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66–3.24 h. Mean half‐life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CLR) clearance rates decreased with deteriorating renal function, whereas area under the concentration–time curve (AUC0–∞) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CLR correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group.

PD 0200390 pharmacokinetic parameters (CL/F, CLR and AUC0–∞) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.