PT  - JOURNAL ARTICLE
AU  - Shields, K
TI  - PONM18 Nerve excitability studies can be used to differentiate between voltage-gated sodium blockers using an in-vitro cutaneous sensory nerve model: potential prospects as a model for drug discovery
AID  - 10.1136/jnnp.2010.226340.191
DP  - 2010 Nov 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - e65--e65
VI  - 81
IP  - 11
4099  - http://jnnp.bmj.com/content/81/11/e65.1.short
4100  - http://jnnp.bmj.com/content/81/11/e65.1.full
SO  - J Neurol Neurosurg Psychiatry2010 Nov 01; 81
AB  - Methods Excitability studies were performed on rat saphenous skin-nerve preparations mounted in a tissue bath. VGSC blockers lidocaine (LID), carbamazepine (CBZ) and lacosamide (LAC) were dissolved in synthetic interstitial fluid at 1, 3, 10, 30 and 100 μM. Measurements were performed before and after perfusion for 20 min, drug responses were compared with baseline values using student's paired and unpaired t-tests for within and between group analysis (p=0.05).Results Lidocaine had reversible dose-dependent effects on all excitability parameters. Strength duration time constant (SD), depolarising threshold electrotonus (TEd) and superexcitability (SX) were all decreased and the I/V curve was shifted towards outward rectification. TEd was the most sensitive parameter; effects being seen at 1 μM (N=8 df=7, t=2.4, p=0.05), indicating use-dependent blockade of VGSCs. Significant differences in SD (N=9, df=8 t=3.66, p=0.006) and SX (N=8, df=7, t=−3.48, p=0.01) were seen at 30 μM. CBZ had qualitatively similar effects but with less efficacy. Lacosamide followed the same trend except for SX which increased at 30 μM (N=5, df=4, t=4.12, p=0.01). Comparison of efficacy (TEd) was LID>CBZ>LAC.Conclusions This model is a sensitive biomarker for drug activity at VGSCs, capable of discriminating quantitative and qualitative differences between VGSC blockers. It may be used to screen for activity and provide comparative information on drug dosing.