Comparison of behavioral deficits and acute neuronal degeneration in rat lateral fluid percussion and weight-drop brain injury models.

The behavioral and histological effects of the lateral fluid percussion (LFP) brain injury model were compared with the weight drop impact-acceleration model with 10 min of secondary hypoxia (WDIA + H). LFP injury resulted in significant motor deficits on the beam walk and inclined plane, and memory deficits on the radial arm maze and Morris water maze. Motor deficits following LFP remained throughout 6 weeks of behavioral testing. WDIA + H injury produced significant motor deficits on the beam walk and inclined plane immediately following injury, but these effects were transient and recovered by 14 days post-injury. In contrast to the LFP injury, the WDIA + H injured animals showed no memory deficits on the radial arm maze and Morris water maze. In order to determine if the differences in behavioral outcome between models were due to differences in injury mechanism or injury severity, 10 LFP-injured animals were matched with 10 WDIA-injured animals based on injury severity (i.e., time to regain righting reflex after brain injury). The LFP-matched injury group showed greater impairment than the WDIA + H matched injury group on the radial arm maze and Morris water maze. Histological examination of LFP-injured brains with Fluoro-Jade staining 24 h, 48 h, and 7 days post-injury revealed degenerating neurons in the cortex, thalamus, hippocampus, caudate-putamen, brainstem, and cerebellum, with degenerating fibers tracts in the corpus callosum and other major tracts throughout the brain. Fluoro-Jade staining following WDIA+H injury revealed damage to fibers in the optic tract, lateral olfactory tract, corpus callosum, anterior commissure, caudate-putamen, brain stem, and cerebellum. While both models produce reliable and characteristic behavioral and neuronal pathologies, their differences are important to consider when choosing a brain injury model.

Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers.

Valproate formulations, divalproex sodium extended-release (ER) and the traditional divalproex sodium delayed-release (DR) formulations, are not bioequivalent. This study evaluated if ER QD regimens with 14 and 20% higher daily doses were equivalent to the corresponding DR BID regimens with respect to exposure (AUC) while achieving lower maximum concentration (C(max)) and higher minimum concentration (C(min)) values. This was a Phase I, multiple-dose, fasting, randomized, open-label, crossover design study in healthy adult volunteers (n=36). The two crossover comparisons of unequal total daily doses were: 1000 mg ER versus 875 mg DR and 1500 mg ER versus 1250 mg DR. For each of 14 and 20% higher ER versus DR dose comparisons, the ER and DR regimens were equivalent with respect to AUC. Furthermore, the ER formulation achieved a lower C(max) central value and a higher C(min) mean than the corresponding values for the DR formulation. The mean peak-to-trough fluctuations of valproic acid plasma concentrations were 42-48% lower for the ER formulation compared with the DR. The higher ER doses were as well tolerated as DR, with a small number of adverse events that were non-serious in nature and mild in intensity. Therefore, increasing the once-daily ER dose 14-20% while converting from a total daily DR dose given twice-daily results in equivalent exposure with lower C(max) and higher C(min) values.

Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker.

Overload of intracellular calcium ([Ca(2+)](i)) following traumatic brain injury (TBI) has been implicated in the pathogenesis of neuronal injury and death. Voltage-gated calcium channels (VGCCs) provide one of the major sources of Ca(2+) entry into cells. Therefore, the potential neuroprotective activity of SNX-185, a specific N-type VGCC blocker, was tested in rats using the lateral fluid percussion (LFP) model of TBI. SNX-185 (50, 100, or 200 pmol) or vehicle was injected 5 min after injury into the CA2-3 subregion of the hippocampus ipsilateral to TBI. Acute neuronal degeneration was visualized in brain sections 24 h postinjury using the histofluorescent marker Fluoro-Jade (FJ), and the number of surviving neurons in the CA2-3 subregion of the hippocampus 42 days after injury was determined stereologically. Behavioral outcome after TBI and drug treatment was assessed in the beam walk test and Morris water maze. Direct injection of SNX-185 into the CA2-3 region of the hippocampus reduced neuronal injury 24 h after TBI and increased neuronal survival at 42 days at each of the three drug concentrations. Behavioral outcome in both the beam walk and Morris water maze were also improved by SNX-185, with 100 and 200 pmol, but not 50 pmol SNX-185 providing neuroprotection. These data support previous studies demonstrating substantial neuroprotection after TBI by treatment with N-type VGCC blockers.

Comparison of the bioavailability of 250 and 500 mg divalproex sodium extended-release tablets in healthy volunteers.

Divalproex sodium extended-release tablet (divalproex-ER), 500 mg strength, is approved for use in the prophylaxis of migraine headaches and epilepsy. The bioavailability of novel 250 mg divalproex-ER formulations, under development to allow greater flexibility in dosing, was compared with the available 500 mg divalproex-ER in a single-dose, fasting and nonfasting, randomized, open-label, crossover study in healthy adult volunteers. One group of 15 subjects was dosed after a 10 h overnight fast and another group of 24 subjects was dosed after a high-fat breakfast. Plasma valproic acid concentration-time profiles were used to assess pharmacokinetics. Bioequivalence assessments were made via the 90% confidence interval for maximum plasma valproic acid concentration (C(max)) and the area under the concentration-time curve from time zero to infinity (AUC(infinity)). The relative bioavailability point estimates (90% confidence interval) for C(max) and AUC(infinity) were 1.05 (0.94-1.16) and 0.95 (0.83-1.09) under fasting conditions, and 1.01 (0.91-1.12) and 0.97 (0.87-1.08) under nonfasting conditions, respectively. The test 250 mg tablet formulation was bioequivalent to the reference 500 mg tablet formulation, under both fasting and nonfasting conditions, as the 90% confidence intervals for both C(max) and AUC(infinity) were within the 0.80-1.25 interval.