The averaged clustering coefficient over the entire network (functional segregation).

<p>The averaged clustering coefficient decreased during attentional control versus the baseline interval.</p

Betweenness centrality (global hub).

<p>Higher centrality was observed in the sensori-motor and prefrontal regions throughout the periods tested.</p

Stimuli used in this study.

<p>Stimuli used in this study.</p

Time-frequency analysis.

<p>Zero on the horizontal axis indicates the onset of target stimuli. Data are expressed in color-coded images as a change relative to the baseline interval. Power increases and decreases are shown in red and blue, respectively.</p

Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

<div><p>Purpose</p><p>To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits.</p><p>Methods</p><p>The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.</p><p>Results</p><p>The half-maximal inhibitory concentration (IC₅₀) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC₅₀ of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC₅₀ at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (<i>P</i> = 0.026) but not the other two NSAIDs.</p><p>Conclusions</p><p>Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.</p></div

Cyclooxygenase (COX) inhibitory activities of diclofenac, bromfenac, and amfenac.

<p>Ratio of IC₅₀: IC₅₀ for COX-2/IC₅₀ for COX-1</p><p>The IC₅₀ of indomethacin was used as a reference compound for COX-1, and its IC₅₀ was 32.8 nM and that of rofecoxib for COX-2 was 202 nM.</p

Pharmacokinetic parameters of single instillation of NSAID eye drops in aqueous humor.

<p>AUC_0–8: The area under the aqueous humor drug concentration-time curve from 0 to 8 hours, k_el: elimination rate constant, MRT: mean residence time, *: Mean ± S.D., †: Mean ± SEM.</p

Pharmacokinetic parameters of single instillation of NSAID eye drops in retinochoroidal tissues.

<p>AUC_0–8: The area under the retinochoroidal drug concentration-time curve from 0 to 8 hours, k_el: elimination rate constant, MRT: mean residence time, * Mean ± S.D., † Mean ± SEM.</p

Comparison of ocular tissue concentrations of topically applied NSAIDs.

<p>Concentrations of diclofenac, bromfenac, nepafenac, and amfenac in the aqueous humor (A) and retinochoroidal tissue (B) after a single topical application in rabbits. Thirty microliters of 0.1% bromfenac sodium ophthalmic solution, 0.1% diclofenac ophthalmic solution, or 0.1% nepafenac ophthalmic suspension were topically applied to the rabbit eye. Samples of aqueous humor and choroid/retina were collected at the designated times. Amfenac is an active metabolite of nepafenac. Each value represents the mean + standard deviation (n = 4/time point).</p

The simulated drug concentrations in aqueous humor and retina/choroid with the IC₅₀ for COX-2.

<p>The pharmacokinetic profiles of diclofenac (A) and amfenac (C) in the aqueous humor were calculated on the basis of a three/day dosing at an interval of eight hours, and the profile of bromfenac (B) was calculated on the basis of a two/day dosing at an interval of twelve hours. The retinochoroidal pharmacokinetic profiles of diclofenac (D), bromfenac (E) and amfenac (F) were also calculated in the same manner. The simulated concentrations (solid line) of diclofenac (A) and bromfenac (B) in the aqueous humor were higher than their corresponding IC₅₀ values of the NSAIDs for COX-2 (dotted line). The concentrations of amfenac (C) were almost always higher than the IC₅₀ of COX-2 although it was slightly less than the IC₅₀ at the trough level. In retinochoroidal tissues, the simulated concentration of bromfenac (E) with a two/day dosing was higher than the IC₅₀ value for COX-2, whereas the concentrations of diclofenac (D) and amfenac (F) with a three/day dosing were lower than the corresponding IC₅₀ values at the troughs. Each value of the IC₅₀ for COX-2 indicated in the figures is referred in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096481#pone-0096481-t001" target="_blank">Table 1</a>.</p