This mechanism-based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF(165) dose regimens that may aid in optimization of drug delivery for future clinical trials.

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

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Effects of bridge and culvert construction or replacement were studied on 41 streams in Tennessee. One 100-m stream reach above and two 100-m reaches below were sampled at each bridge or culvert with a 50-m buffer zone separating each reach. Fish communities were sampled bi-annually for two years following single pass depletion techniques using a backpack electrofishing unit. Sediment depth and silt-clay percentages were measured during the spring at the upper end of each 100-m sampling reach. Sediment depth and percent silt-clay were greater at streams with culverts than at streams with bridges. Sediment depth and silt-clay percentages did not differ between structure and downstream transects for either bridges or culverts; but they were greater at structure transects than at upstream transects only on streams with culverts. Fish diversity, abundance, and richness did not differ between streams with bridges and streams with culverts, nor among sample reaches. Sediment characteristics and fish metrics were not correlated with bridge age in months.This study indicated that culverts, but not bridges, caused sediment accumulation. However, this accumulation was not sufficient to impact fish communities.

These results provide evidence of the consistency of absorption that can be achieved with the use of an appropriate metered dose inhaler, which may translate into a predictable therapeutic response.

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Species diversity and richness, relative abundance, and community structure were compared between simultaneous single-pass electrofishing and depletion sampling. Additionally, the number of fish displaced from sample reaches when not using block nets was estimated at each sample site. A total of 40 depletion samples was obtained during the spring and summer of 1999 and 2000 in small first-and second-order warmwater streams of central Tennessee; first passes were used as single-pass samples. Shannon-Wiener diversity values obtained with the single-pass approach were strongly correlated to those obtained with depletion sampling (r2 = 0.95). The same number of species was captured using both approaches in 15 of 40 streams; depletion sampling richness values exceeded single-pass values by more than two species in only one stream. Using bootstrap analyses, relative abundance values from single-pass samples differed from those of depletion samples in 2 1 of 40 streams. However, community structure comparisons using similarity indices (SIMI) indicated that the singlepass approach effectively sampled fish abundance. SIMI values were above 0.90 in 32 of 40 streams and above 0.75 in the other eight. Fish were displaced from sample reaches when not using block nets in 32 of 40 streams, but displaced fish species represented less than 10% of the total number of species in 29 of these streams. Fish movement from sampled reaches did not negatively affect estimates of diversity, richness, or relative abundance; the single-pass approach effectively sampled fish communities in these streams.