ALBERT

Notes: We applied the stochastic method of Gudmundsson, Davies & Clayton (1990) (which was applied to ISC P-wave data) to teleseismic ISC S-wave data to obtain an independent estimate of mantle structure. We inverted the variance of S-wave traveltime residuals of bundles of rays to obtain a description of the spectrum of lateral heterogeneity as a function of depth through the mantle. The technique yields robust estimates of the traveltime scattering power (the product of a characteristic scalelength of heterogeneity and the mean square of slowness perturbations). We can estimate the characteristic scalelength (half-width), from the autocovariance; which can be reconstructed from the spectra. Hence by division, we can estimate the root mean square slowness. By extrapolating the variance of bundles of rays to bundles of zero cross-sectional area we can also estimate the scale-incoherent signal (which is a plausible estimate of the noise in the data), which is removed from the data.We find that most of the structure generating shear wave traveltime residuals is located in the uppermost mantle. About half of the structure is short scale (harmonic degree l 〉 50). The large-scale structure (l 〉 50) has a half-width of about 500 km in the upper half of the mantle. This S-wave half-width is consistent with the P-wave half-widths determined by Gudmundsson et al. (1990). The S-wave half-width in the lower half of the mantle is poorly constrained. It varies from 500 to 3000 km, which spans the better constrained value of 1200 km found by Gudmundsson et al. (1990) for P-waves. The incoherent scatter suggests that the signal-to-noise ratio of the S-wave data set is around 1.5.Assuming that the compressional and shear wave velocity variations are correlated then the signal weighted value of the ratio d In (Vs)/d In (Vp) is ∼ 2, as also found in normal mode studies. This is much larger than the value of ∼ 0.8–1.4 suggested by laboratory experiments undertaken at atmospheric pressure. There is no evidence of periodicity in the traveltime autocovariance; this suggests little or no periodicity in the underlying convection. The short half-width through most of the mantle suggests high Rayleigh number convection, with its attendant small-scale structures. The power decreases by an order of magnitude or more in going from the upper mantle to the lower mantle, the same as found by Gudmundsson et al. (1990) for P-waves. This large difference suggests either a change in convective regime and/or a difference in the temperature sensitivity of elastic constants in both layers. The increased short-scale structure at the top of the mantle suggests that a large part of the seismic signature at this boundary is compositional, since one would expect a red spectrum for a thermal boundary layer. The derived spectra between l∼ 10 and l∼ 50 are similar in shape to spectra from the mantle convection simulations of Glatzmaier (1988) with a Rayleigh number of 106-107, which would suggest layered convection, if the comparison is valid.

Notes: A 2-D synthetic test study of global traveltime inversion for deep seated earth structure has been undertaken. This was done by generating traveltime residual data using reasonable models for earth structure. The data were then inverted by similar methods to those applied in global studies of earth structure. Our results indicate that models of the aspherical structure in the lower mantle based on traveltime data are only partially successful and only at the largest scales (harmonic degree ≤3) and that maps of the core-mantle boundary based on traveltimes are unsuccessful.

Notes: Abstract Purpose. To evaluate the cellular permeation characteristics and the chemical and enzymatic stability of coumarinic acid-based cyclic pro-drugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ of the opioid peptides [Leu5]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively. Methods. The rates of conversion of the cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ to [Leu5]-enkephalin and DADLE, respectively, in HBSS, pH 7.4 (Caco-2 cell transport buffer) and in various biological media having measurable esterase activity were determined by HPLC. The cell permeation characteristics of [Leu5]-enkephalin, DADLE and cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were measured using Caco-2 cell monolayers grown onto microporus membranes and monitored by HPLC. Results. In HBSS, pH 7.4, cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ degraded chemically to intermediates that further degraded to [Leu5]-enkephalin and DADLE, respectively, in stoichiometric amounts. In 90% human plasma and rat liver homogenate, the disappearance of cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ was significantly faster than in HBSS, pH 7.4. The half-lives in 90% human plasma and in rat liver homogenate were substantially longer after pretreatment with paraoxon, a known inhibitor of serine-dependent esterases. When applied to the AP side of a Caco-2 cell monolayer, cyclic prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ exhibited significantly greater stability against peptidase metabolism than did [Leu5]-enkephalin. Cyclic pro-drug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ and DADLE exhibited similar stability when applied to the AP side of the Caco-2 cell monolayer. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ was 665-fold more able to permeate the Caco-2 cell monolayers than was [Leu5]-enkephalin, in part because of its increased enzymatic stability. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ was shown to be approximately 31 fold more able to permeate a Caco-2 cell monolayer than was DADLE. Conclusions. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , prepared with the coumarinic acid promoiety, were substantially more able to permeate Caco-2 cell monolayers than were the corresponding opioid peptides. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ exhibited increased stability to peptidase metabolism compared to [Leu5]-enkephalin. In various biological media, the opioid peptides were released from the prodrugs by an esterase-catalyzed reaction, which is sensitive to paraoxon inhibition.

Notes: Abstract Purpose. To evaluate the cellular permeation characteristics and the chemical and enzymatic stability of phenylpropionic acid-based cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ of opioid peptides [Leu5]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively. Methods. The rates of conversion of cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ to [Leu5]-enkephalin and DADLE, respectively, in HBSS, pH 7.4 (Caco-2 cell transport buffer) and in various biological media having measurable esterase activity were determined by HPLC. The cell permeation characteristics of [Leu5]-enkephalin, DADLE, and cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were measured using Caco-2 cell monolayers grown onto microporus membranes and monitored by HPLC. Results. In HBSS, pH 7.4, cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ degraded to [Leu5]-enkephalin and DADLE, respectively, in stoichiometric amounts. In 90% human plasma, the rates of disappearance of cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were slightly faster than in HBSS, pH 7.4. These accelerated rates of disappearance in 90% human plasma could be reduced to the rates observed in HBSS, pH 7.4, by pretreatment of the plasma with paraoxon, a known inhibitor of serine-dependent esterases. In homogenates of Caco-2 cells and rat liver, accelerated rates of disappearance of cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were not observed. When applied to the AP side of a Caco-2 cell monolayer, cyclic prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ exhibited significantly greater stability against peptidase metabolism than did [Leu5]-enkepha-lin. Cyclic prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ and DADLE exhibited stability similar to prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ when applied to the AP side of the Caco-2 cell monolayers. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ was 1680 fold more able to permeate the Caco-2 cell monolayers than was [Leu5]-enkephalin, in part because of its increased enzymatic stability. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ was shown to be approximately 77 fold more able to permeate a Caco-2 cell monolayer than was DADLE. Conclusions. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , prepared with the phenylpropionic acid promoiety, were substantially more able to permeate Caco-2 cell monolayers than were the corresponding opioid peptides. Prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ exhibited increased stability to peptidase metabolism compared to [Leu5]-enkephalin. In 90% human plasma but not in Caco-2 cell and rat liver homogenates, the opioid peptides were released from the cyclic prodrugs by an esterase-catalyzed reaction that is sensitive to paraoxon inhibition. However, the rate of this bioconversion appears to be extremely slow.

Notes: Abstract Purpose. To evaluate the chemical and enzymatic stability, as well as the cellular permeation characteristics, of the acyloxyalkoxy-based cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ of the opioid peptides [Leu5]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively. Methods. The rates of conversion of $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ to [Leu5]-enkephalin and DADLE, respectively, were measured by HPLC in HBSS, pH = 7.4, and in various biological media (e.g., human plasma and Caco-2 cell and rat liver homogenates) having measurable esterase activity. The cellular permeation and metabolism characteristics of [Leu5]-enkephalin, DADLE and the cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were measured using Caco-2 cell monolayers grown onto microporous membranes and monitored by HPLC. Results. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ degraded slowly but stoichiometrically to [Leu5]-enkephalin and DADLE, respectively, in HBSS, pH = 7.4. In homogenates of Caco-2 cells and rat liver, as well as 90% human plasma, the rates of disappearance of the cyclic prodrugs were significantly faster than in HBSS. The stabilities of the cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were increased significantly in 90% human plasma and Caco-2 cell homogenates when paraoxon, a potent inhibitor of serine-dependent esterases, was included in the incubation mixtures. A similar stabilizing effect of paraoxon was not observed in 50% rat liver homogenates, but was observed in 10% homogenates of rat liver. When applied to the AP side of a Caco-2 cell monolayer, DADLE and cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ exhibited significantly greater stability than [Leu5]-enkephalin. Based on their physicochemical properties (i.e., lipophilicity), cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ should have exhibited high permeation across Caco-2 cell monolayers. Surprisingly, the AP-to-BL apparent permeability coefficients (PApp) for cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ across Caco-2 cell monolayers were significantly lower than the PApp value determined for the metabolically stable opioid peptide DADLE. When the PApp values for cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ crossing Caco-2 cell monolayers in the BL-to-AP direction were determined, they were shown to be 36 and 52 times greater, respectively, than the AP-to-BL values. Conclusions. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , prepared with an acyloxyalkoxy promoiety, were shown to degrade in biological media (e.g., 90% human plasma) via an esterase-catalyzed pathway. The degradation of cyclic prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ , which contained an ester formed with an L-amino acid, degraded more rapidly in esterase-containing media than did prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , which contained an ester formed with a D-amino acid. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ showed very low AP-to-BL Caco-2 cell permeability, which did not correlate with their lipophilicities. These low AP-to-BL permeabilities result because of their substrate activity for apically polarized efflux systems.