(1/9955) Accumulation of astaxanthin all-E, 9Z and 13Z geometrical isomers and 3 and 3' RS optical isomers in rainbow trout (Oncorhynchus mykiss) is selective.
Concentrations of all-E-, 9Z- and 13Z- geometrical and (3R,3'R), (3R, 3'S) and (3S,3'S) optical isomers of astaxanthin were determined in rainbow trout liver, gut tissues, kidney, skin and blood plasma to evaluate their body distribution. Two cold-pelleted diets containing predominantly all-E-astaxanthin (36.9 mg/kg astaxanthin, 97% all-E-, 0.4% 9Z-, 1.5% 13Z-astaxanthin, and 1.1% other isomers, respectively) or a mixture of all-E- and Z-astaxanthins (35.4 mg/kg astaxanthin, 64% all-E-, 18.7% 9Z-, 12.3% 13Z-astaxanthin, and 2.0% other isomers, respectively), were fed to duplicate groups of trout for 69 d. Individual E/Z isomers were identified by VIS- and 1H-NMR-spectrometry, and quantified by high-performance liquid chromatography. Significantly higher total carotenoid concentration was observed in plasma of trout fed diets with all-E-astaxanthin (P < 0.05). The relative E/Z-isomer concentrations of plasma, skin and kidney were not significantly different among groups, whereas all-E-astaxanthin was higher in intestinal tissues and 13Z-astaxanthin was lower in liver of trout fed all-E-astaxanthin (P < 0.05). The relative amount of hepatic 13Z-astaxanthin (39-49% of total astaxanthin) was higher than in all other samples (P < 0.05). Synthetic, optically inactive astaxanthin was used in all experiments, and the determined dietary ratio between the 3R,3'R:3R, 3'S (meso):3S,3'S optical isomers was 25.3:49.6:25.1. The distribution of R/S-astaxanthin isomers in feces, blood, liver and fillet was similar to that in the diets. The ratio between (3S,3'S)- and (3R,3'R)-astaxanthin in the skin and posterior kidney was ca. 2:1 and 3:1, respectively, regardless of dietary E/Z-astaxanthin composition. The results show that geometrical and optical isomers of astaxanthin are distributed selectively in different tissues of rainbow trout. (+info)
(2/9955) Kinetic study of alpha-chymotrypsin catalysis with regard to the interaction between the specificity-determining site and the aromatic side chain of substrates.
In order to investigate how changes in the structures of side-chain aromatic groups of specific substrates influence binding and kinetic specificity in alpha chymotrypsin [EC 184.108.40.206]-catalyzed reactions, a number of nucleus-substituted derivatives of the specific ester substrates were prepared and steady-state kinetic studies were carried out at pH 6.5 and 7.8. Ac-Trp(NCps)-OMe was hydrolyzed more readily at low substrate concentration than Ac-Trp-OMe due to its smaller Km(app) value, suggesting that the bulky 2-nitro-4-carboxyphenylsulfenyl moiety interacts with outer residues rather than with those in the hydrophobic pocket and that this interaction increases the binding specificity. Inhibition experiments using the corresponding carboxylate and analogous inhibitors, however, showed that the carboxy group at the para position of the phenyl nucleus of the substituent sterically hinders association with the active site of alpha-chymotrypsin at pH 7.8 but not at pH 6.5. The kcat values of Ac-Trp(CHO)-0Me, Ac-Tyr(3-NO2)-OMe, and Ac-m-Tyr-OMe were much higher than those of the corresponding specific substrates, indicating that derivatives with a substitute as large as a formyl, nitro or hydroxyl group at the xi-position are stereochemically favorable to the catalytic process. Remarkable increases in Km(app) were also observed. The individual parameters for Ac-Dopa-OMe, however, were comparable to those for Ac-Tyr-OMe. (+info)
(3/9955) Determination of the anomeric configurations of Corbicula ceramide di- and trihexoside by chromium trioxide oxidation.
The anomeric configurations of Corbicula ceramide dihexoside and ceramide trihexoside were determined by chromium trioxide oxidation and the structures of these lipids were shown to be Man-beta(1 leads to 4)-Glc-beta(1 leads to 1)-ceramide and Man-alpha(1 leads to 4)-Man-beta(1 leads to 4)-Glc-beta(1 leads to 1)-ceramide. These results are compatible with those obtained by enzymic hydrolysis reported previously. (+info)
(4/9955) Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat.
The marked analgesic efficacy of ketorolac in humans, relative to other nonsteroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to whether additional non-NSAID mechanism(s) contribute to its analgesic actions. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmacological properties in vivo and in vitro using the nonselective cyclooxygenase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as well as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writhing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema formation in rats; ID50 values = 0.24, 0. 29, and 0.08 mg/kg, respectively. (R,S)-ketorolac's actions were stereospecific, with (S)-ketorolac possessing the biological activity of the racemate in the above tests. The analgesic potencies for (R,S)-, (S)-, and (R)-ketorolac, INDO, and DS were highly correlated with their anti-inflammatory potencies, suggesting a common mechanism. (R,S)-ketorolac was significantly more potent than INDO or DS in vivo. Neither difference in relative potency of COX inhibition for (R,S)-ketorolac over INDO and DS nor activity of (S)-ketorolac at a number of other enzymes, channels, or receptors could account for the differences in observed potency. The distribution coefficient for (R,S)-ketorolac was approximately 30-fold less than for DS or INDO, indicating that (R,S)-ketorolac is much less lipophilic than these NSAIDs. Therefore, the physicochemical and pharmacokinetics properties of (R,S)-ketorolac may optimize the concentrations of (S)-ketorolac at its biological target(s), resulting in greater efficacy and potency in vivo. (+info)
(5/9955) Comparison of local anesthetic activities between optical isomers of cis-1-benzoyloxy-2-dimethylamino-1,2,3,4-tetrahydronaphthalene.
The optical isomers of cis-1-benzoyloxy-2-dimethylamino-1,2,3,4-tetrahydronaphthalene (YAU-17) were compared for their local anesthetic activity, acute toxicity, spasmolytic activity, and partition coefficient between chloroform and phosphate buffer. 1-YAU-17 was more active than d-YAU-17 in blocking the conduction of action potentials in isolated frog sciatic nerves. The difference in local anesthetic activities between the optical isomers was further substantiated by in vivo tests for corneal anesthesia, intracutaneous anesthesia and sciatic nerve block in quinea-pigs. Similarly, the i.v. injection to mice revealed a higher toxicity for 1-YAU-17 as compared to its d-isomer. In these tests, the potency ratios of the enantiomers ranged from 2 to 4, and the racemate had an intermediate potency. On the contrary, no difference among the compounds was found in their liposolubility, partition coefficient, and spasmolytic activity examined with isolated guinea-pig ileum. These results indicate that the steric factors play an important role in the production of different local anesthetic activities between the optical isomers of YAU-17, and their local anesthetic potency tends to be correlated to their intravenous acute toxicity but not to their spasmolytic activity. (+info)
(6/9955) In vitro activities of aminomethyl-substituted analogs of novel tetrahydrofuranyl carbapenems.
CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically distinct medical centers across North America. The antibacterial activities of the THF carbapenems were equivalent to that of biapenem, and the THF carbapenems were slightly more active than imipenem and less active than meropenem against most of the members of the family Enterobacteriaceae but lacked significant activity against Pseudomonas isolates. In general, CL 191,121 was two- to fourfold more active than CL 188,624 and CL 190,294 against the staphylococcal and enterococcal isolates tested. CL 191,121 was twofold less active than imipenem against methicillin-susceptible staphylococci and was as activity as imipenem against Enterococcus faecalis isolates. Biapenem and meropenem were two- and fourfold less active than CL 191,121, respectively, against the methicillin-susceptible staphylococci and E. faecalis. All the carbapenems displayed equivalent good activities against the streptococci. Biapenem was slightly more active than the other carbapenems against Bacteroides fragilis isolates. Time-kill curve studies demonstrated that the THF carbapenems were bactericidal in 6 h against Escherichia coli and Staphylococcus aureus isolates. The postantibiotic effect exerted by CL 191,121 was comparable to or slightly longer than that of imipenem against isolates of S. aureus, E. coli, and Klebsiella pneumoniae. (+info)
(7/9955) In vivo activities of peptidic prodrugs of novel aminomethyl tetrahydrofuranyl-1 beta-methylcarbapenems.
A series of novel aminomethyl tetrahydrofuranyl (THF)-1 beta-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs with L-amino acids demonstrated improved efficacy after oral administration, while the D forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of < 1 mg/kg against infections caused by S. aureus, E. coli, Enterobacter cloacae, or penicillin-susceptible Streptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii, Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to > 32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs. (+info)
(8/9955) Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate.
1. We have shown previously that the D- and L- enantiomers of isoidide dinitrate (D-IIDN and L-IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D-IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action. 2. In isolated rat aortic strip preparations, exposure to 0.3 microM DPI resulted in a 3.6 fold increase in the EC50 value for D-IIDN-induced relaxation, but had no effect on L-IIDN-induced relaxation. 3. Incubation of aortic strips with 2 microM D- or L-IIDN for 5 min resulted in significantly more D-isoidide mononitrate formed (5.0 +/- 1.5 pmol mg protein(-1)) than L-isoidide mononitrate (2.1 +/- 0.7 pmol mg protein(-1)) and this difference was abolished by pretreatment of tissues with 0.3 microM DPI. DPI had no effect on glutathione S-transferase (GST) activity or GSH-dependent biotransformation of D- or L-IIDN in the 105,000 x g supernatant fraction of rat aorta. 4. Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 microM DPI significantly inhibited D-IIDN-induced cyclic GMP accumulation, but had no effect on L-IIDN-induced cyclic GMP accumulation. 5. In the intact animal, 2 mg kg(-1) DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D-IIDN, but had no effect L-IIDN. 6. These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D-IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH-cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450-NADPH-cytochrome P450 reductase system in this enantioselective biotransformation process. (+info)