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C Eckhoff

Publications and source records attributed to C Eckhoff.

25 records · Page 2Linked to original sources
PubMed1990

Identification and quantitation of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma.

Human plasma was analyzed by high performance liquid chromatography for the presence of retinoic acid and 4-oxoretinoic acid isomers. Peaks that coeluted with the reference compounds all-trans-retinoic acid, 13-cis-retinoic acid, and 13-cis-4-oxoretinoic acid were routinely observed in human plasma. These retinoids were unequivocally identified by the following methods: comigration with reference compounds under several high performance liquid chromatographic conditions; comparison of ultraviolet spectra with those of reference compounds; derivatization with diazomethane and coelution of the methyl esters with reference compounds in a high performance liquid chromatographic system as well as in a gas chromatography system with a mass selective detector. In vitro formation of 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid as artifacts during the analytical procedure was excluded by control experiments. The mean plasma concentrations of the vitamin A metabolites in ten male volunteers were: all-trans-retinoic acid: 1.32 +/- 0.46 ng/ml; 13-cis-retinoic acid: 1.63 +/- 0.85 ng/ml; and 13-cis-4-oxoretinoic acid: 3.68 +/- 0.99 ng/ml. After oral dosing with vitamin A (833 IU/kg body weight) in five male volunteers, mean plasma all-trans-retinoic acid increased to 3.92 +/- 1.40 ng/ml and 13-cis-retinoic acid increased to 9.75 +/- 2.18 ng/ml. Maximal plasma 13-cis-4-oxoretinoic acid concentrations (average 7.60 +/- 1.45 ng/ml) were observed 6 h after dosing which was the last time point in this study. Concentrations of all-trans-4-oxoretinoic acid were low or not detectable. Our findings suggest that, in addition to all-trans-retinoic acid, 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid are present in normal human plasma as metabolites of vitamin A.

Chromatography, Gas↗
PubMed1989

Transplacental pharmacokinetics and teratogenicity of a single dose of retinol (vitamin A) during organogenesis in the mouse.

Pregnant mice received 10 or 100 mg retinol/kg body wt. by gavage on day 11 of gestation (plug day = day 0). One group of animals was used for a pharmacokinetic study. At various times after dosing, plasma and tissue samples were collected and analyzed by HPLC for retinyl esters, retinol, 13-cis- and all-trans-retinoic acid and 13-cis-4-oxo and all-trans-4-oxoretinoic acid. In the other group the fetuses were removed on day 18 and examined for malformations. After 10 mg/kg retinol, no teratogenic effect was observed. The pharmacokinetic investigation revealed a moderate increase of retinyl esters, retinol and all-trans-retinoic acid in plasma, embryonic tissue, placenta, yolk sac membranes and extraembryonic fluid. A high incidence of severe fetal malformations occurred after 100 mg/kg retinol. These malformations included limb defects (81% of fetuses) and cleft palate (55% of fetuses) which are characteristically found after administration of a single teratogenic dose of an active retinoid on day 11 of gestation. The concentration-time profile of retinoids after 100 mg/kg on day 11 showed a pronounced increase of retinyl esters and retinol in all compartments including the embryo and a massive generation of the polar metabolites all-trans-retinoic acid and all-trans-4-oxoretinoic acid. These polar metabolites were found in the embryo with peak concentrations of 327 +/- 115 and 143 +/- 20.7 ng/g (mean +/- SE) wet tissue, respectively. It is likely that all-trans-retinoic acid and all-trans-4-oxoretinoic acid, both well-known teratogens, largely contributed to the teratogenic outcome. The in-vivo oxidation of retinol may be an important factor in the teratogenic activity of high doses of vitamin A.

Abnormalities, Drug-Induced↗
PubMed1988

Effects of two oral antimycotics, ketoconazole and fluconazole, upon steroidogenesis in rat adrenal cells in vitro.

Rat adrenal cells were incubated with various concentrations of two orally active azole antimycotics in order to evaluate the effects on steroidogenesis. The first compound was ketoconazole, a well-known inhibitor not only of fungal cytochrome P-450 but at higher concentrations also of mammalian cytochrome P-450 dependent enzymes. The second was fluconazole, a newly developed oral antimycotic with a triazole structure, which likewise inhibits fungal cytochrome P-450. The influence of both drugs on mammalian cytochrome P-450 dependent enzymes was investigated in this study. Ketoconazole inhibited ACTH-stimulated corticosterone (IC50 = 0.9 microM) and aldosterone secretion (IC50 = 1.4 microM) and enhanced 11-deoxycorticosterone output at low concentrations but reduced it at higher concentrations. Radiotracer experiments with [3H]pregnenolone or [3H]11-deoxycorticosterone as exogenous substrates revealed a 50% inhibition of the oxidative substrate metabolism at about 1 microM ketoconazole. These effects could also be observed with fluconazole but occurred at concentrations approximately two orders of magnitude higher as compared to ketoconazole. We conclude that fluconazole has a much higher selectivity for fungal cytochrome P-450 than ketoconazole. The order of sensitivity of the cytochrome P-450 dependent enzymes of rat adrenal steroidogenesis to ketoconazole was the 11 beta/18-hydroxylase, the cholesterol side chain cleavage enzyme and the 21-hydroxylase with decreasing sensitivities.

Adrenal Glands↗
PubMedDate not supplied

Model predicting the teratogenic potential of retinyl palmitate, using a combined in vivo/in vitro approach.

Retinyl palmitate (RP) is a known laboratory animal teratogen inducing abnormalities of the second visceral arch when administered on day 9 of gestation in the rat. However, there are significant problems when attempting to extrapolate this result to the human. A combined in vivo/in vitro model was developed to assist in human risk assessment. The in vitro teratogenic threshold concentration of a number of retinyl palmitate metabolites was established. Serum concentrations of retinyl palmitate metabolites following a single teratogenic dose of RP in the pregnant rat were also measured. These dosed sera were also used to culture rat embryos. Our hypothesis was that malformations would only be induced by the dosed sera in vitro if the threshold concentration(s) of one or more metabolites was exceeded. Using this approach, it was determined that the teratogenicity of the sera were best predicted by serum retinol levels, with some indication that all-trans-retinoic acid and 4-oxo-all-trans-retinoic acid could be involved in some cases. The available human data suggest that threshold concentrations of these retinoids were unlikely to be exceeded following vitamin A supplements of 25,000 IU/day. While the proposed model does not take into account species differences, protein binding, and transfer to the embryo, it does have potential for human risk assessment.

Animals↗
PubMedDate not supplied

An in vivo model of femtosecond laser intrastromal refractive surgery.

BACKGROUND AND OBJECTIVE: To develop an animal model for evaluation of femtosecond laser intrastromal refractive surgery. METHODS: Intrastromal photodisruption was performed in New Zealand Albino rabbits using a femtosecond laser system. This surgical pattern consisted of a 100 microm-tick pyramid of laser pulses starting 180 microm below the corneal surface. Animals underwent serial slit lamp examinations and corneal thickness measurements at 1,3,7,14, and 28 days, then monthly up to 1 year. RESULTS: Approximately 70 microm of central corneal thinning were seen at 1 week, remaining stable up to 7 months. CONCLUSIONS: Intrastromal photodisruption with femtosecond lasers produced consistent changes in corneal thickness without loss of corneal transparency. These changes were more stable than those produced with excimer laser procedures in a similar animal model.

Animals↗
PubMedDate not supplied

Pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo-, and all-trans-4-oxo retinoic acid after intravenous administration in the cynomolgus monkey.

The intravenous pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo, and all-trans-4-oxo retinoic acid (RA) were determined in nonpregnant female cynomolgus monkeys. All-trans- and 13-cis-RA were injected at two doses (0.25 or 0.0125 mg/kg) and all-trans-4-oxo RA and 13-cis-4-oxo RA at 0.25 mg/kg. Total body clearance, volume of distribution, and volume of distribution at steady state of all-trans-RA were dose-dependent with greater values at the lower dose. Elimination half-life was longer for the cis-compounds and not dose-dependent (N = 1 for 13-cis-4-oxo RA, N = 3 for other compounds, harmonic mean +/- pseudostandard deviation, min): 13-cis-4-oxo RA (837) > or = 13-cis-RA (301 +/- 204) > all-trans-RA (38 +/- 3) > all-trans-4-oxo RA (11 +/- 2). Secondary plasma peaks were noted only after administration of 13-cis-4-oxo RA. The low area under the time concentration curves for observable metabolites after intravenous injection of the oxidated compounds suggests further metabolism plays a minimal role in the elimination of these compounds from the monkey. Plasma-time concentration curves were fitted to multicompartmental models and suggested < 30% of each compound was available in the central compartment for elimination in the postdistribution phase. A comparison of the kinetics of the isomers indicated oxidation of all-trans-RA to all-trans-4-oxo RA increased mean total body clearance values 4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗