Biomedical subjects

K T Hansen

Publications and source records attributed to K T Hansen.

21 records · Page 2Linked to original sources

PubMed1991

Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion.

Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be highly unstable at pH 7.4 and 37 degrees C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.

Amino Acids↗

PubMed1985

Three-year caries increments after fluoride rinses or topical applications with a fluoride varnish.

251 9-12-yr-old children completed a 3-yr, double-blind, clinical trial of two caries preventive fluoride programs. Caries increments and progression patterns were compared in two groups of children who rinsed every fortnight with a 0.2% NaF solution or received biannual topical applications with a fluoride varnish (Fluor-Protector). Clinically recorded mean DFS increments were 3.3 +/- 0.2 (SE) in the rinse group and 3.5 +/- 0.2 in the varnish group. In both groups nearly half of these increments were recorded in the occlusal surfaces of second molars. The mean incremental DFS recorded radiographically on approximal surfaces of posterior teeth were 1.1 +/- 0.2 and 1.5 +/- 0.2 in the rinse and varnish group, respectively. None of the inter-group differences were statistically significant (P greater than 0.05). Detailed analyses of the radiographic scores revealed a similar and extremely slow caries progression in the two study groups and they strengthened the conclusion of equal clinical efficacy of the two treatments. None of the fluoride programs had been able to change preestablished patterns of caries development among the children.

Child↗

PubMedDate not supplied

Glucuronidation of the dopamine D-1 receptor antagonists NNC 0756 and NNC 0772 in liver microsomes.

Glucuronidation of the two enantiomeric dopamine D-1 antagonists, NNC 0756 ([(+)-8-chloro-7-hydroxy-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl- 2,3,4,5,tetrahydro-1H-3-benzazepine, acetate]) and NNC 0772 [(-)-8-chloro-7-hydroxy-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine, HCl], was studied in rat and human liver microsomes. In rats, the reaction exhibited biphasic kinetics for both enantiomers as shown by Eadie-Hofstee plots. Both the high- and low-affinity reactions showed a high degree of stereoselectivity, primarily because of the large differences in Km values. For the high- and low-affinity reactions, the (-)-enantiomer, NNC 0772, had a 4- and 6-fold higher Km value, respectively. The difference in Vmax values were less significant, with 3.0- and 1.1-fold higher values for the (-)-enantiomer. Treatment of rats with known inducers of UDP-glucuronosyltransferases, phenobarbital, and 3-methyl-cholanthrene, did not change the kinetics of the reaction. Glucuronidation of the (+)-enantiomer, NNC 0756, was competitively inhibited in rat liver microsomes by the closely related structure, SCH 23388 [S-(-)-8-chloro-7-hydroxy-5-phenyl-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine], with an apparent Ki value of 90 microM. Morphine and 4-hydroxybiphenyl, both known substrates of glucuronosyltransferase, did also inhibit the reaction with Ki values of 604 and 55 microM, respectively. In contrast to rats, glucuronidation of NNC 0756 in human liver microsomes followed Michaelis-Menten kinetics, suggesting the involvement of a single form of glucuronosyltransferase or possibly two forms, with similar affinity for NNC 0756.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗