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Biomedical subjects

M Luyckx

Publications and source records attributed to M Luyckx.

At least 73 records · Page 4Linked to original sources
PubMed1991

Pharmacokinetics of epirubicin after intravenous administration: experimental and clinical aspects.

A method is described for the extraction and determination of epirubicin and its main metabolites epirubicinol and glucuronides in plasma, using high performance liquid chromatography (HPLC) with fluorescence detection. The extraction was performed with column Sep-Pak C18, which allowed a quantitative recovery of compounds. This method was used first in studies performed in five rabbits after intravenous administration of 3 mg/kg epirubicin, and later in a cancer patient, who received 50 mg/m2 epirubicin in rapid intravenous infusion. Although not statistically significant, kinetics of epirubicin were fitted in both cases to a tri-exponential model. Common metabolites were detected in rabbits and human, particularly the glucuronides. However, kinetics of epirubicin glucuronides and epirubicinol glucuronides were very different. Production and elimination were very fast in rabbit at very low levels and were undetectable two hours after administration, while in human, elimination was slower and greater amounts were detected 1-2 h after administration. The rabbit seemed to be an interesting animal species for pharmacokinetic studies because of easy blood sampling, detection of small amounts of glucuronides and because of a good fit to tri-exponential kinetics model.

Animals↗
PubMed1990

Rapid quantitative determination of epirubicin and its metabolites in plasma using high performance liquid chromatography and fluorescence detection.

A rapid sensitive and selective isocratic technique was developed for the analysis of plasma epirubicin and three of its known fluorescent metabolites epirubicinol, 4'-O-beta-D-glucuronyl-4'-epidoxorubicin and 4'-O-beta-D-glucuronyl 1,3-dihydro-4'-epidoxorubicin, with daunorubicin as an internal standard, by using high performance liquid chromatography (HPLC) with fluorescence detection and a 'Hypersil ODS' column. The drugs were easily and efficiently extracted with a Sep-Pak C18 cartridge and the mean recoveries were greater than 85%. Intraassay and Interassay coefficients of variation (plasma samples) were better than 8.25%. An example of pharmacokinetic study obtained in a cancer patient after intravenous injection of epirubicine is described.

Chromatography, High Pressure Liquid↗
PubMed1987

Synthesis and pharmacological evaluation of gamma-aminobutyric acid analogues. New ligand for GABAB sites.

Baclofen (beta-p-chlorophenyl-GABA) is the only selective agonist for the bicuculline-insensitive GABAB receptor. We report the synthesis of new GABA analogues and baclofen analogues. In vitro, two compounds, 4-amino-3-benzo[b]furan-2-ylbutanoic acid (9g) and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (9h), showed an affinity for the GABAB receptor. The results obtained with racemic compounds of benzofuran structure, new for this series, and the surprising inactivity of compound 3a (4-amino-3-(4-hydroxyphenyl)butanoic acid) permit the proposal of an hypothesis for the structure-activity relationships with regard to GABAB receptor.

Animals↗
PubMed1986

Chemical and pharmacological studies of 2-(amino-methyl)acrylophenones.

The structure-activity relationships of nine products of the acrylophenone family have been studied. In a previous report 2-(4-methyl-1-piperazinylmethyl)acrylophenone was shown to be an antimicrotubular drug. The effects of these drugs on the bovine brain tubulin polymerization were determined by a turbidimetric assay. The median inhibitory concentrations (ID50) ranged from 1.5 X 10(-5) to 5 X 10(-5) mol/l. Their action on the inhibition of 3H-colchicine binding to tubulin was determined by DEAE (diethylaminoethyl)cellulose filter assay. These compounds are weak inhibitors of colchicine binding. Pharmacological studies of these drugs revealed a strong inhibition of the human ADP-induced platelet aggregation. Moreover, they markedly decreased the serum cholesterol, triglycerides and phospholipids levels of rats after injection of Triton WR 1339 (4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane). They inhibited Candida albicans, Penicillium notatum and Aspergillus versicolor growth. Thus, these nine compounds possess interesting pharmacological properties which are very likely to be related to the acrylic moiety of the molecules.

Acrylates↗
PubMed1985

Clinical pharmacokinetics of 6-hour infusion of high-dose methotrexate. Preliminary trial of monitoring high infusion doses.

Methotrexate (MTX) in serum was measured by RIA in 12 cancer patients receiving high doses of MTX (2 to 8 g/m2) in 6 hour infusions 69 treatments were studied. The peak serum level was proportional to the dose administered and was always greater than 10(-4) M. 2 elimination phases were seen: the first had a mean half-life of 2.36 h and the second a mean half-life of 16.14 h. 24 hours after beginning the infusions there were very large variations in individual serum concentrations of MTX, from 2.4 10(-6) M to 1.9 10(-5) M by 24 h after 8 g/m2. To control these variations, a mathematical model for prediction of the individual pharmacokinetic pattern of a 6 hour-infusion of high-dose MTX by kinetic analysis of a low-test dose is proposed. A program was created for an Apple III computer using toxic and therapeutic serum levels of MTX selected by the clinician. The computer program is adaptable to any infused substance for variable infusion times, thus introducing new advances over existing methods.

Adolescent↗
PubMed1985

New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines.

The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.

Administration, Oral↗
PubMed1985

New antihistaminic N-heterocyclic 4-piperidinamines. 2. Synthesis and antihistaminic activity of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-a mines.

The synthesis of a series of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-ami nes and the preliminary evaluation of their in vivo antihistamine activity are described. The title compounds were obtained starting from either 1, 4, 10, or 55 by different synthetic methods. Substitution on the phenyl nucleus of the benzimidazole ring (84-87) was achieved by two different approaches. The in vivo antihistamine activity was evaluated by the compound 48/80 induced lethality test in rats and the antihistamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action was studied in the guinea pig for three compounds (4, 51, and 55). Compound 51, "astemizole", was also studied in histamine- and serotonin-induced cutaneous reaction and for mydriatic activity in the rat and tested for peripheral and central effects not related to histamine antagonism in a variety of systems. Astemizole has been selected for clinical investigation.

Administration, Oral↗
PubMed1985

New antihistaminic N-heterocyclic 4-piperidinamines. 3. Synthesis and antihistaminic activity of N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amines.

To study the bioisosteric replacement of a 2-pyridyl ring for a phenyl nucleus in astemizole, a series of N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amines was synthesized and evaluated. The title compounds were obtained starting from either 8a or 8b by four synthetic methods. The in vivo antihistamine activity was evaluated by the compound 48/80-induced lethality test in rats and the histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. Compound 37, the isostere of astemizole, showed the most potent antihistaminic properties in the rat. However, astemizole is superior to 37 as to duration of action and total potency.

Administration, Oral↗
PubMed1985

Effect of diabetogenic action of streptozotocin on rat serum lipoproteins.

After studying the diabetogenic action of streptozotocin in rats on adipose tissue cellularity, the authors attempted to demonstrate the influence of streptozotocin on cholesterol and phospholipid composition of the different serum lipoproteins. Intravenous injection of that antibiotic induced in rats a diabetes which appears at the latest on about the third day and finally remains at a fixed value at about the second week. All very low density lipoproteins (VLDL) are increased, which is not surprising since diabetes induces a hypertriglyceridemia and VLDL are triglyceride carriers. On the other hand, high density lipoproteins (HDL) are decreased, so that we can ask the question: Is HDL decrease due to diabetes or as a result of hypertriglyceridemia?

Animals↗
PubMed1985

Pharmacological study of nine antimicrotubular drugs with acrylophenone structure on Triton WR 1339-induced hyperlipidemia in rats.

Nine (amino-methyl)-2 acrylophenone derivatives having in vitro antimicrotubular activities very similar to those of colchicine are tested on Triton WR 1339-induced hyperlipidemia in rats. By producing a disorganization of the microtubular system, these drugs reduce the lipoprotein secretory process from hepatocytes, and more particularly the triglyceride-rich VLDL secretory process, such that the serum triglyceride, cholesterol and phospholipid levels are decreased. On the other hand, HDL-cholesterol and HDL-phospholipids are increased in a significant manner. Other studies show that serum apoprotein B levels are decreased while serum apoprotein A1 levels are increased. These results are interesting since atherogenous risk is now known to be dyslipemia-related, and is not the same according to the fact that lipids are bound to one or another lipoprotein. Among the four most effective compounds (5,7,8 and 9) three of them possess a methoxy group on the aromatic ring, which seems to distinguish that series from the other two.

Animals↗
PubMed1984

2-(4-methyl-1-piperazinylmethyl) acrylophenone dihydrochloride: a new antimicrotubular drug.

With the relation between chemical structure and pharmacological activity as a guide, we have been for some time synthetizing a wide range of beta-amino-ketone derivatives. One of them, 2-(4-methyl-1-piperazinylmethyl) acrylophenone, MPMAP, possesses antimicrotubular activities. This product inhibits 50% of the microtubule polymerization at a 3.10(-5) M concentration. It does not prevent tubulin paracrystal formation induced by vinblastine, and binding experiments reveal that this product is a weak inhibitor of colchicine binding. The structure of this compound is different from the other antimicrotubular agents and has the advantage of being far less complex, highly soluble and easy to synthesize. Thus, this product and related compounds should be a new tool for the study of antimicrotubular activities and tubulin assembly.

Animals↗
PubMed1984

Preliminary note: effect of microtubule inhibitors with acrylophenone structure on Triton WR 1339 induced hyperlipidemia in rats.

Acrylophenone derivatives having in vitro antimicrotubular activity very similar to that of Colchicine were tested on Triton WR 1339 induced hyperlipidemia in rats. By inducing a disorganization of the microtubular system these compounds decreased the movement of very low density lipoproteins (VLDL) to the extracellular space and consequently decreased hypertriglyceridemia. On the other hand, contrary to Colchicine, these derivatives decreased cholesterolemia more significantly and this could be explained by a second action mechanism.

Acrylates↗
PubMed1984

[Alkyl-6-benzoxazolinones. A chemical and pharmacodynamic study].

A series of 6-alkylbenzoxazolinones was synthesized by reduction of corresponding acyl derivatives. Two reduction processes were used, Clemmensen reduction and triethylsilane-trifluoroacetic acid reduction, but only the latter represents a general procedure for synthesis of alkyl derivatives. Pharmacological study shows that reduction of the carbonyl group is accompanied by a decrease of analgesic activity with appearance of a psycholeptic profile.

Analgesics↗