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Y Théorêt

Publications and source records attributed to Y Théorêt.

15 recordsLinked to original sources
PubMed2000

Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.

BACKGROUND & AIMS: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype. METHODS: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype. RESULTS: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy. CONCLUSIONS: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Adolescent↗
PubMed1998

Cholinergic cell expression in the developing rat medial septal nucleus in vitro is differentially controlled by GABAA and GABAB receptors.

The early appearance and relative abundance of GABAergic neurons in basal forebrain cholinergic nuclei like the medial septum suggest that the maturation of the later developing cholinergic neurons in these nuclei may be controlled by GABA. To examine this possibility, the effects of both exogenous GABA and specific GABA receptor agonists, as well as that of endogenous GABA on the phenotypic expression and survival of the cholinergic neurons in primary cultures from the fetal rat medial septum, were studied. Treatment of these cultures for six days with GABA significantly decreased the enzymatic activity of choline acetyltransferase (EC 2.3.1.6) (ChAT) in a dose-dependent manner. This response to exogenous GABA was blocked by bicuculline, mimicked by muscimol and slightly potentiated by saclofen. Consistent with this latter observation, the GABAB receptor agonist, baclofen, dose-dependently increased septal ChAT activity. However, while the effect of baclofen on cholinergic expression was lost in the absence of glia, the suppressive effects of GABA or muscimol were more marked. Acetylcholinesterase (EC 3.1.1.7) (AChE) expression in mixed neuronal-glial cultures, was, like ChAT activity, increased or decreased in intensity with the inclusion of baclofen or muscimol, respectively. Although the number of AChE positive neurons in muscimol-treated cultures was significantly lower than that in controls, no changes in neither neuronal nor general cell viability were noted. Finally, as GABAA or GABAB receptor antagonists bicuculline and picrotoxin or saclofen, when applied alone to mixed cultures, increased or decreased ChAT activity, respectively, it appears that endogenous GABA, tonically released in the developing septum, may, via specific receptor types, differentially control the biochemical maturation of the cholinergic neurons.

Acetylcholinesterase↗
PubMed1997

Effects of basic fibroblast growth factor on the differentiation, growth, and viability of a new human medulloblastoma cell line (UM-MB1).

We presently report the effects of human recombinant basic fibroblast growth factor (bFGF) on a newly established medulloblastoma cell line, UM-MB1. This predominantly adherent cell line has a mean doubling time of 39.3 hours and was found, by karyotypic analysis, to be near triploid. UM-MB1 consists of undifferentiated cells expressing markers of neuronal lineage such as the three neurofilament subunits as well as neuron-specific enolase, synaptophysin, and microtubule-associated proteins 1 and 5. In contrast, no immunoreactivity for glial fibrillary acidic protein was evident. When exposed to nanomolar amounts of bFGF, UM-MB1 cells began to extend neurite-like processes with arborizations and growth-cone-like structures. In addition, UM-MB1 cells treated with bFGF exhibited ultrastructural alterations that reflect their enhanced differentiation as well as the increased expression of at least one of the neurofilament subunits as evidenced both immunocytochemically and on Western blots. Furthermore, bFGF significantly decreased UM-MB1 cell growth as well as induced their death. UM-MB1 cells treated with bFGF for several days displayed DNA cleavage, nuclear shrinkage, and chromatin condensation while retaining their cytoplasmic and mitochondrial membrane integrity, all early indices of apoptosis. After this, cell death was evident with the concomitant appearance of the classical apoptotic bodies. By flow cytometry, bFGF was found to increase the proportion of cells in G1 before inducing their death by apoptosis. In conclusion, UM-MB1 cells can, when appropriately stimulated, be induced to differentiate along their neuronal lineage pathway. Their differentiation induced by bFGF, although incomplete, appears to promote or inhibit the expression of apoptotic effectors or suppressors in these cells, respectively, so to induce their death by an apoptotic-like mechanism.

Antigens, Differentiation↗
PubMed1996

6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity.

BACKGROUND: 6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood. AIMS: To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment. PATIENTS: Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months. METHODS: Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography. RESULTS: Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 6-TG (p < 0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p < 0.005), but did not correlate with erythrocyte 6-MP metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels. CONCLUSIONS: These results suggest that high performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.

Adolescent↗
PubMed1996

Quantitation of 6-thioguanine in peripheral blood leukocyte DNA in Crohn's disease patients on maintenance 6-mercaptopurine therapy.

The effects of 6-mercaptopurine (6MP) in inflammatory bowel disease are believed to be primarily mediated by its metabolite 6-thioguanine (6TG). Our aim was to develop an assay for measuring leukocyte DNA 6TG levels in patients with Crohn's disease, and to correlate them with levels of 6TG in erythrocytes. Heparinized blood was obtained from 15 adolescent Crohn's disease patients receiving 6MP at an average dose of 1.3 mg.kg-1 day-1 (range 0.8-1.6 mg.kg-1 day-1) for a mean of 23.7 months (range 3-71 months). Leukocyte DNA and erythrocyte 6TG levels were measured by an HPLC assay. Leukocyte 6TG levels ranged from 100 to 2305 pmol/mg DNA, while erythrocyte 6TG levels ranged from 64 to 1038 pmol/8 x 10(8) red blood cells, demonstrating significant interpatient variability. Leukocyte DNA 6TG levels correlated directly with erythrocyte 6TG levels, as measured by the Spearman rank correlation coefficient (p < 0.05). The HPLC measurement of erythrocyte and leukocyte DNA 6TG levels can be useful clinically in monitoring compliance, as well as perhaps to tailor drug metabolite levels to achieve the desired clinical effect.

Adolescent↗
PubMed1992

Simple, rapid and selective method using high-performance liquid chromatography for the determination of bretylium in plasma.

A high-performance liquid chromatographic method with ultraviolet detection has been developed for the determination of bretylium in plasma. Following a single-step solid-phase extraction procedure, bretylium is selectively isolated and well recovered from plasma. The assay sensitivity is 0.156 micrograms/ml from 250-microliters plasma samples and its linearity was assessed up to 40 micrograms/ml. The method is accurate (101.0 +/- 5.4%) and precise (maximum coefficient of variation of 8%). It provides a simple and time-saving alternative to existing methods and is particularly suitable for pharmacokinetic studies.

Animals↗
PubMed1992

High-performance liquid chromatographic determination of spironolactone and its metabolites in human biological fluids after solid-phase extraction.

A simple and sensitive high-performance liquid chromatographic procedure to determine spironolactone and its three major metabolites in biological specimens is described. The assay involves sequential extraction on C18 and CN solid phases, and subsequent separation on a reversed-phase column. In plasma samples, spironolactone and its metabolites were completely separated within 8 min using an isocratic mobile phase, while in urine samples a methanol gradient was necessary to achieve a good separation within 14 min. Recoveries for all analytes were greater than 80% in plasma and 72% in urine. Linear responses were observed for all compounds in the range 6.25-400 ng/ml for plasma and 31.25-2000 ng/ml for urine. The plasma and urine methods were precise (coefficient of variation from 0.8 to 12.5%) and accurate (-12.1% to 7.4% of the nominal values) for all compounds. The assay proved to be suitable for the pharmacokinetic study of spironolactone in healthy human subjects.

Chromatography, High Pressure Liquid↗
PubMed1992

High-performance liquid chromatography-electrochemical detection of vecuronium and its metabolites in human plasma.

A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.

Chromatography, High Pressure Liquid↗
PubMed1991

Pharmacokinetics and pharmacodynamics of atracurium obtained with arterial and venous blood samples.

To determine the influence of sampling site on atracurium pharmacokinetic-pharmacodynamic relationships, blood was drawn simultaneously from the radial artery and peripheral vein during a 20-minute period after injection of atracurium, 0.2 mg/kg, in eight patients. Atracurium and laudanosine concentrations were measured by HPLC. Neuromuscular blockade was measured at the adductor pollicis, after stimulation of the ulnar nerve. Venous levels were lower than corresponding arterial values for up to 20 minutes, and this difference was marked for the early samples. Neuromuscular blockade was maximum after 5 to 7 minutes, much later than the peak venous concentration (1 to 3 minutes). Nonparametric analysis yielded (mean +/- SEM) a rate constant, concentration for 50% blockade, and slope of the effect-concentration relationship of 0.092 +/- 0.01 min-1, 379 +/- 27 ng/ml, and 7.3 +/- 1.67, respectively, when based on arterial samples. The values were statistically different (0.135 +/- 0.011 min-1, 235 +/- 42 ng/ml, and 3.41 +/- 0.37, respectively) when venous levels were used (p less than 0.05). It is concluded that forearm venous levels do not correspond to adductor pollicis neuromuscular blockade and the kinetics and kinetic-dynamic relationship for atracurium are heavily dependent on sampling site.

Adolescent↗
PubMed1990

Determination of atracurium and laudanosine in human plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method coupled with fluorometric detection has been developed for the determination of atracurium and its major end-product laudanosine in human plasma. The method enables good separation of atracurium from its metabolites after direct precipitation of plasma proteins. The assay is sensitive, reproducible and linear for atracurium concentrations ranging from 31.25 to 8000 ng/ml. In a clinical setting, drugs commonly administered during anesthesia did not interfere with the assay. This method provides a simple and time-saving alternative to existing methods.

Atracurium↗
PubMed1990

Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium.

The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2-hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half-life (19.8 +/- 0.7 versus 19.7 +/- 0.7 minutes), volume of distribution at steady state (8.6 +/- 0.7 versus 8.5 +/- 0.7 L), and total clearance (444 +/- 29 versus 404 +/- 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 +/- 0.2 versus 6.6 +/- 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 +/- 46 versus 312 +/- 33 ng/ml).

Adult↗
PubMed1988

The neurotoxicity of intrahippocampal kainic acid injection in rats is not accompanied by a reduction of Timm stain.

Histopathological changes induced by intrahippocampal injections of low doses of kainic acid (17.5 ng/site) were investigated in rats. Kainic acid produced a selective loss of CA3 pyramidal and hilar neurons. The development of kainic acid-induced neuronal injury was not accompanied by any detectable loss of histologically demonstrable zinc as assessed by means of a modified Timm's sulphide-silver method. It is suggested that the selective injury of hippocampal neurons induced by kainic acid is not contingent on the release of zinc from mossy-fiber terminals.

Animals↗
PubMed1985

Epileptogenic action of penicillin derivatives: structure-activity relationship.

In the hippocampal slice preparation, perfusion with benzyl penicillin evokes multiple population spikes and spontaneous discharges. Doses of 0.25 to 2 mM of the drug produced this effect within 20-40 min. Cleavage products and analogues of benzyl penicillin, penicilloic acid, 6-aminopenicillanic acid, cephalexin, thioproline and penicillamine, were devoid of such action. It is concluded that the structural requirements for epileptogenic action of penicillin include not only the beta-lactam ring and side chain substitution on C-6, but also the thiazolidine ring.

Animals↗
PubMed1983

Effect of phencyclidine on inhibition in the hippocampal slice.

The effects of phencyclidine (PCP) on synaptic transmission were studied in the hippocampal slice. Population spikes evoked by orthodromic or antidromic stimulation were recorded from CAl pyramidal cells. Bath applied PCP (10(-4) M) reduced moderately both the orthodromic and antidromic population spikes. Lower concentrations, 5 X 10(-6) to 5 X 10(-5) M of PCP, which did not depress the population spikes, reduced inhibition of the orthodromically evoked spike in a dose dependent reversible manner. Diazepam (10(-6) to 10(-5) M) restored the inhibition despite the continued presence of PCP. It is suggested that PCP-induced seizures and other signs of hyperexcitability could be a result of reduced inhibition.

Action Potentials↗