PubMed Health⌕ Search

Biomedical subjects

M Gilbert

Publications and source records attributed to M Gilbert.

At least 109 records · Page 6Linked to original sources
PubMed1993

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.

Adult↗
PubMed1993

Self-image as a predictor of outcome in adolescent major depressive disorder.

We investigated the ability of a measure of self-image, two measures of depression, and demographic characteristics to predict the outcome of depressive symptoms. Subjects were 47 adolescents who were referred to outpatient treatment for depression. Subjects were assessed for depressive symptoms at three time periods. Self-image as measured by the Offer Self-image Questionnaire (OSIQ) was a significant predictor of depressive symptoms at both 3 months and 1 year. That was independent of initial levels of depression. The two most predictive scales from the OSIQ were the emotional tone and mastery of the external world scales. The results are consistent with previous research indicating the importance of self-image in adolescent depression. The implications of these findings for treatment of adolescent depression are discussed.

Adolescent↗
PubMed1993

Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits.

Acute elevation in plasma free fatty acid (FFA) levels in nonpregnant rabbits simulates some aspects of insulin resistance observed in late pregnancy. The aim of this study was therefore to evaluate whether lowered FFA induced by nicotinic acid (NA) infusion can improve insulin action in pregnant rabbits. To assess insulin sensitivity we applied euglycemic hyperinsulinemic clamp without (control study) or with concomitant NA infusion (NA study; infusion started 150 min before the glucose clamp) in conscious virgin and pregnant rabbits after an 18-h fast. A primed constant infusion of [3-3H]glucose was used to measure total glucose disposal and hepatic glucose production. Hyperinsulinemia, in association with NA infusion (NA study) brings about a significantly greater stimulation of total glucose disposal in both pregnant (approximately 30%) and nonpregnant (approximately 35%) rabbits compared with the control study. A more pronounced inhibition of hepatic glucose production occurred in NA study in pregnant rabbits (approximately 30 vs. approximately 10%) but it did not reach a statistical significance, whereas there was a total inhibition in nonpregnant rabbits. We conclude that acute decrease in plasma FFA levels mainly improves insulin action at the site of glucose utilization. These results therefore suggest that elevated FFA would contribute to the peripheral insulin resistance in late pregnancy.

Animals↗
PubMed1993

Role of polymorphic debrisoquin 4-hydroxylase activity in the stereoselective disposition of mexiletine in humans.

It was reported previously that mexiletine undergoes stereoselective disposition in humans and that formation of three of its major metabolites co-segregates with polymorphic debrisoquin 4-hydroxylase (CYP2D6) activity. In this study, the hypothesis was tested that the CYP2D6-mediated oxidation pathways of mexiletine are responsible for the stereoselective disposition of the racemate in humans. Fourteen healthy subjects (10 extensive metabolizers [EMs] and 4 poor metabolizers [PMs]) participated in this study. They received a single 200-mg oral dose of racemic mexiletine hydrochloride on two occasions: once alone and once during administration of low-dose quinidine (50 mg four times a day). Blood and urine samples were obtained over 48 hr after the administration of mexiletine and analyzed by a stereoselective high-performance liquid chromatography assay. As reported previously, RS-mexiletine disposition was altered by a genetically determined (PM) or drug-induced (quinidine) decrease in CYP2D6 activity. In contrast, R/S ratio of the apparent total and nonrenal clearances of mexiletine and the R/S ratio of the urinary recovery of both enantiomers were similar in EMs and PMs. Moreover, these ratios were unaltered by quinidine administration. Partial metabolic clearance of N-hydroxymexiletine glucuronide, a non-CYP2D6 dependent metabolite, was highly stereoselective; the R/S ratio was 11.3 +/- 3.4. This ratio was similar in subjects with either an EM or a PM phenotype and was not altered by quinidine administration. Thus, the results obtained in this study suggest that non-CYP2D6-dependent metabolic pathways are responsible for the stereoselective disposition of mexiletine in humans.

Administration, Oral↗
PubMed1992

Improved high-performance liquid chromatographic assay for the stereoselective determination of mexiletine in plasma.

A simple and sensitive high-performance liquid chromatographic procedure for resolution of mexiletine enantiomers has been developed. Proteins from plasma samples containing RS-mexiletine were precipitated with a mixture of barium hydroxide and zinc sulphate before extraction under alkaline conditions with diethyl ether. Organic extracts were evaporated to dryness, and the residues reconstituted with 0.03 M hydrochloric acid (20 microliters). Derivatization with o-phthalaldehyde N-acetyl-L-cysteine reagent was performed after alkalinization with 0.1 M sodium borate. An aliquot of the resulting solution was injected onto a reversed-phase C18 column and resolution of mexiletine diastereoisomeric derivatives was achieved with a mobile phase consisting of methanol-50 mM sodium acetate (65:35), at a flow-rate of 1 ml/min. The retention times of S-(+)- and R-(-)-mexiletine diastereoisomeric peaks were 14 and 15 min, respectively. Product elution was monitored by fluorescence detection using excitation and emission wavelengths fixed at 350 and 445 nm, respectively. Calibration curves were linear over the concentration range 2.5-500 ng/ml for each enantiomer (r greater than 0.99). The assay is shown to be suitable for pharmacokinetic studies after administration of a single oral dose of 200 mg of RS-mexiletine hydrochloride to healthy volunteers.

Administration, Oral↗
PubMed1992

Purification and characterization of a xylanase from the thermophilic ascomycete Thelavia terrestris 255B.

Thielavia terrestris 255B, a thermophilic ascomycete, produced two major forms of xylanase with pIs of 4.6 (xylanase I) and 6.1 (xylanase II). The latter enzyme could be purified to greater than 99% homogeneity using anion-exchange chromatography and gel filtration. Xylanase II had a mol wt of 25.7 kDa (SDS-PAGE) and a pH and a temperature optimum of 3.6-4.0 and 60-65 degrees C, respectively. The ratio of the enzyme's activity against xylan and carboxymethylcellulose was 500-1000 to 1, indicating a possible application of this enzyme in biobleaching processes. The amino acid sequence of this protein is being determined, and initial data suggest that the enzyme belongs to a group of low-mol wt xylanases that have been isolated from both bacteria and fungi.

Amino Acid Sequence↗
PubMed1992

Hepatic metabolism during fasting-refeeding transition in conscious pregnant rabbits.

The aim of the present study was to determine changes induced by pregnancy in the hepatic handling of nutrients during the fasting-refeeding transition. Net hepatic and gut substrate fluxes were determined by the Fick principle in conscious pregnant (day 30) and nonpregnant rabbits in the 2 h after consumption of a mixed meal. Hepatic glucose production was suppressed by approximately 50% in both groups from 15 to 90 min. Pregnant rabbits returned to control levels at 120 min. Pregnant females displayed a larger gut glucose output and a greater arterial hyperglycemia. The hepatic and gut balance of lactate as well as the arterial level was almost unchanged. In pregnant females the hepatic uptake and arterial concentration of free fatty acids (FFA) remained almost unchanged, whereas these measures decreased in nonpregnant females by approximately 55 and approximately 80%, respectively, at 120 min. The decline in hepatic output of beta-hydroxybutyrate was similar in both groups. In pregnant rabbits arterial levels of beta-hydroxybutyrate did not parallel changes in the hepatic release as in nonpregnant females. Pregnant females displayed a greater hyperinsulinemia both in the portal vein and the artery over the first hour. It is concluded that, in pregnant rabbits fed a mixed meal, the ability of the liver to handle glucose is impaired because of insulin resistance. The latter brings about a greater and prolonged arterial hyperglycemia, which is reinforced by peripheral insulin resistance. Furthermore, the higher level of FFA may also contribute to the hyperglycemia. As a result, a greater amount of glucose is diverted to other sites, presumably the uterus.

3-Hydroxybutyric Acid↗
PubMed1992

Alcohol and creative writing.

A repeated-measures design was used to test for the effects of alcohol on creative writing as measured by use of novel figurative language. 11 male social drinkers participated in a creative writing task under two conditions, alcohol (high dose: 1.1 ml. ethanol/kilogram body weight) and placebo. In the alcohol condition, within-subject comparisons indicated significantly greater quantity of creative writing while intoxicated. These results were interpreted as supporting the belief that alcohol can reduce "writer's block," at least amongst nonalcoholic subjects.

Adult↗
PubMed1992

Is tardive anorexia a discrete diagnostic entity?

A study is described in which patients in three diagnostic groups were compared in an effort to delineate features of tardive anorexia (late onset anorexia nervosa). There were 18 patients in each diagnostic group. Patients with "classical" anorexia nervosa of less than 5 years duration were compared with patients older than 25 who had been chronically ill for more than 5 years and with those in whom the symptoms had begun de novo after the age of 25. Statistically significant differences were found to distinguish the third group as a distinct diagnostic entity. The association of loss precipitants and depressive symptoms has practical implications in the management of true anorexia tardive.

Adolescent↗
PubMed1991

Human immunodeficiency virus: novel enzyme-linked immunoassays for quantitation of envelope glycoprotein 120.

Two novel enzyme-linked immunoassays (ELISA) for the quantitation of human immunodeficiency virus type 1 (HIV-1) coded glycoprotein with an Mr 120 (gp120) are described. These are based on the highly specific interaction between gp120 and the mannose-specific lectins from Narcissus pseudonarcissus (NPL) and Galanthus nivalis (GNL). Two systems were developed: (1) an HIV-protein ELISA using HIV-protein (also containing HIV-gp120) for the solid phase and NPL as a detector and (2) a lectin-ELISA using the NPL bound to the solid phase and GNL as detector. The HIV-protein ELISA was validated for quantitation of gp120 within the range 3 to 600 ng/ml; the lectin-ELISA for concentrations between 0.6 and 20000 ng gp120/ml. Serum components did not interfere with the binding of gp120 to the lectins. The ELISAs were used for the quantitation of gp120 in HIV-infected CEM cells in vitro. It was found that gp120 appeared in the medium earlier after infection than HIV-p24 and reverse transcriptase, suggesting that gp120 is released as free glycoprotein. Moreover, the ELISAs were also applied successfully for the detection of compounds that bind to gp120 and for the identification of antibodies directed against the highly pathogenic mannan portion of gp120. These ELISAs are considered to be suitable also for the detection of gp120 in the serum of HIV-infected individuals.

Animals↗
PubMed1991

Plasma C-21 steroids in conscious pregnant and non-pregnant rabbits with chronic catheterization of the femoral artery and the portal and hepatic veins.

In conscious non-pregnant (n = 8) and pregnant (n = 7) rabbits, blood samples were collected by chronic catheterization of the femoral artery and the hepatic and portal veins. In the non-pregnant group, deoxycorticosterone (DOC), corticosterone (B), cortisone (E) and cortisol (F) were determined by RIA. In the pregnant group, progesterone (P) and 20 alpha-dihydroprogesterone were also radioimmunoassayed. The arterio-venous difference of the levels observed has demonstrated the role of the liver and the splanchnic area in steroid metabolism. Moreover, the comparison of the steroid pattern in the two groups showed that gravidity was characterized by a marked increase of F and E but not of B and DOC levels. Thus, the ratio of F/B in the femoral artery was markedly increased in the pregnant animals; this ratio ranged from 0.20 to 1.12 in the non-pregnant group, and from 1.3 to 12.5 in the pregnant group.

20-alpha-Dihydroprogesterone↗
PubMed1991

Posttraumatic recovery of traumatized newborns: effects on neuromotor and cognitive development during their first 6 months.

Recovery after perinatal cerebral traumatism was studied in a group of 20 traumatized infants. The effects on the sequence of development during the next 6 months were observed for both motor and cognitive development and were compared with a control group of 20 normal babies. Results showed a significant delay for the abnormal group and a different recovery pattern between these two aspects of development. Motor development reached a normal level at 4 months, whereas cognitive development was still impaired at 6 months. These results were discussed in terms of possibly longer effects of perinatal traumatism on higher cortical functions than on motor functions.

Brain Damage, Chronic↗
PubMed1991

Group therapy for adolescent depressive disorder: a comparison of social skills and therapeutic support.

Two forms of short-term group therapy for depressed adolescents are compared. Adolescents were assigned to either a social skills training or therapeutic support group. Treatment outcome was based on self-report and semistructured clinical interviews for depression, measures of self-concept, and cognitive distortions. After treatment, adolescents in the therapeutic support groups showed significantly greater reductions in clinical depression and significant increases in self-concept compared with those in the social skills training group. These group differences were no longer evident at 9-month follow-up, as adolescents in the therapeutic support groups maintained their improvement, and adolescents in the social skills training groups caught up.

Adolescent↗
PubMed1991

Enzyme-linked immunoassay for human immunodeficiency virus type 1 envelope glycoprotein 120.

An enzyme-linked immunosorbent assay (ELISA) that can measure picogram quantities of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) in cell culture medium or body fluids has been developed. Recombinant, soluble CD4 immobilized in microtiter trays was used to capture gp120, which was then detected with polyclonal sheep antibody to gp120 followed by biotinylated rabbit anti-sheep immunoglobulin G and an avidin-alkaline phosphatase indicator system. With a reference recombinant gp120, the assay showed a linear relationship between optical density and concentrations ranging from 60 to 6,000 pg/100-microliters well; precision of the assay varied with the concentrations and ranged from +/- 40% with amounts smaller than 200 pg to +/- 10% with amounts larger than 200 pg. In a group of coded samples containing 60 pg (approximately 10(7) molecules) of reference gp120, the assay correctly identified the samples as containing gp120 99% of the time, with no false-positive results recorded for blank samples. Recombinant gp120 prepared in another cell culture system demonstrated a binding coefficient 13-fold lower than that of reference gp120. Mixing standard amounts of reference gp120 with increasing concentrations of human sera reduced assay sensitivity, although the linear relationship between gp120 concentration and optical density remained. With this assay we were able to detect gp120 in HIV-1 suspensions prepared from cultured lymphoblastoid cells and in the sera of HIV-1-infected patients. This ELISA for gp120 should be useful for studying the biological role of gp120 in HIV infection.

CD4 Antigens↗
PubMed1991

Role of free fatty acids in hepatic insulin resistance during late pregnancy in conscious rabbits.

This study addresses whether elevated free fatty acids (FFA) contribute to the hepatic insulin resistance of pregnancy. We applied a euglycemic hyperinsulinemic clamp with or without Intralipid plus heparin infusion in conscious virgin and pregnant rabbits after an 18-h fast coupled with chronic catheterization of the hepatic and portal veins and femoral artery. A primed constant infusion of [3-3H]glucose was used to determine glucose fluxes. Insulin was infused into a mesenteric vein for 140 min. In pregnant rabbits, basal net hepatic uptake of lactate was almost two times that of nonpregnant rabbits. During a euglycemic hyperinsulinemic clamp there was a decline of approximately 65% in hepatic lactate uptake in nonpregnant rabbits at 80 min, whereas a similar decrease was observed only at 140 min in pregnant rabbits. This effect was blocked by lipid infusion. In the basal state the hepatic uptake of FFA was greater in pregnant than in nonpregnant animals. During the hyperinsulinemic clamp the hepatic uptake dropped by approximately 70 and approximately 30% in nonpregnant and pregnant females, respectively. Lipid infusion did not prevent the hepatic FFA uptake and hepatic ketone body output from decreasing. Hepatic glucose production was totally suppressed in the control period in nonpregnant animals but not during lipid infusion (approximately 65%). Hepatic glucose production was not significantly different between pregnant and nonpregnant rabbits during lipid infusion. Glucose utilization was markedly reduced in nonpregnant animals during lipid infusion to levels comparable with that in pregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1991

Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man.

Mexiletine is a low clearance drug which undergoes extensive metabolism in man. In vitro studies with human liver microsomes have suggested that major oxidation pathways of mexiletine are predominantly catalyzed by the genetically determined debrisoquine 4-hydroxylase (cytochrome P450IID6) activity. In this study, we investigated the role of debrisoquine polymorphism and the effects of low dose quinidine, a selective inhibitor of cytochrome P450IID6, on the disposition of mexiletine. Fourteen healthy volunteers, 10 with the extensive metabolizer (EM) and 4 with the poor metabolizer (PM) phenotype, received a single 200-mg dose of mexiletine hydrochloride orally on two occasions (1 week apart), once alone and once under steady-state conditions for quinidine (50 mg QID). During the phase mexiletine alone, total clearance, nonrenal clearance and partial metabolic clearance of mexiletine to hydroxymethylmexiletine, to m-hydroxymexiletine and to p-hydroxymexiletine were decreased in PM compared to EM (all P less than .05). In EM, quinidine decreased mexiletine total clearance from 621 +/- 298 to 471 +/- 214 ml/min (mean +/- S.D.; P less than .05) and mexiletine nonrenal clearance from 583 +/- 292 to 404 +/- 188 ml/min (P less than .05). Moreover, quinidine increased mexiletine elimination half-life in EM from 9 +/- 1 to 11 +/- 2 h (P less than .05). In these subjects, partial metabolic clearance to hydroxymethylmexiletine, m-hydroxymexiletine and p-hydroxymexiletine were decreased by quinidine coadministration 5-, 4- and 7-fold, respectively, whereas partial metabolic clearance to N-hydroxymexiletine was unaffected. Changes induced by quinidine in EM were correlated to their debrisoquine metabolic ratio. Thus, genetically determined or pharmacologically induced modulation of cytochrome P450IID6 activity represents a major determinant of mexiletine disposition.

Administration, Oral↗
PubMed1990

Ontogenesis of calcitonin mRNA in the rabbit.

Since plasma calcium levels are higher in the fetus than in the mother at the end of gestation, it has been suggested that calcitonin (CT) biosynthesis would be very active in the fetus. This hypothesis was tested in rabbit fetuses and newborns by measuring the amount of CT mRNAs found in the thyroid glands and the thyroidal CT stores. Dot-blot and Northern hybridizations with a specific CT cDNA probe (a BglII-NsiI fragment of the human CT cDNA) were used to determine the CT mRNA level. In fetuses, newborns, and mothers, only one molecular species of mRNA around 1 kb was detected by Northern hybridization with the specific CT cDNA probe. By dot-blot, CT mRNAs could be detected at 20 days of gestation on pooled fetal thyroid glands as a weak positive signal. The amount of CT mRNAs increased on day 24; at this stage they were also observed by Northern hybridization. During the last 6 days of gestation a 3-fold increase in CT mRNAs occurred in rabbit fetuses; concomitantly a 5-fold rise in the total thyroidal CT content was observed. Fetal plasma concentrations of both CT and calcium increased slightly between 24 and 30 days of gestation. After birth, the CT mRNA level was 10-fold increased between 2 and 30 days; these changes were not reflected in the plasma CT level but were probably accounted for by a rise in the number of C cells of the thyroid gland.

Animals↗