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Contains fulltext : 49100.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of the present study was to investigate the pharmacokinetic profile of tramadol hydrochloride in neonates, born from mothers who underwent analgesia with tramadol for the relief of labour pain.METHODS: Intramuscular tramadol (100--250 mg) was administered to 22 mothers giving birth who requested pain relief. At the time of birth (1.5--6.0 h after last tramadol dose), maternal and umbilical blood samples were taken. Another venous blood sample was drawn from each neonate, and at the same time from its mother, at 1, 2, 3, 6 or 12 h post-partum, providing the data for a population pharmacokinetic evaluation of tramadol and its metabolite M1. Routine APGAR scores and a standard neurological and adaptive capacity test were considered for evaluation of the effect of tramadol on the neonates.RESULTS: Serum tramadol concentrations at the time of birth (t(0)) were 243+/-102 ng/ml (mean+/-SD, umbilical vein), 258+/-103 ng/ml (umbilical artery) and 250+/-113 ng/ml (maternal vein). Serum M1 concentrations were 52+/-27 ng/ml (umbilical vein), 47+/-24 ng/ml (umbilical artery) and 56+/-21 ng/ml (maternal vein). The two-compartment type elimination profiles during the first 12 h post-partum for neonates (and mothers, respectively) were characterised by terminal t(1/2) (tramadol)=7.0 (7.2) h and t(1/2) (metabolite M1)=85.0 (5.5) h.CONCLUSION: The intramuscular application of tramadol in birth-giving mothers almost freely reaches the neonate, confirming a high degree of placental permeability. The neonates already possess the complete hepatic capacity for the metabolism of tramadol into its active metabolite. However, the renal elimination of the active tramadol metabolite M1 is delayed, in line with the slow maturation process of renal function in neonates. Despite this difference in pharmacokinetics between neonates and adults, the intramuscular application of tramadol at the recommended dosage range during delivery appears to effective in the relief of labour pain.

Isolated hepatocytes from fed rats were exposed for 120 min to D-glucose (10 mM) and either D-[1-13C]fructose, D-[2-13C]fructose or D-[6-13C]fructose (also 10 mM) in the presence of D2O. The identification and quantification of 13C-enriched D-fructose and its metabolites (D-glucose, L-lactate, L-alanine) in the incubation medium and the measurement of their deuterated isotopomers indicated, by comparison with a prior study conducted in the absence of exogenous D-glucose, that the major effects of the aldohexose were to increase the recovery of 13C-enriched D-fructose, decrease the production of 13C-enriched D-glucose, restrict the deuteration of the 13C-enriched isotopomers of D-glucose to those generated by cells exposed to D-[2-13C]fructose, and to accentuate the lesser deuteration of the C, (as compared to C5) of 13C-enriched D-glucose derived from D-[2-13C]fructose. The ratio between C2-deuterated and C2-hydrogenated L-lactate, as well as the relative amounts of the CH3-, CH2D-, CHD, and CD3- isotopomers of 13C-enriched L-lactate were not significantly different, however, in the absence or presence of exogenous D-glucose. These findings indicate that exogenous D-glucose suppressed the deuteration of the C1 of D-[I-13C]glucose generated by hepatocytes exposed to D-[1-13C]fructose or D-[6-13C]fructose, as otherwise attributable, in part at least, to gluconeogenesis from fructose-derived [3-13C]pyruvate, and apparently favoured the phosphorylation of D-fructose by hexokinase isoenzymes, probably through stimulation of D-fructose phosphorylation by glucokinase.

Hepatocytes from fed rats were incubated for 120 min in the presence of alpha-D-[1,2-13C]glucose pentaacetate (1.7 mM), both D-[1,2-13C]glucose (1.7 mM) and acetate (8.5 mM), alpha-D-glucose penta[2-13C]acetate (1.7 mM), or D-[1,2-13C]glucose (8.3 mM). The amounts of 13C-enriched L-lactate and D-glucose and those of acetate and beta-hydroxybutyrate recovered in the incubation medium were comparable under the first two experimental conditions. The vast majority of D-glucose isotopomers consisted of alpha- and beta-D[1,2-13C]glucose. The less abundant single-labeled isotopomers of D-glucose were equally labeled on each C atom. The output of 13C-labeled L-lactate, mainly L-[2-13C]lactate and L-[3-13C]lactate, was 1 order of magnitude lower than that found in hepatocytes exposed to 8.3 mM D-[1,2-13C]glucose, in which case the total production of the single-labeled species of D-glucose was also increased and that of the C3- or C4-labeled hexose was lower than that of the other 13C-labeled isotopomers. In cells exposed to alpha-D-glucose penta[2-13C]acetate, the large majority of 13C atoms was recovered as [2-13C]acetate and, to a much lesser extent, beta-hydroxybutyrate labeled in position 2 and/or 4. Nevertheless, L-[2-13C]lactate, L-[3-13C]lactate, and single-labeled D-glucose isotopomers were also produced in amounts higher or comparable to those found in cells exposed to alpha-D-[1,2-13C]glucose pentaacetate. However, a modest preferential labelling of the C6-C5-C4 moiety of D-glucose, relative to its C1-C2-C3 moiety, and a lesser isotopic enrichment of the C3 (or C4), relative to that of C1 (or C6) and C2 (or C5), were now observed. These findings indicate that, despite extensive hydrolysis of alpha-D-glucose pentaacetate (1.7 mM) in the hepatocytes, the catabolism of its D-glucose moiety is not more efficient than that of unesterified D-glucose, tested at the same molar concentration (1.7 mM) in the presence of the same molar concentration of unesterified acetate (8.5 mM), and much lower than that found at a physiological concentration of the hexose (8.3 mM). The present results also argue against any significant back-and-forth interconversion of D-glucose 6-phosphate and triose phosphates, under conditions in which sizeable amounts of D-glucose are formed de novo from 13C-enriched Krebs cycle intermediates generated from either D-[1,2-13C]glucose or [2-13C]acetate.

Hepatocytes prepared from overnight fasted rats were incubated for 120 min in the presence of the dimethyl ester of [2,3-(13)C]succinic acid (10 mM). The identification and quantification of 13C-enriched metabolites in the incubation medium were performed by a novel computational strategy for the deconvolution of NMR spectra with multiplet structures and constraints. The generation of 13C-labelled metabolites, including succinate, fumarate, malate, lactate, alanine, aspartate and glucose accounted for about half of the initial amount of the ester present in the incubation medium. A fair correlation was observed between the experimental abundance of each 13C-labelled glucose isotopomer and the corresponding values derived from a model for the metabolism of [2,3-(13)C]succinate. Newly formed glucose was more efficiently labelled in the carbon C5 than C2, as well as the carbon C6 than C1, supporting the concept that D-glyceraldehyde-3-phosphate may undergo enzyme-to-enzyme channelling between glyceraldehyde-3-phosphate dehydrogenase and phosphofructoaldolase.

From 40 Flemish dairy farms the nitrogen balances have been calculated, based on sampling and analysing of the inputs (concentrates, litter, …) and outputs (milk, roughage,…). The average N surplus was 329, 296 and 290 kg N ha−1, respectively, for the years 1991, 1992 and 1993. The decline of the surplus was the result of using less mineral fertilizer, feeding less moist concentrates and producing more milk per ha. The most important measures (resulting from a multiple regression analysis) are minimizing the input of manure from pig or poultry farms and using less N fertilizer on grassland. Fodder beets on the farm seems to be a better alternative than increasing the maize area.

During the grazing season of 1993 one group of cows (n=34) grazed day and night while an other group (n=40) grazed only during the day ; these were housed at night receiving maize silage (5.3 kg per cow per day). Although N-input and N-output, in kg N per ha, was different for both grazing systems, the N-surplus was the same. The area of grassland covered by dung pats and urine scorch, the N-content of the cow faeces and the grass and the urea content of the milk (Azotest) were significantly higher on the day + night grazing system. From these results, it can be concluded that the choice of the grazing and management system has a real influence on the nitrogen cycle on grassland.

Two S-(2-aminoethyl)L-cysteine (AEC) resistant lines were isolated by screening mutagenized protoplasts from diploid N. sylvestris plants. Both lines accumulated free lysine at levels 10 to 20-fold higher than in controls. Lysine overproduction and AEC-resistance were also expressed in plants regenerated from the variant cultures. A feedback insensitive form of dihydrodipicolinate synthase (DHPS), the pathway specific control enzyme for lysine synthesis, was detected in callus cultures and leaf extracts from the resistant lines. Aspartate kinase (AK), the other key enzyme in the regulation of lysine biosynthesis, was unaltered in the mutants. Crosses with wild type plants indicated that the mutation conferring insensitivity to feedback in DHPS, with as result overproduction of lysine and resistance to AEC, was inherited as a single dominant nuclear gene.

Summary A lysine plus threonine resistant line was isolated by screening embryoid populations induced from a suspension culture of Daucus carota treated with N-methyl-N’-nitro-N-nitrosoguanidine.Amino add analysis showed that embryoids and callus of the resistant line contained at least 8 times more free threonine and 2.5 times more free isoleucine than the wild type.Lysine levels remained unchanged, methionine was hardly detectable both in wild type and resistant line tissues.The overproduction of threonine and isoleucine has been correlated with a decreased sensitivity to feedback inhibition of the lysine sensitive aspartate kinase.Resistant plants are cultivated further for genetical analysis.