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Pharmacokinetic variables of several dietary anthocyanins (potent natural antioxidants) following consumption of elderberry (Sambucus nigra L.) extract were evaluated in urine and plasma of six healthy volunteers. They were given a single oral dose of either 30 ml (278 mg total anthocyanins) or 200 ml (1852 mg total anthocyanins) of a commercially available elderberry extract. Within 7 h, the fraction of orally administered total anthocyanins (calculated as the sum of cyanidin-3-sambubioside and cyanidin-3-glucoside) excreted unchanged was 0.39% and 0.27% following ingestion of 30 and 200 ml, respectively. The elimination half-life of total anthocyanins was slightly lower following the consumption of 278 mg (1.85 h) than that after the consumption of 1852 mg (2.57 h). The renal clearance (median) of total anthocyanins was 196 and 169 ml/min, respectively. The peak and average systemic exposure to the major elderberry anthocyanidin glycosides in plasma as well as their renal excretion exhibited approximate dose-proportional characteristics within the administered range. The low dose-normalized area under the concentration-time curve (AUC) and the fraction of orally administered anthocyanins recovered unchanged in urine indicate a low bioavailability of these compounds.

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We investigated the urinary pharmacokinetics of monomeric anthocyanins in seven healthy volunteers. The volunteers were administered a single oral dose of 3.57 g total anthocyanins contained in 150 ml of a concentrated elderberry juice under fasting conditions. Within 24 h the urinary excretion of unchanged cyanidin-3,5-diglucoside (cyanidin-3-sambubioside-5-glucoside and cyanidin-3,5-diglucoside were calculated as cyanidin-3,5-diglucoside equivalents), cyanidin-3-glucoside, cyanidin-3-sambubioside and total anthocyanins (i.e., the sum of all quantifiable anthocyanidin glycosides) was 0.16, 0.06, 0.05 and 0.06% of the administered doses, respectively. Maximum excretion rates were determined within 1.0 h after intake. The estimates (arithmetic mean +/- SD) of t1/2 were 1.25 +/- 0.25, 1.53 +/- 0.36, 1.38 +/- 0.20 and 1.35 +/- 0.18 h for cyanidin-3,5-diglucoside, cyanidin-3-glucoside, cyanidin-3-sambubioside and total anthocyanins, respectively. The urinary excretion of intact anthocyanins was fast and the decline of excretion rates appeared to be monophasic, suggesting a one-compartment pharmacokinetic model. The low urinary excretion of dietary anthocyanidin glycosides with values below 1% indicates that a large proportion of these plant pigments consumed are metabolized before entry into the circulation.

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Pharmacokinetic parameters and the bioavailability of several dietary anthocyanins following consumption of blackcurrant juice and elderberry extract were compared exploratorily in 6 healthy volunteers. They were given a single oral dose of either 137 ml of blackcurrant juice (144.8 mg total anthocyanins) or 30 ml of elderberry extract (147.3 mg total anthocyanins). Within 7 hours, the urinary excretion of total anthocyanins (i.e. the sum of all assayed anthocyanidin glycosides) was 0.04% and 0.37% of the administered dose following blackcurrant juice and elderberry extract ingestion, respectively. Pharmacokinetic parameters based on non-compartmental methods for plasma and urine concentrations exhibited higher variability in urinary excretion after ingestion of elderberry extract. Anthocyanin absorption was significantly greater following the intake of elderberry extract than after the intake of blackcurrant juice as shown by the 5.3- and 6.2-fold higher estimates of dose-normalized Cmax and AUC(0-tZ) of total anthocyanins, respectively. The geometric means of t(1/2) were not significantly different following elderberry extract (1.74 h) and blackcurrant juice ingestion (1.73 h, p > 0.05). The urinary excretion rate of intact anthocyanins was fast, appeared to be monoexponential for both blackcurrant juice and elderberry extract. However, in order to evaluate the contribution of anthocyanins to the health-protecting effects of blackcurrant juice and elderberry extract it will be necessary to perform further studies on the unchanged glycosides and their in vivo metabolites in human plasma and urine.

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In rats with streptozotocin (STZ) induced diabetes the effect of (watersoluble) thiamine nitrate and of (lipidsoluble) benfotiamine on peripheral nerve function (motor nerve conduction velocity) as well as on the formation of advanced glycation end-products in peripheral nerve tissue was studied. In one group of animals drug administration was started immediately after diabetes induction (prevention study) and in another group two months after diabetes induction (treatment study). Motor nerve conduction velocity (NCV) dropped by 10.5% in diabetic animals, carboxymethyl-lysine (CML) rose to a 3.5fold concentration, deoxyglucosone (3DG)-type AGE formation was increased 5.1fold compared with controls. After three months preventive administration of both vitamin B(1) preparations NCV had increased substantially compared with results in diabetic controls. It was nearly normal after six months with benfotiamine, while the administration of thiamine nitrate resulted in no further amelioration. NCV was nearly normalized after six months of benfotiamine application but not with thiamine. Furthermore, benfotiamine induced a major inhibition of neural imidazole-type AGE formation and completely prevented diabetes induced glycoxidation products (CML). Treatment with thiamine did not significantly affect AGE or cmL levels. Unlike treatment with water-soluble thiamine nitrate timely administration of liposoluble prodrug benfotiamine was effective in the prevention of functional damage and of AGE and cmL formation in nerves of diabetic rats.

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Anthocyanins are a group of very efficient bioactive compounds that are widely distributed in plant food. Several fruits (blackcurrant, blackberry, red grape) and some vegetables (eggplant, onion, red radish) are rich sources of these natural pigments. Extracts of some of them are used as food colorants as well as components of pharmaceutical preparations and functional foods. Anthocyanins, through their ability to inhibit radical reactions, are considered to exert several protective effects in the human body. Until now there has been only a small amount of data available on their capability, in intact or metabolized form, to reach the systemic circulation of humans. The present study was designed to determine the potential bioavailability in humans of the most important anthocyanins of blackcurrants: delphinidine-3-glucoside, delphinidine-3-rutinoside, cyanidine-3-glucoside, and cyanidine-3-rutinoside. Urinary samples from 4 healthy volunteers (2 women and 2 men) were collected before (baseline) and over a period of 5 hours with intervals of 30 minutes after the ingestion of 200 mL of blackcurrant juice (containing 153 mg of anthocyanins). Using high-performance liquid chromatography (HPLC), it was possible to quantify the 4 main anthocyanins of blackcurrants, excreted unchanged in the urine (0.020-0.050% of the oral doses). We present data on the bioavailability in humans of blackcurrant anthocyanins, which are dietary antioxidants with possible biological effects.

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Gallic acid (GA), a food component that is especially abundant in tea, is an antimutagenic, anticarcinogenic and anti-inflammatory agent. We conducted a study using acidum gallicum tablets that contained 10% GA and 90% glucose and a black tea brew that contained 93% of its GA in free form to determine the pharmacokinetics and relative bioavailability of GA in healthy humans. After the administration of a single oral dose of acidum gallicum tablets or tea (each containing 0.3 mmol GA) to 10 volunteers, plasma and urine samples were collected over various time intervals. Concentrations of GA and its metabolite, 4-O-methylgallic acid (4OMGA), were determined, and the pharmacokinetic parameters were calculated. GA from both the tablets and tea was rapidly absorbed and eliminated with mean half-lives of 1.19 +/- 0.07 and 1.06 +/- 0.06 h and mean maximum concentrations of 1.83 +/- 0.16 and 2.09 +/- 0.22 micromol/L (plasma), respectively. After oral administration of the tablets and black tea, 36.4 +/- 4.5 and 39.6 +/- 5.1% of the GA dose were extracted in urine as GA and 4OMGA, respectively. The relative bioavailability of GA from tea compared with that from the tablets was 1.06 +/- 0.26, showing that GA is as available from drinking tea as it is from swallowing tablets of GA.

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The bioavailability of thiamin mononitrate, thiamin chloride-hydrochloride and benfotiamin was compared in broiler chickens. A thiamin-deficient diet was supplemented with either 1.8 and 1.5 mg/kg thiamin equivalent as water-soluble salts, or with 1.5 and 1.2 mg/kg thiamin equivalent as benfotiamin, respectively, and fed to 3 replicate groups/treatment for 21 days. Weight gain, feed consumption and feed conversion rate were not significantly affected by solubility or dietary level of thiamin. Likewise, using biochemical indices of thiamin status (erythrocyte transketolase activation coefficient, and thiamin concentrations in blood and liver), no differences were found between the water-soluble thiamin salts, indicating that they have identical potency. In contrast, biochemical indices of thiamin status showed a significantly higher bioavailability for benfotiamin than for the water-soluble sources.

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In thirteen preterm infants, 45 full-term infants, and their mothers thiamin was analyzed in plasma from maternal veins, umbilical arteries, umbilical veins, and placental tissue. The blood flow in the umbilical veins was determined by pulsed Doppler ultrasonography. Thiamin-dependent transketolase was measured in erythrocytes from full-term infants and their mothers. Plasma thiamin concentrations in umbilical veins from preterm infants (227.0 +/- 85.0 nmol/L) and full-term infants (121.3 +/- 103.3 nmol/L) were seven times greater than maternal concentrations (p < 0.005). Maternal and umbilical thiamin concentrations were lower in the full-term group compared to the preterm group (p < 0.05). Arteriovenous concentration gradients were not feasible. The blood flow in the umbilical veins was higher in full-term compared to preterm infants (p < 0.05). However, intrauterine thiamin supply (plasma thiamin concentration times umbilical plasma flow) and placental thiamin concentrations were not different between preterm and full-term infants. Thiamin saturation of transketolase was greater in fetal than in maternal erythrocytes (p < 0.005); severe thiamin deficiency was not observed. Our findings suggest that thiamin turnover is similar in early and late pregnancy. Fetal tissue uptake of thiamin is not substantial. Transketolase activities suggest that thiamin status is sufficient even in late pregnancy.

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Gallic acid occurs naturally in plants and has been found to be pharmacologically active as antioxidant, antimutagenic and anticarcinogenic agent. In this work, the metabolism of gallic acid in the human body was investigated. Two methods were developed for the identification and determination of gallic acid and its phenolic metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography using UV detection and involving isocratic elution. One of these methods enables the simultaneous separation and determination of gallic acid (GA), 4-O-methylgallic acid (4OMGA), pyrogallol (PY), 2-O-methylpyrogallol (2OMPY) and resorcinol (RE) in biological fluids. This method is of interest because it allows the separation of a large number of phenolic compounds by isocratic elution using a solution of 4.4 x 10(-3) M phosphoric acid in water as mobile phase. The analysis time for this method, however, is not optimal (57 min). After oral administration of 50 mg GA, 4OMGA rapidly appeared in the plasma and urine besides unchanged GA. Other phenolic compounds, PY, 2OMPY and RE, were not detected. The second method was developed to determine GA and 4OMGA with a short analysis time (25 min).

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A confocal laser scanning microscope (with a 543 nm laser) was used for imaging rat Purkinje cell dendritic spines at high 3-D resolution. In a nutritionally controlled study of the rat, 5 months of ethanol consumption was demonstrated to alter the spines of Purkinje cell dendrites in rat cerebellum. Intact spines showed significant elongation after ethanol exposure, whereas this neuromorphological alteration could not be detected in controls. Spine elongation could be regarded as compensative growth of spines in search of new synaptic contacts due to alcohol induced cell loss.

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In the present study of nutrition control of Wistar white rats, the ultrastructure of cerebellar Purkinje cells was studied after chronic ethanol exposure and a subsequent period of prolonged abstinence: a qualitative investigation of the perikarya of Purkinje cells was performed in age-matched controls (group A) and rats alcohol-fed for 5 months and withdrawn from this diet for 3 months (group B). The results showed massive accumulation of small dense bodies as well as obvious deposition of lipofuscin in the Purkinje cells of group B. Furthermore, ring-shaped Golgi apparatus units, lamellar bodies and degenerative foci dispersed throughout the cytoplasm of the alcohol-treated animals referred to degeneration processes and neuronal cell death, the morphological characteristics and the aetiology of which are discussed.

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The specific aim of this study was to evaluate whether high doses of thiamine can compensate or prevent alcohol-induced damages of rat hippocampus CA1 pyramids. Twenty weeks of ethanol consumption together with a dose of thiamine in the range of 1.19 mg/100 mg food induced significant enlargement (parameters measured were length of the whole spine and diameter of the end-bulb) of dendritic spines. Hypertrophy can be interpreted as a compensation process due to alcohol-induced cell death because viable spines are in search of new synaptic contacts. In contrast, dendritic spines of the alcohol group fed at the same time with a high dose of thiamine (119 mg/ 100 g food = megavitamintherapy) showed normal data concerning these parameters. From these results it may be concluded that a megavitamin therapy supports a neuron's carbohydrate metabolism and therefore could be able to prevent or reduce alcohol-induced damages of hippocampal CA1 pyramidal cells in rat central nervous system.

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Several phenolic acids, e.g. caffeic acid, chlorogenic acid, ferulic acid, gallic acid and ellagic acid, which occur naturally, are inhibitors of carcinogenesis. In this paper we present a new method for the simultaneous determination of all of these compounds, except ellagic acid, in juices by reversed-phase high-performance liquid chromatography (HPLC) using ultraviolet detection and involving isocratic elution, and we have devised an HPLC method for the determination of ellagic acid in juices. The experimental results showed that cherry juice contains a high concentration of chlorogenic acid and the content of bound gallic acid in black and green grape juices is high compared to that of other phenolic acids.

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Using the Golgi-impregnation technique we could document that twenty weeks of ethanol consumption induce significant elongation of dendritic spines of rat cerebellar Purkinje cells, and as demonstrated for the first time in the present study, of hippocampal pyramidal neurons. Spine hypertrophy might be the result of compensative growth of spines in search of new synaptic contacts due to neuronal cell loss caused by the prolonged ethanol intake. In contrast, this neuromorphological alteration could not be detected in the alcohol group fed at the same time with a high dose of thiamine (119 mg/100 g food) = thiaminemegadose). As thiamine participates in a number of enzymatic reactions primarily concerned with carbohydrate metabolism, it may be concluded that megadoses of thiamine are able to support neuronal energy metabolism, which was initially impaired by ethanol-induced thiamine deficiency. Therefore, a megavitamintherapy in association with chronic alcohol intake could be able to attenuate or prevent ethanol-induced damages in rat central nervous system.

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Intrauterine uptake of vitamin B2 in preterm and full-term infants was examined. Factors of influence on vitamin supply were considered. Forty-four women and their infants were included in the study. Fetal vitamin uptake was calculated as arteriovenous concentration gradient in cord plasma times umbilical plasma flow. Concentration of vitamin B2 (free riboflavin and flavocoenzymes) was determined by high performance liquid chromatography of placental tissue and blood plasma (maternal vein, umbilical artery, umbilical vein). Flavocoenzymes were analyzed as flavin mononucleotide after acid hydrolysis of flavin adenine dinucleotide. Umbilical plasma flow was measured using pulsed Doppler sonography. Both free riboflavin and flavocoenzymes were transferred from the maternal plasma to the umbilical vein, but only free riboflavin was accumulated (approximately 1:4 for preterm and full-term infants, respectively). Flavocoenzyme concentration was higher in the umbilical vein than in the umbilical artery (p < 0.05). This indicated a median uptake of flavocoenzymes of 1.5 nmol/min.kg in preterm infants and 0.4 nmol/min.kg in full-term infants (preterm versus full-term, p < 0.01). Fetal vitamin supply depended on umbilical plasma flow and on maternal vitamin status (the latter was shown only in full-term infants). No dependence on placental vitamin concentration was observed (p > 0.05). Concentration of free riboflavin was higher in umbilical artery than in umbilical vein (p < 0.05). This indicated a release of free riboflavin from fetal tissues independent of gestational age (0.4 nmol/min.kg, preterm; 0.2 nmol/min.kg, full-term; p > 0.05).

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A HPLC method for the determination of TPPK activity in rat liver is presented. The assay comprises an extraction of TPPK from the liver into sodium phosphate buffer, pH 7.3. TPP formed in the TPPK reaction from thiamin was converted to thiochrome and thiochrome was absorbed onto Shandon APS Hypersil. The mobile phase was acetonitrile/potassium phosphate buffer, pH 8.2, and elution was monitored spectrofluorometrically.

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The Pharmacokinetics of ethanol and its metabolites were examined in 10 young healthy women and men after 1-hr intravenous ethanol application of 7.8 mmol/kg body weight. Therefore, a new pharmacokinetic model takes into account Michaelis-Menten-elimination kinetics of ethanol as well as kinetics of acetaldehyde and acetate, which are defined by first order processes. The metabolite-model adequately describes the ethanol and acetate concentration courses. In fact, the observed ethanol concentrations are so close to the model-predicted values, that the metabolite-model allows an evaluation of half-life-times of acetaldehyde and acetate. The analyses of ethanol infusion studies showed, that there are no sex differences in parameters of ethanol elimination: Maximal elimination velocity Vmax was 3.41 +/- 0.61 mmol/l.h in females and 3.98 +/- 0.69 mmol/l.h in males. Michaelis-Menten-constant kM was 1.49 +/- 0.44 mmol/l and 1.69 +/- 0.88 mmol/l, respectively. In the female group, the volume of distribution of ethanol V1 was with 38.4 +/- 5.01 significant smaller than in males with 50.5 +/- 3.51. In conclusion, the new metabolite-model can be used as a basis for the investigation of the entire alcohol metabolism.

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The pharmacokinetics of ethanol and its metabolites were examined in 10 young healthy women and men after 1-hr intravenous ethanol application of 7.8 mmol/kg body weight. Therefore, a new pharmacokinetic model takes into account Michaelis-Menten-elimination kinetics of ethanol as well as kinetics of acetaldehyde and acetate, which are defined by first order processes. The metabolite-model adequately describes the ethanol and acetate concentration courses. In fact, the observed ethanol concentrations are so close to the model-predicted values, that the metabolite-model allows an evaluation of half-life-times of acetaldehyde and acetate. The analyses of ethanol infusion studies showed, that there are no sex differences in parameters of ethanol elimination: Maximal elimination velocity Vmax was 3.41 +/- 0.61 mmol/l.h in females and 3.98 +/- 0.69 mmol/l.h in males. Michaelis-Menten-constant kM was 1.49 +/- 0.44 mmol/l and 1.69 +/- 0.88 mmol/l, respectively. In the female group, the volume of distribution of ethanol V1 was with 38.4 +/- 5.0 l significant smaller than in males with 50.5 +/- 3.5 l. In conclusion, the new metabolite-model can be used as a basis for the investigation of the entire alcohol metabolism.

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