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Biomedical subjects

A Biber

Publications and source records attributed to A Biber.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of rats with the Pelargonium sidoides extract EPs 7630 has no effect on blood coagulation parameters or on the pharmacokinetics of warfarin.

Umckaloabo is a herbal drug for the treatment of respiratory tract infections. It contains an aqueous ethanolic extract from roots of Pelargonium sidoides DC (EPs) 7630) as the active ingredient. Polymeric polyphenols and coumarins have been identified as the principal ingredients of EPs 7630. In view of the coumarin content, it has been suggested that the administration of Umckaloabo could possibly be associated with an increased risk of bleeding. This study, therefore, investigated whether a change in blood coagulation parameters or an interaction with coumarin-type anticoagulants occurred after administration of EPs 7630 to rats. No effect on thromboplastin time (TPT), partial TPT (PTPT) or thrombin time (TT) was observed after oral administration of EPs 7630 (10, 75, 500 mg/kg) for 2 weeks, while treatment with warfarin (0.05 mg/kg) for the same period resulted in significant changes in TPT and PTPT. If EPs 7630 (500 mg/kg) and warfarin (0.05 mg/kg) were given concomitantly, the anticoagulant action of warfarin was not influenced. Similarly, the pharmacokinetics of warfarin were unchanged after pre-treatment with EPs 7630 for 2 weeks. Coumarin-type anticoagulants inhibit the synthesis of vitamin K-dependent coagulation factors via an identical mechanism in rat and man, and have a similar pattern of metabolism in both species. Moreover, as the coumarins so far identified in EPs 7630 do not posses the structural characteristics needed for anticoagulant activity, it appears unlikely that an increased tendency to haemorrhage arises in patients after intake of Umckaloabo.

Administration, Oral↗
PubMed2003

Pharmacokinetics of Ginkgo biloba extracts.

EGb 761 (definition see editorial) Ginkgo extract is produced by a validated production process. Its pharmacologically active constituents, flavonol glycosides and terpene lactones, are kept within a narrow range of 22 to 27 % and 5 to 7 %, respectively, by standardisation. The concentration of ginkgolic acids is below 5 ppm. The constant production process also maintains the concentrations of other constituents such as proanthocyanidins, carboxylic acids and non-flavone glycosides at a fairly constant level. In this article, we will summarise the data on the pharmacokinetics of flavonol glycosides and terpene lactones.

Adult↗
PubMed2002

Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations.

To be effective, herbal medicinal products are expected to meet comparable standards concerning the assessment of efficacy, safety and biopharmaceutical quality as chemically defined synthetic drugs as food supplements. However, these requirements are often not fulfilled, particularly regarding the characterization of biopharmaceutical properties such as in-vitro dissolution and in-vivo bioavailability. With respect to the relevance of biopharmaceutical quality of herbal medicinal products, two different Ginkgo biloba brands (test product: Ginkgo biloba capsules; reference product: Ginkgold) were analysed for dissolution rates and bioavailability of the most relevant active ingredients. Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was investigated after single oral administration of 120 mg Ginkgo biloba extract as tablets or capsules. Bioavailability data (area under the curve and peak concentration in plasma) were clearly different and did not show bioequivalence of test and reference products. The slow in-vitro dissolution of the test product resulted in a large decrease in bioavailability. These results indicate for the first time that the pharmaceutical properties of a herbal medicinal product have a significant impact on the rate and extent of drug absorption, and very likely on efficacy in humans.

Administration, Oral↗
PubMed2001

Stimulation of glutamate, aspartate and gamma-aminobutyric acid release from synaptosomes by hyperforin.

Hyperforin is one pharmacologically active constituent of the medicinal herb Hypericum perforatum. The mechanism of its antidepressant-like activity is currently considered to be the inhibition of synaptic reuptake of neurotransmitters. Here, we will demonstrate that it also stimulates the release of glutamate from rat cortical synaptosomes, and that this effect is preceded by an increase in their free calcium [Ca2+]i levels. These hyperforin-related effects were also observed in the absence of Ca2+ in the medium. Although we noted enhanced glutamate, aspartate and GABA release under the influence of hyperforin, the release of various other amino acids was not enhanced. In contrast, reserpine did not influence the release of any of the amino acids studied. Adding hyperforin to synaptosomal suspension decreased their pHi, which returned to basal levels under certain incubation conditions. It also prevented the generation of ATP-induced pH gradients of isolated synaptic vesicles, and preformed pH-gradients were reversed by it. We will discuss the implications of our studies in understanding the mechanisms of hyperforin activity in relation to current findings on its pharmacological activity profile. Our observations suggest that neurotransmitter release stimulation from synaptosomes and the previously reported reuptake inhibitory properties of hyperforin are consequences of its effects on synaptosomal ionic homeostasis, and that it is not a reserpine-like agent.

Adenosine Triphosphate↗
PubMed1999

Bioavailability of ginkgolides and bilobalide from extracts of ginkgo biloba using GC/MS.

The bioavailability of ginkgolides A, B and bilobalide was studied in rats after single oral administration of 30, 55 and 100 mg/kg Ginkgo extract EGb 761. The plasma levels of the terpene lactones were measured by a specific GC/MS method. The pharmacokinetics of the mentioned substances were found to be dose-linear. For the lowest dose maximum concentrations were 68, 40 and 159 ng/ml and half-lives 1.7, 2.0 and 2.2 h for ginkgolide A, B and bilobalide, respectively. Clearance values ranged from 24.2 to 37.6 ml/min/kg.

Animals↗
PubMed1998

KA 672-HCl, a neuronal activator against dementia: tolerability, safety, and preliminary pharmacokinetics after single and multiple oral doses in healthy male and female volunteers.

In vitro and animal experiments have characterized KA 672-HCl as a potent functional antagonist of excitatory amino acid-induced convulsions and mortality. In receptor-binding studies, the compound displayed high affinities to several serotoninergic, adrenergic, and dopaminergic receptors and to the sigma receptor. The potential for short- and long-term toxicity of KA 672-HCl in rats and dogs was found to be low. Double-blind, randomized, placebo-controlled studies were undertaken in healthy volunteers ranging from 52 to 74 years of age to determine tolerability, safety, and preliminary pharmacokinetics of single and repeated doses in humans. Single doses up to 40 mg were well tolerated, with no difference in effect from placebo. At 60 mg, approximately half of the volunteers experienced a moderate drug-related orthostatic syndrome. After repeated doses of 10 or 20 mg KA 672-HCl for 14 days only minor adverse events of mild intensity were reported with no clear relation to dose or a clinically relevant difference from placebo. A mild decrease in semisupine and standing blood pressure 4 hours after administration was observed in the 20 mg group with no occurrence of orthostasis. Linear pharmacokinetics were observed after repeated doses. However, this was not the case after single-dose administration, as generally higher plasma concentrations were observed after the 20-mg dose than would have been predicted from the 10-mg data. The mean terminal phase half-life after the 20 mg dose was 11.1 hours and 13.7 hours after repeated and single doses, respectively. The safety and tolerability data support a continuation of therapeutic trials. KA 672-HCl is currently entering phase II development.

Administration, Oral↗
PubMed1998

Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers.

Validated analytical methods suitable for determining hyperforin in plasma after administration of alcoholic Hypericum perforatum extracts containing hyperforin are described. After oral administration of 300 mg/kg Hypericum extract (WS 5572, containing 5% hyperforin) to rats maximum plasma levels of approximately 370 ng/ml (approx. 690 nM) were reached after 3 h, as quantified by a HPLC and UV detection method. Estimated half-life and clearance values were 6 h and 70 ml/min/kg respectively. Since therapeutic doses of Hypericum extracts are much lower than that used in rats, a more sensitive LC/MS/MS method was developed. The lower limit of quantification of this method was 1 ng/ml. Using this method, plasma levels of hyperforin could be followed for up to 24 h in healthy volunteers after administration of film coated tablets containing 300 mg hypericum extracts representing 14.8 mg hyperforin. The maximum plasma levels of approximately 150 ng/ml (approx. 280 nM) were reached 3.5 h after administration. Half-life and mean residence time were 9 and 12 h respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg of extract resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. Plasma concentration curves in volunteers fitted well in an open two-compartment model. In a repeated dose study, no accumulation of hyperforin in plasma was observed. Using the observed AUC values from the repeated dose study, the estimated steady state plasma concentrations of hyperforin after 3 x 300 mg/day of the extract, i.e., after normal therapeutic dose regimen, was approximately 100 ng/ml (approx. 180 nM).

Administration, Oral↗
PubMed1996

Enzymatic cleavage of thymopoietin oligopeptides by pancreatic and intestinal brush-border enzymes.

The intestinal enzymatic degradation of the immunomodulating peptides thymotrinan (TP3), thymocartin (TP4), and thymopentin (TP5), three oligopeptides derived from the naturally occurring thymus hormone thymopoietin, was investigated to evaluate their potential for peroral drug delivery. In the presence of brush-border membrane vesicles, crude pancreas extract and everted rings from duodenum, jejunum, ileum, and colon, all peptides were shown to be degraded both by pancreatic enzymes and brush-border aminopeptidases. Degradation clearances (Cldeg) of TP3, TP4, and TP5 were calculated for a quantitative comparison of peptide stability. In the presence of crude pancreas extract, there was a rapid degradation of TP5 (Cldeg 17.9 ml/min) in comparison with TP3 and TP4 (Cldeg 0.95 and 0.56 ml/min, respectively, at 0.2 mM peptide concentration) caused by the cleavage of the C-terminal tyrosine by carboxypeptidase A, whereas TP3 and TP4 underwent hydrolysis by aminopeptidase N. In the presence of brush-border membrane vesicles, the degradation clearances were 3.9, 3.1, and 2.4 ml/min at 0.2 mM concentrations of TP4, TP5, and TP3, respectively. The clearance of all peptides was lowered with increasing peptide concentrations, indicating saturable degradation processes. The degradation of the thymopoietin oligopeptides in the presence of brush-border membrane enzymes was exclusively catalyzed by aminopeptidase N. The degradation of all peptides was highly dependent on the intestinal segment, with the lowest degradation clearance observed in the colon.

Animals↗
PubMed1996

Antiviral and antiphlogistic activities of Hamamelis virginiana bark.

A crude hydroalcoholic extract from Hamamelis virginiana bark was subjected to ultrafiltration (UF) with a cut-off limit of 3 kDa to obtain a higher and a lower molecular weight fraction. Characterisation of the fractions was attempted with TLC, HPLC, acidic hydrolysis, and chromatography over Sephadex LH-20. The UF-concentrate was shown to consist mainly of oligomeric to polymeric proanthocyanidins (PA). This fraction was found to exhibit significant antiviral activity against Herpes simplex virus type 1 (HSV-1). In addition, the UV-concentrate displayed radical scavenging properties, inhibited alpha-glucosidase as well as human leukocyte elastase (HLE), and exhibited strong antiphlogistic effects in the croton oil ear edema test in the mouse. With the exception of the antioxidant potential and the inhibition of HLE-action the lower molecular fraction possessed weaker activities and contained mainly hamamelitannin, catechin, and further, unidentified constituents.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Pharmacokinetics of losigamone, a new antiepileptic drug, in healthy male volunteers.

Losigamone (AO-33), a new potential antiepileptic drug, was tested in 52 healthy male volunteers in 4 placebo-controlled phase I studies. In study 1 single doses of 100, 200, 300, 500, 700, and 1,000 mg losigamone were given as a fast releasing capsule to 12 subjects. The pharmacokinetics of losigamone measured after administration of 100, 300, and 700 mg was linear. Clearance and t1/2 were about 350 ml/min and 4 h, respectively, the Cmax values of 0.7, 1.7, and 4.4 micrograms/ml were reached after 2.5 h. In study 2,500 mg losigamone were given as a fast release capsule for 6 days (t.i.d.) to 12 subjects. There was a small but statistically significant decrease for the AUC but no change in t1/2, Cmax or tmax comparing single dose kinetics on day 1 and 8. There appeared to be no change in caffeine clearance on days 1 and 9. Study 2 was repeated in 20 volunteers with a film-coated tablet. Pharmacokinetic parameters appeared to be unaffected by this change in galenical formulation. In study 4 daily doses of 400, 1,200, and 1,800 mg losigamone were given 28 days to 24 subjects. The kinetics of caffeine and antipyrine were compared on days 1 and 29. With the exception of t1/2 for antipyrine in the 400 mg group there was no statistically significant change in pharmacokinetic parameters. Generally, losigamone was well tolerated and no serious adverse side-effects occurred. In some subjects a reversible increase in transaminases was observed.

Administration, Oral↗
PubMed1996

[Pharmaokinetics of beta-escin after administration of various Aesculus extract containing formulations].

With a specific radioimmunoassay the pharmacokinetics and relative bioavailability of escin was measured after administration of different formulations containing Aesculus-extract. Of special interest was the relative bioavailability of escin after administration of a newly developed film-coated tablet with sustained release in comparison to a reference formulation. In a cross-over steady-state study in 24 volunteers bioequivalence of test and reference preparation could be demonstrated. The 90% confidence interval of the AUC (O-tau) was 98.3 to 120.9%.

Adult↗
PubMed1988

Local cerebral glucose utilization of the awake rat during chronic administration of nicotine.

Local cerebral glucose utilization (LCGU) was measured in 45 regions of the rat brain during chronic nicotine infusion using the quantitative autoradiographic 2-deoxy-D-[1-14C]glucose method described by Sokoloff et al. [J. Neurochem., 28 (1977) 897-916]. Osmotic minipumps, filled with L-nicotine, were implanted 14 days before the measurement of LCGU. The infused nicotine dose of 12.5 micrograms/kg/min resulted in a plasma nicotine concentration of 77 +/- 17 and a plasma cotinine concentration of 504 +/- 137 (mean +/- S.E.M.) ng/ml plasma. One day before the LCGU experiment was performed, spontaneous locomotor activity was measured and found to be reduced significantly. Measurement of LCGU showed a significant increase in 6 of the 45 brain structures examined, i.e. globus pallidus, septal nucleus, lateral geniculate body, superior colliculus (superficial grey layer), interpeduncular nucleus and optic chiasm. These results are partly congruent with previous data of our group obtained during acute nicotine infusion, insofar as LCGU was increased in the optic chiasm, the lateral geniculate body, the superior colliculus, and the interpeduncular nucleus. On the other hand, the increased LCGU in the globus pallidus and septal nucleus occurred during chronic infusion only; other structures were not affected by chronic infusion although their LCGU had been raised during acute infusion. It is concluded that chronic nicotine infusion has distinct effects on the functional activity of several brain structures which are partly congruent with those affected during acute nicotine infusion and partly divergent from them.

Animals↗
PubMed1988

Pharmacokinetics of nicotine, cotinine, and 3'-hydroxycotinine in cigarette smokers.

The trans-isomer of 3'-hydroxycotinine has recently been identified as a major metabolite of nicotine in urine of cigarette smokers. We, therefore, investigated the pharmacokinetics of 3'-hydroxycotinine in six male smokers after intravenous infusion of nicotine, cotinine, and 3'-hydroxycotinine. Serum concentrations of 3'-hydroxycotinine were lower than those of cotinine throughout the observation period of 60 h after infusion of nicotine or cotinine, whereas the amounts excreted in the urine were similar or higher than those of cotinine. The following means and ranges for the pharmacokinetic parameters were derived from the 3'-hydroxycotinine infusion experiment: half-life (t1/2 beta) = 5.9 (4.2-9.5) h; apparent volume of distribution (Vd) = 0.87 (0.51-1.14) l/kg; total clearance (Cl total) = 1.79 (1.08-2.59) ml/min/kg; renal clearance (Clr) = 1.31 (0.85-1.78) ml/min/kg; percentage of renal clearance (Clr/Cl total) = 75.4 +/- 12.8 (60.3-98.2). The high percentage of renal clearance suggests that further metabolization of this compound is limited. No evidence for a mutagenic activity of 3'-hydroxycotinine or of urine extracts from subjects dosed with hydroxycotinine was found with the S. typhimurium (TA 98) microsome assay.

Adult↗
PubMed1987

Production of mycotoxins by Fusarium species isolated in Germany. 2. Time course of deoxynivalenol and 3-acetyldeoxynivalenol formation by Fusarium graminearum in different liquid media.

Several semisynthetic liquid media were examined for the large-scale production of deoxynivalenol (DON) und 3-acetyldeoxynivalenol (AcDON) by Fusarium graminearum 183. Only in three of the eight media used could high toxin yields of DON and AcDON be detected. The maximum levels of DON in a medium according to Miller were 3 mg/l and of AcDON 32 mg/l. In glucose-yeast extract-peptone (GYEP) medium containing 1% glucose, the AcDON concentrations reached 33 mg/l and the DON yields were 19 mg/l. In a rice flour liquid medium, however, the mean levels of AcDON and DON increased to 170 mg/l and 9 mg/l, respectively. The maximum amounts observed were 480 mg/l for AcDON and 65 mg/l for DON. The addition of trifluoracetic acid sodium salt or malonic acid, which are suggested to cause an accumulation of acetyl-CoA by inhibiting enzymes of the tricarboxylic acid cycle, did not stimulate the toxin formation.

Culture Media↗
PubMed1987

Measuring problems in estimating the exposure to passive smoking using the excretion of cotinine.

Quality control studies on cotinine measurements following low level environmental tobacco smoke (ETS) exposure are rare. The exposure to ETS was controlled and systematically changed in a series of experiments in a climatic chamber. Healthy nonsmoking volunteers were exposed to ETS simultaneously. The duration and level of exposure varied using high (8, 17 and 25 ppm CO), and low (2 and 5 ppm CO) exposure levels. The variation between radioimmunoassay (RIA) and gas chromatography (GC) was high as was the variation between the results of RIA laboratories. There was also a high within-laboratory-variation. A 1:10 dilution seems to be preferable over a 1:3 dilution. Freezing the urine samples immediately after collection led to the detection of higher cotinine values than freezing the samples 24 h after collection. Highly reliable data for cotinine were obtained when the urine samples were kept frozen immediately after collection and fractionated sampling over 48-72 h was used. Our data show that estimating low-level ETS exposure by measuring urinary cotinine is highly susceptible to uncontrolled variation and errors. Sufficiently reliable estimates of low-level ETS exposure can be made only when fractionated sampling over 48-72 h is used and when the urine samples are kept frozen just after collection.

Chromatography, Gas↗
PubMed1987

Determination of nicotine and cotinine in human serum and urine: an interlaboratory study.

An interlaboratory study aimed at determining nicotine and cotinine in human serum and urine was carried out. 11 laboratories from 6 countries, all experienced in performing nicotine and cotinine determinations in biological fluids by radioimmunoassay (RIA) and/or gas chromatography (GC) were involved. Each of them received 18 serum and 18 urine samples. The specimens were obtained from 8 smokers and 10 non-smokers; 2 samples from non-smokers were spiked with defined amounts of nicotine and cotinine. All the laboratories distinguished perfectly between the smokers and the non-smokers and according to cotinine levels in serum the laboratories ranked the samples with good agreement. There were systematic differences in the absolute values between the laboratories. The ratios of urinary cotinine concentrations between active and passive smokers differed widely from laboratory to laboratory. The reasons for this are not yet known and necessitate further investigation.

Chromatography, Gas↗