Flavonoids and hydroxycinnamic acids are polyphenolic compounds present in our daily diet in form of tea and vegetables as well as in herbal remedies used in phytomedicine. A wide range of
in-vitro ...activities, in particular their antioxidant properties, have been studied intensively. However,
in-vivo-data on absorption, bioavailability and metabolism after oral intake are scarce and contradictory. In order to examine the metabolism and renal excretion of these compounds a standardized extract from horsetail (
Equisetum arvense) was administered to 11 volunteers following a flavonoid-free diet for 8 d. 24h urine samples were collected and analyzed by HPLC-DAD. The putative quercetin metabolites 3,4-dihydroxy-phenylacetic acid or 3,4-dihydroxytoluene could not be detected in urine in any sample. The endogenous amount of homovanillic acid, generally regarded as one of the main quercetin metabolites, was 4 ± 1 mg/d and did not increase significantly. However, hippuric acid, the glycine conjugate of benzoic acid, increased twofold after drug intake. Thus, the degradation to benzoic acid derivatives rather than phenylacetic acid derivatives seems to be a predominant route of metabolism. The results of this pilot study give rise to additional, substantial pharmacokinetic investigations in humans.
Clinical sedation assessment becomes insufficient in deeply sedated patients. Bispectral index as a processed electroencephalogram parameter provides a continuous and observer-independent value ...reported to change with sedation. The aim of this prospective observational study was to determine the reliability and possible confounding factors of the bispectral index to assess sedation in surgical intensive care patients.
Following major surgery, bispectral index, body temperature and electromyographic activity of 44 ventilated patients were recorded. Sedation levels were assessed with Ramsay sedation score.
Although bispectral index correlated with Ramsay sedation score (-0.64; P < 0.01) we found that in deeply sedated patients temperature instability and electromyographic activity increased bispectral index. Bispectral index correlated significantly with electromyographic activity (0.80; P < 0.01) and with an increase of body temperature (0.55; P < 0.01) not only in all patients but also in clinically deeply sedated patients (0.57; P < 0.01 and 0.46; P < 0.05).
Only under certain conditions, such as low muscular activity and body temperature stability, may the bispectral index be a useful addition to clinical scoring in the sedation assessment of critically ill patients.
The objective of this study was to examine if hyperhomocysteinemia is associated with occlusive vascular disease in hemodialysis patients. The study design included risk factor analysis and ...determination of serum homocysteine in hemodialysis patients. Fifty chronic uremic patients on regular hemodialysis treatment were studied. Twenty-four patients had coronary, cerebral, or peripheral signs of occlusive vascular disease. Cerebral vascular disease was diagnosed by computed tomography, arterial angiography, or Doppler sonography of the carotid and vertebral arteries. Coronary vascular disease was diagnosed by documented history of myocardial infarction or by coronary angiography. The diagnosis of peripheral vascular disease was established by angiography of the lower limb arteries. In all control patients, Doppler sonography of the carotid, vertebral, and lower limb arteries and thallium-201 exercise imaging were without pathologic results. Measurements included blood pressure, body mass index, smoking behavior, serum homocysteine (measured by gas chromatography/mass spectrometry), serum total, low-density lipoprotein, and high-density lipoprotein cholesterol, lipoprotein (a), triglycerides, and plasma fibrinogen. In a stepwise multiple logistic regression analysis, high serum homocysteine was significantly associated with occlusive arterial disease (R = 0.23; P = 0.031). Furthermore, hypertension (R = 0.18; P = 0.058), but not serum total, low-density lipoprotein, and high-density lipoprotein cholesterol, lipoprotein (a), triglycerides, diabetes mellitus, body mass index, plasma fibrinogen, and smoking behavior, was significantly associated with atherosclerosis. Our results support the hypothesis that hyperhomocysteinemia is an independent risk factor for vascular disease in hemodialysis patients.
The introduction of temporary grassland into an annual crop rotation is recognized to improve soil ecosystem services, and resulting legacies can be beneficial for the following crops. In this ...context, the aim of the present study was to evaluate legacy effects of introducing temporary grassland into an annual crop rotation on five ecosystem services (i) soil structure maintenance (aggregate stability), (ii) water regulation (saturated hydraulic conductivity), (iii) biodiversity conservation (microbial biomass and microbial metabolic activity, as well as microorganism, enchytraeid, springtail and earthworm communities), (iv) pathogen regulation (soil suppressiveness to Verticillium dahliae), and (v) forage production and quality. Three crop rotation schemes, maintained for twelve years, were compared in four random blocks, one being an annual crop rotation without grassland (0%), another with a medium percentage of grassland (50%, corresponding to 3 years of continuous grassland in the crop rotation), and a third one with a high percentage of grassland in the crop rotation (75%, corresponding to 6 years of continuous grassland in the crop rotation). The results showed that the grassland introduction into an annual crop rotation improved, whatever the duration of the grassland, soil structure maintenance and biodiversity conservation, while it decreased pathogen regulation and did not modify water regulation. Comparing the two crop rotations that included grassland, indicated a stronger beneficial grassland legacy effect for the higher proportion of grassland concerning soil structure maintenance and biodiversity conservation. By contrast, water regulation, pathogen regulation and forage production were not affected by the legacy of the 75% grassland during the rotation. Overall, our findings demonstrated the extent to which grassland legacies are affecting the current state of soil properties and possible ecosystem services provided. To improve ecosystem services, soil management should take legacy effects into account and consider longer timeframes to apply beneficial practices.
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•Five ecosystem services were studied in crop rotations with or without grasslands.•Grassland introduction improves soil structure maintenance and biodiversity conservation.•Grassland introduction decreases pathogen regulation.•Grassland legacy effect improves soil structure maintenance and biodiversity conservation.•There is no legacy effect on water and pathogen regulation, nor on forage production.
The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the ...P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (
n
= 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (≥35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC
τ,ss
,
C
max,ss
and renal clearance (CL
R
,0
–
24,ss
) of digoxin were all within the bioequivalence range 80–125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.
New stable carbon and oxygen isotope data from an Upper Cretaceous section in Tibet are presented, and compared to carbon isotope records from England, Italy, and Germany. Together with a ...stratigraphic re-interpretation of published carbon isotope data from a nearby section in Tibet, our data can surprisingly well be correlated with the European sections. This indicates that, similar to the distinct positive carbon isotope excursion at the Cenomanian-Turonian boundary, also the broad positive carbon isotope shift in the middle-late Coniacian and early Santonian reflects a major perturbation of the carbon cycle on a global scale, even though organic-rich sediments related to the OAE3 appear to be mainly restricted to the Atlantic Ocean and adjacent basins. The data further show that, apart from the broad Coniacian-Santonian carbon isotope excursion, also isotopic shifts on a smaller scale in the Turonian and Coniacian, such as the Round Down, Pewsey, and Hitchwood Events, can be correlated over both hemispheres. This demonstrates that the development of global oceanic anoxic conditions and associated burial of large amounts of organic carbon do not constitute a prerequisite for globally reflected carbon isotopic shifts. The data from Tibet support the concept of a relation between main carbon isotope excursions and major sea-level variations. Cyclic fluctuations of geochemical and lithological parameters are likely to be orbitally driven. These cycles appear to be preferably reflected in the sediments during periods of lower or variable sea-level, whereas the ocean-atmosphere system seems to have operated in a different mode during long phases of high, stable sea-level, as during the Coniacian-Santonian OAE3.
Background: Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of ...action: it competitively inhibits factor (F) Xa and FIIa. Aims: To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers. Methods: In three randomized, double‐blind, placebo‐controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results. Results: In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h−1 and Vss about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half‐life of about 6 h. The terminal half‐life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability. Conclusion: BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.
A new and very small European species of terrestrial enchytraeids is described, Enchytronia pygmaea sp. nov. (Enchytraeidae, Oligochaeta). It differs from all enchytraeids known so far in the chaetal ...pattern: lateral bundles have 2 chaetae from segment II to V, 0 from segment VI to XII–XV, and only 1 chaeta in lateral postclitellar bundles; ventral bundles have 2 chaetae. A further peculiarity is the presence of only 1 pair of preclitellar nephridia. The species must be considered as widespread as it is recorded here from 17 different localities distributed over seven European countries ranging from the Atlantic to the Mediterranean zone.
The use of herbs for treating various ailments dates back several centuries. Usually, herbal medicine has relied on tradition that may or may not be supported by empirical data. The belief that ...natural medicines are much safer than synthetic drugs has gained popularity in recent years and led to tremendous growth of phytopharmaceutical usage. Market driven information on natural products is widespread and has further fostered their use in daily life. In most countries there is no universal regulatory system that insures the safety and activity of phytopharmaceuticals. Evidence-based verification of the efficacy of HMPs (herbal medicinal products, botanicals) is still frequently lacking. However, in recent years, data on evaluation of the therapeutic and toxic activity of herbal medicinal products became available. The advances in analytical technology have led to discovery of many new active constituents and an ever-increasing list of putatively active constituents. Establishing the pharmacological basis for efficacy of HMPs is a constant challenge. Of particular interest is the question of bioavailability to assess to what degree and how fast compounds are absorbed after administration of HMPs. Of further interest is the elucidation of metabolic pathways (yielding potentially new active compounds), and the assessment of elimination routes and their kinetics. These data become an important issue to link data from pharmacological assays and clinical effects. Of interest are currently also interactions of herbal medicinal products with synthetically derived drug products. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimens. In this review, pharmacokinetic and bioavailability studies that have been conducted for some of the more important or widely used phytopharmaceuticals are critically evaluated. Furthermore, various drug interactions are discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived active pharmaceutical ingredients.
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