Teicoplanin pharmacokinetics in critically ill patients on continuous veno-venous hemofiltration.

Pharmacokinetics of teicoplanin (TP) was assessed in critically ill patients on continuous veno-venous hemofiltration (CVVH), in eleven patients, after the first dose and in another four after repeated administration. The TP peak concentration amounted to 55.44 +/- 15.90 microg/ml and 81.28 +/- 28.55 microg/ml (mean +/- SD), the trough concentration 6.4 +/- 1.7 microg/ml and 21.3 +/- 5.0 microg/ml, the half-life 15.7 +/- 5.7 and 35.1 +/- 12.3 h, the apparent volume of distribution 0.84 +/- 0.22 and 0.48 +/- 0.09 l/kg and the TP clearance 39 +/- 12 and 11 +/- 4 ml/h/kg after the first dose and after repeated administration, respectively. The mean sieving coefficient of TP was 0.15. After a 1,200 mg loading dose, daily maintenance doses of 600 - 1,800 mg were required for achieving trough levels of 15 - 25 microg/ml. Therapeutic drug monitoring is indispensable during CVVH because of a considerable variability of TP pharmacokinetics.

Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects.

UNLABELLED: ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis. BACKGROUND: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. MATERIALS AND METHODS: Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry. MAIN RESULTS: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. CONCLUSIONS: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.

Preserved verb generation priming in global amnesia.

In the verb generation task, participants are presented with nouns and generate for each one an appropriate verb. Raichle et al. (Cerebral Cortex, 1994, 4, 8-26) found that when participants generated verbs to repeated nouns, generation latencies were reduced and different patterns of brain activation were present. In order to examine whether verb generation priming is dependent or independent of declarative memory, verb generation priming was compared between 13 amnesic (seven with alcoholic Korsakoff's syndrome, six with other etiologies) and 19 control participants (10 with a history of alcoholism). Both amnesic and control participants became faster across blocks on repeated nouns and slowed when novel nouns were introduced. Priming was verb specific for both groups: it was equivalent whether generated to a repeated or a novel noun. Verb generation priming, therefore, can occur independently of declarative memory.

Hemispheric asymmetries and individual differences in visual concept learning as measured by functional MRI.

Dynamic changes in brain regions active while learning novel visual concepts were examined in humans using functional magnetic resonance imaging. Participants learned to distinguish between exemplars of two categories, formed as distortions of different unseen prototype stimuli. Regions of the right hemisphere (dorsolateral prefrontal and inferior parietal areas) were active early in learning and throughout task performance, whereas homologous portions of the left hemisphere were active only in later stages of learning. Left dorsolateral prefrontal activation was found only in participants who showed superior conceptual learning. Such a progression from initial right-hemisphere processing of specific instances to bilateral activity as left-hemisphere conceptual processes are recruited may underlie the development of many forms of visual knowledge.

Implicit learning.

Implicit learning is nonepisodic learning of complex information in an incidental manner, without awareness of what has been learned. Implicit learning experiments use 3 different stimulus structures (visual, sequence, and function) and 3 different dependent measures or response modalities (conceptual fluency, efficiency, and prediction and control). Implicit learning may require a certain minimal amount of attention and may depend on attentional and working memory mechanisms. The result of implicit learning is implicit knowledge in the form of abstract (but possibly instantiated) representations rather than verbatim or aggregate representations. Implicit learning shows biases and dissociations in learning different stimulus structures. The dependence of implicit learning on particular brain areas is discussed, some conclusions are drawn for modeling implicit learning, and the interaction of implicit and explicit learning is considered.

Striatal activation during acquisition of a cognitive skill.

The striatum is thought to play an essential role in the acquisition of a wide range of motor, perceptual, and cognitive skills, but neuroimaging has not yet demonstrated striatal activation during nonmotor skill learning. Functional magnetic resonance imaging was performed while participants learned probabilistic classification, a cognitive task known to rely on procedural memory early in learning and declarative memory later in learning. Multiple brain regions were active during probabilistic classification compared with a perceptual-motor control task, including bilateral frontal cortices, occipital cortex, and the right caudate nucleus in the striatum. The left hippocampus was less active bilaterally during probabilistic classification than during the control task, and the time course of this hippocampal deactivation paralleled the expected involvement of medial temporal structures based on behavioral studies of amnesic patients. Findings provide initial evidence for the role of frontostriatal systems in normal cognitive skill learning.

Functional magnetic resonance imaging evidence for right-hemisphere involvement in processing unusual semantic relationships.

Brain areas active in generating usual (typical) or unusual (atypical) noun-verb relations were examined using functional magnetic resonance imaging. Seven adults generated the 1st verb to come to mind (usual verb) in response to novel and repeated nouns (priming test) and then generated either an unusual verb or the 1st verb to come to mind in response to novel nouns (unusual test). The left inferior prefrontal cortex (LIPC) and right cerebellum were more active when generating usual verbs to novel nouns than to repeated nouns. When participants generated unusual verbs, there was no increased activation in LIPC, but there was increased activity in the right middle and superior frontal gyri, left middle frontal gyrus, and bilateral cerebellum. Results support theories that the right hemisphere is involved in the processing of distant associations that may be useful in creative thought and problem solving.

Serological detection of multiple retroviral infections in cattle: bovine leukemia virus, bovine syncytial virus and bovine visna virus.

Individual experimental animals used in our studies on bovine leukemia virus (BLV) are routinely screened for the presence of antibodies to the three bovine lymphotropic retroviruses. We utilized these screening methods to examine frozen sera from eight herds for antibodies to BLV, bovine visna virus (BVV) and bovine syncytial virus (BSV). Serum samples from 235 animals in four dairy and four beef herds were analyzed. Detection methods used included indirect fluorescent antibody tests of virus-infected cell cultures (BLV, BSV, BVV) and agar gel immunodiffusion (BLV). Sera from the BLV-infected animals in the dairy herds showed the highest single (50%, 49/97) and multiple (30%, 29/97) infections compared with 5% (7/138) and less than 1% (1/138), respectively in the beef herds. Single BVV infections were not detected in the dairy herds, but 11% (11/97) of the sera contained antibodies to BVV plus BLV or BSV. Five sera from beef cattle had antibodies only to BVV and four were obtained from one herd. Only one beef serum of the 138 tested demonstrated multiple antibodies (BLV, BVV).

Characterization of infertility and bovine leukemia virus infection in beef bulls on southwestern Louisiana coastal range.

One hundred and twenty-six beef bulls on southwestern Louisiana coastal range were evaluated for breeding soundness. Samples were taken to determine the incidence of bovine leukemia virus (BLV) infection, and the prepuce was cultured for potential pathogens. A high incidence (47.6%) of questionable and unsatisfactory potential breeders resulted mainly from 37.0% of the bulls exhibiting high numbers of abnormal sperm cells in the semen. Only bulls in the 4-to 5-yr age group exhibited the expected incidence of normal spermiograms. Genital campylobacteriosis was not diagnosed but there was genital trichomoniasis in three of the seven herds. Hemophilus somnus , mycoplasma and ureaplasma were isolated from the prepuce of 13.3, 48.8 and 36.7% of the bulls, respectively. Isolation of these organisms from the prepuce did not appear to be associated with abnormal spermiograms. Of the bulls studied, 34.4% had positive AGID reactions for BLV. Bulls seropositive to BLV had an increased incidence of leukocyte counts that were above the normal range. There was no apparent relationship between BLV infection and abnormal spermiograms.

Toxic Bermuda grass tremor in the goat: an electroencephalographic study.

Tremorgenic Bermuda grass hay harvested during the 1971 Louisiana outbreak of toxicosis and kept in cold storage until 1979 was fed to a female Nubian cross goat. Cortical EEG from chronically implanted screw electrodes was recorded daily during hay consumption. Typical clinical signs of toxicosis were manifested as ataxia on day 8 and tremor on day 11. Motor activity returned to normal 2 days after reinstitution of nontoxic Bermuda grass hay. Changes in EEG amplitudes, frequency content, or wave-forms were not seen during the development or after the appearance of toxicosis. The administration of diazepam at the height of toxicosis suppressed the tremor for several hours.

Effects of a Cassia occidentalis extract in the domestic chicken (Gallus domesticus).

The effects of an orally administered Cassia occidentalis extract were studied in chickens. A 25 mM sodium bicarbonate solution effectively extracted the toxic principle. Toxic activity was reduced, but not eliminated, when the heated extract (90 C, 40 minutes) was administered. The toxic principle was in the pellet after centrifuging the extract at 38,000 X g. Daily administration of the extract produced weight loss and muscular weakness. Microscopic examination revealed skeletal and cardiac muscle degeneration and hepatocyte vacuolation. Electron microscopic examination revealed mitochondrial disruption. Respiratory studies on liver mitochondria isolated from treated chickens demonstrated lower phosphorylation ratios, lower respiratory control ratios, and lower rates of oxygen use.

Preliminary isolation of a myodegenerative toxic principle from Cassia occidentalis.

Aqueous and organic extractions of ground seeds of Cassia occidentalis were obtained. Chickens were dosed with extracted material to assess the toxicity of the extracts. Organic extracts with methanol, ethanol, chloroform, ethyl acetate, and benzene were ineffective in removing the toxin from the seeds. Aqueous extractions, using 25 mM sodium bicarbonate or 250 mM sodium citrate, removed the toxin from the seeds, but left the toxin bound to particulate matter in the extract. Addition of Triton X-100 to the aqueous buffers effectively solubilized the toxin from the particulate matter. Signs of intoxication in the chickens were loss of weight, weakness, diarrhea, hypothermia, occasionally ataxia, and recumbency; then death. Gross lesions included paleness of skeletal and cardiac muscles and congestion of the liver. Microscopic lesions in muscle tissue were vacuolation, proliferation of sarcolemmal nuclei, and separation of myofibrils. Electron microscopic examination revealed disruption of mitochondrial cristae and swelling and rupture of mitochondria.

An immunodiffusion test for detection of bovine viral diarrhea virus antibodies in bovine serum.

An immunodiffusion test (IDT) was developed for detecting bovine viral diarrhea virus antibodies in bovine serum. The antigen utilized in the IDT was prepared from bovine viral diarrhea virus-infected monolayer cultures. Results of the IDT were obtained within 48 hours and correlated with the virus-neutralization test.

A rapid staining procedure for Anaplasma marginale in bovine erythrocytes.

A commercial product that stains cells in less than 1 minute was compared with the Giemsa and the Wright-Giemsa methods for detection of the intraerythrocytic parasite, Anaplasma marginale, in bovine blood smears. The total number of A marginale-infected erythrocytes detected in 5 microscope fields of 18 different samples was determined for each staining procedure. In samples where less than 2% to greater than 25% of the RBC were infected, statistical analysis of the data indicated that the rapid staining method was superior to the Giemsa and Wright-Giemsa methods with regard to determination of the percentage of bovine erythrocytes infected with A marginale.

Microimmunodiffusion test for detection of antibodies to infectious bovine rhinotracheitis virus in bovine serum.

A microimmunodiffusion test (MIDT) specific for detection of antibodies to infectious bovine rhinotracheitis (IBR) in bovine serum has been developed. The antigen used in the MIDT was prepared from IBR virus-infected Madin-Darby bovine kidney cells grown in tissue culture. The antigen was stable, and relatively high yields were obtained readily. Results of the MIDT were obtained within 48 hours and agreed with those of the serum-neutralization test.

Transmission of bovine leukemia virus by Tabanus fuscicostatus.

Bovine leukemia virus (BLV) was transmitted by horse flies, Tabanus fuscicostatus, from a cow with a lymphocyte count of 31,500/mm3 to goats and dairy calves. As few as 10 and 20 flies transmitted BLV to goats and calves respectively, but the minimal number of flies required to transmit the infection was not established. Groups of 150 and 100 T fuscicostatus transmitted BLV to beef calves from a cow with a lymphocyte count of 14,600/mm3. These results support a role for horse flies in the horizontal transmission of BLV.

Development and validation of a rapid ultra-high performance liquid chromatography diode array detector method for Vitex agnus-castus.

A rapid ultra-high performance liquid chromatography diode array detector (UHPLC-DAD) method was developed and validated for the simultaneous determination of all classes of non-volatile phytochemicals (iridoids, flavonoids and diterpenes) in Vitex agnus-castus (Lamiaceae) fruits, a traditional medicinal plant used against premenstrual symptoms (PMS) and other disorders. Seven marker compounds, 3,4-dihydroxybenzoic acid, p-hydroxybenzoic acid, agnuside, 5-hydroxykaempferol-3,6,7,4'-tetramethylether, 1,2-dibenzoic acid glucose, methoxy-vitexilactone, and vitetrifolin D were isolated from the methanol extract of V. agnus-castus to be used as reference substances. Chromatographic separation was performed on a Zorbax Eclipse XDB-C18 (50mm×2.1mm) UHPLC column with 1.8µm particle size, within 20min. A solvent gradient from 0.5% acetic acid to acetonitrile at a flow rate of 0.6mL/min was used as mobile phase. Analyte detection and quantification was realized at 210nm and 260nm. The UHPLC-DAD assay was validated for the quantitative analysis of agnuside, isovitexin, casticin, 5-hydroxykaempferol-3,6,7,4'-tetramethylether and vitetrifolin D. It was found to be specific, accurate, precise, and reproducible for the quantification of these compound within a concentration range of 0.7-500.0µg/mL for casticin and 5-hydroxykaempferol-3,6,7,4'-tetramethylether, 1.4-1000.0µg/mL for isovitexin and agnuside, and 12.4-1000.0µg/mL for vitetrifolin D. Intra- and inter-day variations showed relative standard deviations (RSD) of less than 3.9% and 6.4%, respectively. Tentatively assignment of 62 chromatographic features found in the UHPLC-DAD assay was carried out by coupling the UHPLC instrument to a quadrupole time-of-flight mass spectrometer via an electrospray ionization interface (ESI-QTOF-MS) operated in positive and negative ion mode. By using the established quantitative UHPLC-DAD assay to asses agnuside, isovitexin, casticin, 5-hydroxykaempferol-3,6,7,4'-tetramethylether and vitetrifolin D in V. agnus-castus derived preparations as extracts, tinctures and tablets, the applicability of the developed assay to phytopharmaceuticals was successfully proven.

Destruxins: fungal-derived cyclohexadepsipeptides with multifaceted anticancer and antiangiogenic activities.

Destruxins (Dtx) are secondary metabolites of the entomopathogenic fungus Metarhizium anisopliae. Recently, Dtx came into focus of interest as anticancer therapeutics. However, data on human and especially on cancer cells are fragmentary. In order to successfully establish novel anticancer therapeutics, a broad knowledge on the cellular and molecular mechanisms underlying their activity is essential. Consequently, this study aimed to investigate the impact of the most common Dtx derivatives A, B and E on human cancer cell growth and survival with a focus on colon cancer cell models. Summarizing, the experimental data showed that (i) Dtx A and B exert potent antiproliferative activity in the micromolar and Dtx E in the nanomolar range in KB-3-1, A549, CaCo-2, and especially in HCT116 colon cancer cells, (ii) all three Dtx derivatives cause imbalance of cell cycle distribution, (iii) their cytostatic/cytotoxic effects are widely p53-independent but reduced by p21- and bax-deletion, respectively, (iv) cytotoxicity is based on intrinsic apoptosis induction and associated with phosphoinositide-3-kinase (PI3K)/Akt pathway inhibition, (v) anticancer activity of Dtx E but not Dtx A and B involves disturbance of the intracellular redox balance, (vi) Dtx inhibit the migration and tube formation of human endothelial cells indicating antiangiogenic potential, and (vii) all three Dtx derivatives possess ionophoric properties not differing in conductivity, ion selectivity and single channel kinetics. Thus, Dtx represent feasible, multifunctional anticancer drug candidates for preclinical development especially against colorectal cancer.