23,663 research outputs found
Retreatment with interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C
No full textBackground/Aims: Combination therapy with interferon-alpha (IFN-alpha) plus ribavirin is more efficacious than IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C and patients with IFN-alpha relapse. Only limited data are available in IFN-alpha non-responders. In a multicenter trial we therefore evaluated the efficacy of combination therapy in IFN-alpha-resistant chronic hepatitis C. Methods: Eighty-two patients (mean age 46.8 years, 54 males, 28 females) with chronic hepatitis C were treated with IFN-alpha-2a (3 x 6 MIU/week) and ribavirin (14 mg/kg daily) for 12 weeks. Thereafter, treatment was continued only in virological responders (undetectable serum HCV RNA at week 12) with an IFN-alpha dose of 3 x 3 MIU/week and without ribavirin for a further 9 months. The primary study endpoint was an undetectable HCV RNA by RT-PCR at the end of the 24-week follow-up period. Results: After 12 weeks of combination therapy, an initial virological response was observed in 29 of 82 (35.4%) patients. Due to a high breakthrough rate after IFN-a dose reduction and ribavirin discontinuation, an end-of-treatment response was only achieved in 12 of 82 (14.6%) patients. After the follow-up period, a sustained virological response was observed in 8 of 82 (9.8%) patients. Infection with HCV genotype 3 was the only pretreatment parameter, which could predict a sustained response (HCV-1, 5%; HCV-3, 57.1%; p < 0.001). Conclusions: Despite a high initial response rate of 35.4%, sustained viral clearance was achieved only in 9.8% of the retreated primary IFN-alpha non-responders. Higher IFN-alpha induction and maintenance dose, as well as prolonged ribavirin treatment may possibly increase the virological response rates in non-responders, particularly in those infected by HCV-1
Development and application of a LC-MS/MS method for the analysis of plasma bioavailabilities of different cannabinoids after the administration of "Cannabis sativa L." extracts and MarinolTM
No full textA lively interest in the cannabis plant can be verified for a long time. As a drug in the
traditional medicine, different pieces of the cannabis plant were used against a
palette of diseases such as pain (head- and stomach-ache), menstrual problems and
diarrhoea. Further, it was used as a sedative and to induce sleep [1].
At the beginning of the 20th century, a scientific interest for cannabis has emerged.
Research was done to detect the pharmacokinetic and pharmacodynamic effects of
cannabis. The discovery of the endogenous cannabinoid system opened a broad
field for research. This system gradually helped to better understand the molecular
mechanisms of the cannabis effects. Links to other modulating or regulatory systems
in our body are now possible [2].
The special applications of cannabis in traditional medicine, have to be clinically
investigated with the scientific knowledge of today. Some applications are already
established. The United States Food and Drug Administration (FDA) approved
MarinolTM (a soft gelatine capsule containing THC dissolved in sesame oil) to treat
nausea and vomiting associated with cancer chemotherapy in patients who have
failed to respond adequately to conventional therapies. The antiemetic effects are
comparable to conventional therapy such as domperidone [3]. Furthermore, the FDA
approved MarinolTM to treat appetite loss associated with weight reduction in people
with acquired immunodeficiency syndrome (AIDS). It was shown in recent studies
that THC or cannabis preparations have a promising potential as a releasing factor,
in moving disorders and as a pain reducer in patients suffering from multiple
sclerosis. Therefore further research is required.
Worldwide, the use of natural cannabis products for medical purposes is practically
not allowed. In contrast, drugs containing synthetic cannabinoids like dronabinol, a
synthetic THC are often exempt from these restrictions. Synthetic products, however,
have a disadvantage: they do not contain a well-balanced combination of active
substances which can be found in the natural cannabis plant. Patients having
consumed natural cannabinoids for their medical therapy report more adverse effects
after the administration of synthetic cannabis preparations [4, 5]. The principle of
phytotherapy is the treatment with a mixture of bioactive compounds. The idea is that
a complex pathophysiological process can be influenced more effectively and with
fewer adverse effects by a combination of several low-dosage extract compounds
than by a single isolated compound [6]. Therefore, it is important to develop and
clinically investigate oral cannabis extract formulations to prove pharmacodynamic
and pharmacokinetic properties and to compare them with the existing synthetic THC
products and against placebo is important.
The aim in project one of the present work (publication 3, chapter 3.3) was to
approve the performance of an open, randomised, single-center, three-periods crossover
study with different, standardised Cannabis sativa L. extract capsule
formulations and MarinolTM, to analyse the pharmacokinetics and pharmacodynamics
of the cannabinoids and to evaluate the best Cannabis sativa L. extract capsule
formulation in this clinical phase I study for a possible future implementation as a
new, concomitant medication in cancer, HIV and AIDS therapies.
In the first study part, the heating-effect on the relative content of cannabinoids in the
Cannabis sativa L. extract capsule formulation was assessed. Data were compared
to the commercial formulation MarinolTM. The reason for this is that in naturally grown
Cannabis sativa L., up to 95% of the occurring total cannabinoids (THCtot) are in the
form of D9-tetrahydrocannabinolic acid A (THCA-A). By heating, THCA-A is
quantitatively decarboxylised to phenolic THC [7]. Although THCA-A is described as
pharmacologically inactive and devoid of psychotropic effects [7], reports of popular
medicinal use of unheated cannabis or cannabis preparations show pharmacological
effects often accompanied with a lower rate of adverse effects (anecdotal reports). It
also possesses some anti-inflammatory and analgesic effects [8]. Recently, it was
shown that unheated cannabis extracts were able to inhibit tumor necrosis factor
alpha in macrophage culture and peripheral marcrophages after LPS stimulation [9].
In the second study part, the effect of different Cannabis sativa L. extract capsule
formulations, containing different concentrations of TPGS, on the bioavailabilities of
different active cannabinoids was assessed. The reason for this is that the enteral
absorption of cannabinoids under optimal conditions would be up to 95%, but due to
the extensive liver first-pass metabolism and the poor solubility the effective,
measured bioavailability is very low (10-20%) [10]. Further the activity of Pglycoprotein
(P-gp), a membrane efflux transporter also expressed in the intestine,
may reduce the oral bioavailability of cannabinoids. Therefore, it is important to
increase the bioavailabilities of oral drugs with substances possessing absorption
enhancement, drug solubilising and inhibiting effects on P-gp. Previous work has
shown that D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) has an
accelerating effect on gastrointestinal transit and a modulating influence on drug
absorption in humans [11]. A P-gp inhibition could be demonstrated [12-14].
Further study endpoints were a) to assess the relative bioavailabilities of THC and its
metabolites assessed as area under the plasma concentration/time curve from time T
= 0 h extrapolated to infinity (AUC(0-¥)), b) to assess the relative tolerability and
safety of six different oral formulations of 20 mg THCtot (THC and THCA-A), c) to
assess the effect of six different oral formulations of 20 mg THCtot on psychomotor
function assessed as simulator assisted evaluation of driving ability, d) to assess
repetitive heart rate, blood pressure and a visual analogue scale (VAS) for
psychotropic effects.
The pharmacokinetics of the cannabinoids was highly variable between the subjects.
Due to this variability, no statistically significant differences between the AUC of the
different forms could be detected, neither in part I nor in part II of the study. Addition
of different amounts of TPGS resulted in an increase in relative bioavailability of the
sum of cannabinoid metabolites (THC + 11-OH-THC + THC-COOH + CBN) to
122.5% (7.5% TPGS), 134.9% (0.5% TPGS) and 135.9% (5% TPGS) compared with
the AUC of the unheated extract (=100%) in study part I. The administration of
cannabis extracts as well as the addition of TPGS leads to a qualitatively different
pattern of cannabinoid metabolites. After administration of the unheated extract, a
significantly higher proportion of THC AUC and a significantly lower THC-COOH AUC
of all cannabinoids were observed compared to the heated extract or MarinolTM. After
administration of the synthetic MarinolTM, no plasma concentrations of CBD could be
detected. This was expected, since THC is not converted to CBD in vivo and is found
only in cannabis plants. Heating of extracts decreased the proportion of CBD
significantly. The future approach will address further research. Further, clinical
studies with the 0.5% or 5% TPGS Cannabis sativa L. extract capsule formulations
may be helpful. The study should be placebo controlled and later tested in the future
patient group.
In the present work, only the pharmacokinetics of the study are described, evaluated
and discussed. The pharmacodynamic results are reported in two separate
publications.
The aim in project two (publication 1, chapter 3.1) was the development of a sensitive
high-performance liquid chromatographic separation method with tandem-mass
spectrometry detection for the simultaneous detection of THC and its major
metabolites 11-OH-THC and THC-COOH as well as the components CBD and CBN
in human EDTA-plasma and urine. Optimal conditions for the analysis method, such
as extraction procedure, matrices, column, quality controls, wavelength, mobile
phases, run time, optimal separation (gradient, retention times), temperature,
voltages, vacuum and internal standards, resulting in the best sensitivity and
selectivity, were developed in preliminary experiments. The validation of the method
was performed according to the FDA Good Laboratory Practice guidelines,
containing linear measuring range, quantification, lower limit of quantification (LLOQ),
lower limit of detection (LLOD), quality controls, precision, accuracy, recovery,
stability and matrix effects. In conclusion, the described high-performance liquid
chromatographic separation method with tandem-mass spectrometry detection
showed a satisfactory overall analytical performance well suited for applications in
medical science. The combination of SPE/LLE, LC and APCI-MS/MS represents an
attractive alternative to the well-established technique of GC-MS.
In project three (publication 2, chapter 3.2), the sensitivity and specificity of two
immunoassays (CEDIA, FPIA) were established in urinary samples from volunteers
receiving oral synthetic THC or Cannabis sativa L. extracts. Urinary THC-COOH
excretion was evaluated by the immunoassays with a cut-off value of 50 ng/ml as
well as the described LC-MS/MS method (gold standard) with a cut-off value of 15
ng/ml. It was demonstrated that LC-MS/MS is an excellent confirmation method for
immunoassays allowing the qualitative and quantitative detection of many
cannabinoids. The ROC analysis indicated that the FPIA test discriminates better
between users and non-users than the CEDIA test. The results of both
immunoassays show that the National Institute on Drug Abuse (NIDA) set general
immunoassay cut-off of 50 ng/ml is possibly not applicable for analysis of samples
from persons consuming the Cannabis sativa L. extracts orally instead of smoking. It
has to be discussed, whether a lower cut-off value would be advantageous. It is
supposed that metabolite concentrations differ strongly depending on the route of
application. The amount and appearance of different metabolites may disturb the
immunoassay methods. The hydrolysation procedure showed a total transformation
of the THC-COOH-glucuronides to THC-COOH confirmed by the nearly 100%
agreement of the concentrations in the different samples analysed with the two
immunoassays and the LC-MS/MS comparisons. The glucuronide is automatically
detected together with THC-COOH and it is direct de-glucuronated in the APCI unit
of the detector.
The present work is structured into a theoretical and a publication section. The
theoretical section gives an overview about cannabis, mass spectrometry, assay
validation and GLP-guidelines related to the aspects used in the work of this thesis.
The publication section describes the results of the investigations, submitted for
publication to different scientific journals
Community Artists' Collective records (MS 620)
No full textPamphlet containing information about the "Alpha Kappa Omega Chapter of Alpha Kappa Alpha Sorority, Inc Salutes Black History Month Annual Song Fest" taking place on February 19, 1989 at Trinity United Methodist Church in Houston
Development of techniques for high-resolution spatially-resolved elemental analysis in materials of interest in luminescence dating
No full textA series of analytical techniques have been developed to characterise the surface distribution of elements in a number of materials of archaeological interest, in support of current and future research in luminescence dating techniques.
Under certain circumstances, sample heterogeneity, with respect to naturally occurring radionuclides, may significantly reduce the levels of accuracy associated with experimentally determined luminescence dates.
The aim of this thesis is to develop a series of high-resolution, spatially resolved techniques to assess and quantify the degree of matrix (material fabric) radionuclide heterogeneity present in a number of archaeological materials.
Digital analysis and mineralogical staining techniques were combined to provide initial data regarding matrix heterogeneity and the distribution patterns of potassium-bearing minerals and in some cases, provided data that were comparable to those derived from SEM-EDX analyses.
Alpha autoradiographic techniques using solid state nuclear track detectors (CR-39) were applied initially to map localised differences in surface alpha activity, and were subsequently developed to provide semi-quantitative data about the concentration of alpha emitters present, and by association, the likely concentrations of uranium and thorium.
Micro-sampling techniques were developed to produce material for instrumental analysis (ICP-MS and AAS), to provide quantitative information about the concentrations of uranium, thorium and potassium in the areas of interest, highlighted by the application of the aforementioned techniques.
The techniques were successfully applied in a number of case studies, providing both quantitative and qualitative information relating to material characteristics with respect to luminescence dating techniques
alpha-xone/xbbg: Custom config and etc. for reference exchange (author hceh)
No full textIntuitive Bloomberg data AP
Alpha-band rhythms in visual task performance: phase-locking by rhythmic sensory stimulation
No full textOscillations are an important aspect of neuronal activity. Interestingly, oscillatory patterns are also observed in behaviour, such as in visual performance measures after the presentation of a brief sensory event in the visual or another modality. These oscillations in visual performance cycle at the typical frequencies of brain rhythms, suggesting that perception may be closely linked to brain oscillations. We here investigated this link for a prominent rhythm of the visual system (the alpha-rhythm, 8-12 Hz) by applying rhythmic visual stimulation at alpha-frequency (10.6 Hz), known to lead to a resonance response in visual areas, and testing its effects on subsequent visual target discrimination. Our data show that rhythmic visual stimulation at 10.6 Hz: 1) has specific behavioral consequences, relative to stimulation at control frequencies (3.9 Hz, 7.1 Hz, 14.2 Hz), and 2) leads to alpha-band oscillations in visual performance measures, that 3) correlate in precise frequency across individuals with resting alpha-rhythms recorded over parieto-occipital areas. The most parsimonious explanation for these three findings is entrainment (phase-locking) of ongoing perceptually relevant alpha-band brain oscillations by rhythmic sensory events. These findings are in line with occipital alpha-oscillations underlying periodicity in visual performance, and suggest that rhythmic stimulation at frequencies of intrinsic brain-rhythms can be used to reveal influences of these rhythms on task performance to study their functional roles
Event-related alpha suppression in response to facial motion
No full textThis article has been made available through the Brunel Open Access Publishing Fund.While biological motion refers to both face and body movements, little is known about the visual perception of facial motion. We therefore examined alpha wave suppression as a reduction in power is thought to reflect visual activity, in addition to attentional reorienting and memory processes. Nineteen neurologically healthy adults were tested on their ability to discriminate between successive facial motion captures. These animations exhibited both rigid and non-rigid facial motion, as well as speech expressions. The structural and surface appearance of these facial animations did not differ, thus participants decisions were based solely on differences in facial movements. Upright, orientation-inverted and luminance-inverted facial stimuli were compared. At occipital and parieto-occipital regions, upright facial motion evoked a transient increase in alpha which was then followed by a significant reduction. This finding is discussed in terms of neural efficiency, gating mechanisms and neural synchronization. Moreover, there was no difference in the amount of alpha suppression evoked by each facial stimulus at occipital regions, suggesting early visual processing remains unaffected by manipulation paradigms. However, upright facial motion evoked greater suppression at parieto-occipital sites, and did so in the shortest latency. Increased activity within this region may reflect higher attentional reorienting to natural facial motion but also involvement of areas associated with the visual control of body effectors. © 2014 Girges et al
Continuous-cooling alpha-to-gamma transformation behaviour of Ti-45.5 at.% Al-0.05 at.% B alloy
No full textThe continuous-cooling transformation behaviour of Ti - 45.5 at.% Al-0.05 at.% B alloy was quantitatively measured using a real-time resistivity temperature - time measurement apparatus operating under a high vacuum. The addition of a small amount of B does not significantly alter the alpha - gamma-phase equilibria but significantly raises the alpha - gamma lamellar start temperature of Ti - 45.5 at.% Al alloy at most cooling rates. Furthermore, it markedly increases the critical cooling rate for the ordering reaction. The effect of B addition, which greatly stabilizes the lamellar structure up to a fast cooling rate, is to accelerate the lamellar formation kinetics; the lamellar spacing was nevertheless distinctively larger in a B-doped alloy. This is because lamellae in B-doped alloy nucleate heterogeneously on titanium borides at the grain boundary; the borides are effective nucleation sites particularly since local Ti depletion can occur near the interface of the growing titanium borides during cooling. In the absence of B addition, the lamellar structure starts to form only at temperatures below T-0, suggesting that a large undercooling is required for the nucleation of lamellae even at the grain boundaries. On the other hand, the B addition greatly retards the kinetics of the alpha-to-alpha(2) ordering reaction by markedly increasing its critical cooling rate without a large change in the ordering temperature. This is believed to be due to its tendency to segregate strongly to the antiphase boundaries
Sensitivity of DF-ICP-MS, PERALS and alpha-spectrometry for the determination of actinides: A comparison
No full textWe applied three techniques (DF-ICP-MS, PERALS and alpha-spectrometry) for the determination of minor actinides at environmental levels. For each method the limit of detection and the resolution were estimated in order to study the content and isotopic composition of the actinides. Two international reference materials, IAEA-135 (Irish Sea Sediment) and IAEA-300 (Baltic Sea sediment) were analyzed for activity concentrations of 238Pu, 239Pu, 240Pu, 241Pu and 241Am. The sensitivities of the three determination techniques were compared
Amino acid sequence of the alpha subunit and computer modelling of the alpha and beta subunits of echicetin from the venom of Echis carinatus (saw-scaled viper)
No full textEchicetin, a heterodimeric protein from the venom of Echis carinatus, binds to platelet glycoprotein Ib (GPIb) and so inhibits platelet aggregation or agglutination induced by various platelet agonists acting via GPIb. The amino acid sequence of the beta subunit of echicetin has been reported and found to belong to the recently identified snake venom subclass of the C-type lectin protein family. Echicetin alpha and beta subunits were purified. N-terminal sequence analysis provided direct evidence that the protein purified was echicetin. The paper presents the complete amino acid sequence of the alpha subunit and computer models of the alpha and beta subunits. The sequence of alpha echicetin is highly similar to the alpha and beta chains of various heterodimeric and homodimeric C-type lectins. Neither of the fully reduced and alkylated alpha or beta subunits of echicetin inhibited the platelet agglutination induced by von Willebrand factor-ristocetin or alpha-thrombin. Earlier reports about the inhibitory activity of reduced and alkylated echicetin beta subunit might have been due to partial reduction of the protein
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