159 research outputs found
Mode of action of asenapine vs. other antipsychotic drugs : an experimental analysis
Antipsychotic drugs (APDs) are used in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Generally, the so-called atypical APDs, such as clozapine, may in contrast to typical APDs improve not only positive, but also negative symptoms and some aspects of cognitive impairment associated with schizophrenia. However, as also the atypical APDs may be associated with severe side effects such as weight gain, dyslipidemia, increased prolactin levels and even agranulocytosis, the need for novel and improved pharmacotherapy in this area is considerable. This need is underlined by the fact that in recent years, the beneficial effects of low doses of atypical APDs in the treatment of depressive symptoms in uni- as well as bipolar depression have been increasingly recognized.
The APD risperidone is one of the most commonly prescribed APDs in the world. In similarity with clozapine, risperidone has, however to a smaller extent, affinity for α2- adrenoceptors, an effect that otherwise distinguishes clozapine from most other APDs. We therefore examined if additional α2-adrenoceptor blockade could enhance the efficacy of risperidone. The antipsychotic-like effect, extrapyramidal side effect (EPS) liability and effects on critical neurotransmitter systems in the brain were studied. Our data propose that the α2:D2 ratio by risperidone is indeed not optimal and that its antipsychotic-like efficiency can be enhanced by adjunctive treatment with an α2- adrenoceptor antagonist, e.g. idazoxan, allowing for reduced dosage and a subsequent reduced EPS liability, yet with maintained efficacy.
Asenapine is a recently approved APD with a unique receptor binding profile, developed for the treatment of schizophrenia and bipolar disorder. Clinical studies have shown that asenapine possesses, in addition to its effect on psychosis and mania, a well tolerated side effect profile. Using a range of well established preclinical methods we therefore analyzed experimentally the mode of action of asenapine, demonstrating an antipsychotic-like activity, low EPS liability and an atypical profile as regards its effects on critical neurotransmitter systems in the brain. Notably, asenapine increased prefrontal dopamine release and subsequently, via a D1 receptor-mediated mechanism, glutamatergic NMDA-induced transmission in the medial prefrontal cortex (mPFC), mechanisms implicated in cognitive functioning. Moreover, the release of noradrenaline and serotonin was also increased in the mPFC, generally indicating antidepressant activity. The profile of asenapine was shown to be similar in several important aspects to other potent atypical APDs, e.g. clozapine, which is the most efficacious APD presently known, but differs from typical APDs, e.g. haloperidol. It was furthermore shown that differential mechanisms are involved in the effects of asenapine on subcortical and cortical dopamine regulation. These data indicate that the dopamine release in the mPFC may largely depend on an intracortical action. Specifically, asenapine in the mPFC was shown to exhibit a pharmacologically significant 5-HT2A receptor and α2-adrenoceptor antagonistic activity in vivo, which may contribute to the enhanced prefrontal monoamine release.
In other experiments, the combination of low doses of asenapine and the SSRI escitalopram was studied, demonstrating an augmentation of monoaminergic effects of escitalopram as well as facilitation of glutamatergic NMDA- and AMPA receptor- mediated transmission in the mPFC. The results may indicate a mode of action similar to that recently proposed to mediate the rapid and potent antidepressant effects of ketamine and scopolamine. Collectively, our results support, in principle, the clinical utility of adjunctive asenapine in treatment-resistant MDD, and indicate a fast onset of action
Îł-Secretase Dependent Production of Intracellular Domains Is Reduced in Adult Compared to Embryonic Rat Brain Membranes
BACKGROUND: gamma-Secretase is an intramembrane aspartyl protease whose cleavage of the amyloid precursor protein (APP) generates the amyloid beta-peptide (Abeta) and the APP intracellular domain. Abeta is widely believed to have a causative role in Alzheimer's disease pathogenesis, and therefore modulation of gamma-secretase activity has become a therapeutic goal. Besides APP, more than 50 substrates of gamma-secretase with different cellular functions during embryogenesis as well as adulthood have been revealed. Prior to gamma-secretase cleavage, substrates are ectodomain shedded, producing membrane bound C-terminal fragments (CTFs).
PRINCIPAL FINDINGS: Here, we investigated gamma-secretase cleavage of five substrates; APP, Notch1, N-cadherin, ephrinB and p75 neurotrophin receptor (p75-NTR) in membranes isolated from embryonic, young or old adult rat brain by analyzing the release of the corresponding intracellular domains (ICDs) or Abeta40 by western blot analysis and ELISA respectively. The highest levels of all ICDs and Abeta were produced by embryonic membranes. In adult rat brain only cleavage of APP and Notch1 could be detected and the Abeta40 and ICD production from these substrates was similar in young and old adult rat brain. The CTF levels of Notch1, N-cadherin, ephrinB and p75-NTR were also clearly decreased in the adult brain compared to embryonic brain, whereas the APP CTF levels were only slightly decreased.
CONCLUSIONS: In summary our data suggests that gamma-secretase dependent ICD production is down-regulated in the adult brain compared to embryonic brain. In addition, the present approach may be useful for evaluating the specificity of gamma-secretase inhibitors
TITAN's Digital RFQ Ion Beam Cooler and Buncher, Operation and Performance
We present a description of the Radio Frequency Quadrupole (RFQ) ion trap
built as part of the TITAN facility. It consists of a gas-filled, segmented,
linear Paul trap and is the first stage of the TITAN setup with the purpose of
cooling and bunching radioactive ion beams delivered from ISAC-TRIUMF. This is
the first such device to be driven digitally, i.e., using a high voltage
(), wide bandwidth ()
square-wave as compared to the typical sinusoidal wave form. Results from the
commissioning of the device as well as systematic studies with stable and
radioactive ions are presented including efficiency measurements with stable
Cs and radioactive Cs. A novel and unique mode of
operation of this device is also demonstrated where the cooled ion bunches are
extracted in reverse mode, i.e., in the same direction as previously injected.Comment: 34 pages, 17 figure
Semantic IoT Solutions - A Developer Perspective
Semantic technologies have recently gained significant support in a number of communities,
in particular the IoT community. An important problem to be solved is that, on the one hand,
it is clear that the value of IoT increases significantly with the availability of information from
a wide variety of domains. On the other hand, existing solutions target specific applications
or application domains and there is no easy way of sharing information between the
resulting silos. Thus, a solution is needed to enable interoperability across information silos.
As there is a huge heterogeneity regarding IoT technologies on the lower levels, the
semantic level is seen as a promising approach for achieving interoperability (i.e. semantic
interoperability) to unify IoT device description, data, bring common interaction, data
exploration, etc.This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements No.732240 (SynchroniCity) and No. 688467 (VICINITY); from ETSI under Specialist Task Forces 534, 556, 566 and 578. This work is partially funded by Hazards SEES NSF Award EAR 1520870, and KHealth NIH 1 R01 HD087132-01
Towards Semantic Interoperability Standards based on Ontologies
The paper is structured as follows: Section 2 introduces semantic interoperability and its benefits; Section 3 provides industry requirements for semantic interoperability practice; Section 4 describes various initiatives for ontology-driven interoperability; Section 5 explains the various life cycles for ontology-driven interoperability; and finally, Section 6 provides recommendations on ontology-based semantic interoperability.This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements No.732240 (SynchroniCity) and No. 688467 (VICINITY); from ETSI under Specialist Task Forces 534, 556, and 566. This work is partially funded by Hazards SEES NSF Award EAR 1520870, and KHealth NIH 1 R01 HD087132-01
A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology
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