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- Furmark, Tomas, et al.
(författare)
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Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo.
- 2005
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Ingår i: Biol Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 58:2, s. 132-42
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia. METHODS: Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale. RESULTS: Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction. CONCLUSIONS: Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.
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- Eriksson, Mats, et al.
(författare)
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Biotic dynamics and carbonate microfacies of the conspicuous Darriwilian (Middle Ordovician) 'Taljsten' interval, south-central Sweden
- 2012
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Ingår i: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 1872-616X .- 0031-0182. ; 367, s. 89-103
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Tidskriftsartikel (refereegranskat)abstract
- Enclosed in the Darriwilian (Middle Ordovician) part of the reddish 'orthoceratite limestone' of Baltoscandia is a conspicuous c. 1.5 m thick unit colloquially known as the 'Taljsten' interval. It has a wide geographical distribution in the Baltoscandian paleocontinent but is particularly well exposed in south-central Sweden. The unit is characterized by its deviant gray color and beds with a mass occurrence of cystoid echinoderms. Moreover, the recent discovery of an anomalous abundance of extraterrestrial chromite grains and micrometeorites in the 'Taljsten' and immediately adjacent strata bear witness of a time of deposition correlating to an increased influx of extraterrestrial matter to Earth. In this study we analyze the faunal dynamics, based primarily on microfossils and carbonate microfacies, across this intriguing interval. Generally known as a macrolithologically monotonous succession, the 'Taljsten' proved more heterogeneous than previously believed in terms of fossil content and preservation, as well as mineral content and composition. The general texture is wackestone/packstone, but local heterogeneities are frequent. A microfaunal reorganization occurred with a transition from a trilobite- and brachiopod-dominated community to one dominated by echinoderms, which is mirrored also macroscopically by the cystoids. The latter pelmatozoans seem to have flourished and might even have aided in the formation of the numerous hardgrounds. The increase in echinoderms is linked to a Volkhovian increase in echinoderms in eastern Baltica. In the immediate post-'Taljsten' strata there is no distinct change back to the pre-'Taljsten' biota. Conodont and ostracod faunal diversity data reveal peak values in the 'Taljsten' compared to the enclosing strata, suggesting that the paleoenvironment was more suitable for higher diversity faunas of these metazoan groups. All data collectively support a regression in the beginning of the 'Taljsten', likely followed by transgression in its upper part. (C) 2012 Elsevier B.V. All rights reserved.
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- Ribom, Dan, et al.
(författare)
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Positron emission tomography 11C-methionine and survival in patients with low-grade gliomas
- 2001
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Ingår i: Cancer. - 0008-543X .- 1097-0142. ; 92:6, s. 1541-1549
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDConsiderable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the 11C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2.METHODSThe authors identified 89 patients with histologically confirmed low-grade gliomas in whom an 11C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The 11C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses.RESULTSAt the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, 11C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake.CONCLUSIONSBaseline 11C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.
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- Tehler, Ulrika, et al.
(författare)
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Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:6, s. 2690-2694
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Tidskriftsartikel (refereegranskat)abstract
- Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.
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- Wechalekar, Ashutosh, et al.
(författare)
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Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis : an open-label Phase 2 study and an adjunctive immuno-PET imaging study
- 2022
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Ingår i: BMC Cardiovascular Disorders. - : BioMed Central (BMC). - 1471-2261 .- 1471-2261. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. Methods Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received <= 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), <= 2 doses of non-radiolabelled dezamizumab plus [Zr-89]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [Zr-89]Zr-dezamizumab cardiac uptake assessed via PET. Results Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [Zr-89]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. Conclusions Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).
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- Wymenga, Feng, et al.
(författare)
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Uptake of 14C- and 11C-labeled glutamate, glutamine and aspirtate in vitro and in vivo
- 2000
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 20:1A, s. 251-256
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Tidskriftsartikel (refereegranskat)abstract
- To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in tumor cell aggregates, in vivo in rats and a few pilot studies with positron emission tomography (PET) in patients. The uptake in aggregates increased linearly with time, and was competitively inhibited by the same amino acids. The uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L-norleucine (a glutamine analogue) and Substance P had different effect on the uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was evaluated with protein separation and with HPLC. The in vivo distribution in rats showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas had the highest uptake followed by kidney with 11C-glutamate, and followed by spleen with 11C-aspartate. A primary pancreas tumour and metastases in liver were difficult to identify except in one case.
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| 22. |
- Örlefors, Håkan
(författare)
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Positron Emission Tomography in the Management of Neuroendocrine Tumors
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine tumors (NET´s) are often characterized by overproduction of peptide hormones. In spite of pronounced clinical symptoms, the tumor lesions can be small and difficult to detect. The general aim of this thesis was to investigate, in vitro and in vivo, some of the potential monoamine pathways present in NET´s, using radiolabeled tracers for positron emission tomography (PET), with the intention to explore the value of PET-imaging in the management of NET´s. We used the 11C-labeled serotonin precursor 5-hydroxy tryptophan (HTP) as the tracer for imaging of NET´s. More than 95% of the subjects displayed a high tracer uptake on PET and tumor detection rate with PET was higher in >50% of the patients compared both to computed tomography (CT) and somatostatin receptor scintigraphy (SRS). The primary tumor was imaged by PET in 84% (16/19), compared to 47% and 42% for SRS and CT, respectively. Tumor visibility was better with PET due to a higher tumor-to-background ratio and a better spatial resolution. There was a strong correlation (r = .907) between changes in urinary-5-hydroxy indole acetic acid and changes in transport rate of 11C-5-HTP during treatment, indicating the use of PET in treatment monitoring of NET´s. Pretreatment with carbidopa decreased the urinary radioactivity concentration four-fold and significantly (p<0.001) increased the tumor tracer uptake. This greatly improved image interpretation and tumor lesion detection. A screening for expression of monoamine pathways in NET´s revealed a high in vitro binding of the monoamineoxidase-A ligand harmine to tumor sections. PET examinations with 11C-harmine could visualize tumors in all patients, including non-functioning endocrine pancreatic tumors (EPT´s). Finally, the in vitro turnover and in vivo distribution of the amino acids glutamate, glutamine and aspartate was investigated. Limited uptake in vivo indicates the lack of utility for these substances as PET-tracers for imaging and characterization of NET´s.
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