1.
Hall, Håkan, et al.
(författare)
In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting
2012
Ingår i: American Journal of Nuclear Medicine and Molecular Imaging. - 2160-8407. ; 2:2, s. 141-150
Tidskriftsartikel (refereegranskat) abstract
The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with (67)Ga or (68)Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of (67/68)Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using (67)Ga and SPECT or (68)Ga and PET.
2.
Rask-Andersen, Mathias, et al.
(författare)
Advances in kinase targeting : current clinical use and clinical trials
2014
Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
Forskningsöversikt (refereegranskat) abstract
Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
3.
Stan, Tiberiu Loredan, et al.
(författare)
Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis
2024
Ingår i: Neurotherapeutics. - : Elsevier. - 1878-7479 .- 1933-7213. ; 21:2, s. 1-12
Tidskriftsartikel (refereegranskat) abstract
Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.
4.
van West, Dirk, et al.
(författare)
Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression
2006
Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 31:3, s. 620-627
Tidskriftsartikel (refereegranskat) abstract
Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.
5.
Svensberg, Karin, et al.
(författare)
Nordic Pharmacy Students' Opinions of their Patient Communication Skills Training
2018
Ingår i: American Journal of Pharmaceutical Education. - : American Association of Colleges of Pharmacy (AACP). - 0002-9459 .- 1553-6467. ; 82:2, s. 152-165
Tidskriftsartikel (refereegranskat) abstract
Objective. To describe Nordic pharmacy students' opinions of their patient communication skills training (PCST), and the association between course leaders' reports of PCST qualities and students' perceptions of their training. Secondary objective was to determine what factors influence these associations. Methods. A cross-sectional questionnaire-based study was performed. The various curricula were categorized into three types (basic, intermediate and innovative training) and students were divided into three groups according to the type of training they had received. Multivariable logistic regression models were fitted with different opinions as outcomes and three types of training as exposure, using generalized estimation equations. Results. There were 370 students who responded (response rate: 77%). Students within the innovative group were significantly more likely to agree that they had received sufficient training, and to agree with the assertion that the pharmacy school had contributed to their level of skills compared to students in the basic group. Conclusion. There appears to be an association between larger and varied programs of training in patient communication skills and positive attitudes toward this training on the part of the students, with students reporting that they received sufficient training, which likely enhanced their skills.
6.
Marwaha, Sania, et al.
(författare)
N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis
2014
Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 58:5, s. 2968-2971
Tidskriftsartikel (refereegranskat) abstract
Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.
7.
Horvath, Istvan, et al.
(författare)
Immunochemical Detection of alpha-Synuclein Autoantibodies in Parkinson's Disease : Correlation between Plasma and Cerebrospinal Fluid Levels
2017
Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 8:6, s. 1170-1176
Tidskriftsartikel (refereegranskat) abstract
Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, a-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of a-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of a-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF a-synuclein antibody levels for mild, moderate, and combined PD groups. This indicates the potentiality of a-synuclein antibodies as PD biomarker and the increased diagnostic power of their simultaneous analysis in plasma and CSF.
8.
Löfgren, Magnus, 1979-, et al.
(författare)
The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats
2019
Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 76
Tidskriftsartikel (refereegranskat) abstract
The progesterone metabolite, allopregnanolone (AlloP), is a GABA(A) receptor modulating steroid and is known to have orexigenic and pro-obesity effects. The neurobiological mechanisms underpinning these effects are most likely due to enhanced GABAergic signaling in the lateral arcuate nucleus (ARC) and medial paraventricular nucleus (PVN) of the hypothalamus. Inspired by the finding that GABAergic signaling is also important for the orexigenic effects of the circulating hormone, ghrelin, we sought to determine the extent to which AlloP (one of the most potent endogenous GABA(A)-receptor modulators) operates alongside ghrelin to enhance food intake. Male rats with ad libitum access to standard chow were injected intravenously with AlloP and/or ghrelin, alone or in combination. The intake of the standard chow was greater after AlloP 1 mg/kg together with ghrelin 30 mu g/kg than with 30 mu g/kg ghrelin alone. Food intake was also increased for the combined treatment of AlloP 0.5 mg/kg + ghrelin 10 mu g/kg, AlloP 1 mg/kg + ghrelin 10 mu g/kg, and AlloP 0.5 mg/kg + ghrelin 30 mu g/kg. There was no significant difference in food intake between the two ghrelin doses or between the two doses of AlloP and the vehicle. In electrophysiological studies, physiologically relevant concentrations of AlloP prolonged the current decay time of spontaneous inhibitory post-synaptic current of dissociated cells of the ARC and PVN. We conclude that AlloP enhances the hyperphagic effect of ghrelin, findings of potential relevance for the hyperphagia associated with the luteal phase of the reproductive cycle.
9.
Makatini, Maya M., et al.
(författare)
Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease
2011
Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:8, s. 2274-2277
Tidskriftsartikel (refereegranskat) abstract
In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC50 activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.
10.
Nevalainen, Nina, 1984-
(författare)
Dysfunction in the nigrostriatal system : effects of L-DOPA and GDNF
2013
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.
