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1.	Ackley, K., et al. (author) Observational constraints on the optical and near-infrared emission from the neutron star-black hole binary merger candidate S190814bv 2020 In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 643 Journal article (peer-reviewed)abstract Context. Gravitational wave (GW) astronomy has rapidly reached maturity, becoming a fundamental observing window for modern astrophysics. The coalescences of a few tens of black hole (BH) binaries have been detected, while the number of events possibly including a neutron star (NS) is still limited to a few. On 2019 August 14, the LIGO and Virgo interferometers detected a high-significance event labelled S190814bv. A preliminary analysis of the GW data suggests that the event was likely due to the merger of a compact binary system formed by a BH and a NS.Aims. In this paper, we present our extensive search campaign aimed at uncovering the potential optical and near infrared electromagnetic counterpart of S190814bv. We found no convincing electromagnetic counterpart in our data. We therefore use our non-detection to place limits on the properties of the putative outflows that could have been produced by the binary during and after the merger.Methods. Thanks to the three-detector observation of S190814bv, and given the characteristics of the signal, the LIGO and Virgo Collaborations delivered a relatively narrow localisation in low latency - a 50% (90%) credible area of 5 deg(2) (23 deg(2)) - despite the relatively large distance of 26752 Mpc. ElectromagNetic counterparts of GRAvitational wave sources at the VEry Large Telescope collaboration members carried out an intensive multi-epoch, multi-instrument observational campaign to identify the possible optical and near infrared counterpart of the event. In addition, the ATLAS, GOTO, GRAWITA-VST, Pan-STARRS, and VINROUGE projects also carried out a search on this event. In this paper, we describe the combined observational campaign of these groups.Results. Our observations allow us to place limits on the presence of any counterpart and discuss the implications for the kilonova (KN), which was possibly generated by this NS-BH merger, and for the strategy of future searches. The typical depth of our wide-field observations, which cover most of the projected sky localisation probability (up to 99.8%, depending on the night and filter considered), is r similar to 22 (resp. K similar to 21) in the optical (resp. near infrared). We reach deeper limits in a subset of our galaxy-targeted observations, which cover a total similar to 50% of the galaxy-mass-weighted localisation probability. Altogether, our observations allow us to exclude a KN with large ejecta mass M greater than or similar to 0.1 M-circle dot to a high (> 90%) confidence, and we can exclude much smaller masses in a sub-sample of our observations. This disfavours the tidal disruption of the neutron star during the merger.Conclusions. Despite the sensitive instruments involved in the campaign, given the distance of S190814bv, we could not reach sufficiently deep limits to constrain a KN comparable in luminosity to AT 2017gfo on a large fraction of the localisation probability. This suggests that future (likely common) events at a few hundred megaparsecs will be detected only by large facilities with both a high sensitivity and large field of view. Galaxy-targeted observations can reach the needed depth over a relevant portion of the localisation probability with a smaller investment of resources, but the number of galaxies to be targeted in order to get a fairly complete coverage is large, even in the case of a localisation as good as that of this event.
2.	Bengtsson, H. Jörgen, et al. (author) Interaction of the antidepressant mirtazapine with alpha2-adrenoceptors modulating the release of 5-HT in different rat brain regions in vivo. 2000 In: Naunyn-Schmiedeberg's archives of pharmacology. - 0028-1298. ; 362:4-5, s. 406-12 Journal article (peer-reviewed)abstract Mirtazapine (MIR) is a novel antidepressant, reported to raise extracellular noradrenaline (NA) through blockade of alpha2-autoreceptors and serotonin (5-HT) output via (1) indirect activation of facilitatory alpha1-adrenoceptors on the cell bodies of ascending 5-HT neurones and (2) blockade of presynaptic release-modulating alpha2-heteroreceptors on 5-HT terminals in the forebrain. To further assess the effect of MIR on NA/5-HT system interplay, including putative regional differences in the effects of the drug on 5-HT release in rat forebrain, we used in vivo microdialysis in anaesthetised rats. Probes were implanted in the dorsal hippocampus (DH) and frontal cortex (FCx), representing median and dorsal raphe 5-HT projection areas, respectively. In the DH, MIR (10 mg/kg s.c.) completely blocked the 5-HT release-suppressing action of the selective alpha2-adrenoceptor agonist clonidine (0.1 mg/kg s.c.), but had no effect per se on the 5-HT output. Neither drug significantly changed the 5-HT levels in the FCx. MIR perfused locally (10 microM via reverse-dialysis) also failed to significantly elevate 5-HT output, and did not affect the clonidine response in either brain area. Thus, the data confirm the basic alpha2-adrenoceptor-blocking properties of MIR, but are only partly concordant with previous studies reporting an increase of 5-HT output after MIR alone. Moreover, we find no elevation in 5-HT by the reference alpha2-adrenoceptor antagonist idazoxan (0.3-1.0 mg/kg s.c.). The discrepancies encountered, and the potential ability of alpha2-adrenoceptor antagonists in general to raise the output of 5-HT, are discussed with particular reference to methodological and other factors that may influence the experimental outcome (e.g., brain regional aspects, different alpha2-adrenoceptor subtypes, potential differences in adrenoceptor tone under varying experimental conditions).
3.	Bjursell, Mikael, 1977, et al. (author) Deletion of Gpr55 Results in Subtle Effects on Energy Metabolism, Motor Activity and Thermal Pain Sensation 2016 In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12 Journal article (peer-reviewed)abstract The G-protein coupled receptor 55 (GPR55) is activated by cannabinoids and non-cannabinoid molecules and has been speculated to play a modulatory role in a large variety of physiological and pathological processes, including in metabolically perturbed states. We therefore generated male mice deficient in the gene coding for the cannabinoid/lysophosphatidylinositol (LPI) receptor Gpr55 and characterized them under normal dietary conditions as well as during high energy dense diet feeding followed by challenge with the CB1 receptor antagonist/GPR55 agonist rimonabant. Gpr55 deficient male mice (Gpr55 KO) were phenotypically indistinguishable from their wild type (WT) siblings for the most part. However, Gpr55 KO animals displayed an intriguing nocturnal pattern of motor activity and energy expenditure (EE). During the initial 6 hours of the night, motor activity was significantly elevated without any significant effect observed in EE. Interestingly, during the last 6 hours of the night motor activity was similar but EE was significantly decreased in the Gpr55 KO mice. No significant difference in motor activity was detected during daytime, but EE was lower in the Gpr55 KO compared to WT mice. The aforementioned patterns were not associated with alterations in energy intake, daytime core body temperature, body weight (BW) or composition, although a non-significant tendency to increased adiposity was seen in Gpr55 KO compared to WT mice. Detailed analyses of daytime activity in the Open Field paradigm unveiled lower horizontal activity and rearing time for the Gpr55 KO mice. Moreover, the Gpr55 KO mice displayed significantly faster reaction time in the tail flick test, indicative of thermal hyperalgesia. The BW-decreasing effect of rimonabant in mice on long-term cafeteria diet did not differ between Gpr55 KO and WT mice. In conclusion, Gpr55 deficiency is associated with subtle effects on diurnal/nocturnal EE and motor activity behaviours but does not appear per se critically required for overall metabolism or behaviours.
4.	Bogren, Mats, et al. (author) Remission of Persistent Negative Symptoms and Psychosocial Consequences by Combined Clozapine and Cariprazine Treatment in a Patient With Long-Standing Treatment-Resistant Schizoaffective Disorder 2022 In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 13 Journal article (peer-reviewed)abstract This patient case report describes a 45-year old white unmarried man with disability pension due to schizoaffective disorder, diagnosed at the age of 24. He lives in an apartment and has housing support. Retrospectively, the patient displayed prodromal markers of a disorder within the schizophrenia spectrum many years before the onset of frank psychosis, indeed since childhood. Over the years several symptoms and signs across schizophrenia domains have been manifest: positive, negative, cognitive, and affective, among which the negative and affective symptoms and signs were the earliest to appear. While the positive, disorganized, and catatonic symptoms responded to treatment – when duly tested and complied with – the negative and affective symptoms have been notoriously difficult to handle. We now report on the successful introduction of cariprazine (CAR) to his ongoing clozapine (CLZ) medication, the result of which has been a near-complete remission of his persistent negative and psychosocial issues. We interpret this remarkable alleviation of the patient's disease – and concomitant improvement of his quality of life – in terms of neuroreceptor target complementarity between CLZ and CAR, with particular emphasis on the contributions from the D3 and D2 receptor partial agonist components of the latter agent.
5.	Bohlooly-Yeganeh, Mohammad, 1966, et al. (author) Osteoporosis in MCHR1-deficient mice. 2004 In: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 318:4, s. 964-9 Journal article (peer-reviewed)abstract It is well recognized that the hypothalamus is of central importance in the regulation of food intake and fat mass. Recent studies indicate that it also plays an important role in the regulation of bone mass. Melanin concentrating hormone (MCH) is highly expressed in the hypothalamus and has been implicated in regulation of energy homeostasis. We developed MCHR1 inactivated mice to evaluate the physiological role of this receptor. Interestingly, the MCHR1(-/-) mice have osteoporosis, caused by a reduction in the cortical bone mass, while the amount of trabecular bone is unaffected. The reduction in cortical bone mass is due to decreased cortical thickness. Serum levels of c-telopeptide, a marker of bone resorption, are increased in MCHR1(-/-) mice, indicating that the MCHR1(-/-) mice have a high bone turnover osteoporosis. In conclusion, the MCHR1(-/-) mice have osteoporosis, indicating that MCHR1-signalling is involved in a tonic stimulation of bone mass.
6.	Carlsson, Lena M S, 1957, et al. (author) Long-term incidence of microvascular disease after bariatric surgery or usual care in patients with obesity, stratified by baseline glycaemic status: a post-hoc analysis of participants from the Swedish Obese Subjects study. 2017 In: The lancet. Diabetes & endocrinology. - 2213-8595. ; 5:4, s. 271-279 Journal article (peer-reviewed)abstract Bariatric surgery is associated with remission of diabetes and prevention of diabetic complications in patients with obesity and type 2 diabetes. Long-term effects of bariatric surgery on microvascular complications in patients with prediabetes are unknown. The aim of this study was to examine the effects of bariatric surgery on incidence of microvascular complications in patients with obesity stratified by baseline glycaemic status.Patients were recruited to the Swedish Obese Subjects (SOS) study between Sept 1, 1987, and Jan 31, 2001. Inclusion criteria were age 37-60 years and BMI of 34 kg/m(2) or greater in men and 38 kg/m(2) or greater in women. Exclusion criteria were identical in surgery and control groups and designed to exclude patients not suitable for surgery. The surgery group (n=2010) underwent gastric bypass (265 [13%]), gastric banding (376 [19%]), or vertical-banded gastroplasty (1369 [68%]). Participants in the control group (n=2037) received usual care. Bodyweight was measured and questionnaires were completed at baseline and at 0·5 years, 1 year, 2 years, 3 years, 4 years, 6 years, 8 years, 10 years, 15 years, and 20 years. Biochemical variables were measured at baseline and at 2 years, 10 years, and 15 years. We categorised participants into subgroups on the basis of baseline glycaemic status (normal [fasting blood glucose concentration <5·0 mmol/L], prediabetes [5·0-6·0 mmol/L], screen-detected diabetes [≥6·1 mmol/L at baseline visit without previous diagnosis], and established diabetes [diagnosis of diabetes before study inclusion]). We obtained data about first incidence of microvascular disease from nationwide registers and about diabetes incidence at study visits at 2 years, 10 years, and 15 years. We did the main analysis by intention to treat, and subgroup analyses after stratification by baseline glycaemic status and by diabetes status at the 15 year follow-up. The SOS study is registered with ClinicalTrials.gov, NCT01479452.4032 of the 4047 participants in the SOS study were included in this analysis. We excluded four patients with suspected type 1 diabetes, and 11 patients with unknown glycaemic status at baseline. At baseline, 2838 patients had normal blood glucose, 591 had prediabetes, 246 had screen-detected diabetes, and 357 had established diabetes. Median follow-up was 19 years (IQR 16-21). We identified 374 incident cases of microvascular disease in the control group and 224 in the surgery group (hazard ratio [HR] 0·56, 95% CI 0·48-0·66; p<0·0001). Interaction between baseline glycaemic status and effect of treatment on incidence of microvascular disease was significant (p=0·0003). Unadjusted HRs were lowest in the subgroup with prediabetes (0·18, 95% CI 0·11-0·30), followed by subgroups with screen-detected diabetes (0·39, 0·24-0·65), established diabetes (0·54, 0·40-0·72), and normoglycaemia (0·63, 0·48-0·81). Surgery was associated with reduced incidence of microvascular events in people with prediabetes regardless of whether they developed diabetes during follow-up.Bariatric surgery was associated with reduced risk of microvascular complications in all subgroups, but the greatest relative risk reduction was observed in patients with prediabetes at baseline. Our results suggest that prediabetes should be treated aggressively to prevent future microvascular events, and effective non-surgical treatments need to be developed for this purpose.US National Institutes of Health, Swedish Research Council, Sahlgrenska University Hospital Regional Agreement on Medical Education and Research, and Swedish Diabetes Foundation.
7.	Carlsson, Lena M S, 1957, et al. (author) Long-term incidence of serious fall-related injuries after bariatric surgery in Swedish obese subjects. 2019 In: International journal of obesity (2005). - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 43:4, s. 933-937 Journal article (peer-reviewed)abstract Obesity increases risk of falling, but the effect of bariatric surgery on fall-related injuries is unknown. The aim of this study was therefore to study the association between bariatric surgery and long-term incidence of fall-related injuries in the prospective, controlled Swedish Obese Subjects study. At inclusion, body mass index was≥34kg/m2 in men and ≥38kg/m2 in women. The surgery per-protocol group (n=2007) underwent gastric bypass (n=266), banding (n=376), or vertical banded gastroplasty (n=1365), and controls (n=2040) received usual care. At the time of analysis (31 December 2013), median follow-up was 19 years (maximal 26 years). Fall-related injuries requiring hospital treatment were captured using data from the Swedish National Patient Register. During follow-up, there were 617 first-time fall-related injuries in the surgery group and 513 in the control group (adjusted hazard ratio 1.21, 95% CI, 1.07-1.36; P=0.002). The incidence differed between treatment groups (P<0.001, log-rank test) and was higher after gastric bypass than after usual care, banding and vertical banded gastroplasty (adjusted hazard ratio 0.50-0.52, P<0.001 for all three comparisons). In conclusion, gastric bypass surgery was associated with increased risk of serious fall-related injury requiring hospital treatment.
8.	Gabrielsson, Johan, et al. (author) Dose-Response-Time Data Analysis: An Underexploited Trinity 2019 In: Pharmacological Reviews. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0081 .- 0031-6997. ; 71:1, s. 89-122 Research review (peer-reviewed)abstract The most common approach to in vivo pharmacokinetic and pharmacodynamic analyses involves sequential analysis of the plasma concentration-and response-time data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, in situations when plasma sampling may jeopardize the effect measurements or is scarce, nonexistent, or unlinked to the effect (e.g., in intensive care units, pediatric or frail elderly populations, or drug discovery), focusing on the response-time course alone may be an adequate alternative for pharmacodynamic analyses. Response-timedata inherently contain useful information about the turnover characteristics of response (target turnover rate, half-life of response), as well as the drug's biophase kinetics (biophase availability, absorption half-life, and disposition half-life) pharmacodynamic properties (potency, efficacy). The use of pharmacodynamic time-response data circumvents the need for a direct assay method for the drug and has the additional advantage of being applicable to cases of local drug administration close to its intended targets in the immediate vicinity of target, or when target precedes systemic plasma concentrations. This review exemplifies the potential of biophase functions in pharmacodynamic analyses in both preclinical and clinical studies, with the purpose of characterizing response data and optimizing subsequent study protocols. This article illustrates crucial determinants to the success of modeling dose-response-time (DRT) data, such as the dose selection, repeated dosing, and different input rates and routes. Finally, a literature search was also performed to gauge how frequently this technique has been applied in preclinical and clinical studies. This review highlights situations in which DRT should be carefully scrutinized and discusses future perspectives of the field.
9.	Gabrielsson, Johan, et al. (author) In vivo potency revisited - Keep the target in sight 2018 In: Pharmacology & Therapeutics. - : Elsevier BV. - 0163-7258 .- 1879-016X. ; 184, s. 177-188 Journal article (peer-reviewed)abstract Potency is a central parameter in pharmacological and biochemical sciences, as well as in drug discovery and development endeavors. It is however typically defined in terms only of ligand to target binding affinity also in in vivo experimentation, thus in a manner analogous to in in vitro studies. As in vivo potency is in fact a conglomerate of events involving ligand, target, and target-ligand complex processes, overlooking some of the fundamental differences between in vivo and in vitro may result in serious mispredictions of in vivo efficacious dose and exposure. The analysis presented in this paper compares potency measures derived from three model situations. Model A represents the closed in vitro system, defining target binding of a ligand when total target and ligand concentrations remain static and constant. Model B describes an open in vivo system with ligand input and clearance (Cl-(L)),a adding in parallel to the turnover (k(syn), k(deg)) of the target. Model C further adds to the open in vivo system in Model B also the elimination of the target-ligand complex (km) via a first-order process. We formulate corresponding equations of the equilibrium (steady-state) relationships between target and ligand, and complex and ligand for each of the three model systems and graphically illustrate the resulting simulations. These equilibrium relationships demonstrate the relative impact of target and target-ligand complex turnover, and are easier to interpret than the more commonly used ligand-, target- and complex concentration-time courses. A new potency expression, labeled L-50, is then derived. L-50 is the ligand concentration at half-maximal target and complex concentrations and is an amalgamation of target turnover, target-ligand binding and complex elimination parameters estimated from concentration-time data. L-50 is then compared to the dissociation constant K-d (target-ligand binding affinity), the conventional Black & Leff potency estimate EC50, and the derived Michaelis-Menten parameter K-m (target-ligand binding and complex removal) across a set of literature data. It is evident from a comparison between parameters derived from in vitro vs. in vivo experiments that L-50 can be either numerically greater or smaller than the K-d (or K-m,) parameter, primarily depending on the ratio of k(deg)-to-k(e(RL)). Contrasting the limit values of target R and target-ligand complex RL for ligand concentrations approaching infinity demonstrates that the outcome of the three models differs to a great extent. Based on the analysis we propose that a better understanding of in vivo pharmacological potency requires simultaneous assessment of the impact of its underlying determinants in the open system setting. We propose that L-50 will be a useful parameter guiding predictions of the effective concentration range, for translational purposes, and assessment of in vivo target occupancy/suppression by ligand, since it also encompasses target turnover - in turn also subject to influence by pathophysiology and drug treatment. Different compounds may have similar binding affinity for a target in vitro (same K-d), but vastly different potencies in vivo. L-50 points to what parameters need to be taken into account, and particularly that closed-system (in vitro) parameters should not be first choice when ranking compounds in vivo (open system).
10.	Gabrielsson, Johan, et al. (author) Lost in translation: What's in an EC50? Innovative PK/PD reasoning in the drug development context 2018 In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 835, s. 154-161 Journal article (peer-reviewed)abstract Translation across species and from in vitro to in vivo is a central tenet in drug discovery pharmacology. Successful implementation requires proper assessment of both in vivo potency and efficacy. This notwithstanding, in vivo data is typically defined mostly in terms of ligand-to-target binding affinity, similar to in vitro studies. As in vivo potency and efficacy involve a combination not only of drug, but also partitioning, target, and drug-target-complex events and processes, ignoring some of the central differences between in vivo and in vitro may result in serious miscalculations of in vivo efficacious exposure for translational predictions. We compare potency measures derived from two basic pharmacodynamic model situations: A 'closed' in vitro system defining target binding of a ligand when both concentrations remain essentially static, and an 'open' in vivo system where target turnover dynamics and elimination of the drug-target complex are also included. Corresponding equilibrium (steady-state) expressions in the central pharmacokinetic compartment are derived and presented. Three representative variants of 'open' in vivo systems are discussed, showing relationships for ligand-target complex and ligand for each of the systems and graphically illustrating corresponding shapes. The examples include i) two ligands competing for one target, ii) two targets competing for one ligand (/drug), and iii) target-ligand (/drug) interactions in a peripheral PK compartment. The expanded in vivo potency EC50 expression emphasises the contribution from target-related biology parameters that need accounting for, and particularly that 'closed' system (in vitro) properties should not be first choice when ranking compounds in vivo ('open' system).
11.	Gabrielsson, Johan, et al. (author) Pattern Recognition in Pharmacodynamic Data Analysis 2016 In: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 18:1, s. 64-91 Journal article (peer-reviewed)abstract Pattern recognition is a key element in pharmacodynamic analyses as a first step to identify drug action and selection of a pharmacodynamic model. The essence of this process is going from data to insight through exploratory data analysis. There are few formal strategies that scientists typically use when the experiment has been done and data collected. This report attempts to ameliorate this deficit by identifying the properties of a pharmacodynamic model via dissection of the pattern revealed in response-time data. Pattern recognition in pharmacodynamic analyses contrasts with pharmacokinetic analyses with respect to time course. Thus, the time course of drug in plasma usually differs markedly from the time course of the biomarker response, as a consequence of a myriad of interactions (transport to biophase, binding to target, activation of target and downstream mediators, physiological response, cascade and amplification of biosignals, homeostatic feedback) between the events of exposure to test compound and the occurrence of the biomarker response. Homing in on this important—but less often addressed—element, 20 datasets of varying complexity were analyzed, and from this, we summarize a set of points to consider, specifically addressing baseline behavior, number of phases in the response-time course, time delays between concentration- and response-time courses, peak shifts in response with increasing doses, saturation, and other potential nonlinearities. These strategies will hopefully give a better understanding of the complete pharmacodynamic response-time profile. © 2015, American Association of Pharmaceutical Scientists.
12.	Gall, Christa, et al. (author) Lanthanides or Dust in Kilonovae : Lessons Learned from GW170817 2017 In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 849:2 Journal article (peer-reviewed)abstract The unprecedented optical and near-infrared lightcurves of the first electromagnetic counterpart to a gravitationalwave source, GW170817, a binary neutron star merger, exhibited a strong evolution from blue to near-infrared (a so-called kilonova or macronova). The emerging near-infrared component is widely attributed to the formation of r-process elements that provide the opacity to shift the blue light into the near-infrared. An alternative scenario is that the light from the blue component gets extinguished by dust formed by the kilonova and subsequently is reemitted at near-infrared wavelengths. We test here this hypothesis using the lightcurves of AT 2017gfo, the kilonova accompanying GW170817. We find that of the order of 10(-5) M-circle dot. of carbon is required to reproduce the optical/near-infrared lightcurves as the kilonova fades. This putative dust cools from similar to 2000. K at similar to 4 days after the event to similar to 1500 K over the course of the following week, thus requiring dust with a high condensation temperature, such as carbon. We contrast this with the nucleosynthetic yields predicted by a range of kilonova wind models. These suggest that at most 10(-9) M-circle dot of carbon is formed. Moreover, the decay in the inferred dust temperature is slower than that expected in kilonova models. We therefore conclude that in current models of the blue component of the kilonova, the near-infrared component in the kilonova accompanying GW170817 is unlikely to be due to dust.
13.	Gennemark, Peter, 1974, et al. (author) Modeling energy intake by adding homeostatic feedback and drug intervention 2015 In: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 42:1, s. 79-96 Journal article (peer-reviewed)abstract Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both acute and chronic settings. A drug mechanism function inhibits (or stimulates) EI. The deviation of EI relative to a reference level (set-point) serves as input to a non-linear appetite control signal which in turn impacts EI in parallel to the drug intervention. Three examples demonstrate the potential usefulness of the model in both acute and chronic dosing situations. The model shifts the predicted concentration-response relationship rightwardly at lower concentrations, in contrast to models that do not handle functional adaptation. A fourth example further shows that the model may qualitatively explain differences in rate and extent of adaptation in observed EI and its concomitants in both rodents and humans.
14.	Hjorth, Stephan, 1953, et al. (author) (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752)-a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent 2020 In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:3, s. 404-419 Journal article (peer-reviewed)abstract Here we describe for the first time the distinctive pharmacological profile for (35)-3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mu mol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypo-activity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to similar to 250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to similar to 250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptannine 7 receptor and alpha 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on cate-cholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
15.	Hjorth, Stephan, 1953 (author) Looking back (and in)to the future: A personal reflection on 'Serotonin autoreceptor function and antidepressant drug action' (Hjorth et al.2000) 2016 In: Journal of Psychopharmacology. - : SAGE Publications. - 0269-8811 .- 1461-7285. ; 30:11, s. 1129-1136 Journal article (peer-reviewed)abstract Our article in this journal some 15 years ago focussed on the role of serotonin (5-HT) autoreceptors in the mechanism of action of antidepressant drugs. Specifically in this regard, the results were summarised of rat microdialysis studies carried out to examine: (a) the relative importance of 5-HT1A and 5-HT1B autoreceptors, including (b) possible regional variation, and (c) potential changes in autoreceptor responsiveness following chronic selective serotonin reuptake inhibitor administration. In the present reflection piece, I recap some of the key findings against a brief background and provide an account of their bearing within the context of subsequent endeavours in the antidepressant drug research and development field. I conclude by shortly commenting on selected topics relevant to novel, interesting advances and avenues for future research. © The Author(s) 2016.
16.	Hjorth, Stephan, 1953, et al. (author) Reoperations After Bariatric Surgery in 26 Years of Follow-up of the Swedish Obese Subjects Study. 2019 In: JAMA surgery. - : American Medical Association (AMA). - 2168-6262 .- 2168-6254. ; 154:4, s. 319-326 Journal article (peer-reviewed)abstract Bariatric surgery is an established treatment for obesity, but knowledge on the long-term incidence of revisional surgery is scarce.To determine the incidence and type of revisional surgery after bariatric surgery in 26 years of follow-up of participants in the Swedish Obese Subjects (SOS) study.The SOS study is a prospective nonrandomized controlled study comparing bariatric surgery (banding, vertical banded gastroplasty [VBG], and gastric bypass [GBP]) with usual care. The bariatric surgeries in the SOS study were conducted at 25 public surgical departments in Sweden. Men with body mass index values of 34 or higher and women with body mass indexes of 38 or higher were recruited to the surgery group of the SOS study between September 1, 1987, and January 31, 2001, and follow-up continued until December 31, 2014. Data analysis occurred from November 2016 to April 2018.Banding, VBG, or GBP.Revisional surgeries, analyzed using data from questionnaires, hospital records, and the Swedish National Patient register through December 31, 2014.A total of 2010 participants underwent surgery. The age range was 37 to 60 years. A total of 376 participants underwent banding (18.7%), while 1365 had VBG (67.9%) and 266 had GBP (13.2%). During a median follow-up of 19 years, 559 participants (27.8%) underwent first-time revisional surgery, including 354 conversions to other bariatric procedures (17.6%), 114 corrective surgeries (5.6%), and 91 reversals to normal anatomy (4.5%). Revisional surgeries (conversions, corrective surgery, and reversals) were common after banding (153 of 376 [40.7%]) and VBG (386 of 1365 [28.3%]) but relatively rare after GBP (20 of 266 [7.5%]). Patients who had banding and VBG primarily underwent conversions to GBP or reversals. Incidence of reversals was 5 times higher after banding than after VBG (40.7% vs 7.5%; unadjusted hazard ratio, 5.19 [95% CI, 3.43-7.87]; P<.001). Corrective surgeries were equally common irrespective of the index surgery (72 of 1365 patients who had VBG [5.3%]; 23 of 376 patients who had banding [6.1%]; 19 of 266 patients who had GBP [7.1%]). Revisional surgery indications, including inadequate weight loss, band-associated complications (migration, stenosis, and slippage), staple-line disruptions, and postsurgical morbidity, varied depending on index surgery subgroup. Most corrections occurred within the first 10 years, whereas conversions and reversals occurred over the entire follow-up period.Corrective surgeries occur mainly within the first 10 years and with similar incidences across all 3 surgical subgroups, but indications varied. Conversions (mainly to GBP) and reversals occurred after many years and were most frequent after banding and VBG, reflecting a higher overall revisional surgery demand after these operations.
17.	Hjorth, Stephan, 1953 (author) The More, the Merrier…? Antipsychotic Polypharmacy Treatment Strategies in Schizophrenia From a Pharmacology Perspective. 2021 In: Frontiers in psychiatry. - : Frontiers Media SA. - 1664-0640. ; 12 Journal article (peer-reviewed)abstract Antipsychotic polypharmacy/drug combination treatment (APP) is a remarkably common practice in the schizophrenia context, given the lack of general support in treatment Guidelines. There is also a vast literature on APP outcomes, but a paucity of high-quality evidence-based data to guide and optimize adequate use of APP. This seems particularly true regarding many pharmacology-based considerations involved in APP treatment strategies. This paper first briefly summarizes clinical literature related to the use of APP. Against this backdrop, the pharmacological target profile features are then described of frequently used antipsychotic agents, in relation to estimated free plasma exposure levels at clinically efficacious dosing. APP strategies based on the properties of these drugs are then scrutinized and gauged within the background literature framework. The anticipated usefulness of APP from the pharmacological standpoint is detailed regarding efficacy, adverse effect (AE)/tolerability, and safety perspective, including why, when, and how it may be used to its advantage. For the purpose, a number of theoretically beneficial combinations as well as instances with suboptimal-and even futile-APP approaches are exemplified and discussed from the rational pharmacodynamic and pharmacokinetic pros and cons point-of-view. In this exposé, particular attention is paid to the utility and features of 3rd Generation Antipsychotic dopamine (DA) D2-D3 agonists within an APP setting.
18.	Holm-Waters, Susanna, et al. (author) Preclinical Pharmacology of 2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl (Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease 2020 In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:1, s. 113-125 Journal article (peer-reviewed)abstract IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing L-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine L-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype.
19.	Jansson-Lofmark, R., et al. (author) Does In Vitro Potency Predict Clinically Efficacious Concentrations? 2020 In: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 108:2, s. 298-305 Journal article (peer-reviewed)abstract The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.
20.	Lamb, G. P., et al. (author) Short GRB 160821B : A Reverse Shock, a Refreshed Shock, and a Well-sampled Kilonova 2019 In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 883:1 Journal article (peer-reviewed)abstract We report our identification of the optical afterglow and host galaxy of the short-duration gamma-ray burst sGRB 160821B. The spectroscopic redshift of the host is z = 0.162, making it one of the lowest redshift short-duration gamma-ray bursts (sGRBs) identified by Swift. Our intensive follow-up campaign using a range of ground-based facilities as well as Hubble Space Telescope, XMM-Newton, and Swift, shows evidence for a late-time excess of optical and near-infrared emission in addition to a complex afterglow. The afterglow light curve at X-ray frequencies reveals a narrow jet, theta(j) similar to 1.9(-0.03)(+0.10) deg, that is refreshed at >1 day post-burst by a slower outflow with significantly more energy than the initial outflow that produced the main GRB. Observations of the 5 GHz radio afterglow shows a reverse shock into a mildly magnetized shell. The optical and near-infrared excess is fainter than AT2017gfo associated with GW170817, and is well explained by a kilonova with dynamic ejecta mass M-dyn = (1.0 +/- 0.6) x 10(-3) M-circle dot and a secular (post-merger) ejecta mass with M-pm = (1.0 +/- 0.6) x 10(-2) M-circle dot, consistent with a binary neutron star merger resulting in a short-lived massive neutron star. This optical and near-infrared data set provides the best-sampled kilonova light curve without a gravitational wave trigger to date.
21.	Lehmann, Anders, et al. (author) Discovery of New Drugs for Weight Loss and Prevention of Weight Regain 2016 In: Neuroendocrinology of Appetite. S Dickson & J Mercer (eds.). - Chichester, UK : John Wiley & Sons, Ltd. - 9781118839324 ; , s. 247-284 Book chapter (peer-reviewed)
22.	Levan, A. J., et al. (author) The Environment of the Binary Neutron Star Merger GW170817 2017 In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 848:2 Journal article (peer-reviewed)abstract We present Hubble Space Telescope (HST) and Chandra imaging, combined with Very Large Telescope MUSE integral field spectroscopy of the counterpart and host galaxy of the first binary neutron star merger detected via gravitational-wave emission by LIGO and Virgo, GW170817. The host galaxy, NGC 4993, is an S0 galaxy at z - 0.009783. There is evidence for large, face-on spiral shells in continuum imaging, and edge-on spiral features visible in nebular emission lines. This suggests that NGC 4993 has undergone a relatively recent (less than or similar to 1 Gyr) dry merger. This merger may provide the fuel for a weak active nucleus seen in Chandra imaging. At the location of the counterpart, HST imaging implies there is no globular or young stellar cluster, with a limit of a few thousand solar masses for any young system. The population in the vicinity is predominantly old with less than or similar to 1% of any light arising from a population with ages <500 Myr. Both the host galaxy properties and those of the transient location are consistent with the distributions seen for short-duration gamma-ray bursts, although the source position lies well within the effective radius (r(e) similar to 3 kpc), providing an r(e)-normalized offset that is closer than similar to 90% of short GRBs. For the long delay time implied by the stellar population, this suggests that the kick velocity was significantly less than the galaxy escape velocity. We do not see any narrow host galaxy interstellar medium features within the counterpart spectrum, implying low extinction, and that the binary may lie in front of the bulk of the host galaxy.
23.	Lyman, J. D., et al. (author) The optical afterglow of the short gamma-ray burst associated with GW170817 2018 In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 2:9, s. 751-754 Journal article (peer-reviewed)abstract The binary neutron star merger GW170817 was the first multi-messenger event observed in both gravitational and electromagnetic waves(1,2). The electromagnetic signal began approximately two seconds post-merger with a weak, short burst of gamma rays(3), which was followed over the next hours and days by the ultraviolet, optical and near-infrared emission from a radioactively powered kilonova(4-11). Later, non-thermal rising X-ray and radio emission was observed(12,13). The low luminosity of the gamma rays and the rising non-thermal flux from the source at late times could indicate that we are outside the opening angle of the beamed relativistic jet. Alternatively, the emission could be arising from a cocoon of material formed from the interaction between a jet and the merger ejecta(13-15). Here we present late-time optical detections and deep near-infrared limits on the emission from GW170817 at 110 days post-merger. Our new observations are at odds with expectations of late-time emission from kilonova models, being too bright and blue(16,17). Instead, the emission arises from the interaction between the relativistic ejecta of GW170817 and the interstellar medium. We show that this emission matches the expectations of a Gaussian-structured relativistic jet, which would have launched a high-luminosity, short gamma-ray burst to an aligned observer. However, other jet structure or cocoon models can also match current data-the future evolution of the afterglow will directly distinguish the origin of the emission.
24.	Olsen, Jogvan Magnus Haugaard, et al. (author) Dalton Project : A Python platform for molecular- and electronic-structure simulations of complex systems 2020 In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 152:21 Journal article (peer-reviewed)abstract The Dalton Project provides a uniform platform access to the underlying full-fledged quantum chemistry codes Dalton and LSDalton as well as the PyFraME package for automatized fragmentation and parameterization of complex molecular environments. The platform is written in Python and defines a means for library communication and interaction. Intermediate data such as integrals are exposed to the platform and made accessible to the user in the form of NumPy arrays, and the resulting data are extracted, analyzed, and visualized. Complex computational protocols that may, for instance, arise due to a need for environment fragmentation and configuration-space sampling of biochemical systems are readily assisted by the platform. The platform is designed to host additional software libraries and will serve as a hub for future modular software development efforts in the distributed Dalton community.
25.	Rodriguez Cruz, José, et al. (author) Case Report: Cariprazine in a Patient With Schizophrenia, Substance Abuse, and Cognitive Dysfunction 2021 In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 12 Journal article (peer-reviewed)abstract This case report describes a 30-year old male diagnosed with schizophrenia at the age of 23, and with a long history of drug abuse. He had previously received a wide range of antipsychotic drug treatment regimens, all with some degree of effect, but never with complete symptom relief. He was also suffering from persistent cognitive and negative symptoms. At the time of admission in our clinic, he was on Quetiapine (QUE) and Haloperidol (HAL). It was therefore decided to substitute HAL for Cariprazine (CAR)-an agent with a novel pharmacological and clinical profile-in the hope of gaining increased efficacy, particularly in the cognitive and negative symptom domains. Within 3 weeks of the switch from HAL to CAR the patient clearly improved, and notably so in the aforementioned symptom areas. A number of subsequent adjustments of antipsychotic dosages and adjunct medications during the ensuing months resulted in an apparently more stable alleviation of positive as well as negative and cognitive symptoms, including markedly improved personal and social capabilities. Interestingly, some time after initiating CAR treatment the patient also reported that from being a heavy smoker (60 cig/d) he had cut down and eventually ceased smoking entirely; furthermore, he has remained clean of other substance abuse since his first admission in 2020. The joint treatment with CAR in combination with QUE thus seems to have improved the patient's cognitive functioning as well as possibly his susceptibility to substance abuse.
26.	Sjöholm, Kajsa, 1971, et al. (author) Long-term incidence of haematological cancer after bariatric surgery or usual care in the Swedish Obese Subjects study: a prospective cohort study 2023 In: Lancet Healthy Longevity. ; 4:10 Journal article (peer-reviewed)
27.	Stan, Tiberiu Loredan, et al. (author) Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis 2024 In: Neurotherapeutics. - : Elsevier. - 1878-7479 .- 1933-7213. ; 21:2, s. 1-12 Journal article (peer-reviewed)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.
28.	Tanvir, N. R., et al. (author) The Emergence of a Lanthanide-rich Kilonova Following the Merger of Two Neutron Stars 2017 In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 848:2 Journal article (peer-reviewed)abstract We report the discovery and monitoring of the near-infrared counterpart (AT2017gfo) of a binary neutron-star merger event detected as a gravitational wave source by Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)/Virgo (GW170817) and as a short gamma-ray burst by Fermi Gamma-ray Burst Monitor (GBM) and Integral SPI-ACS (GRB 170817A). The evolution of the transient light is consistent with predictions for the behavior of a kilonova/ macronova powered by the radioactive decay of massive neutron-rich nuclides created via r-process nucleosynthesis in the neutron-star ejecta. In particular, evidence for this scenario is found from broad features seen in Hubble Space Telescope infrared spectroscopy, similar to those predicted for lanthanide-dominated ejecta, and the much slower evolution in the near-infrared K-s-band compared to the optical. This indicates that the late-time light is dominated by high-opacity lanthanide-rich ejecta, suggesting nucleosynthesis to the third r-process peak (atomic masses A approximate to 195). This discovery confirms that neutron-star mergers produce kilo-/macronovae and that they are at least a major-if not the dominant-site of rapid neutron capture nucleosynthesis in the universe.
29.	Wikell, Cecilia, et al. (author) Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy 2001 In: Clinical neuropharmacology. - : Ovid Technologies (Wolters Kluwer Health). - 0362-5664 .- 1537-162X. ; 24:6, s. 324-333 Journal article (peer-reviewed)abstract Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.

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