Janhunen S.K.,University Utrecht |
Janhunen S.K.,Orion Corporation Orion Pharma |
Van Der Zwaal E.M.,University Utrecht |
La Fleur S.E.,University Utrecht |
And 2 more authors.
Obesity | Year: 2011
Because the use of monoamine reuptake inhibitors as weight-reducing agents is limited by adverse effects, novel antiobesity drugs are needed. We studied acute effects of the noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor sibutramine (SIB), alone and after pretreatment with α1-and α2-adrenoceptor (AR), and 5-HT1/2/7, 5-HT1B and 5-HT2C receptor antagonists in order to determine which ARs and 5-HT receptors act downstream of SIB on feeding and locomotion. Acute effects on caloric and water intake, meal microstructure and locomotion were assessed, using an automated weighing system and telemetry in male rats with restricted 18-h access to Western style diet. SIB 3mg/kg reduced meal size and frequency, which suggests enhanced within-and postmeal satiety. Imiloxan (α2B-AR), WB4101 (α1-AR), SB-224289 (5-HT1B), and modestly BRL 44408 (α2A/D-AR) attenuated SIB's effect on meal size, suggesting that α2B-and α1-ARs and 5-HT1B receptors mediate within-meal satiety, with a modest role for α2A/D-ARs. Only prazosin (α1/2B/2C-AR) counteracted SIB's effect on meal frequency. At 3mg/kg, SIB modestly increased locomotion. This effect was blocked by metergoline (5-HT1/2/7), WB4101 (α1-AR), and RX821002 (α2-AR). Interestingly, the α2-AR antagonists atipamezole and RX821002 enhanced SIB's effect on caloric intake, probably due to inverse agonistic actions at α2A-autoreceptors that further enhanced release of NA that regulates caloric intake. Thus, an inverse agonist of presynaptic α2A-ARs might beneficially enhance SIB's weight-reducing effect and offer novel treatment for obesity. All in all, the present data supports the ARs and 5-HT receptors involved in the effects of SIB on different aspects of caloric intake and locomotion. © 2011 The Obesity Society.
Lehto J.,University of Turku |
Lehto J.,Clinical Research Services Turku |
Johansson J.,University of Turku |
Vuorilehto L.,University of Turku |
And 6 more authors.
Psychopharmacology | Year: 2015
Rationale: No validated methods have been available for studying brain noradrenergic neurotransmission in vivo in humans. Positron emission tomography (PET) radiotracers are widely used in clinical drug development targeted to brain receptors and can also in some cases be employed to monitor extracellular (synaptic) neurotransmitter concentrations. Objectives: The objective of this study is to test the sensitivity of [11C]ORM-13070 uptake to increased concentrations of extracellular (synaptic) noradrenaline in the human brain. Methods: Eight subjects underwent a control PET scan with [11C]ORM-13070, a subtype-selective α2C-adrenoceptor antagonist radioligand, and two PET scans after two different noradrenaline challenges, i.e. during ketamine infusion and after a dose of atomoxetine combined with cold stimulation. Tracer uptake in the caudate nucleus and putamen was described with AUC values in scan time windows of 10-20 and 5-30 min post injection and quantified with the ratio method. Voxel-based analysis was performed with average bound per free (B/F) ratio images. Results: Both noradrenaline challenges were consistently associated with 10-20 % (p<0.05) reductions in tracer uptake in the dorsal striatum, as determined with region-of-interest-based analysis. Voxel-based analysis revealed significant reductions in B/F ratios in the dorsal striatum, in the brain stem and in several cortical areas. Reductions of 24 and 23 % were detected in the peak putamen clusters with ketamine and atomoxetine + cold, respectively. Conclusion: Direct experimental support was gained for the suitability of [11C]ORM-13070 for imaging of brain noradrenergic neurotransmission. © 2015 Springer-Verlag.
Parkkinen L.,University of Oxford |
Parkkinen L.,University College London |
O'Sullivan S.S.,University College London |
Kuoppamaki M.,University of Turku |
And 8 more authors.
Neurology | Year: 2011
Background: Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of α-synuclein. We investigated the relationship between cumulative lifetime dose of L-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). Methods: Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with welldocumented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. Results: Mean lifetime dose of L-dopa correlated significantly (p < 0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p= 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density. Conclusion: Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities. © 2011 by AAN Enterprises, Inc.
Van Der Zwaal E.M.,University of Amsterdam |
Janhunen S.K.,Orion Corporation Orion Pharma |
La Fleur S.E.,University of Amsterdam |
Adan R.A.H.,University Utrecht
International Journal of Neuropsychopharmacology | Year: 2014
The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms. © 2013 CINP.
Malmberg L.P.,University of Helsinki |
Everard M.L.,Sheffield Childrens Hospital |
Haikarainen J.,Orion Corporation Orion Pharma |
Lahelma S.,Orion Corporation Orion Pharma
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2014
Methods: Inspiratory flow parameters via EH and Symbicort® Turbuhaler® (TH) inhalers were evaluated in 187 patients with asthma and COPD. The 10th, 50th, and 90thpercentile flow rates achieved by patients were utilized to study in vitro flow rate dependency of budesonide/formoterol EH and Symbicort TH. In addition, an exploratory pharmacokinetic study on pulmonary deposition of active substances for budesonide/formoterol EH in healthy volunteers was performed.Results: Mean inspiratory flow rates through EH were 64 and 56 L/min in asthmatics and COPD patients, and through TH 79 and 72 L/min, respectively. Children with asthma had marginally lower PIF values than the adults. The inspiratory volumes were similar in all groups between the inhalers. Using weighted 10th, 50th, and 90thpercentile flows the in vitro delivered doses (DDs) and fine particle doses (FPDs) for EH were rather independent of flow as 98% of the median flow DDs and 89%-93% of FPDs were delivered already at 10thpercentile air flow. Using±15% limits, EH and TH had similar flow rate dependency profiles between 10thand 90thpercentile flows. The pharmacokinetic study with budesonide/formoterol EH in healthy subjects (n=16) revealed a trend for a flow-dependent increase in lung deposition for both budesonide and formoterol.Conclusions: Comparable in vitro flow rate dependency between budesonide/formoterol EH and Symbicort TH was found using the range of clinically relevant flow rates. The results of the pharmacokinetic study were in accordance with the in vitro results showing only a trend of flow rate-dependant increase in lung deposition of active substances with EH.Background: The Easyhaler® (EH) device-metered dry powder inhaler containing budesonide and formoterol is being developed for asthma and chronic obstructive pulmonary disease (COPD). As a part of product optimization, a series of in vitro and in vivo studies on flow rate dependency were carried out. © 2014 Mary Ann Liebert, Inc.