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Janhunen S.K.,University Utrecht | Janhunen S.K.,Orion Corporation Orion Pharma | La Fleur S.E.,University Utrecht | La Fleur S.E.,University of Amsterdam | Adan R.A.H.,University Utrecht
Obesity | Year: 2013

Objective Anti-obesity drugs have adverse effects which limit their use, creating a need for novel anti-obesity compounds. We studied effects of dopamine (DA) and norepinephrine (NE) reuptake inhibitor bupropion (BUP), alone and after blocking α1-or α2-adrenoceptors (AR), D1/5, D2/3, or D4 receptors, to determine which receptors act downstream of BUP. Design and Methods Effects on caloric intake, meal patterning and locomotion were assessed, using an automated weighing system and telemetry in male rats with 18-h access to Western Human style diet. Results BUP (30 mg/kg) induced hypophagia by reducing meal size and postponing meal initiation. WB4101 (α1-AR; 2 mg/kg) and imiloxan (α2B-AR; 5 mg/kg) attenuated BUP's effect on meal size, while WB4101 and BRL 44408 (α2A/D-AR; 2 mg/kg) counteracted effect on meal initiation. Atipamezole (α2-AR; 1 mg/kg) and imiloxan further postponed initiation of meals. SKF 83566 (D1/5; 0.3 mg/kg), raclopride (D2/3; 0.5 mg/kg) and to a lesser extent FAUC 213 (D4; 0.5 mg/kg), attenuated BUP-induced hypophagia. BUP stimulated locomotion, which was blocked by all antagonists, except FAUC 213 or BRL 44408. Conclusions Alpha1-, α2A/D-and α2B-ARs, and DA receptors underlie BUP's effects on size and initiation of meals, while blocking pre-synaptic α2-ARs enhanced BUP-induced hypophagia. An inverse agonist of (pre-synaptic) α2A-ARs could enhance BUP-induced anorexia and treat eating disorders and obesity. Copyright © 2013 The Obesity Society.


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.


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.


Lahelma S.,Orion Corporation ORION PHARMA | Sairanen U.,Orion Corporation ORION PHARMA | Haikarainen J.,Orion Corporation ORION PHARMA | Korhonen J.,Orion Corporation ORION PHARMA | And 3 more authors.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2015

Background: Easyhaler® device-metered dry powder inhaler containing budesonide and formoterol fumarate dihydrate (hereafter formoterol) for the treatment of asthma and chronic obstructive pulmonary disease has been developed. The current approvals of the product in Europe were based on several pharmacokinetic (PK) bioequivalence (BE) studies, and in vitro-in vivo correlation (IVIVC) modeling. Methods: Four PK studies were performed to compare the lung deposition and total systemic exposure of budesonide and formoterol after administration of budesonide/formoterol Easyhaler and the reference product, Symbicort Turbuhaler. The products were administered concomitantly with oral charcoal (lung deposition) and in two of the studies also without charcoal (total systemic exposure). Demonstration of BE for lung deposition (surrogate marker for efficacy) and non-inferiority for systemic exposure (surrogate marker for safety) were considered a proof of therapeutic equivalence. In addition, IVIVC models were constructed to predict study outcomes with different reference product fine particle doses (FPDs). Results: In the first pivotal study, the exposure and lung dose via Easyhaler were higher compared to the reference product (mean comparison estimates between 1.07 and 1.28) as the FPDs of the reference product batch were low. In the following studies, reference product batches with higher FPDs were utilized. In the second pivotal study, non-inferiority of Easyhaler compared to Turbuhaler was shown in safety and BE in efficacy for all other parameters except the formoterol AUCt. In the fourth study where two reference batches were compared to each other and Easyhaler, budesonide/formoterol Easyhaler was bioequivalent with one reference batch but not with the other having the highest FPDs amongst the 28 reference batches studied. In the IVIVC based study outcome predictions, the test product was bioequivalent with great proportion of the reference batches. For the test product and the median FPD reference product BE was predicted. Conclusions: Equivalence regarding both safety and efficacy between budesonide/formoterol Easyhaler and Symbicort Turbuhaler was shown based on totality of evidence from the PK studies and IVIVC analyses, and therefore, therapeutic equivalence between the products can be concluded. The results of the PK studies are likely dependent on the variability of FPDs of the reference product batches. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


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.


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.


Turunen H.,Orion Corporation Orion Pharma | Jakob S.M.,University of Bern | Ruokonen E.,Kuopio University Hospital | Kaukonen K.-M.,Monash University | And 4 more authors.
Critical Care | Year: 2015

Introduction: Dexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation. Methods: The total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only. Results: Based on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs-€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)-and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam). Conclusions: From an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation. Trial registration: ClinicalTrials.gov NCT00479661 (PRODEX), NCT00481312 (MIDEX). © Turunen et al.; licensee BioMed Central.


Fizazi K.,University Paris - Sud | Massard C.,University Paris - Sud | Bono P.,University of Helsinki | Jones R.,Velindre Cancer Center | And 11 more authors.
The Lancet Oncology | Year: 2014

Background: ODM-201 is a novel androgen receptor (AR) inhibitor designed to block the growth of prostate cancer cells through high-affinity binding to the AR and inhibition of AR nuclear translocation. This trial assessed ODM-201's safety, pharmacokinetics, and activity in men with metastatic castration-resistant prostate cancer. Methods: The ARADES trial is an open-label phase 1-2 trial undertaken in 23 hospitals across Europe and USA with ongoing long-term follow-up. Men with progressive metastatic castration-resistant prostate cancer, who had castrate concentrations of testosterone and an Eastern Cooperative Oncology Group score of 0-1 were enrolled. In the phase 1 part of the trial, patients were given oral ODM-201 at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. In phase 2, patients were randomly assigned centrally and stratified by previous chemotherapy and treatment with CPY17 inhibitors, to receive one of three daily doses of ODM-201 (200 mg, 400 mg, and 1400 mg). The primary endpoint in phase 1 was safety and tolerability, whereas in phase 2 it was the proportion of patients with a PSA response (50% or greater decrease in serum PSA) at week 12. All analyses included patients who had received at least one dose of ODM-201. This trial is registered with ClinicalTrials.gov, number NCT01317641, and NCT01429064 for the follow-up after 12 weeks. Findings: We enrolled patients between April 5, 2011, and March 12, 2013. In phase 1, 24 patients were enrolled to six sequential cohorts of three to six patients and received a daily dose of ODM-201, 200-1800 mg. No dose-limiting toxic effects were reported and the maximum tolerated dose was not reached. In phase 1, three patients reported eight adverse events of grade 3 (fracture, muscle injury, laceration, paralytic ileus, pain, presyncope, urinary retention, and vomiting) and one patient had a grade 4 adverse event (lymphoedema). None of the grade 3-4 adverse events were deemed to be related to ODM-201. Of the phase 1 patients, the four who received 200 mg, seven who received 400 mg, and three who received 1400 mg entered the phase 2 part of the trial. In addition to these patients, 110 were randomly assigned to three groups: 200 mg (n=38), 400 mg (n=37), and 1400 mg (n=35). For these patients, the most common treatment-emergent adverse events were fatigue or asthenia (15 [12%] of 124 patients), hot flush (six [5%]), and decreased appetite (five [4%]). One patient (<1%) had a grade 3 treatment-emergent adverse event (fatigue); no patients had a treatment-emergent grade 4 adverse event. 38 patients who received 200 mg, 39 who received 400 mg, and 33 who received 1400 mg were assessable for PSA response at 12 weeks. 11 (29%) patients in the 200 mg group, 13 (33%) in the 400 mg group, and 11 (33%) in the 1400 mg group had a PSA response at 12 weeks. Interpretation: Our results suggest that ODM-201 monotherapy in men with progressive metastatic castration-resistant prostate cancer provides disease suppression and that ODM-201 has a favourable safety profile. These findings support further investigation of clinical responses with ODM-201 in men with castration-resistant prostate cancer. © 2014 Elsevier Ltd.


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.


PubMed | Selye Janos Hospital, Hospital and Outpatient Clinic of Siofok, Medical Center Tara, Specialized Hospital for Active Treatment of Pulmonary Diseases and 2 more.
Type: | Journal: Respiratory medicine | Year: 2016

Therapeutic equivalence of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler has been previously demonstrated with invitro and pharmacokinetic studies. This study was performed to confirm equivalent bronchodilator efficacy of the products in asthmatic patients.A randomised, single-dose, 4-period crossover study was carried out in a double-blind, double-dummy manner in 11 study sites. The studied doses were 320/9g and 1280/36g of budesonide/formoterol delivered by Easyhaler and Turbuhaler. Spirometry was performed before and 10min, 20min and 1, 2, 3, 4, 6, 8, 10 and 12h after administration of the study treatments. The primary efficacy endpoint was average 12-h forced expiratory volume in 1s (FEV72 asthma patients with reversible airway obstruction were randomised to receive study treatments. 53 patients completed all study periods according to the protocol and had sufficient data available to calculate the primary endpoint. They were included in the per-protocol analyses. The assay sensitivity of the study was shown as the common slope of average 12-h FEVThe results confirm equivalent bronchodilator efficacy of Budesonide/formoterol Easyhaler compared to Symbicort Turbuhaler.This trial was registered on ClinicalTrials.gov, Identifier: NCT02308098.

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