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Lehto J.,University of Turku | Lehto J.,Clinical Research Services Turku | Scheinin A.,University of Turku | Johansson J.,University of Turku | And 5 more authors.
Synapse | Year: 2016

PET imaging can for some neurotransmitters be used to measure synaptic neurotransmitter concentrations. The objective of this study was to test whether the receptor binding of the α2C-AR antagonist PET tracer [11C]ORM-13070 would increase in response to reductions in synaptic noradrenaline, evoked by dexmedetomidine as a sympatholytic drug challenge. Six subjects underwent a control PET scan and two dexmedetomidine PET scans. Dexmedetomidine was infused with target plasma concentrations of 0.6 and 0.2 ng/ml. Tracer binding was measured by voxel-based analysis of bound per free (B/F) images. ROI-based analysis was performed in the dorsal striatum and in the thalamus. Vital signs and drug concentrations in plasma were measured and the sedative effect was estimated with the visual analog scale. In the voxel-based analysis, dexmedetomidine administration was associated with a tendency to increased B/F tracer in the right thalamus (mean, +17%, P=0.14, and +19%, P=0.05, with the low and high dose, respectively). Tracer binding in the dorsal striatum was unaffected by dexmedetomidine. A cluster with significantly increased B/F tracer (+42%, P=0.01) was seen in the right superior temporal gyrus with low-dose dexmedetomidine, but not after the high dose. Brain uptake of [11C]ORM-13070 has previously been shown to be reduced in conditions of increased synaptic noradrenaline concentrations. In this study, tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, but statistical significance was not reached. Synapse 70:57-65, 2016. © 2015 Wiley Periodicals, Inc.


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.


Iirola T.,University of Turku | Aantaa R.,University of Turku | Laitio R.,University of Turku | Kentala E.,University of Turku | And 5 more authors.
Critical Care | Year: 2011

Introduction: Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.Methods: Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.Results: The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2= 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.Conclusions: The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population. Trial Registration: ClinicalTrials.gov: NCT00747721. © 2011 Iirola et al.; licensee BioMed Central Ltd.


Koskimies P.,Hormos Medical Ltd. | Turunen J.,4Pharma Ltd. | Lammintausta R.,Hormos Medical Ltd. | Scheinin M.,Clinical Research Services Turku
International Journal of Clinical Pharmacology and Therapeutics | Year: 2013

Objective: To characterize the pharmacokinetics of the oral, non-estrogen agent ospemifene, an estrogen agonist/antagonist with tissue-selective effects (also called a selective estrogen receptor modulator) that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Methods: Two open-label, Phase 1 studies were conducted to determine the pharmacokinetics of ospemifene in healthy postmenopausal women. In the single-dose study, 60 mg of [3H]-ospemifene was orally administered to 6 subjects. Blood, urine, and fecal samples were collected predose and serially up to 240 hours postdose. In the multiple-dose study, 12 subjects received 60 mg of ospemifene once daily for 9 days. Blood samples were collected predose and serially postdose on Day 1, predose on Days 7 and 8, and predose and serially postdose on Day 9. Results: Ospemifene exhibited high plasma protein binding and was extensively metabolized, predominantly to 4-hydroxyospemifene and 4?-hydroxyospemifene. In the single-dose study, ospemifene was rapidly absorbed, with a median tmax of 1.50 hours and geometric mean Cmax of 612 ng/ml. The geometric mean (CV%) t1/2 was 24.5 (21.3) hours and 29.0 (18.0) hours for ospemifene and 4-hydroxyospemifene, respectively. Fecal elimination accounted for 75% of the administered [ 3H]-ospemifene dose in 240 hours. In the multipledosing study, steady state was reached by Day 7. The mean t1/2 at steady state for ospemifene was 29.1 hours. High values for volume of distribution and total clearance suggested extensive tissue distribution and efficient elimination of ospemifene. Conclusions: In healthy postmenopausal women, ospemifene 60 mg/day reached steadystate concentrations by Day 7 and showed minimal accumulation of parent drug or its two main metabolites, indicating that oncedaily dosing is appropriate. ©2013 Dustri-Verlag Dr. K. Feistle.


Lehtinen T.,Clinical Research Services Turku | Tolonen A.,Admescope Ltd. | Turpeinen M.,University of Oulu | Uusitalo J.,Technopolis Plc | And 4 more authors.
Biopharmaceutics and Drug Disposition | Year: 2013

Purpose: The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics. Methods: In vitro metabolism studies were conducted using human liver microsomes; CYP-selective inhibitors and CYP-specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics. Results: Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4-hydroxyospemifene and 4′-hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment. Conclusions: The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.


Lehto J.,Clinical Research Services Turku | Virta J.R.,University of Turku | Oikonen V.,University of Turku | Roivainen A.,University of Turku | And 14 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2015

Purpose: α2C-Adrenoceptors share inhibitory presynaptic functions with the more abundant α2A-adrenoceptor subtype, but they also have widespread postsynaptic modulatory functions in the brain. Research on the noradrenergic system of the human brain has been hampered by the lack of suitable PET tracers targeted to the α2-adrenoceptor subtypes.Methods: PET imaging with the specific α2C-adrenoceptor antagonist tracer [11C]ORM-13070 was performed twice in six healthy male subjects to investigate the test–retest reliability of tracer binding.Results: The bound/free ratio of tracer uptake relative to nonspecific uptake into the cerebellum during the time interval of 5 – 30 min was most prominent in the dorsal striatum: 0.77 in the putamen and 0.58 in the caudate nucleus. Absolute test–retest variability in bound/free ratios of tracer ranged from 4.3 % in the putamen to 29 % in the hippocampus. Variability was also <10 % in the caudate nucleus and thalamus. Intraclass correlation coefficients (ICC) ranged from 0.50 in the hippocampus to 0.89 in the thalamus (ICC >0.70 was also reached in the caudate nucleus, putamen, lateral frontal cortex and parietal cortex). The pattern of [11C]ORM-13070 binding, as determined by PET, was in good agreement with receptor density results previously derived from post-mortem autoradiography. PET data analysis results obtained with a compartmental model fit, the simplified reference tissue model and a graphical reference tissue analysis method were convergent with the tissue ratio method.Conclusion: The results of this study support the use of [11C]ORM-13070 PET in the quantitative assessment of α2C-adrenoceptors in the human brain in vivo. Reliable assessment of specific tracer binding in the dorsal striatum is possible with the help of reference tissue ratios. © 2014, Springer-Verlag Berlin Heidelberg.


Rinne J.O.,Clinical Research Services Turku | Brooks D.J.,Medical Research Council Clinical science Center | Rossor M.N.,University College London | Fox N.C.,University College London | And 13 more authors.
The Lancet Neurology | Year: 2010

Background: Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease. Methods: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was -0·09 (95% CI -0·16 to -0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0·24 (95% CI -0·39 to -0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation: Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo. Funding: Elan Pharmaceuticals and Wyeth Research. © 2010 Elsevier Ltd. All rights reserved.


Pelttonen J.M.,Clinical Research Services Turku | Pelttonen J.M.,University of Turku | Pylkkanen L.,BioCis Pharma Ltd | Jansen C.T.,University of Turku | And 4 more authors.
Acta Dermato-Venereologica | Year: 2014

New treatment modalities are needed in atopic dermatitis. We evaluated the pharmacokinetics, safety, tolerability, and efficacy of topical cis-urocanic acid (cis-UCA) cream in randomised vehicle-controlled double-blinded clinical trials. The subjects received 5% cis-UCA emulsion cream and control vehicle on volar forearms after right-left randomisation. Study 1: 16 healthy subjects received one dose on the skin and, a week later, on DMSO- irritated skin. Study 2: 16 healthy subjects received 2 daily doses for 10 days. Study 3: 13 patients with mild to moderate disease were treated on selected skin lesions twice daily for 28 days. Study treatments were well tolerated. cis-UCA remained close to endogenous levels in plasma and urine. cis-UCA reduced transepidermal water loss (TEWL) both in healthy subjects and in the patients. Eczema area severity index and physician's global assessment improved from baseline with both treatments. cis-UCA cream improved skin barrier function and suppressed inflammation in the human skin. © 2014 The Authors.


PubMed | Clinical Research Services Turku, University of Helsinki, FinnMedi, Kerava Health Center and 4 more.
Type: | Journal: EBioMedicine | Year: 2016

The gut microbiota is interlinked with obesity, but direct evidence of effects of its modulation on body fat mass is still scarce. We investigated the possible effects of Bifidobacterium animalisssp. lactis 420 (B420) and the dietary fiber Litesse Ultra polydextrose (LU) on body fat mass and other obesity-related parameters.225 healthy volunteers (healthy, BMI 28-34.9) were randomized into four groups (1:1:1:1), using a computer-generated sequence, for 6months of double-blind, parallel treatment: 1) Placebo, microcrystalline cellulose, 12g/d; 2) LU, 12g/d; 3) B420, 10There were marked differences in the results of the Intention-To-Treat (ITT; n=209) and Per Protocol (PP; n=134) study populations. The PP analysis included only those participants who completed the intervention with >80% product compliance and no antibiotic use. In addition, three participants were excluded from DXA analyses for PP due to a long delay between the end of intervention and the last DXA measurement. There were no significant differences between groups in body fat mass in the ITT population. However, LU+B420 and B420 seemed to improve weight management in the PP population. For relative change in body fat mass, LU+B420 showed a-4.5% (-1.4kg, P=0.02, N=37) difference to the Placebo group, whereas LU (+0.3%, P=1.00, N=35) and B420 (-3.0%, P=0.28, N=24) alone had no effect (overall ANOVA P=0.095, Placebo N=35). A post-hoc factorial analysis was significant for B420 (-4.0%, P=0.002 vs. Placebo). Changes in fat mass were most pronounced in the abdominal region, and were reflected by similar changes in waist circumference. B420 and LU+B420 also significantly reduced energy intake compared to Placebo. Changes in blood zonulin levels and hsCRP were associated with corresponding changes in trunk fat mass in the LU+B420 group and in the overall population. There were no differences between groups in the incidence of adverse events.This clinical trial demonstrates that a probiotic product with or without dietary fiber controls body fat mass. B420 and LU+B420 also reduced waist circumference and food intake, whereas LU alone had no effect on the measured outcomes.


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