Publications by authors named "Mika Scheinin"

146 Publications

Effects of Bifidobacterium animalis ssp. lactis 420 on gastrointestinal inflammation induced by a nonsteroidal anti-inflammatory drug: A randomized, placebo-controlled, double-blind clinical trial.

Br J Clin Pharmacol 2021 Apr 27. Epub 2021 Apr 27.

Danisco Sweeteners Oy, IFF Health & Biosciences, ,Sokeritehtaantie 20, Kantvik, FI-02460, Finland.

Aims: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the gastric and duodenal mucosa. Some probiotics have proven useful in ameliorating the harmful side-effects of NSAIDs. Our aim was to evaluate whether oral administration of Bifidobacterium animalis ssp. lactis 420 (B420) can attenuate the increase of calprotectin excretion into faeces induced by intake of diclofenac sustained-release tablets.

Methods: A double-blind, parallel-group, placebo-controlled and randomized clinical study was performed in 50 healthy male and female volunteers aged 20-40 years, in Finland. Study participation consisted of 4 phases: run-in, intervention with B420 or placebo, B420 or placebo + NSAID treatment, and follow-up. The primary outcome was the concentration of calprotectin in faeces. Secondary outcomes were haemoglobin and microbial DNA in faeces and blood haemoglobin levels.

Results: Intake of diclofenac increased the faecal excretion of calprotectin in both groups. The observed increases were 48.19 ± 61.55 μg/g faeces (mean ± standard deviation) in the B420 group and 31.30 ± 39.56 μg/g in the placebo group (difference estimate 16.90; 95% confidence interval: -14.00, 47.77; P = .276). There were no significant differences between the treatment groups in changes of faecal or blood haemoglobin. Faecal B. lactis DNA was much more abundant in the B420 group compared to the placebo group (ANOVA estimate for treatment difference 0.85 × 10 /g faeces; 95% confidence interval: 0.50 × 10 , 1.21 × 10 ; P < .0001).

Conclusions: Short-term administration of the probiotic B420 did not protect the healthy adult study participants from diclofenac-induced gastrointestinal inflammation as determined by analysis of faecal calprotectin levels.
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http://dx.doi.org/10.1111/bcp.14880DOI Listing
April 2021

Kinetic analysis and optimisation of F-rhPSMA-7.3 PET imaging of prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Apr 12. Epub 2021 Apr 12.

Clinical Research Services Turku - CRST Ltd, Turku, Finland.

Purpose: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer.

Methods: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (K) were calculated using Patlak plots.

Results: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. K, SUV and lesion-to-reference ratio estimates showed good agreement.

Conclusion: F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer.

Trial Registration: NCT03995888 (24 June 2019).
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http://dx.doi.org/10.1007/s00259-021-05346-8DOI Listing
April 2021

A randomized pharmacokinetic-pharmacodynamic evaluation of the potential biosimilar interferon beta-1a product, CinnoVex®.

Expert Opin Biol Ther 2021 Mar 8:1-10. Epub 2021 Mar 8.

CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran.

: The objective of the trial was to evaluate the bioequivalence of the interferon beta-1a (IFN beta-1a) biosimilar product candidate CinnoVex® with the reference product Avonex® by comparing the pharmacokinetics/pharmacodynamics (PK/PD), safety and immunogenicity of the two products in healthy subjects.: A total of 41 healthy subjects were randomized in a two-stage design to receive single doses of CinnoVex® and Avonex®. The primary PK endpoint was the area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC). Additional PK parameters, safety and immunogenicity were evaluated as secondary endpoints. The main secondary PD endpoints were the areas under the concentration-time curves from time 0 to 168 hours (AUC) of the PD biomarkers.: The two products demonstrated similar PK parameters, and the 90% confidence interval (CI) of the primary PK endpoint was within the bioequivalence acceptance limit. No serious adverse events were reported, and all adverse events (AE) were mild or moderate in severity. Anti-drug antibodies were not observed in any of the study participants.: This study demonstrated PK/PD bioequivalence between CinnoVex® and Avonex®. The safety and tolerability profiles of both products were similar.: EudraCT Number 2016-000139-41.
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http://dx.doi.org/10.1080/14712598.2021.1895745DOI Listing
March 2021

Hydroxychloroquine in the treatment of adult patients with Covid-19 infection in a primary care setting (LIBERTY): A structured summary of a study protocol for a randomised controlled trial.

Trials 2021 Jan 11;22(1):44. Epub 2021 Jan 11.

Institute of Biomedicine, University of Turku, Turku, Finland.

Objectives: The primary objective of this study is to evaluate the therapeutic potential of hydroxychloroquine (HCQ) in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo. The study hypothesis is that treatment with HCQ will reduce the risk of hospitalization because of Covid-19 infection, and the sample size estimate of the study is based on the need to test this hypothesis. The secondary objectives of the study are: to evaluate the safety and tolerability of HCQ in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo; to collect experience of the use of HCQ in the treatment of Covid-19 infection in outpatients, in order to be able to identify patient characteristics that predict specific treatment responses (favourable or unfavourable); this objective will also be addressed by post-hoc subgroup analysis of the study results and by meta-analysis of pooled patient data from other clinical trials of HCQ in outpatients; and to evaluate the impact of Covid-19 infection and its treatment on the mental health and well-being of the study participants. In addition, if the data allow, the study has the following exploratory objectives: to evaluate the extent and duration of SARS-CoV-2 viral shedding by PCR testing of nasopharyngeal swab samples in study subjects treated with HCQ, as compared to placebo; to evaluate the extent and time course of SARS-CoV-2 virus-specific antibody responses in serum of study subjects treated with HCQ, as compared to placebo; to evaluate other possible biomarker changes in blood in study subjects treated with HCQ, as compared to placebo; to explore the possible effects of genetic variation in drug metabolizing enzymes on HCQ-related outcomes in the study population; to explore the associations of HCQ-related outcome variables with other patient characteristics, e.g. HLA haplotypes, HCQ concentrations, demographic variables, disease history and concomitant medications.

Trial Design: This is a phase 2, placebo-controlled, double-blind, randomized, parallel-group treatment trial comparing HCQ with placebo in outpatients with Covid-19 infection. Participants will be randomized in a 1:1 ratio to the two treatment arms.

Participants: Main inclusion criteria: 1. Males and females >40 years of age, or 18-40 years of age with one or both of the following: i. diabetes mellitus (type 1 or type 2); ii. BMI > 35 kg/m; 2. Valid independent informed consent obtained; 3. Symptoms typical of Covid-19 infection, according to criteria specified in the study protocol. The onset of symptoms must be within 5 days of enrolment; 4. Positive SARS-CoV-2 PCR test result of a nasopharyngeal swab sample. Main exclusion criteria: 1. Suspected severe or moderately severe pneumonia, presenting with any of the following: respiratory rate > 26 breaths/min; significant respiratory distress; or SpO ≤94% on room air; 2. Requiring treatment in the hospital, according to the treating physician's judgement; 3. Any contraindication to treatment with HCQ; 4. Pregnancy or lactation. The trial will be conducted at seven study sites in a primary public health care setting in the region of Satakunta, Finland.

Intervention And Comparator: Participants will be randomized to receive either HCQ capsules at 300 mg twice a day for one day and then 200 mg twice a day for 6 days, or placebo capsules for 7 days.

Main Outcomes: The primary endpoint of the study is the number of hospitalizations due to Covid-19 infection within four weeks of entry into the study. The secondary endpoints of the study include the following: duration and severity of Covid-19-related symptoms, as reported by daily self-assessments; number of Intensive Care Unit treatment episodes due to Covid-19 infection within four weeks of entry into the study; number of deaths due to Covid-19 infection within four weeks of entry into the study; number of treatment-related adverse events (AEs) and serious AEs (SAEs); all-cause hospitalizations and mortality within six months of entry into the study; and self-assessed symptoms of anxiety, as assessed with repeated administration of the Generalized Anxiety Disorder 7-item scale (GAD-7). The exploratory endpoints of the study include the following: extent and duration of SARS-CoV-2 viral shedding and virus-specific antibody responses in serum; and possible other blood biomarker changes.

Randomisation: Eligible study participants are randomly allocated into two treatment arms (1:1 ratio). The randomization list has been generated using Viedoc™ (Viedoc Technologies AB, Uppsala, Sweden) that is used as an electronic data capture system for this study.

Blinding (masking): The participants and all study personnel remain blinded to the treatment allocation by having both IMPs packed in identical containers. Masking of the treatments was performed by re-formulation of the IMPs so that the HCQ capsules and the placebo capsules have identical appearance.

Numbers To Be Randomised (sample Size): 600 participants are to be randomised with 300 in each arm.

Trial Status: Protocol version 2, dated 14 July 2020; recruitment is expected to start in December, 2020, and to be completed in June, 2021.

Trial Registration: EudraCT 2020-002038-33 , registered 26 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). The protocol has been redacted to conform with privacy regulations by deleting the names and contact information of individuals mentioned in the protocol but not listed as authors in this communication. In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04989-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797713PMC
January 2021

Assessing an Electronic Health Record research platform for identification of clinical trial participants.

Contemp Clin Trials Commun 2021 Mar 18;21:100692. Epub 2020 Dec 18.

Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FI-20520, Turku, Finland.

Electronic health records (EHR) are a potential resource for identification of clinical trial participants. We evaluated how accurately a commercially available EHR Research Platform, InSite, is able to identify potential trial participants from the EHR system of a large tertiary care hospital. Patient counts were compared with results obtained in a conventional manual search performed for a reference study that investigated the associations of atrial fibrillation (AF) and cerebrovascular incidents. The Clinical Data Warehouse (CDW) of Turku University Hospital was used to verify the capabilities of the EHR Research Platform. The EHR query resulted in a larger patient count than the manual query (EHR Research Platform 5859 patients, manual selection 2166 patients). This was due to the different search logic and some exclusion criteria that were not addressable in structured digital format. The EHR Research Platform (5859 patients) and the CDW search (5840 patients) employed the same search logic. The temporal relationship between the two diagnoses could be identified when they were available in structured format and the time difference was longer than a single hospital visit. Searching for patients with the EHR Research Platform can help to identify potential trial participants from a hospital's EHR system by limiting the number of records to be manually reviewed. EHR query tools can best be utilized in trials where the selection criteria are expressed in structured digital format.
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http://dx.doi.org/10.1016/j.conctc.2020.100692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773855PMC
March 2021

Foundations of Human Consciousness: Imaging the Twilight Zone.

J Neurosci 2021 02 28;41(8):1769-1778. Epub 2020 Dec 28.

Turku PET Centre, University of Turku and Turku University Hospital, FI-20521 Turku, Finland

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (experiment 1, = 39), and during sleep-deprived wakefulness and non-rapid eye movement sleep (experiment 2, = 37). In experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected versus unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices, and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration, and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness. Trying to understand the biological basis of human consciousness is currently one of the greatest challenges of neuroscience. While the loss and return of consciousness regulated by anesthetic drugs and physiological sleep are used as model systems in experimental studies on consciousness, previous research results have been confounded by drug effects, by confusing behavioral "unresponsiveness" and internally generated consciousness, and by comparing brain activity levels across states that differ in several other respects than only consciousness. Here, we present carefully designed studies that overcome many previous confounders and for the first time reveal the neural mechanisms underlying human consciousness and its disconnection from behavioral responsiveness, both during anesthesia and during normal sleep, and in the same study subjects.
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http://dx.doi.org/10.1523/JNEUROSCI.0775-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115882PMC
February 2021

Application of the PET ligand [C]ORM-13070 to examine receptor occupancy by the α-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

EJNMMI Res 2020 Dec 9;10(1):152. Epub 2020 Dec 9.

Orion Corporation, Orion Pharma, Research and Development, Tengströminkatu 8, 20380, Espoo, Finland.

Background: Availability of the α-adrenoceptor (α-AR) positron emission tomography (PET) tracer, [C]ORM-13070, and the α-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [C]ORM-13070 autoradiography and PET to determine α-AR occupancy by ORM-12741 in rat and human brain, respectively.

Results: ORM-12741 has high affinity (K: 0.08 nM) and potent antagonist activity (K: 0.04 nM) as well as selectivity (K estimates for the human α-AR and α-AR were 8.3 nM and 0.8 nM, respectively) for the human α-AR subtype. [C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α-AR occupancy was detected with EC estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively.

Conclusions: ORM-12741 is a selective α-AR antagonist which penetrates the rat and human brain to occupy α-ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .
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http://dx.doi.org/10.1186/s13550-020-00741-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726058PMC
December 2020

Safety, Biodistribution, and Radiation Dosimetry of F-rhPSMA-7.3 in Healthy Adult Volunteers.

J Nucl Med 2021 May 16;62(5):679-684. Epub 2020 Oct 16.

Clinical Research Services Turku-CRST Ltd., Turku, Finland.

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, F-rhPSMA-7.3. Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of F-rhPSMA-7.3 was excreted into urine. The safety, biodistribution, and internal radiation dosimetry of F-rhPSMA-7.3 are considered favorable for PET imaging.
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http://dx.doi.org/10.2967/jnumed.120.252114DOI Listing
May 2021

Speech is special: The stress effects of speech, noise, and silence during tasks requiring concentration.

Indoor Air 2021 Jan 14;31(1):264-274. Epub 2020 Sep 14.

Psychophysical Research Laboratory, Turku University of Applied Sciences, Turku, Finland.

Effects of noise on people depend on sound level but also on other sound properties. A systematic comparison of the stress effects of speech and noise with the same frequency content is missing. This study compared stress reactions under sound conditions speech (sound level 65 dB L ), noise (65 dB), and silence (35 dB), all having similar relative frequency contents. Fifty-nine participants were exposed to one out of three sound conditions on average for 48 minutes while performing tasks requiring concentration. Acute physiological stress was estimated by measuring stress hormone concentrations in plasma (cortisol and noradrenaline), heart rate variability (HRV), and blood pressure. Psychological stress measures were subjective noise annoyance, workload, and fatigue. Compared to silence and noise, working during speech was more annoying, loading, but less tiring, and led to elevated HRV LF/HF ratio with time. Speech also raised cortisol levels compared with silence. Although noise was more annoying, and raised cortisol levels compared with silence, working during speech was more loading and caused more physiological stress than other sound conditions. Special care should be paid to noise control in workplaces requiring concentration because already exposure to moderate sound level sounds caused clear physiological effects on people.
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http://dx.doi.org/10.1111/ina.12733DOI Listing
January 2021

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs.

Vet Anaesth Analg 2020 Sep 11;47(5):604-613. Epub 2020 Jun 11.

Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Objective: To investigate the impact of intramuscular (IM) co-administration of the peripheral α-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal.

Study Design: Randomized, masked crossover study.

Animals: A total of eight purpose-bred Beagle dogs aged 3 years.

Methods: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 μg kg) and butorphanol (100 μg kg) premedication with vatinoxan (500 μg kg; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg). Atipamezole (100 μg kg) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed.

Results: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB.

Conclusions And Clinical Relevance: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.
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http://dx.doi.org/10.1016/j.vaa.2020.05.008DOI Listing
September 2020

Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers.

Nutrients 2020 Jun 2;12(6). Epub 2020 Jun 2.

Dietetic Department, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham B4 6NH, UK.

Several disorders of amino acid (AA) metabolism are treated with a protein-restricted diet supplemented with specific AA mixtures. Delivery kinetics impacts AA absorption and plasma concentration profiles. We assessed plasma profiles after ingestion of an AA mixture engineered to prolong AA absorption with Physiomimic Technology (Test) in a randomized, single-dose, four-way crossover trial in healthy volunteers (Trial Registration: ISRCTN11016729). In a two-step hypothesis, the primary endpoints were (i) significant reduction in peak plasma concentrations (C) of essential amino acids (EAAs) while (ii) maintaining EAA bioavailability (AUC) compared to a free AA mixture (Reference). Secondary endpoints included effects on plasma profiles of other AA groups and effects on several metabolic markers. Thirty subjects completed the study. Both co-primary endpoints were met: C for EAAs was 27% lower with the Test product compared to the Reference product (ratio, 0.726, < 0.0001); overall plasma EAA levels from the two AA mixtures was within the pre-specified bioequivalence range (AUC ratio, 0.890 (95% CI: 0.865, 0.915)). These findings were supported by the results of secondary endpoints. Prolongation of AA absorption was associated with modulation of several metabolic markers. It will be important to understand whether this can improve the long-term management of disorders of AA metabolism.
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http://dx.doi.org/10.3390/nu12061653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352445PMC
June 2020

Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration.

Clin Pharmacokinet 2020 11;59(11):1467-1482

Department of Anaesthesiology and Intensive Care, University of Turku, Kiinamyllynkatu 4-8 (11A5), P.O. Box 52, 20521, Turku, Finland.

Background And Objective: Dexmedetomidine is a potent agonist of α-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing.

Methods: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion.

Results: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals.

Conclusions: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.
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http://dx.doi.org/10.1007/s40262-020-00900-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658092PMC
November 2020

Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.

Am J Vet Res 2020 Apr;81(4):299-308

Objective: To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone.

Animals: 8 healthy Beagles.

Procedures: Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 μg/kg], medetomidine [20 μg/kg] and vatinoxan [400 μg/kg], and medetomidine [40 μg/kg] and vatinoxan [800 μg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments.

Results: Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20.

Conclusions And Clinical Relevance: Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.
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http://dx.doi.org/10.2460/ajvr.81.4.299DOI Listing
April 2020

Lipase A-Based Enantiorecognition of a Highly Strained 4-Dibenzocyclooctynol (DIBO) Used for PET Imaging.

Molecules 2020 Feb 17;25(4). Epub 2020 Feb 17.

Laboratory of Synthetic Drug Chemistry, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland.

The enantiomers of aromatic 4-dibenzocyclooctynol (DIBO), used for radiolabeling and subsequent conjugation of biomolecules to form radioligands for positron emission tomography (PET), were separated by kinetic resolution using lipase A from (CAL-A). In optimized conditions, ()-DIBO [()-, ee 95%] and its acetylated ()-ester [()-, ee 96%] were isolated. In silico docking results explained the ability of CAL-A to differentiate the enantiomers of DIBO and to accommodate various acyl donors. Anhydrous MgCl was used for binding water from the reaction medium and, thus, for obtaining higher conversion by preventing hydrolysis of the product ()- into the starting material. Since the presence of hydrated MgCl6HO also allowed high conversion or effect on enantioselectivity, Mg ion was suspected to interact with the enzyme. Binding site predictions indicated at least two sites of interest; one in the lid domain at the bottom of the acyl binding pocket and another at the interface of the hydrolase and flap domains, just above the active site.
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http://dx.doi.org/10.3390/molecules25040879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070869PMC
February 2020

Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

Hum Psychopharmacol 2019 11 3;34(6):e2716. Epub 2019 Dec 3.

Sleep Disorders and Research, Henry Ford Hospital Sleep Disorders Center, Detroit, Michigan.

Objective: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated.

Methods: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography.

Results: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually.

Conclusions: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.
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http://dx.doi.org/10.1002/hup.2716DOI Listing
November 2019

Evidence that the multiflorine-derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α -adrenoceptors in mice.

Diabetes Obes Metab 2020 03 7;22(3):290-302. Epub 2019 Nov 7.

Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Aims: To investigate the mechanism of action of 55P0251, a novel multiflorine-derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use.

Materials And Methods: Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head-to-head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti-hyperglycaemic multiflorine derivatives discovered in our programme.

Results: 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P < .0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose-stimulated insulin release, fmol*islet *30 min : without α -adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α -adrenoceptor agonist: 250 μmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P < .0001). Since receptor binding assays suggested antagonism at α -adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α -antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P < .0001). Lack of association between glucose-lowering activities and α -adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties.

Conclusions: Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α -adrenoceptor antagonists with potential to lower blood glucose by blocking α -adrenoceptors on pancreatic β cells.
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http://dx.doi.org/10.1111/dom.13895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065191PMC
March 2020

Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α-adrenoceptor antagonist vatinoxan hydrochloride.

Am J Vet Res 2019 Oct;80(10):912-922

Objective: To investigate the cardiovascular and sedation reversal effects of IM administration of atipamezole (AA) in dogs treated with medetomidine hydrochloride (MED) or MED and vatinoxan (MK-467).

Animals: 8 purpose-bred, 2-year-old Beagles.

Procedures: A randomized, blinded, crossover study was performed in which each dog received 2 IM treatments at a ≥ 2-week interval as follows: injection of MED (20 μg/kg) or MED mixed with 400 μg of vatinoxan/kg (MEDVAT) 30 minutes before AA (100 μg/kg). Sedation score, heart rate, mean arterial and central venous blood pressures, and cardiac output were recorded before and at various time points (up to 90 minutes) after AA. Cardiac and systemic vascular resistance indices were calculated. Venous blood samples were collected at intervals until 210 minutes after AA for drug concentration analysis.

Results: Heart rate following MED administration was lower, compared with findings after MEDVAT administration, prior to and at ≥ 10 minutes after AA. Mean arterial blood pressure was lower with MEDVAT than with MED at 5 minutes after AA, when its nadir was detected. Overall, cardiac index was higher and systemic vascular resistance index lower, indicating better cardiovascular function, in MEDVAT-atipamezole-treated dogs. Plasma dexmedetomidine concentrations were lower and recoveries from sedation were faster and more complete after MEDVAT treatment with AA than after MED treatment with AA.

Conclusions And Clinical Relevance: Atipamezole failed to restore heart rate and cardiac index in medetomidine-sedated dogs, and relapses into sedation were observed. Coadministration of vatinoxan with MED helped to maintain hemodynamic function and hastened the recovery from sedation after AA in dogs.
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http://dx.doi.org/10.2460/ajvr.80.10.912DOI Listing
October 2019

Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.

Lancet Gastroenterol Hepatol 2019 12 4;4(12):948-959. Epub 2019 Sep 4.

Tampere University Hospital, Tampere, Finland; Faculty of Medicine and Health Technologies, Tampere University, Tampere, Finland.

Background: Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge.

Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial was done at three clinical sites in Finland. Inclusion criteria included age 18-80 years, a confirmed diagnosis of coeliac disease, and adherence to a gluten-free diet for at least 12 months before screening. Patients were randomly assigned (1:1:1) to 150 mg AMG 714, 300 mg AMG 714, or placebo using permuted blocks and stratified by study site and sex. Patients and study staff were masked to treatment assignment. Treatments were administered by two subcutaneous injections every 2 weeks for 10 weeks (total six doses). Patients without severe villous atrophy at baseline received a gluten challenge (2-4 g daily) during weeks 2-12. Small bowel biopsy samples were obtained for histological assessments at baseline and week 12. The primary efficacy endpoint was the percentage change from baseline to week 12 in villous height-to-crypt depth (VHCD) ratio. Secondary endpoints were CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), coeliac disease GSRS, and Bristol stool form scale (BSFS); and changes in anti-tTG and anti-DGP antibodies from baseline. The primary analysis was done in the per-protocol 1 population of patients who received at least one dose of study drug and who underwent the gluten challenge. Safety analyses were done in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19.

Findings: Between April 13, 2016, and Nov 22, 2016, 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group (n=22), the 300 mg AMG 714 group (n=22), or the placebo group (n=20). Two patients did not start treatment and two did not provide post-treatment biopsy samples. 49 patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The least square mean difference in the relative change from baseline in VHCD ratio was -2·49% (95% CI -16·82 to 11·83; p=0·73) between 150 mg AMG 714 and placebo and 6·39% (-7·07 to 19·85; p=0·34) between 300 mg AMG 714 and placebo. Neither comparison was statistically significant. The density of CD3-positive intraepithelial lymphocytes increased in all groups, with smaller increases in the 300 mg group (-41·24% [95% CI -79·28 to -3·20] vs placebo, nominal p=0·03) but not the 150 mg group (-14·32% [-54·39 to 25·74], nominal p=0·47). Clinical symptoms were ameliorated with AMG 714 treatment between baseline and week 12, particularly diarrhoea as measured by the BSFS (nominal p=0·01 for 150 mg vs placebo, and nominal p=0·0002 for 300 mg vs placebo). Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 714 and placebo. Treatment-emergent adverse events occurred in 21 (95%) patients in the 150 mg AMG 714 group, 0 (95%) in the 300 mg AMG 714 group, and 19 (100%) in the placebo group. The most common treatment-emergent adverse events were gastrointestinal disorders (17 [77%] participants in the 150 mg AMG 714 group, 16 [76%] in the 300 mg AMG 714 group, and 13 [68%] in the placebo group). Injection site reactions were the most common individual adverse event, reported in eight (36%) patients in the 150 mg AMG 714 group, 11 (52%) in the 300 mg group, and five (26%) in the placebo group. No serious adverse events occurred.

Interpretation: The primary endpoint, change in VHCD ratio from baseline after 12 weeks of treatment in patients with coeliac disease undergoing gluten challenge, was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. Effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 may be warranted in patients with non-responsive coeliac disease.

Funding: Celimmune and Amgen.
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http://dx.doi.org/10.1016/S2468-1253(19)30264-XDOI Listing
December 2019

Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression.

EBioMedicine 2019 Sep 26;47:170-183. Epub 2019 Aug 26.

Institute of Biomedicine, University of Turku, Finland; Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland. Electronic address:

Background: Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function.

Methods: Ovarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression.

Findings: Herein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers.

Interpretation: Our results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer. FUND: This work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Foundation (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW).
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http://dx.doi.org/10.1016/j.ebiom.2019.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796594PMC
September 2019

Treating gambling disorder with as needed administration of intranasal naloxone: a pilot study to evaluate acceptability, feasibility and outcomes.

BMJ Open 2019 08 21;9(8):e023728. Epub 2019 Aug 21.

Alcohol, Drugs and Addictions Unit, Terveyden ja hyvinvoinnin laitos, Helsinki, Finland.

Background And Aim: There is growing interest in the use of medication-assisted treatments for gambling disorder (GD). Opioid receptor antagonists are hypothesised to blunt the craving associated with gambling. This study was designed to assess the feasibility of using an intranasal naloxone spray to treat GD.

Design: An 8-week, open-label, uncontrolled pilot study.

Setting: A single study site in the capital region of Finland.

Subjects: Twenty problem gamblers (nine men) were randomised into two groups. Group A (n=10) took one dose into one nostril (2 mg naloxone), as needed, with a maximum of 4 doses/day (max. 8 mg/day). Group B (n=10) took one dose into each nostril (4 mg naloxone) as needed, with a maximum of 4 doses/day (max. 16 mg/day).

Intervention: Naloxone hydrochloride nasal spray.

Measures: Acceptability and feasibility of the intervention were assessed. Use of study medication, adverse events, gambling frequency and gambling expenditure were recorded in a mobile diary. Problem gambling: South Oaks Gambling Screen (SOGS), depressive symptoms: Beck Depression Inventory (BDI) and alcohol use: Alcohol Use Disorders Identification Test were recorded.

Results: Study completion rate was 90%. Acceptability and feasibility scores were high. Group B used intranasal naloxone more frequently than group A, and consequently used more naloxone. No serious adverse events were reported. The postintervention SOGS scores were lower (median=4 (IQR=3.75) versus preintervention scores (median=12 (IQR=4.75)). Depressive symptoms were reduced during the trial (preintervention BDI median=9, IQR=9 vs postintervention BDI median=6, IQR=6).

Conclusions: The acceptability and feasibility of using intranasal naloxone were high, and no serious adverse events were reported. Preliminary results suggest mixed results in terms of gambling behaviour (ie, reduced frequency but not expenditure) and decreased depressive symptoms.

Trial Registration Number: EudraCT2016-001828-56.
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http://dx.doi.org/10.1136/bmjopen-2018-023728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707653PMC
August 2019

Upper Airway Collapsibility during Dexmedetomidine and Propofol Sedation in Healthy Volunteers: A Nonblinded Randomized Crossover Study.

Anesthesiology 2019 11;131(5):962-973

From the Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, and the Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care, Karolinska Institutet, Stockholm, Sweden (A.L., L.I.E., M.J.F.) the West Australian Sleep Disorders Research Institute, Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia (K.J.M., P.R.E., D.R.H., J.H.W.) the Centre for Sleep Science, School of Human Sciences (K.J.M., P.R.E., D.R.H., J.H.W.) the Department of Anaesthesia, Sir Charles Gairdner Hospital (B.K.L.), Nedlands, Western Australia, Australia the Institute of Biomedicine, University of Turku, and Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland (M.S.).

Background: Dexmedetomidine is a sedative promoted as having minimal impact on ventilatory drive or upper airway muscle activity. However, a trial recently demonstrated impaired ventilatory drive and induction of apneas in sedated volunteers. The present study measured upper airway collapsibility during dexmedetomidine sedation and related it to propofol.

Methods: Twelve volunteers (seven female) entered this nonblinded, randomized crossover study. Upper airway collapsibility (pharyngeal critical pressure) was measured during low and moderate infusion rates of propofol or dexmedetomidine. A bolus dose was followed by low (0.5 μg · kg · h or 42 μg · kg · min) and moderate (1.5 μg · kg · h or 83 μg · kg · min) rates of infusion of dexmedetomidine and propofol, respectively.

Results: Complete data sets were obtained from nine volunteers (median age [range], 46 [23 to 66] yr; body mass index, 25.4 [20.3 to 32.4] kg/m). The Bispectral Index score at time of pharyngeal critical pressure measurements was 74 ± 10 and 65 ± 13 (mean difference, 9; 95% CI, 3 to 16; P = 0.011) during low infusion rates versus 57 ± 16 and 39 ± 12 (mean difference, 18; 95% CI, 8 to 28; P = 0.003) during moderate infusion rates of dexmedetomidine and propofol, respectively. A difference in pharyngeal critical pressure during sedation with dexmedetomidine or propofol could not be shown at either the low or moderate infusion rate. Median (interquartile range) pharyngeal critical pressure was -2.0 (less than -15 to 2.3) and 0.9 (less than -15 to 1.5) cm H2O (mean difference, 0.9; 95% CI, -4.7 to 3.1) during low infusion rates (P = 0. 595) versus 0.3 (-9.2 to 1.4) and -0.6 (-7.7 to 1.3) cm H2O (mean difference, 0.0; 95% CI, -2.1 to 2.1; P = 0.980) during moderate infusion of dexmedetomidine and propofol, respectively. A strong linear relationship between pharyngeal critical pressure during dexmedetomidine and propofol sedation was evident at low (r = 0.82; P = 0.007) and moderate (r = 0.90; P < 0.001) infusion rates.

Conclusions: These observations suggest that dexmedetomidine sedation does not inherently protect against upper airway obstruction.
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http://dx.doi.org/10.1097/ALN.0000000000002883DOI Listing
November 2019

Pharmacokinetics and Sedative Effects of Intranasal Dexmedetomidine in Ambulatory Pediatric Patients.

Anesth Analg 2020 04;130(4):949-957

From the Department of Anesthesiology and Intensive Care, University of Turku, Turku, Finland.

Background: Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation.

Methods: This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years).

Results: We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline.

Conclusions: Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.
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http://dx.doi.org/10.1213/ANE.0000000000004264DOI Listing
April 2020

Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects.

Neuropsychopharmacology 2019 08 13;44(9):1667-1673. Epub 2019 Mar 13.

Clinical Research Services Turku - CRST Ltd, Turku, Finland.

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
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http://dx.doi.org/10.1038/s41386-019-0368-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785104PMC
August 2019

Premedication with intranasal dexmedetomidine decreases barbiturate requirement in pediatric patients sedated for magnetic resonance imaging: a retrospective study.

BMC Anesthesiol 2019 02 13;19(1):22. Epub 2019 Feb 13.

Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 51, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland.

Background: Barbiturates are commonly used in ambulatory sedation of pediatric patients. However, use of barbiturates involve risks of respiratory complications. Dexmedetomidine, a highly selective α-adrenoceptor agonist, is increasingly used for pediatric sedation. Premedication with intranasal (IN) dexmedetomidine offers a non-invasive and efficient possibility to sedate pediatric patients undergoing magnetic resonance imaging (MRI). Our hypothesis was that dexmedetomidine would reduce barbiturate requirements in procedural sedation.

Methods: We included 200 consecutive pediatric patients undergoing MRI, and analyzed their hospital records retrospectively. Half of the patients received 3 μg/kg of IN dexmedetomidine (DEX group) 45-60 min before MRI while the rest received only thiopental (THIO group) for procedural sedation. Sedation was maintained with further intravenous thiopental dosing as needed. Thiopental consumption, heart rate (HR) and peripheral oxygen saturation were recorded.

Results: The cumulative thiopental requirement during MRI was (median and interquartile range [IQR]) 4.4 (2.7-6.0) mg/kg/h in the DEX group and 12.4 (9.8-14.8) mg/kg/h in the THIO group (difference 7.9 mg/kg/h, 95% CI 6.8-8.8, P <  0.001). Lowest measured peripheral oxygen saturation remained slightly higher in the DEX group compared to the THIO group (median nadirs and IQR: 97 (95-97) % and 96 (94-97) %, P <  0.001). Supplemental oxygen was delivered to 33% of the patients in the THIO group compared to 2% in the DEX group (P <  0.001). The lowest measured HR (mean and SD) was lower (78 (16) bpm) in the DEX group compared to the THIO group (92 (12) bpm) (P <  0.001).

Conclusion: Premedication with IN dexmedetomidine (3 μg/kg) was associated with markedly reduced thiopental dosage needed for efficient procedural sedation for pediatric MRI.
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http://dx.doi.org/10.1186/s12871-019-0690-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374898PMC
February 2019

Radiosynthesis and Preclinical Evaluation of an α-Adrenoceptor Tracer Candidate, 6-[F]Fluoro-marsanidine.

Mol Imaging Biol 2019 10;21(5):879-887

Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.

Purpose: The α-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α and α are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α-adrenoceptors has been limited to the α subtype. Here, we report the synthesis of 6-[F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α-adrenoceptors, and its preclinical evaluation in rats and mice.

Procedures: 6-[F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[F]fluoro-marsanidine were also analyzed.

Results: 6-[F]Fluoro-marsanidine was synthesized with [F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.

Conclusion: 6-[F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[F]fluoro-marsanidine unsuitable for α-adrenoceptor targeting in rodents in vivo.
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http://dx.doi.org/10.1007/s11307-019-01317-6DOI Listing
October 2019

Effects of the peripherally acting α-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole.

Am J Vet Res 2018 Sep;79(9):921-932

OBJECTIVE To evaluate effects of the peripherally acting α-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.
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http://dx.doi.org/10.2460/ajvr.79.9.921DOI Listing
September 2018

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors.

Neuroendocrinology 2018 24;107(4):324-339. Epub 2018 Jul 24.

Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.

The alpha2A-adrenoceptors (α2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α2A-/- mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α2A-/- mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α2A-/- mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α2A-/- mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α2A-/- mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α2A-AR signalling promoted weight loss more efficiently than exercise with normal α2A-AR function. These results suggest that blockade of α2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.
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http://dx.doi.org/10.1159/000492387DOI Listing
September 2019

Peripheral α-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

Vet Anaesth Analg 2018 Jul 3;45(4):405-413. Epub 2018 Feb 3.

Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.

Objective: We determined the possible effects of a peripherally acting α-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam.

Study Design: Randomized, experimental, blinded crossover study.

Animals: Six healthy Beagle dogs.

Methods: Two IM treatments were administered: 1) medetomidine hydrochloride (20 μg kg) + butorphanol (100 μg kg) + midazolam (200 μg kg; MBM) and 2) MBM + MK-467 hydrochloride (500 μg kg; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (C) and time to C (T) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments.

Results: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The T values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively.

Conclusions And Clinical Relevance: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.
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http://dx.doi.org/10.1016/j.vaa.2018.01.008DOI Listing
July 2018

Effect of oral KETOPROFEN treatment in acute respiratory disease outbreaks in finishing pigs.

Porcine Health Manag 2018 6;4. Epub 2018 Mar 6.

1Faculty of Veterinary Medicine, University of Helsinki, Paroninkuja 20, 04920 Saarentaus, FI Finland.

Background: Infection with respiratory pathogens can influence production as well as animal welfare. There is an economical and ethical need to treat pigs that suffer from respiratory diseases. Our aim was the evaluation of the possible effects of oral NSAID medication given in feed in acute outbreaks of respiratory disease in finishing pigs. The short- and long-term impact of NSAID dosing on clinical signs, daily weight gain, blood parameters and behaviour of growing pigs in herds with acute respiratory infections were evaluated. Four finishing pig farms suffering from acute outbreaks of respiratory disease were visited thrice after outbreak onset (DAY 0, DAY 3 and DAY 30). Pigs with the most severe clinical signs ( = 160) were selected as representative pigs for the herd condition. These pigs were blood sampled, weighed, evaluated clinically and their behaviour was observed. After the first visit, half of the pens (five pigs per pen in four pens totalling 20 representative pigs per herd, altogether 80 pigs in four herds) were treated with oral ketoprofen (target dose 3 mg/kg) mixed in feed for three days and the other half (80 pigs) with a placebo. In three of the herds, some pigs were treated also with antimicrobials, and in one herd the only pharmaceutical treatment was ketoprofen or placebo.

Results: Compared to the placebo treatment, dosing of ketoprofen reduced sickness behaviour and lowered the rectal temperature of the pigs. Clinical signs, feed intake or blood parameters were not different between the treatment groups. Ketoprofen treatment was associated with somewhat reduced weight gain over the 30-day follow-up period. Concentration analysis of the - and -enantiomers of ketoprofen in serum samples collected on DAY 3 indicated successful oral drug administration.

Conclusions: Ketoprofen mainly influenced the behaviour of the pigs, while it had no effect on recovery from respiratory clinical signs. However, the medication may have been started after the most severe clinical phase of the respiratory disease was over, and this delay might complicate the evaluation of treatment effects. Possible negative impact of ketoprofen on production parameters requires further evaluation.
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http://dx.doi.org/10.1186/s40813-018-0081-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838944PMC
March 2018

Sedative Plasma Concentrations and Delirium Risk in Critical Illness.

Ann Pharmacother 2018 06 24;52(6):513-521. Epub 2018 Jan 24.

1 Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The relationship between plasma concentration of sedatives and delirium is unknown.

Objective: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk.

Methods: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses.

Results: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45).

Conclusions: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.
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http://dx.doi.org/10.1177/1060028017753480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930024PMC
June 2018