11 results on '"Pasi Pohjanjousi"'
Search Results
2. Impact of activating androgen receptor (AR) mutations on AR sensitivity to alternative ligands and response to ODM-208, a selective, first-in-class CYP11A1 inhibitor, in patients with advanced metastatic castration-resistant prostate cancer (mCRPC)
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Alice Bernard-Tessier, Tapio Utriainen, Natalie Cook, Philippe Barthélémy, Nada Lallous, Martin Gleave, Tarja Ikonen, Reetta Riikonen, Pasi Pohjanjousi, Chris Garratt, and Karim Fizazi
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Cancer Research ,Oncology - Abstract
5057 Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P
- Published
- 2022
3. Session 5: Primary practice and the profession; ophthalmology
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Beth Greene, Stratos Papakonstantinou, Susan Penelope Knowler, Padraig Egan, Clare Rusbridge, Mira Korpivaara, Beatrice Carlone, Chiara Mariti, Mirja Huhtinen, Pasi Pohjanjousi, Clara Palestrini, Karen Overall, Carrie Tooley, Sarah Heath, Emily Macnish, Emily Hall, Karen Humm, Marjanne Descamps, Genever Morgan, Nicola Williams, Vanessa Schmidt, Gina Pinchbeck, Yahui Yin, Roser T. Pont, Camilla Pegram, David B. Church, Dave C. Brodbelt, Dan G. O'Neill, Thomas Kearns, David Williams, Lucy Gimson, and Emma Denny
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Medical education ,business.industry ,Medicine ,Session (computer science) ,business - Published
- 2021
4. Tasipimidine, a Novel Orally Active Alpha-2 Adrenoceptor Agonist, Alleviates Canine Acute Anxiety Associated With Owner Departure - a Pilot Study
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Karen L. Overall, Mirja Huhtinen, Pasi Pohjanjousi, and Mira Korpivaara
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Orally active ,business.industry ,Medicine ,Alpha-2 adrenergic receptor ,Pharmacology ,Adrenoceptor agonist ,business ,Acute anxiety - Published
- 2021
5. Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES)
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Karim Fizazi, Natalie Cook, Philippe Barthélémy, Alice Bernard-Tessier, Capucine Baldini, Niamh Peters, Pirjo Nykänen, Tarja Ikonen, Pasi Pohjanjousi, Leena Mattila, Lauri Jouhi, Annamari Vuorela, Chris Garratt, and Tapio Utriainen
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Cancer Research ,Oncology - Abstract
18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.
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- 2022
6. A multinational, drug utilization study to investigate the use of dexmedetomidine (Dexdor®) in clinical practice in the EU
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Chris Garratt, Riku Aantaa, Pasi Pohjanjousi, Michael A Lewis, Giorgio Conti, Nicholas Moore, Susana Perez-Gutthann, and Mary Weatherall
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medicine.medical_specialty ,Sedation ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,Informed consent ,law ,medicine ,media_common.cataloged_instance ,Pharmacology (medical) ,030212 general & internal medicine ,Dosing ,European union ,Dexmedetomidine ,Intensive care medicine ,media_common ,Pharmacology ,business.industry ,Retrospective cohort study ,Intensive care unit ,Emergency medicine ,Observational study ,medicine.symptom ,business ,medicine.drug - Abstract
Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.
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- 2017
7. The clinical effects of levosimendan are not attenuated by sulfonylureas
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Piero Pollesello, Markku S. Nieminen, Pasi Pohjanjousi, Wilson S. Colucci, Matti Kivikko, John R. Teerlink, and Alexandre Mebazaa
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Male ,endocrine system ,medicine.medical_specialty ,Acute decompensated heart failure ,medicine.drug_class ,Vasodilator Agents ,Hemodynamics ,Vasodilation ,Risk Assessment ,KATP Channels ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,Humans ,Hypoglycemic Agents ,Medicine ,Drug Interactions ,Propensity Score ,Adverse effect ,Simendan ,Aged ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,Heart Failure ,business.industry ,Hydrazones ,nutritional and metabolic diseases ,Levosimendan ,Middle Aged ,medicine.disease ,Sulfonylurea ,Pyridazines ,Logistic Models ,Sulfonylurea Compounds ,Treatment Outcome ,Heart failure ,Multivariate Analysis ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Levosimendan is an inodilator indicated for acute heart failure (AHF). Its vasodilatory and anti-ischemic effects are mediated by the opening of ATP-dependent potassium channels (K(ATP) channels). Diabetes mellitus is common in AHF patients and sulfonylureas are often prescribed. Sulfonylureas act by blocking the K(ATP) channels. An interaction between levosimendan and sulfonylureas has been shown in preclinical models and could be hypothesized in clinical practice.We produced a pooled analysis of six randomized levosimendan trials (in total of 3004 patients of which 1700 were treated with levosimendan and 226 both with levosimendan and sulfonylureas) with the aim to study the influence of concurrent sulfonylurea treatment to the levosimendan effects. Invasive and non-invasive hemodynamics, biomarkers (BNP), adverse events related to myocardial ischemia, and survival were evaluated.In our relatively small data set, we could not detect any clinically relevant interactions between the sulfonylureas and levosimendan. Similar decreases in systolic and diastolic blood pressure, pulmonary capillary wedge pressure and BNP, and similar survival and adverse event profiles were seen in sulfonylurea users and non-users exposed to levosimendan.Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan.
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- 2012
8. Acetylation status does not affect levosimendan's hemodynamic effects in heart failure patients
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Pasi Pohjanjousi, Stig Sundberg, Wilson S. Colucci, Matti Kivikko, and Mats O. Karlsson
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Male ,medicine.medical_specialty ,Cardiac output ,Vasodilator Agents ,Population ,Hemodynamics ,030204 cardiovascular system & hematology ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Heart rate ,Acetamides ,medicine ,Humans ,education ,Pulmonary wedge pressure ,Simendan ,Heart Failure ,education.field_of_study ,business.industry ,Hydrazones ,Acetylation ,Levosimendan ,Middle Aged ,medicine.disease ,3. Good health ,Pyridazines ,Blood pressure ,Treatment Outcome ,Anesthesia ,Heart failure ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,medicine.drug ,Follow-Up Studies - Abstract
Levosimendan is indicated for acute heart failure. The formation of levosimendan's active metabolite OR-1896 is dependent on the acetylator status. We evaluated whether acetylator status affects the hemodynamic responses after levosimendan infusion.Forty-one NYHA III to IV heart failure patients were divided into rapid and slow acetylators by population kinetic modeling. Invasive hemodynamics and plasma concentrations of levosimendan and its metabolites were followed serially.Fifty-six percent of the patients were rapid and 44% slow acetylators. Levosimendan induced increases in heart rate and cardiac output, and decreases in pulmonary capillary wedge pressure (PCWP) and blood pressure, which were sustained at 24 hours after stopping the infusion. At this time, levosimendan levels were undetectable, and OR-1896 levels were about two-fold higher in rapid acetylators. However, hemodynamic effects were similar; mean(SEM) change from baseline in cardiac output was +2.0(0.3) vs. +1.6(0.3) l/min (p = 0.309), and in PCWP -8(2) vs. -7(1) mmHg (p = 0.536), in rapid and slow acetylators, respectively.The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.
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- 2010
9. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study
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Mathias M. Borst, Franz X. Kleber, Matti Kivikko, Pasi Pohjanjousi, Ralf Ewert, A. Costard‐Jäckle, Tom Bollmann, Steffen Sonntag, Tiina Petterson, and Gerhard Wikström
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Male ,medicine.medical_specialty ,Hypertension, Pulmonary ,Vasodilator Agents ,Pilot Projects ,law.invention ,Right heart failure ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,In patient ,Dosing ,Pulmonary hemodynamics ,Simendan ,Pharmacology ,business.industry ,Hemodynamics ,Hydrazones ,Levosimendan ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Pyridazines ,Anesthesia ,Cardiology ,Potassium channel opener ,Female ,business ,medicine.drug - Abstract
Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension : results of a pilot study
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- 2008
10. Pharmacokinetics, activity, and safety of ODM-201 in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: An open-label phase I trial with long-term extension
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Christophe Massard, Egils Vjaters, Pasi Pohjanjousi, Teuvo L.J. Tammela, Annamari Vuorela, Heidi Penttinen, Karim Fizazi, Pirjo Nykänen, Vilnis Lietuvietis, and Petri Bono
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Cancer Research ,medicine.medical_specialty ,business.industry ,Urology ,Capsule ,Castration resistant ,medicine.disease ,Surgery ,Prostate cancer ,Oncology ,Pharmacokinetics ,medicine ,Open label ,Until Disease Progression ,Adverse effect ,business ,Chemotherapy naive - Abstract
230 Background: The open phase I trial, ARAFOR, with long-term extension evaluated pharmacokinetics (PK), antitumor activity and safety of ODM-201 in chemotherapy-naïve patients with progressive mCRPC. Methods: PK phase: Patients received one 600 mg dose of ODM-201 capsules (6 x 100 mg) in fed state and one dose of either tablet formulation (TabA or TabB, 2 x 300 mg) in fed and fasted state in random order. Extension: Patients received ODM-201 600 mg (capsule) twice daily until disease progression/ intolerable adverse event (AE). A data cut-off date Apr 4, 2014 was used for analyses. Results: 30 patients were enrolled in PK and treated in the extension phase. Baseline characteristics: median age 68 yrs, ECOG score 0 in 67%, and ECOG 1 in 33% patients, median PSA 18.2 ng/mL. Median time from PC diagnosis to start of ODM-201 treatment was 39 months. Median time on ODM-201 treatment was 9.5 months (trial is on-going). ODM-201 plasma concentration–time curves were similar for the capsule, TabA, and TabB at fed state. Median tmax at fed state was longer than in fasted state (5–6 h vs. 4 h). Absorption was slower and plasma exposure about 2-fold greater at fed state compared to fasted state (AUCt, AUC¥ and Cmax values). All 30 patients completed the first 12 weeks of the extension phase. Prostate-specific antigen (PSA) responses (≥50% reduction from baseline) were seen in 25 (83%) patients (PSA reductions ≥90% in 9 [30%] patients). At 12 weeks, RECIST responses in soft tissue were noted in 6 patients (29%) and stable disease in 13 (62%) patients, 3 (11%) had improvement in skeletal metastases and 18 (67%) stabilised bone disease. 21 (70%) reported at least 1 AE, and treatment-related AEs occurred in 6 (20%) patients. No treatment-related AEs of grade 2 or higher were reported. Conclusions: Tablet and capsule formulations showed comparable single-dose pharmacokinetics. Dose level of 600 mg twice daily (capsule) showed significant antitumor activity and had a favourable safety profile. Updated results from the extension phase will be presented. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Clinical trial information: NTC01784757.
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- 2015
11. Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan
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Jaan Eha, Pasi Pohjanjousi, Saila Antila, Matti Kivikko, Aira Heikkilä, Lasse Lehtonen, and Pertti J. Pentikäinen
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Male ,Cardiotonic Agents ,Heart disease ,Metabolite ,chemistry.chemical_compound ,Pharmacokinetics ,Acetamides ,medicine ,Humans ,Pharmacology (medical) ,In patient ,Infusions, Intravenous ,Simendan ,Pharmacology ,Heart Failure ,business.industry ,Hydrazones ,Levosimendan ,medicine.disease ,Pyridazines ,chemistry ,Heart failure ,Anesthesia ,Female ,business ,Perfusion ,medicine.drug ,Protein Binding - Abstract
The purpose of the study was to characterize the pharmacokinetics of levosimendan and its metabolites OR-1855 and OR-1896 in patients with congestive heart failure.Levosimendan was administered as a continuous intravenous infusion for 7 days. Twelve subjects received the drug at an infusion rate of 0.05 micro g kg(-1) min(-1) and 12 at a rate 0.1 micro g kg(-1) min(-1).Steady state concentrations of levosimendan were achieved within 4 h. Peak concentrations of the metabolites occurred after termination of the infusion. The mean (+/- SD) half-life of the active metabolite OR-1896 was 81 +/- 37 h after the lower dose and 81 +/- 28 h after the higher dose (P = 0.992, 95% confidence interval on the difference -27.5, 27.7).The metabolites of levosimendan, OR-1855 and OR-1896, were formed and eliminated slowly, their peak concentrations occurring after termination of the 7-day infusion of the drug.
- Published
- 2004
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