18 results on '"Ivan Ulč"'
Search Results
2. Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose
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Tom B. Vree, Erik Dammers, Ivan Ulc, Stefan Horkovics-Kovats, Miroslav Ryska, and IJsbrand Merkx
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Technology ,Medicine ,Science - Abstract
The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 � 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50�100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = mg.h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation.There is a large variation in the ramiprilat t1/2β (50�60% CV). There is a group of subjects who showed a t1/2β of approximately 80 h (15% CV), and two apparent groups with a longer t1/2βfor each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean � SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt /kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females.This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.
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- 2003
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3. Relative bioavailability of a pediatric dispersible tablet and adult film‐coated tablet of macitentan in healthy volunteers
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Patricia N. Sidharta, Radka Štěpánová, Susanne Globig, Ivan Ulč, and Dénes Csonka
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bioavailability ,clinical trials ,pediatrics ,respiratory medicine ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film‐coated tablet formulation of macitentan in healthy subjects. A randomized, open‐label, single‐dose, two‐sequence, two‐period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film‐coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non‐compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax), plasma concentration‐time curve from zero to the time of the last quantifiable concentration (AUC0‐t), and plasma concentration‐time curve from zero to infinity (AUC0‐∞) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film‐coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film‐coated tablet formulation.
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- 2020
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4. The dual orexin receptor antagonist daridorexant does not affect the pharmacokinetics of the BCRP substrate rosuvastatin
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Clemens Muehlan, Ivan Ulč, Isabelle Zenklusen, Jasper Dingemanse, and Jiří Liška
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Adult ,0301 basic medicine ,Pyrrolidines ,Physiology ,Cmax ,Pharmacology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Physiology (medical) ,medicine ,Humans ,Distribution (pharmacology) ,Drug Interactions ,Rosuvastatin ,Rosuvastatin Calcium ,IC50 ,Chemistry ,Imidazoles ,Antagonist ,nutritional and metabolic diseases ,Middle Aged ,Orexin receptor ,030104 developmental biology ,Tolerability ,030220 oncology & carcinogenesis ,medicine.drug - Abstract
Daridorexant is a dual orexin receptor antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 μmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.
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- 2020
5. Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol
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Ivan Ulč, Juri Hodisch, Pavla Kadlecová, G. Krumpl, Michaela Trebs, and Bernhard Husch
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medicine.medical_specialty ,Cross-Over Studies ,business.industry ,Morpholines ,Pharmaceutical Science ,Blood Pressure ,Landiolol ,Esmolol ,Crossover study ,Propanolamines ,Blood pressure ,Internal medicine ,Pharmacodynamics ,Dobutamine ,Heart rate ,Renin–angiotensin system ,medicine ,Cardiology ,Humans ,Urea ,Pharmacology (medical) ,Prospective Studies ,business ,medicine.drug - Abstract
We investigated the hemodynamic effects of 2 short-acting β1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 μg/kg/min esmolol or 10 μg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of β-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of β-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for β-blockers, whereas the blood pressure effects are likely due to direct and indirect β-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.
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- 2021
6. Dobutamine Alters the Pharmacokinetic and Pharmacodynamic Behavior of Esmolol
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Bernhard Husch, Pavla Kadlecová, Michaela Trebs, G. Krumpl, Juri Hodisch, and Ivan Ulč
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medicine.medical_specialty ,business.industry ,General Engineering ,Healthy subjects ,Cardiology ,dobutamine ,esmolol ,Esmolol ,Blood pressure ,Pharmacokinetics ,Pharmacodynamics ,Internal medicine ,Heart rate ,medicine ,pharmacodynamics ,Dobutamine ,Adverse effect ,business ,pharmacokinetics ,medicine.drug ,cardioselective β-blocker - Abstract
Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes. Results In the presence of dobutamine, esmolol elimination was substantially faster than without dobutamine, Esmolol infusion reduced dobutamine-induced elevation of HR reversibly whereas the dobutamine-induced systolic blood pressure (SBP) reduction did not recover after the termination of the esmolol infusion. No serious adverse events (AEs) were observed. Conclusions The accelerated elimination of esmolol was likely due to higher cleavage through tissue esterases induced by dobutamine-induced increased tissue passage cycles per time unit. The HR effect was characteristic of a beta-blocker, whereas the blood pressure effect was likely due to a mechanism other than direct beta-blockade. HR remained elevated after the infusion of esmolol and dobutamine, most likely due to persistent blood pressure reduction.
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- 2021
7. Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults
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Pavla Kadlecová, Juri Hodisch, Ivan Ulč, G. Krumpl, and Michaela Trebs
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Adult ,Male ,medicine.medical_specialty ,Cardiotonic Agents ,Morpholines ,Cardioselective β-blocker ,Adrenergic beta-Antagonists ,Blood Pressure ,030204 cardiovascular system & hematology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Pharmacokinetics ,Heart Rate ,Dobutamine ,Internal medicine ,Heart rate ,Humans ,Urea ,Medicine ,Pharmacology (medical) ,Prospective Studies ,030212 general & internal medicine ,Infusions, Intravenous ,Adverse effect ,Pharmacology ,Cross-Over Studies ,business.industry ,Antagonist ,Landiolol ,Healthy Volunteers ,Blood pressure ,Pharmacodynamics ,Cardiology ,Female ,business ,Research Article ,medicine.drug - Abstract
Background To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol. Results Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20–60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. Conclusion Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. Trial registration Registration number 2010–023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.
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- 2020
8. Pharmacodynamic and -kinetic Behavior of Low-, Intermediate-, and High-Dose Landiolol During Long-Term Infusion in Whites
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Juri Hodisch, Gabriele Maurer, Michaela Trebs, G. Krumpl, Bernhard Husch, Ivan Ulč, and Pavla Kadlecová
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Adult ,Male ,Morpholines ,Adrenergic beta-Antagonists ,Diastole ,030204 cardiovascular system & hematology ,Pharmacology ,030226 pharmacology & pharmacy ,White People ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Pharmacokinetics ,Heart rate ,Humans ,Urea ,Medicine ,Prospective Studies ,Infusions, Intravenous ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Landiolol ,Adrenergic beta-1 Receptor Antagonists ,Crossover study ,Blood pressure ,Tolerability ,Pharmacodynamics ,Anesthesia ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective β-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 μg/kg BW/min for 2 hours, 20 μg/kg BW/min for 2 hours, 40 μg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.
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- 2017
9. Pharmacokinetics and pharmacodynamics of two different landiolol formulations in a healthy Caucasian group
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Michaela Trebs, Juri Hodisch, Ivan Ulč, G. Krumpl, and Pavla Kadlecová
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Adult ,Male ,Adolescent ,Drug Compounding ,Morpholines ,Adrenergic beta-Antagonists ,Pharmaceutical Science ,Blood Pressure ,030204 cardiovascular system & hematology ,Pharmacology ,030226 pharmacology & pharmacy ,White People ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Pharmacokinetics ,Heart Rate ,Heart rate ,Humans ,Urea ,Medicine ,Cross-Over Studies ,business.industry ,Antagonist ,Landiolol ,Crossover study ,Healthy Volunteers ,Blood pressure ,Tolerability ,Anesthesia ,Pharmacodynamics ,Female ,business ,medicine.drug - Abstract
Background To date, no data have been reported on the pharmacokinetic and pharmacodynamic properties of landiolol, a fast-acting cardioselective β1-adrenergic antagonist, in non-Asian subjects. The aim of this study was to compare two landiolol formulations in healthy Caucasian subjects. Materials and methods We conducted a single-center, prospective, double-blinded, randomized study in two cross-over periods with 12 healthy subjects (7 women and 5 men) each receiving three doses (0.1, 0.2, and 0.3 mg/kg BW) of Onoact® 50 Lyophilized powder (50 mg) or Rapibloc® concentrate IV (20 mg/2 mL) to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the two landiolol formulations. Results For both formulations, maximum blood concentrations of landiolol were rapidly reached (median tmax 2.3 ± 0.65 and 2.8 ± 1.13 min for the high dose of each formulation). The compounds had a short half-life (t1/2 = 3.2 ± 1.2 min and 3.0 ± 1.1 min for the low dose of the concentrate formulation and the lyophilized powder, respectively). The results showed no statistically significant differences between both formulations of landiolol for any PK parameters, at study doses. Both formulations dose-dependently and significantly decreased the heart rate values from 62.2 bpm at baseline to minimum values of 55–56, 52–53, and 50–52 bpm after 0.1, 0.2, and 0.3 mg/kg respectively. This bradycardic effect was achieved within 1 to 3 min. The decrease in systolic blood pressure (baseline: 107 mm Hg, minimum values were around 99 mm Hg) was significant but not dose dependent, and occurred within 3 to 12 min. Seven mild to moderate AEs occurred after administration of the concentrate formulation. No SAEs were reported in this study. Conclusion In Caucasians, both landiolol formulations showed similar pharmacokinetic behaviours, displaying very short half-lives (3.0 to 3.6 min). In addition, after administration of both formulations, the landiolol-induced heart rate reduction showed fast onset and dose dependence, whilst the decrease of systolic blood pressure occurred more slowly, was less pronounced, and dose independent. In summary, both landiolol formulations delivered comparable plasma concentration profiles and showed good local tolerability. Overall, the pharmacokinetic and pharmacodynamic reactions observed in Caucasians were comparable to those described in Japanese subjects.
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- 2016
10. Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment
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Atef Halabi, Priska Kaufmann, Hans G. Cruz, Jasper Dingemanse, Andreas Krause, and Ivan Ulč
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Pharmacology ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,Renal function ,030204 cardiovascular system & hematology ,Selexipag ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Pharmacokinetics ,Tolerability ,Internal medicine ,Severity of illness ,medicine ,Pharmacology (medical) ,business ,Prospective cohort study ,Prostacyclin receptor - Abstract
Aim The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. Methods Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. Results Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with mild hepatic impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. Conclusions Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.
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- 2016
11. Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites
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Bernhard Husch, Gabriele Maurer, Michaela Trebs, Pavla Kadlecová, Juri Hodisch, G. Krumpl, and Ivan Ulč
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Adult ,Male ,Adolescent ,Morpholines ,Adrenergic beta-Antagonists ,Blood Pressure ,030204 cardiovascular system & hematology ,030226 pharmacology & pharmacy ,Drug Administration Schedule ,White People ,Propanolamines ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Double-Blind Method ,Heart Rate ,Healthy volunteers ,medicine ,Humans ,Urea ,Prospective Studies ,Infusions, Intravenous ,Czech Republic ,Pharmacology ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Hemodynamics ,Landiolol ,Middle Aged ,Esmolol ,Adrenergic beta-1 Receptor Antagonists ,Healthy Volunteers ,Clinical trial ,Tolerability ,Therapeutic Equivalency ,Anesthesia ,Pharmacodynamics ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective β-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.
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- 2017
12. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment
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Ivan Ulč, Nicolas Lindegger, Patricia N. Sidharta, and Jasper Dingemanse
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Pharmacology ,medicine.medical_specialty ,business.industry ,Endothelin receptor antagonist ,Hepatic impairment ,Healthy subjects ,Area under the curve ,Renal function ,Gastroenterology ,Single oral dose ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,Internal medicine ,Medicine ,Pharmacology (medical) ,business ,Macitentan - Abstract
Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.
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- 2013
13. Prolonged Corrected QT Interval as a Predictor of Clinical Outcome in Acute Ischemic Stroke
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Daniel Rajdl, Ivan Ulč, Milan Hromádka, Jakub Šedivý, Jan Baxa, Jiří Polívka, Petr Sevcik, Vladimir Rohan, Richard Rokyta, and Jitka Seidlerová
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Male ,Time Factors ,Computed Tomography Angiography ,Action Potentials ,030204 cardiovascular system & hematology ,law.invention ,Brain Ischemia ,Disability Evaluation ,Electrocardiography ,0302 clinical medicine ,Patient Admission ,Modified Rankin Scale ,law ,Heart Rate ,Risk Factors ,Natriuretic Peptide, Brain ,Odds Ratio ,Medicine ,Hospital Mortality ,Stroke ,Aged, 80 and over ,Neurologic Examination ,Univariate analysis ,Rehabilitation ,Middle Aged ,Brain natriuretic peptide ,Intensive care unit ,Intensive Care Units ,Treatment Outcome ,Anesthesia ,cardiovascular system ,Female ,Cardiology and Cardiovascular Medicine ,circulatory and respiratory physiology ,Adult ,QT interval ,03 medical and health sciences ,Heart Conduction System ,Predictive Value of Tests ,Humans ,cardiovascular diseases ,Aged ,business.industry ,Troponin I ,Odds ratio ,Recovery of Function ,medicine.disease ,Confidence interval ,Cerebral Angiography ,Logistic Models ,Multivariate Analysis ,Surgery ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
This study aimed to investigate changes of corrected QT (QTc) interval during acute ischemic stroke and its correlation with high-sensitivity troponin I (hsTnI), brain natriuretic peptide (BNP), neurological outcome, and 1-year mortality.We registered electrocardiogram in 69 patients immediately after admission to the intensive care unit and then after 24 and 48 hours. Computed tomography was performed on admission to determine brain infarct size and localization. Neurological outcome was assessed by modified Rankin scale (mRS) at discharge.Forty-five (65.2%) patients had prolonged QTc at baseline; only 18 (26.1%) patients had prolonged QTc after 48 hours. Baseline QTc was not associated with neurological outcome (P = .27). However, prolonged QTc after 48 hours was associated with worse mRS at discharge (4.5 [4.0-6.0] versus 2.0 [1.0-3.0]; P .0001). Patients who deceased during hospitalization (n = 7 [10.1%]) as compared with survivors had more frequently prolonged QTc after 48 hours (38.9 versus 0%; P .0001), higher level of hsTnI (48.4 [36.1-75.0] versus 8.6 [3.4-26.5]; P = .003), and BNP (334 [224-866] versus 109 [30-190]; P = .014). In univariate analysis, 1-year mortality was associated with prolonged QTc after 48 hours, hsTnI, and BNP. In multivariate analysis, only BNP remained to be associated with 1-year mortality (odds ratio 3.41, 95% confidence interval 1.06-11.03).QTc interval in patients with acute ischemic stroke is a dynamic parameter. Prolonged QTc after 48 hours, but not baseline QTc, correlated with neurological outcome and 1-year mortality. Patients with prolonged QTc had higher level of hsTnI.
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- 2016
14. The variability of automated QRS duration measurement
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Ivan Ulč, Vlastimil Vančura, Jiří Šmíd, Marek Brabec, Dan Wichterle, Marta Zarybnicka, and Richard Rokyta
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Systematic difference ,medicine.medical_specialty ,medicine.medical_treatment ,Cardiac resynchronization therapy ,030204 cardiovascular system & hematology ,Sensitivity and Specificity ,Pattern Recognition, Automated ,03 medical and health sciences ,QRS complex duration ,QRS complex ,Electrocardiography ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,030212 general & internal medicine ,Diagnosis, Computer-Assisted ,Aged ,business.industry ,Reproducibility of Results ,Equipment Design ,University hospital ,Equipment Failure Analysis ,Electrocardiographs ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Algorithms - Abstract
Aims Previous studies have demonstrated substantial variability in manual assessment of QRS complex duration (QRSd). Disagreements in QRSd measurements were also found in several automated algorithms tested on digitized electrocardiogram (ECG) recordings. The aim of our study was to investigate the variability of automated QRSd measurements performed by two commercially available electrocardiographs. Methods and results Two GE MAC 5000 (GE-1 and GE-2) electrocardiographs and two Mortara ELI 350 (Mortara-1 and Mortara-2) electrocardiographs were used in the study. Participants for the study were recruited from patients hospitalized in the department of cardiology of a university hospital. Participants underwent up to four recording sessions within a single day with a different electrocardiograph at each session when two to four immediately successive ECG recordings were undertaken. In 76 patients, 683 ECGs were recorded; the mean QRSd was 109.0 ± 26.1 ms. The QRSd difference ≥10 ms between the first and second intra-session ECG was found in 7, 3, 20, and 14% of ECG pairs for GE-1, GE-2, Mortara-1, and Mortara-2, respectively. No inter-session difference in QRSd was found within both manufacturers. In individual patients, Mortara calculated the mean QRSd to be longer by 7.3 ms (95% CI: 6.2–8.5 ms, P < 0.0001) with a 2.1-times (95% CI: 1.9–2.4) greater standard deviation of the mean QRSd (7.1 vs. 3.3 ms, P < 0.001). Conclusion Electrocardiographs from two manufacturers measured QRSd values with a systematic difference and a significantly different level of precision. This may have important clinical implications in selection of suitable candidates for cardiac resynchronization therapy.
- Published
- 2015
15. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment
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Patricia N, Sidharta, Nicolas, Lindegger, Ivan, Ulč, and Jasper, Dingemanse
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Adult ,Endothelin Receptor Antagonists ,Male ,Sulfonamides ,Pyrimidines ,Liver Diseases ,Humans ,Female ,Prospective Studies ,Renal Insufficiency ,Middle Aged ,Aged - Abstract
Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.
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- 2013
16. Single-Dose Pharmacokinetics, Safety, and Tolerability of Macitentan, a New Dual Endothelin Receptor Antagonist, in Subjects With Severe Renal Function Impairment
- Author
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Patricia N. Sidharta, Nicolas Lindegger, Ivan Ulč, Paul L. M. van Giersbergen, and Jasper Dingemanse
- Subjects
Pulmonary and Respiratory Medicine ,business.industry ,Endothelin receptor antagonist ,Renal function ,Pharmacology ,Critical Care and Intensive Care Medicine ,Single dose regimen ,chemistry.chemical_compound ,chemistry ,Tolerability ,Pharmacokinetics ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Macitentan - Published
- 2012
17. Optimization of pacing intervals in cardiac resynchronization therapy
- Author
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Vlastimil Vančura and Ivan Ulč
- Subjects
medicine.medical_specialty ,Reproducibility ,Cardiac resynchronization therapy ,business.industry ,Finger plethysmography ,medicine.medical_treatment ,Av interval ,Hemodynamics ,Statistical data analysis ,medicine.disease ,Confidence interval ,Hemodynamics of pacing ,Internal medicine ,Heart failure ,Optimization of pacing intervals ,medicine ,Cardiology ,In patient ,Cardiology and Cardiovascular Medicine ,business - Abstract
In patients with heart failure, left ventricular systolic dysfunction and prolonged QRS complex, cardiac resynchronization therapy (CRT) is a treatment method aimed at restoration of myocardial depolarization synchronicity. However, the extent of clinical and echocardiographic improvement depends on anatomical relations in individual patients, on structural changes in the heart, on intrinsic electrical activation, and on the position of pacing leads. Many parameters of CRT devices may be changed in order to tailor the function of CRT to the needs of a particular patient; the most important among them is AV and VV interval. The largest trials studying CRT used various methods for optimization of these intervals but unequivocal proof of the benefit brought by optimization is still lacking. Many methods were evaluated, most frequently based on echocardiography and intracardiac electrogram interval measurement. However, drawbacks in statistics make the studies of limited value for establishing a reference method or guidance for daily practice. Echocardiography has inherent variability of results and is highly operator dependent. Optimization based on intracardiac electrogram intervals has not proved yet to be of clear benefit above arbitrary AV interval. The most promising method is hemodynamic assessment by finger plethysmography. Measured data are highly reproducible and operator-independentA randomized multicenter double-blind study using finger plethysmography is needed to prove the value of this method and of CRT optimization in general. The measurement of information content in any data suitable for CRT optimization, analysis of reproducibility and general usage of confidence intervals may show other methods appropriate for it, too. The cooperation with a statistician is oftentimes a necessity.
- Full Text
- View/download PDF
18. Differences Between Lovastatin and Simvastatin Hydrolysis in Healthy Male and Female Volunteers: Gut Hydrolysis of Lovastatin is Twice that of Simvastatin
- Author
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Tom B. Vree, Erik Dammers, Ivan Ulc, Stefan Horkovics-Kovats, Miroslav Ryska, and IJsbrand Merkx
- Subjects
Technology ,Medicine ,Science - Abstract
The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-β-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: 1-The group of female volunteers showed a higher yield of the active metabolite β-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. 2-In the male/female groups, subject-dependent yield of active metabolite β-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the β-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtβ-hydroxy acid). 3-Lovastatin hydrolysis was higher than simvastatin hydrolysis. 4-It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity.
- Published
- 2003
- Full Text
- View/download PDF
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