BackgroundNebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood.MethodsUsing amperometric NO and peroxynitrite (ONOO-) nanosensors, β3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 ± 2 μm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507.ResultsNebivolol stimulates endothelial NO release through β3-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 ± 5 nM/s) as compared to the kinetics of ATP (194 ± 10 nM/s), L-755,507 (108 ± 6 nM/s), and 2-MeSATP (105 ± 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 ± 0.10 and significantly higher than that for ATP (0.80 ± 0.08), L-755,507 (1.08 ± 0.08), and 2-MeSATP (1.09 ± 0.09). Nebivolol induced ATP release in a concentration-dependent manner.ConclusionThe two major pathways (ATP efflux/P2Y receptors and β3 receptors) and several steps of nebivolol-induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.

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This study evaluates the administration time-of-day effects on propofol pharmacokinetics and sedative response in rabbits. Nine rabbits were sedated with 5 mg/kg propofol at three local clock times: 10:00, 16:00, and 22:00 h. Each rabbit served as its own control by being given a single infusion at the three different times of day on three separate occasions. Ten arterial blood samples were collected during each clock-time experiment for propofol assay. A two-compartment model was used to describe propofol pharmacokinetics, and the pedal withdrawal reflex was used as the sedation pharmacodynamic response. The categorical data comprising the presence or absence of pedal withdrawal reflex was described by a logistic model. The typical volume of the central compartment equaled 7.67 L and depended on rabbit body weight. The elimination rate constant depended on drug administration time; it was lowest at 10:00 h, highest at 16:00 h, and intermediate at 22:00 h. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment, with the rate constant for the distribution to the effector compartment equal to 0.335 min(-1). Drug concentration had a large effect on the probability of anesthesia. The degree of anesthesia was largest at 10:00 h, lowest at 16:00 h, and intermediate at 22:00 h. In summary, both the pharmacokinetics and pharmacodynamics of propofol in rabbits depended on administration time. The developed population approach may be used to assess chronopharmacokinetics and chronopharmacodynamics of medications in animals and humans.

Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol–fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, biochemical and hemodynamic parameters was collected for the purpose of covariate analysis. Nonlinear mixed effect modeling in NONMEM was used to analyze the collected data. A three-compartment model was sufficient to describe PK of propofol. The anesthetic effect (AAI index) was linked to the propofol effect site concentrations through a sigmoidal Emax model. A slightly higher value of clearance, a lower value of distribution clearance, and a decreased volume of peripheral compartment were observed in our patients, as compared with the literature values reported for healthy volunteers by Schnider et al. and by Eleveld et al. Despite these differences, both models led to a clinically insignificant bias of −8 and −1 % in concentration predictions, as reflected by the median performance error. The Ce50 and propofol biophase concentration at the time of postoperative orientation were low and equaled 1.40 and 1.13 mg/L. The population PK/PD model was proposed for cancer patients undergoing a major lung surgery. The large body of studied covariates did not affect PK/PD of propofol significantly. The modification of propofol dosage in the group of patients under study is not necessary when TCI-guided administration of propofol by means of the Schnider model is used.Electronic supplementary materialThe online version of this article (doi:10.1007/s10928-015-9404-6) contains supplementary material, which is available to authorized users.

We did not find any time-of-day effects for the pharmacokinetic and pharmacodynamics parameters of midazolam. For 1-OH midazolam, statistically significant time-of-day differences in the apparent volume of distribution and clearance were noticed. They corresponded well with the rabbits' water intake. The noncompartmental and model-based parameters were essentially similar. However, more information can be obtained from the population model and this method should be preferred in chronopharmacokinetic and chronopharmacodynamic studies.

Trigonelline is a pyridine alkaloid found in fenugreek seeds and coffee beans. Most of the previous studies are concerned with the quantification of trigonelline along with other constituents in coffee herbs or beverages. Only a few have focused on its determination in animal or human tissues by applying different modes of HPLC with UV or MS detection. The aim of the study was to develop and validate a fast and simple method for trigonelline determination in serum by the use of hydrophilic interaction liquid chromatography (HILIC) with ESI-MS/MS detection. Separation of trigonelline was achieved on a Kinetex HILIC column operated at 35°C with acetonitrile-ammonium formate (10 mm, pH = 3) buffer mixture (55:45, v/v) as the mobile phase. The developed method was successfully applied to determine trigonelline concentration in mouse serum after intravenous administration of 10 mg/kg. The developed assay is sensitive (limit of detection = 1.5 ng/mL, limit of quantification = 5.0 ng/mL) and linear in a concentration range from 5.0 to 250.0 ng/mL. Sample preparation is limited to deproteinization, centrifugation and filtration. The application of the HILIC mode of chromatography with MS detection and selection of deuterated trigonelline as internal standard allowed a rapid and precise method of trigonelline quantification to be to developed.

Background Human recombinant erythropoietin (rHuEPO) is often used in the treatment of diseases associated with a decreased production of red blood cells (RBC), such as chronic renal failure. rHuEPO is typically administered as an intravenous or subcutaneous (SC) injection every few days. The low minimum effective concentration (MEC) of rHuEPO, compared to the concentrations observed after standard doses, suggests that a low dose of the drug administered as a long-term infusion should be efficacious. This study aimed to compare the efficacy observed after a single subcutaneous administration of rHuEPO with that observed after a long-term infusion of rHuEPO via implanted osmotic pumps at a similar or lower dose. Materials and methods In this study three rats received rHuEPO as a single SC injection at a dose of 1350 IU/kg, nine via osmotic pumps at a rate of 0.25, 0.5 and 1 IU/kg and at a total dose of 333 IU/kg, 667 IU/kg, 1333 IU/kg. Three rats served as a control group. The erythropoietin concentrations, RBC count and hemoglobin were measured. Results An increase in RBC count and hemoglobin was observed after SC infusion of rHuEPO. The baseline corrected area under the effect curve for hemoglobin and RBC count was more than 10-times higher for the SC infusion than for a single SC administration with a comparable dose. Conclusions This study demonstrates that administration of rHuEPO as a long-term infusion at a rate ensuring MEC allows to achieve a high efficacy of therapy using relatively small doses of the drug.

Myo-inositol is the most popular inositol in living organisms, where it is present as a sugar alcohol, in a free form, and can also be described as a lipid. The aim of this study was to check the concentration change of a myo-inositol solution from the time of oral administration and over a 48 h period in Wistar-type rats. All rats received 2 g/kg of inositol as a solution in distilled water by oral gavage. Estimated parameters were based on the serum concentration of myo-inositol observed in nine individual rats with regard to time. Observations were described as a one-compartment pharmacokinetic model with first-order absorption and zero-order endogenous input of checked inositol. The highest myo-inositol concentration was observed in the first hour after oral administration in the serum of all tested rats. Then, the concentration began decreasing immediately after the maximal peak. The inositol concentration continued to decrease, but after 24 h its level was still higher than before the administration. The plasma profile of the myo-inositol concentration showed a rapid decline over time, possibly due to the metabolism of this compound.