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The 2019 coronavirus pandemic has caused serious health crises around the world such as psychological reactions of health workers. The way we work (stress, anxiety) and the activities assigned to pharmacists, such as vaccination, have changed. In addition to these problems, numerous ethical questions and moral doubts are increasingly emerging are inevitable during the treatment and care of patients in this extremely difficult situation. Work in the oncology department is stressful even when there is no epidemic/pandemic. Constant changes in hospital protocols, reorganization of work, influx of patients, work in intensive conditions and other new challenges of adaptation to the new situation affect both the physical and mental health of healthcare workers. Together with physicians and nurses, pharmacists were one of the professional categories most exposed to the risk of SARS- CoV-2 infection since the pandemic onset. Together with this crisis, pharmaceutical care entered a new phase demonstrating the ability of pharmacists to be competent and accessible providers of public health. Preserving the mental health of healthcare workers are very important so that they can perform their work with quality and conscientiousness. Health care corporations should consider providing coverage for mental health treatment for employees who experience COVID-19 traumas.

Probability of target attainment (PTA) curves are commonly used to support dose recommendations of antibiotics for different patient groups. In this study we propose PTA analysis to optimize sugammadex dosing in children.This study involved data from an observational cohort study of 30 American Society of Anesthesiologists (ASA) Physical Status I and II children undergoing surgery requiring muscle relaxation. All patients received 0.6 mg/kg rocuronium, with sugammadex administered at the end of surgery in three different doses (0.5, 1.0, and 2.0 mg/kg) to reverse the neuromuscular blockade.The data were analyzed using a population Bayesian-based approach. The developed model was used to simulate pharmacokinetic-pharmacodynamic profiles for different patient groups and dosing regimens before the PTA analysis was performed to translate these simulations into a clinically useful measure. The target was defined as neuromuscular blockade reversal measured by Train-of-Four (TOF ratio 90%) at 1.5, 3, and 5 min post sugammadex dose. The sugammadex doses leading to 90% PTA were determined for different patients' body weights, rocuronium doses, and time gaps between rocuronium and sugammadex administration assuming the model, priors, and gathered data. For comparison, PTA curves for a range of clinical scenarios are provided to illustrate the usefulness of PTA analysis in selecting the appropriate dose for a given patient.The proposed PTA analysis is useful to support the sugammadex dose selection in different clinical scenarios.The study was registered by ClinicalTrials.gov under number NCT04851574 on 21 April 2021.

Cardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2–3 µg/kg each time analgesia appeared to be inadequate. Hemodynamic measurements as well as bispectral index were monitored and recorded throughout the surgery. Data analysis was performed by using a non-linear mixed-effect population modeling (NONMEM 7.4 software). Three compartment models that incorporated blood flows as parameters were used to describe propofol and fentanyl pharmacokinetics. The delay of the anesthetic effect, with respect to plasma concentrations, was described using a biophase (effect) compartment. The bispectral index was linked to the propofol and fentanyl effect site concentrations through a synergistic Emax model. An empirical linear model was used to describe CO changes observed during the surgery. Cardiac output was identified as an important predictor of propofol and fentanyl pharmacokinetics. Consequently, it affected the depth of anesthesia and the recovery time after propofol-fentanyl TIVA infusion cessation. The model predicted (not observed) CO values correlated best with measured responses. Patients‘ age was identified as a covariate affecting the rate of CO changes during the anesthesia leading to age-related difference in individual patient’s responses to both drugs. Electronic supplementary material The online version of this article (10.1007/s10928-020-09712-1) contains supplementary material, which is available to authorized users.

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 μg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.

Aim: The aim of this study was to assess the analgesic efficacy and safety of 1 mg and 0.5 mg oxycodone administration in a spinal block procedure for a total hip arthroplasty (THA). Patients and Methods: Forty-two THA patients aged 59-81 with American Society Anesthesiology (ASA) II-III were included. All patients received anesthesia using spinal blockade, with bupivacaine 0.5% spinal heavy 2.5 ml, with 0.5 ml oxycodone hydrochloride 1.0 mg (group A; n = 28) or 0.5 mg (group B; n = 14). During surgery, each patient was sedated with 2-4 mg/kg/h intravenous propofol infusion. They received 100 mg intravenous ketoprofen at the end of the surgery at 8 pm and 8 am, with recommended doses every 12 h thereafter. Subcutaneous morphine 5 mg was used as a rescue analgesic, and the time to morphine use was recorded. After surgery, pain intensity (at the moment of patient report) was assessed using an 11-point numerical rating scale (NRS). The incidence of adverse effects was monitored. Blood samples were taken for assays of serum oxycodone, noroxycodone and bupivacaine levels. Results: The time to rescue analgesia was 9.6 ± 5.6 h in group A and 7.3 ± 1.9 h in group B, and it did not differ between patient groups (P = 0.179). The mean NRS pain score was 4.5 in group A and 4.2 in group B. Three group A patients had detectable oxycodone levels: two < 7.1 ng/ml and in 1 spinal block induced anesthesia was unsuccessful and so he/she underwent general anesthesia (this patient was excluded from the analysis). Four group B patients had single values < 5 ng/ml. Noroxycodone levels were in all patients undetectable, and bupivacaine levels were 70-300 ng/ml. Regarding adverse effects, one patient had hypotension, one had bradycardia, and one had pruritus. Conclusion: Oxycodone in spinal block prolongs analgesia period, does not cause serious adverse effects and seems to be safe and effective opioid for patients undergoing THA.

Dexmedetomidine is a hepatically eliminated drug with sedative, anxiolytic, sympatholytic, and analgesic properties that has been increasingly used for various indications in the form of a short or continuous intravenous infusion. This study aimed to propose a population pharmacokinetic (PK) model of dexmedetomidine in a heterogeneous group of intensive care unit patients, incorporating 29 covariates potentially linked with dexmedetomidine PK. Data were collected from 70 patients aged between 0.25 and 88 years and treated with dexmedetomidine infusion for various durations at 1 of 4 medical centers. Statistical analysis was performed using a nonlinear mixed-effect model. Categorical and continuous covariates including demographic data, hemodynamic parameters, biochemical markers, and 11 single-nucleotide polymorphisms were tested. A 2-compartment model was used to describe dexmedetomidine PK. An allometric/isometric scaling was used to account for body weight difference in PK parameters, and the Hill equation was used to describe the maturation of clearance. Typical values of the central and peripheral volume of distribution and the systemic and distribution clearance for a theoretical adult patient were central volume of distribution = 22.50 L, peripheral volume of distribution = 86.1 L, systemic clearance = 34.7 L/h, and distribution clearance = 40.8 L/h. The CYP1A2 genetic polymorphism and noradrenaline administration were identified as significant covariates for clearance. A population PK model of dexmedetomidine was successfully developed. The proposed model is well calibrated to the observed data. The identified covariates account for

University of Medical Sciences participates in the realization of the project titled: „Development of the technology of producing cannabinoids from low THC hemp for use as preparations supporting treatment in oncological patients” awarded by the National Centre for Research and Development under project number: INNOMED/I/11/NCBR/2014. The duration of the grant is 36 months, and the total value of the grant is 28011845 PLN. The project is run by University of Life Sciences in Poznan. Laboratory of Experimental Pharmacogenetics at the Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences (PUMS) is realizing the task number 4 titled “Evaluation of efficacy and mechanisms of action of Cannabis sativa extracts with analgesic, anti-inflammatory and antiemetic properties in an in vivo model.” The aim of this project is the development of cannabinoid extract with reduced psychoactive component (THC), which due to its high content of cannabidiol (CBD) is meant to provide analgesic properties, and at the same time to reduce the risk of addiction and overdose. University of Medical Sciences is evaluating the analgesic, anti-inflammatory and antiemetic properties of the extract of Cannabis sativa in animal models coupled with neuropathic pain. Pharmacodynamic effects of plant extracts will be later assessed taking into account the level of selected genes and proteins expression.

Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit. This study was performed in the group of 17 males and 10 females patients with a median age of 59.5 years and median body weight of 75 kg. Blood samples for dexmedetomidine assay were collected from arterial catheter, during and after discontinuation of a standard infusion, that ranged from 24 to 102 h. The following covariates were examined to influence dexmedetomidine PK: age, sex, body weight, patients’ health status described by Sequential Organ Failure Assessment Score (SOFA), inotropes usage, and infusion duration. The dexmedetomidine PK was best described by a two-compartment model. The typical values of PK parameters were estimated as 27 L for the volume of the central compartment, 87.6 L for the volume of the peripheral compartment, 38.5 L/h (9.2 mL/min/kg for a 70 kg patient) for systemic clearance and 46.4 L/h for the distribution clearance. Those values are consistent with literature findings. We were unable to show any significant relationship between collected covariates and dexmedetomidine PK. This study does not provide sufficient evidence to support the individualization of dexmedetomidine dosing based on age, sex, body weight, SOFA, and infusion duration. Electronic supplementary material The online version of this article (10.1007/s10928-017-9564-7) contains supplementary material, which is available to authorized users.

The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis—20 infants aged 3–36 months receiving sufentanil as an epidural infusion and 41 children 0–17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2-compartment model with first-order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model-building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70-kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip-flop pharmacokinetics of sufentanil after epidural administration.

Aim: The purpose of this work was to develop and validate a rapid and robust LC–MS/MS method for the determination of dexmedetomidine (DEX) in plasma, suitable for analysis of a large number of samples. Method: Systematic approach, Design of Experiments, was applied to optimize ESI source parameters and to evaluate method robustness, therefore, a rapid, stable and cost-effective assay was developed. The method was validated according to US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (5–2500 pg/ml), Results: Experimental design approach was applied for optimization of ESI source parameters and evaluation of method robustness. The method was validated according to the US FDA guidelines. LLOQ was determined at 5 pg/ml. The assay was linear over the examined concentration range (R2 > 0.98). The accuracies, intra- and interday precisions were less than 15%. The stability data confirmed reliable behavior of DEX under tested conditions. Conclusion: Application of Design of Experiments approach allowed for fast and efficient analytical method development and validation as well as for reduced usage of chemicals necessary for regular method optimization. The proposed technique was applied to determination of DEX pharmacokinetics in pediatric patients undergoing long-term sedation in the intensive care unit.

Introduction. Acute postoperative pain continues to be a dilemma to patients and clinicians.Aim. To define the efficacy, tolerability and pharmacokinetics of paracetamol and ketoprofen in patients after the abdominal aortic surgery. Setting and design in University hospital – intensive therapy unit (clinical part), clinical pharmacy and biopharmacy unit (biochemical part), and pharmaceutical company (statistical part). Prospective randomized study.Material and Methods. 40 adult patients (50–84 years) undergoing abdominal aortic surgery were randomized equally into two groups. After extubation the patients in group 1 (G1) were administered a 1 g paracetamol infusion, and in group 2 (G2) – a 100 mg ketoprofen infusion, both within 15 minutes. All the patients received an epidural infusion of bupivacaine with fentanyl. The following parameters were recorded: mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), plasma concentration of paracetamol and ketoprofen. Postoperative pain was assessed with the visual analogue scale (VAS).Results. The mean values of the MAP, HR and CVP were within normal limits in the both groups. No significant differences were noticed in the assessment of postoperative pain and total use of an opioid. The mean therapeutic plasma concentration of paracetamol and ketoprofen remained up to 180 minutes and up to 120 minutes, respecively.Conclusions. The study enabled us to conclude that intravenous paracetamol as well as ketoprofen have good effectiveness and tolerability. There is no need to modify dosage of these drugs to elderly patients. After paracetamol infusion the therapeutic plasma concentration remains longer than after the ketoprofen infusion.

The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd.

Paracetamol is one of the most common analgesics and antipyretics applied in health care. The aim of the study was to investigate the influence of the time-of-day administration on the paracetamol pharmacokinetics and its penetration into aqueous humour (AH). Rabbits were divided into three groups: I—receiving paracetamol at 08.00 h, II—receiving paracetamol at 16.00 h, and III—receiving paracetamol at 24.00 h. Paracetamol was administered intravenously at a single dose of 35 mg/kg. The concentrations of paracetamol and its metabolite (paracetamol glucuronide) in the plasma, as well as in AH were measured with the validated HPLC–UV method. No significant differences in the pharmacokinetic parameters of paracetamol was observed. When the drug was administered at 24.00 h, elimination half-life (t 1/2kel) of paracetamol glucuronide was longer than when the drug was administered 08.00 h (P = 0.0193). In addition, a statistically significant increase in the paracetamol glucuronide/paracetamol ratio was observed when the drug was administered at 08.00 vs. 16.00 h (P ≤ 0.0001) and 24.00 h (P ≤ 0.0001). There was no chronobiological effect on the pharmacokinetic parameters of paracetamol.

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.

Objective. Development of midazolam (MDZ) pharmacokinetic model is pivotal for predicting drug response and determining appropriate dosing in patients who undergo surgical procedures. The aim of this study was to provide population pharmacokinetic analysis describing MDZ and its main metabolite 1-OH-midazolam (1-OH-MDZ) used during oral premedication in surgical paediatric patients. The influence of gender, age, and body weight on MDZ pharmacokinetics was also investigated. Material and Methods The analyzed data set included 27 patients, aged 1 to 17 years, who received oral midazolam syrup before various surgical procedures. The 1‑OH‑MDZ concentration was approximated by a proportional relationship to MDZ concentration. Population nonlinear mixed-effect modeling was done using NONMEM 7.2. Non-parametric bootstrap and VPC were conducted to evaluate the adequacy of the model to describe the observations. Results Midazolam pharmacokinetic model was developed to describe the time course of MDZ and 1-OH-MDZ concentrations. High inter-individual variability in volume of central compartment (93%) and clearance (60%) of MDZ w ere observed. The effect of body weight was accounted for by the allometric scaling. Significant differences in MDZ pharmacokinetics due to the age and gender were not found. Conclusions The population MDZ pharmacokinetic model was successfully developed for paediatric patients. Age, gender do not explain inter-individual variation in the pharmacokinetics of MDZ. No effect of maturation was detected.

The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3-fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge. Electronic supplementary material The online version of this article (doi:10.1007/s10928-016-9474-0) contains supplementary material, which is available to authorized users.

Introduction: Rectal tenesmus pain in cancer patients most frequently appears in patients with colon cancer, and as a consequence of radiotherapy of the hypogastrium region. Treatment with opioids and adjuvant analgesics is often ineffective. Patients and methods: Here, we report on two female patients diagnosed with colon and ovary cancer, respectively, who had very severe tenesmus pain (numerical rating scale 8–10) despite using high doses of opioids, including methadone with corticosteroids, anticonvulsants, antidepressants and ketamine. Results: In both patients, bupivacaine was administered via a rectal enema. In the first patient, bupivacaine was administered at a dose of 100 mg 0.1% (100 mL), and subsequently 100 mg 0.2% (50 mL), leading to effective analgesia for 8 and 12 hrs, respectively. In the second patient, 100 mg 0.1% (100 mL) was initially administered, followed by 100 mg 0.2% (50 mL), leading to effective analgesia for 12 and 17 hrs, respectively, with only dull abdominal pain reported that was relieved by 100 mg IV ketoprofen and complete disappearance of tenesmus pain. Rectal bupivacaine administration did not cause neurologic adverse effects, heart function disturbances or decreased blood pressure. A volume of 50 mL was enough to cover a painful area in the colon. Initial bupivacaine concentrations in the blood serum did not exceed 50 ng/mL and eventually dropped to 20 ng/mL and below. Conclusions: Administration of 100 mg bupivacaine as a rectal enema is safe and provides effective analgesia, and this procedure may be conducted in hospital departments and out-patient clinics. Furthermore, this procedure in the case of pain recurrence, can be repeated, and by providing effective pain relief often allows time for the patient to be transferred to a specialized pain center.

Aim. This study aimed to evaluate the pharmacodynamics of dexmedetomidine in elderly cardiac patients.Material and Methods. Twelve patients of 60 years or older and need for analgesia after surgery or as a result of critical health conditions were included into our study. Dexmedetomidine was administered intravenously as a continuous infusion without the initial dose. At the beginning the infusion was started at the rate of 0.7 µg/kg/h and then it was continued in the range of 0.17–1.39 µg/kg/h according to desired level of sedation. Information about heart rate, systolic, diastolic and mean arterial blood pressure, bispectral index and cardiac index were collected a few minutes before, during and in 12 hours after infusion of dexmedetomidine.Results. The hemodynamic data as well as BIS level were collected from 12 patients. The duration of dexmedetomidine infusion was less than 9 hours. For each patient the reduction in blood pressure and heart rate compared to the value before dexmedetomidine infusion was observed. We did not observe bradycardia in any patient. Appropriate sedation level was achieved using only dexmedetomidine and ranged from 60 to 80. In only 2 cases it was necessary to give a single dose of another sedative.Conclusions. To conclude, in the patients’ population involved in the study, which included older cardiac patients dexmedetomidne has been shown as a sedative agent which enabled to achieve desire level of sedation in the recommended ranges without episodes of bradycardia, however hypotension events were noted.

The aims of this study were to develop a population pharmacokinetic model of sufentanil coadministered with 0.2% ropivacaine as an epidural infusion in infants and describe the sufentanil absorption profile from epidural space. Data from 2 previously published studies were merged for analysis-20 infants aged 3-36 months receiving sufentanil as an epidural infusion and 41 children 0-17 years old receiving sufentanil as a long-term intravenous infusion. A population nonlinear mixed-effects model was built in NONMEM. Sufentanil pharmacokinetics were described by a 2-compartment model with first-order absorption. The effect of body size on all volume and clearance parameters was included in the model according to allometric scaling with theoretical exponents. The maturation process of metabolic clearance was described by the Hill model. During the model-building process the population was divided into 2 fractions with different typical values of metabolic clearance (CL1 and CL2). The typical values of systemic clearance scaled to a 70-kg patient for the 2 subpopulations were CL1 = 52.6 L/h and CL2 = 158 L/h. The parameters of the Hill function were 54.9 weeks for the postmenstrual age of 50% clearance maturation and 0.802 for the Hill coefficient. The typical values of distribution clearance and volumes of the central and peripheral compartments for a patient with a weight of 70 kg were Q = 40.5 L/h, VC = 7.63 L, and VT = 473 L, respectively. The value of the absorption rate constant from the epidural space was 0.0459/h, which suggests flip-flop pharmacokinetics of sufentanil after epidural administration.

Recently oral melatonin has been proposed as an agent for premedication. In this study, we compared melatonin with clonidine, considering its anxiolytic properties as well as the influence of both agents on the pharmacokinetic, hypnotic, and hemodynamic effects of propofol during propofol-remifentanil total intravenous anesthesia (TIVA). The dataset under analysis included 32 patients scheduled for a functional endoscopic sinus surgery. The population pharmacokinetic modeling was done with NONMEM. The PK of propofol was described with a two-compartment disposition model, whereas the BIS and AAI were described with a sigmoidal Emax model linked with the propofol concentration via the biophase compartment. The anxiolytic effect was assessed by means of the visual analog scale for anxiety (VAS-A). The population PK/PD model was successfully developed to describe the data. No significant differences in the PK/PD of propofol were noted due to the premedication with clonidine and melatonin. Melatonin was less effective than clonidine in reducing patients' anxiety at the induction of anesthesia, whereas clonidine premedication was associated with greater decrease in heart rate and blood pressure. A decreased EC50 (2.47 vs. 3.17 mg/L) and increased slope (2.71 vs. 1.30) of the sigmoidal Emax relationship was observed for the AAI index, as compared with the BIS measurements.

Aim. This study aimed to examine the influence of maturation and dosage on the sedative and haemodynamic response observed in rabbits after the administration of dexmedetomidine. Material and methods. The pharmacodynamics of dexmedetomidine was studied on 14 healthy New Zealand white rabbits at three periods of maturation; stage 1–1.5 months old, stage 2–2.5 months old and stage 3–6.5 months old ones. The administered dose of dexmedetomidine ranged from 25 µg/kg to 300 µg/kg of body weight. The pedal withdrawal reflex was used to measure the duration of anaesthesia. The heart rate and mean arterial pressure were measured at the third stage of the study to evaluate the haemodynamic response. A simple pharmacodynamic relationship between the dose and the duration of anesthesia was used to describe the data.Results. We observed that young rabbits were less sensitive to dexmedetomidine than adult animals, as was reflected by the pedal withdrawal reflex, and we found that the haemodynamic response to dexmedetomidine depended on dosage of the drug. Dexmedetomidine decreased the mean blood pressure in a dosage-dependent manner with the highest decrease observed for the lowest dose. As the dose increased, the hypotensive effect of the drug was less noticeable. After the administration of dexmedetomidine the heart rate decreased to the same value regardless of the dose applied.

Endoscopic procedures involving the gastrointestinal tract have been successfully developed in paediatric practice over the last two decades, improving both diagnosis and treatment in many children's gastrointestinal diseases. In this group of patients, experience and co-operation between paediatricians/endoscopists and paediatric anaesthesiologists should help to guarantee the quality and safety of a procedure and should additionally help to minimise the risk of adverse events which are greater the smaller the child is. This principle is more and more important especially since the announcement of the Helsinki Declaration on Patient Safety in Anaesthesiology in 2010, emphasising the role of anaesthesiology in promoting safe perioperative care. The Helsinki Declaration has been endorsed by all European anaesthesiology institutions as well as the World Health Organisation's 'Safe Surgery Saves Lives' initiative including the 'Surgical Safety Checklist'. Although most of these procedures could be performed by paediatricians under procedural sedation and analgesia, children with congenital defects and serious coexisting diseases (ASA ≥ III) as well as the usage of anaesthetics (e.g. propofol) must be managed by paediatric anaesthesiologists. We have reviewed the specific principles employed during qualification and performance of procedural sedation and analgesia for gastrointestinal endoscopy in paediatrics. We have also tried to answer the questions as to how, with what, and by whom, procedural sedation for gastrointestinal endoscopy in children should be performed.

The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia, regardless of whether the patient is a new-born, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-pharmacodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and dynoptogenesis) occurs during the foetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safety of general anaesthesia in humans. Prospective trials should continue being carried out, and anaesthesia and surgery, delayed if possible among the smallest patients. The simultaneous use of different anaesthetics with the same potential neurotox

Endoscopic procedures of the gastrointestinal tract were successfully introduced into paediatric practice in the 1970s. Recent expansive development has become useful for improvement of both diagnosis and treatment in many children with gastrointestinal diseases. Most of these procedures are performed under procedural sedation (PSA) knowing anatomical, physiological and psychological differences and requiring good experience from the paediatrician and anaesthesiologist. These principles help to provide the procedure safely and minimise adverse events, which are greater the smaller the child is. Procedural sedation and analgesia in healthy children can be performed by a paediatrician, but children with congenital defects and serious coexisting diseases (ASA ≥ III) and also during the usage of anaesthetics (e.g. propofol), should be managed by an anaesthesiologist.

Background This study evaluates the time-of-day effect on midazolam and 1-OH midazolam pharmacokinetics, and on the sedative pharmacodynamic response in rabbits. Also, circadian fluctuations in rabbits’ vital signs, such as the blood pressure, heart rate and body temperature were examined. The water intake was measured in order to confirm the presence of the animals’ diurnal activity. The secondary aim involved the comparison of two methods of data analysis: a noncompartmental and a population modeling approach. Methods Twelve rabbits were sedated with intravenous midazolam 0.35 mg/kg at four local times: 09.00, 14.00, 18.00 and 22.00 h. Each rabbit served as its own control by being given a single infusion at the four different times of the day on four separate occasions. The values of the monitored physiological parameters were recorded during the experiment and arterial blood samples were collected for midazolam assay. The pedal withdrawal reflex was used as the measurement of the sedation response. Two and one compartmental models were successfully used to describe midazolam and 1-OH midazolam pharmacokinetics. The categorical pharmacodynamic data were described with a logistic model. Results and conclusions 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.

This study evaluates possible circadian rhythms during prolonged midazolam infusion in 27 pediatric intensive care unit (PICU) children under mechanical ventilation.Blood samples for midazolam and 1-OH-midazolam assay were collected throughout the infusion at different times of the day. The blood pressure, heart rate and body temperature were recorded every hour for the rhythms analysis. Population nonlinear mixed-effect modeling with NONMEM was used for data analysis.A two-compartment model for midazolam pharmacokinetics and a one-compartment model for midazolam metabolite adequately described the data. The 24 h profiles of all monitored physiological parameters were greatly disturbed/abolished in comparison with the well-known 24 h rhythmic patterns in healthy subjects. There was no significant circadian rhythm detected with respect to midazolam pharmacokinetics, its active metabolite pharmacokinetics and all monitored parameters.We concluded that the light-dark cycle did not influence midazolam pharmacokinetics in intensive care units children. Also, endogenous rhythms in critically ill and sedated children are severely disturbed and desynchronized. Our results confirmed that it is necessary to adjust the dose of midazolam to the patient's body weight. The low value of midazolam clearances observed in our study was probably caused by mechanical ventilation, which was shown to decrease the cardiac output.

Research Project Objectives. Project entitled “Maturation, pharmacogenomics, and metabolomics as factors determining pharmacokinetic and pharmacodynamic profile of alpha‑agonist in pediatric intensive care unit patients” was founded by the Polish National Science Center (NCN) under project number: 2015/17/B/NZ7/03032. The duration of the grant is 36 months, and the total grant value is 688800 PLN. The project is run by the Medical University of Gdansk and Poznan University of Medical Sciences. The aim of this grant is to examine the influence of maturation, pharmacogenetics, metabolomics and physiological (or pathophysiological) status of the patients on the pharmacokinetics and pharmacodynamics (PK/PD) of α2-adrenergic drugs (dexmedetomidine and clonidine) in pediatric population. The project was proposed to explain the unusual PK of dexmedetomidine reported in literature and in our preliminary experiments, in which a two‑fold increase in dexmedetomidine clearance was observed during prolonged (lasting more than 24 hr) infusions in the intensive care unit patients. General information. Project entitled “Maturation, pharmacogenomics, and metabolomics as factors determining pharmacokinetic and pharmacodynamics profile of alpha‑agonist in pediatric intensive care unit patients” was founded by the Polish National Science Center (NCN) under project number: 2015/17/B/NZ7/03032. The duration of the grant is 36 months, from 2016-04-27 to 2019-04-26 and the total grant value is 688800 PLN. The project is run by the Medical University of Gdansk and Poznan University of Medical Sciences. The research group consists of: principal investigator dr hab. Paweł Wiczling and co‑investigators: dr hab. Agnieszka Bienert, dr Alicja Bartkowska‑Śniatkowska, dr Joanna Bartkowiak‑Wieczorek, mgr Justyna Mocarska, prof. Edmund Grześkowiak, dr Jan Matysiak, mgr Agnieszka Klupczyńska, dr Danuta Siluk, mgr Agnieszka Borsuk and prof. dr hab. Zenon J. Kokot. The Ethical Committee permission number is 261/15.

The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long-term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration-time profiles were collected from 29 patients. Non-linear mixed-effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three-compartment disposition model. Non-parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C-reactive protein concentration. The population PK model was developed successfully to describe the time-course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John WileySons, Ltd.

Target controlled infusion (TCI) devices are increasingly used in clinical practice. These devices unquestionably aid optimization of drug dosage. However, it still remains to be determined if they sufficiently address differences in pharmacological make up of individual patients. The algorithms guiding TCI pumps are based on pharmacological data obtained from a relatively small number of healthy volunteers, which are then extrapolated, on the basis of sophisticated pharmacokinetic and pharmacodynamic modeling, to predict plasma concentrations of the drug and its effect on general population. One has to realize the limitation of this approach: these models may be less accurate when applied to patients in extreme clinical conditions: in intensive care units, with a considerable loss of blood, severe hypothermia or temporary changes in the composition of plasma, e.g., hypoalbuminemia. In the future, data obtained under these "extreme" clinical circumstances, may be used to modify the dosage algorithms of propofol TCI systems to match the clinical scenario.

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V C = 24.7 1, V T = 112 1, Cl = 2.64 1/min and Q = 0.989 1/min. 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 0.240 min –1 . The BIS index was linked to the effect site concentrations through a sigmoidal E max model with EC 50 = 2.19 mg/1. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John WileySons, Ltd.

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V(C) = 27.7 l, V(T) = 801 l, and CL(D) = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65 x (1-0.00714 x (SBP-135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC(50) equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light-dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night-day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients.

Objective Preeclampsia (PE) is a major cause of mortality of mothers, fetuses and newborns around the world. The etiology of preeclampsia has not yet been clarified, but many studies indicate a multifactorial basis of PE. Aldosterone synthase (CYP11B2) is responsible for synthesis of aldosterone responsible for regulating blood pressure. Similarly, natriuretic peptide (ANP) regulates blood pressure through a variety of mechanisms affecting the sodium concentration and the amount of extracellular fluid. Currently, attention is paid to the role of the polymorphisms in the expression level of these genes. The aim of the study was to determine the frequencies of genotypes and alleles for polymorphisms of −344C > T CYP11B2 gene and 2238T > C ANP gene in women with preeclampsia and healthy pregnant women from the Caucasian population. Study design The study included a group of 165 pregnant women (59 women with preeclampsia and 109 healthy pregnant women). DNA was extracted from peripheral blood. Determination of the polymorphism of −344C > T CYP11B2 gene and 2238T > C ANP gene was performed by PCR-RFLP method. Results The results showed that the frequencies of the TC and CC genotypes of 2238T > C polymorphism in ANP gene were significantly higher in patients with PE compared to control group. For −344C > T polymorphism of CYP11B2 gene, the frequency of TT genotype was significantly higher in patients with hypertension than in controls (32.2% vs. 23.58%). Conclusions Our findings showed that gene polymorphism of CYP11B2 (−344C > T) and ANP (2238T > C) may be associated with developing PE during pregnancy.

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, μg/h) × (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

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 material The online version of this article (doi:10.1007/s10928-015-9404-6) contains supplementary material, which is available to authorized users.