Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used “off-label” as pain management during labour. Side effects in parturients during labour, and in ...the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3–5 ng mL
. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL
. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL
in neonatal, and maternal samples, respectively.
Summary
Background
During transitions of care, patient’s medications are prone to medication errors. This study evaluated the impact of pharmacist-led medication reconciliation at hospital admission ...on unintentional medication discrepancies and adverse drug events.
Methods
A randomized controlled clinical trial was conducted in 120 adult medical patients hospitalized in a tertiary hospital in Slovenia. In the intervention group, a pharmacist-led medication reconciliation was performed on admission, while the control group received usual care. Patient’s drug treatment before admission was compared with their admission and inpatient treatment to identify discrepancies. The intention of discrepancies and related adverse drug events were assessed as a consensus of an expert panel.
Results
Included patients were elderly (median 72 years) and treated with polypharmacy (median 7 medications). Upon admission, discrepancies and unintentional discrepancies, representing a medication error, were identified in 61.2% (825/1347) and 18.3% (247/1347) of medications, respectively. In the intervention group, only 29.1% (37/127) of unintentional discrepancies were reported to the physicians in person. The majority of admission discrepancies (88%) persisted through hospitalization. Unintentional discrepancies resulted in 51 adverse drug events even during hospitalization. There were no differences between the intervention and control group in the occurrence of unintentional discrepancies (
p
= 0.481) or adverse drug events (
p
= 0.801).
Conclusions
Medication reconciliation at hospital admission failed to reduce unintentional discrepancies and adverse drug events, possibly due to its poor integration into clinical practice. Discrepancies resulted in patient harm even during the short period of hospitalization, which warrants the implementation of medication reconciliation at hospital admission.
: Patients with schizophrenia are often exposed to polypharmacotherapy, which may lead to drug-drug interactions. The aim of the study was to investigate the prevalence of potential drug-drug ...interactions (pDDIs) in hospitalized patients with schizophrenia spectrum disorders and to identify factors associated with pDDIs and manifested symptoms and signs.
: This cross-sectional observational study included 311 inpatients admitted to a psychiatric hospital. The LexiComp drug interaction program was used to identify pDDIs in 2014. Factors associated with the prevalence of pDDIs and factors related to clinically observed symptoms and signs were assessed using multivariable regression. In addition, replicate analysis of pDDI was performed using 2021 program updates.
The prevalence of pDDIs was 88.7%. Our study showed that more than half of the patients received at least one drug combination that should be avoided. The most common pDDIs involved combinations of two antipsychotics or combinations of antipsychotics and benzodiazepines, which can lead to cardio-respiratory depression, sedation, arrhythmias, anticholinergic effects, and neuroleptic malignant syndrome. The number of prescribed drugs was a risk factor for pDDIs (OR 2.85; 95% CI 1.84-5.73). All groups of clinically observed symptoms and signs were associated with the number of drugs. In addition, symptoms and signs characteristic of the nervous system and psychiatric disorders were associated with antipsychotic dosage (IRR 1.33; 95% CI 1.12-1.58), which could contribute to the development of extrapyramidal syndrome, insomnia, anxiety, agitation, and bipolar mania. The 2021 version of the drug interaction program showed a shift in drug interactions toward a lower risk rating, implying less severe patient management and possibly less alert fatigue.
Patients with schizophrenia spectrum disorders are at high risk of developing drug-drug interactions. Optimization of drug therapy, patient monitoring, and use of drug interaction programs could help to prevent pDDIs and subsequent adverse drug events.
Purpose
Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop ...a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of
ABCB1
gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects.
Methods
Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects.
Results
A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with
ABCB1
expression. Compared to base line before the surgery, a significant
ABCB1
downregulation was observed 5 days after the surgery (
p
< 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration.
Conclusions
We confirmed that variable rivaroxaban CL/F is associated with
ABCB1
expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of
ABCB1
expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.
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In this study individual data on tablet gastrointestinal transit times (i.e. gastric emptying, small intestinal transit, ileocecal junction residence, and colon arrival times) were ...obtained from literature in order to present and analyze their distributions and relationships. The influence of the time of food intake after tablet administration in fasted state on gastrointestinal transit times was additionally evaluated.
There were 114 measurements from subjects who received the first meal at 4h after tablet administration. Approximately 32% of the tablets arrived into the colon before the meal intake at 4h. An evident increase in the frequency of colon arrival of tablets within 40min after the meal intake at 4h post-dose was observed, where approximately 39% of all tablets arrived into the colon. This is in accordance with findings described in literature where a meal ingested several hours post-dose accelerates tablet transit through the terminal ileum and shortens the transit through the small intestine. The median (min, max) of gastric emptying, small intestinal transit, and colon arrival times in the group where the first meal intake was at 4h post-dose is 35 (0,192), 215 (60,544), and 254 (117,604) minutes, respectively. The dependence of colon arrival times on gastric emptying times was described by the nonparametric regression curve, and compared with the presumed interval of colon arrival times, calculated by summation of observed gastric emptying times and frequently cited small intestinal transit time interval, i.e. 3–4h. For shorter gastric emptying times the trend of colon arrival times was within the presumed interval. At short gastric emptying times many observation points are also within the presumed interval since this interval coincides with short period after meal intake at 4h post-dose. Additionally, in numerous occasions relatively long ileocecal junction residence times were obtained, which may be important information from the point of view of drug absorption. The findings of gastrointestinal transit times are important and should be taken into consideration when predicting the in vivo performance of dosage forms after oral administration.
The endocrine disruptor bisphenol A (BPA) is a frequently used chemical in the manufacture of consumer products. In humans, BPA is extensively metabolized to BPA glucuronide (BPAG) by different ...UDP-glucuronosyltransferase (UGT) isoforms. The study has been performed with the intention to improve the accuracy of published physiologically based pharmacokinetic models and to improve regulatory risk assessments of BPA. In order to gain insight into intestine, kidney, liver, and lung glucuronidation of BPA, human microsomes of all tested organs were used. BPAG formation followed Michaelis–Menten kinetics in the intestine and kidney, but followed substrate inhibition kinetics in the liver. Human lung microsomes did not show glucuronidation activity towards BPA. While the liver intrinsic clearance was very high (857
mL
min
−1
kg body weight
−1), the tissue intrinsic clearances for the kidney and intestine were less than 1% of liver intrinsic clearance. Since BPA is a UGT1A1 substrate, we postulated that the common
UGT1A1*28 polymorphism influences BPA glucuronidation, and consequently, BPA detoxification. Hepatic tissue intrinsic clearances for
UGT1A1*1/*1,
UGT1A1*1/*28, and
UGT1A1*28/*28 microsomes were 1113, 1075, and 284
mL
min
−1
kg body weight
−1, respectively. Prior to microsomal experiments, the bioproduction of BPAG and stable isotope-labeled BPAG (BPAG
d16) was performed for the purpose of the reliable and accurate quantification of BPAG. In addition, a sensitive LC–MS/MS analytical method for the simultaneous determination of BPA and BPAG based on two stable isotope-labeled internal standards was developed and validated. In conclusion, our
in vitro results show that the liver is the main site of BPA glucuronidation (
K
m
8.9
μM,
V
max 8.5
nmol
min
−1
mg
−1) and BPA metabolism may be significantly influenced by a person's genotype (
K
m
10.0–13.1
μM,
V
max 3.4–16.2
nmol
min
−1
mg
−1). This discovery may be an important fact for the currently on-going worldwide BPA risk assessments and for the improvement of physiologically based pharmacokinetic models.
Purpose To develop a mathematical model that would adequately describe human gastric emptying of pellets under fasting conditions of healthy subjects. Methods Scintigraphic profiles representing the ...gastric emptying of pellets were obtained from the literature. Altogether 19 individual and three mean scintigraphic profiles were collected. Three mathematical models namely; the lag-time exponential (two parameters), the Weibull (two parameters), and the double Weibull (five parameters) model were proposed and fitted to the gastric emptying profiles. Results Different patterns of gastric emptying (immediate and rapid, delayed but rapid, delayed and slow, and interruptive emptying) were observed, with the emptying time varied from approximately 15 min to more than 3 h. The best model for fitting to the individual profiles was the double Weibull model. This model also provided an insight into the mechanism of interruptive emptying of pellets, observed for some patients. In addition, mean gastric emptying of pellets was calculated using the Weibull model. Conclusions Mean gastric emptying of pellets was adequately described by the Weibull model (η = 61.9 min, β = 0.895), which could be applied in the design of in vitro dissolution experiments for pellet formulations with pH dependent dissolution.
Risperidone is a commonly prescribed antipsychotic drug. An enantioselective HPLC method with electrochemical detection was developed and validated for simultaneous determination of plasma ...concentrations of risperidone and its active metabolites, 9-hydroxyrisperidone enantiomers. Following solid phase extraction of 1.0
mL blood plasma, a baseline separation of the analytes was achieved on an AGP (α
1 acid glycoprotein) column using isocratic mobile phase consisting of methanol–phosphate buffer (pH 6.2; 0.1
M) (15:85, v/v). Total analysis run time was 11
min. For the detection of the analytes analytical cell potentials were set at 500, 650, 950, and 950
mV. The method linearity was attained in the range from 1.0 to 100
ng/mL for risperidone and both 9-hydroxyrisperidone enantiomers. The limit of detection was 0.5
ng/mL for all three analytes. The method was precise and accurate and was successfully applied in a clinical study investigating the stereoselectivity of risperidone 9-hydroxylation.
