Search Results (11)

Introduction: Postoperative delirium, including emergence agitation, is recognized in the post-anesthesia care unit as a fluctuating disturbance of attention and cognition. The current evidence examined suggests that both anesthetic agents and postoperative pain intensity may influence the risk of delirium. The aim of this review is to discuss the significance of pharmacological agents used during anesthesia and the relationship between the intensity of postoperative pain and the occurrence of postoperative delirium in patients undergoing surgical procedures, regardless of age. Methods: A scoping review was conducted from December 2024 to December 2025. The articles identified in each search were limited to those published between 2015 and 2025. Results: Agents such as dexmedetomidine, remimazolam, and magnesium sulfate were examined in the included trials and were reported to be associated with reducing the incidence and severity of postoperative delirium, particularly in pediatric and elderly patients. Analysis of clinical trial outcomes conducted in pediatric populations undergoing various surgical procedures suggests that dexmedetomidine (administered intranasally and intravenously) and alfentanil were associated with lower incidence and severity of emergence delirium compared to standard care or other agents (e.g., midazolam). Higher doses of dexmedetomidine (2 µg/kg) were reported to be associated with improved postoperative analgesia and reduced agitation, without prolonging recovery time or causing serious adverse effects. Propofol, due to its rapid metabolism, was suggested to contribute to shorter emergence times; however, its impact on cognitive function requires further investigation. Additionally, there remains a lack of agreed-upon and/or validated tools and strategies for pain assessment in patients experiencing delirium. Conclusions: The current evidence examined suggests that the use of intranasal dexmedetomidine at appropriate doses may be associated with reduced postoperative pain and agitation without prolonging recovery time or increasing the risk of serious adverse events. Hydromorphone was reported in the included trials to be associated with better postoperative pain control than sufentanil, whereas remimazolam, although associated with reduced delirium incidence in some trials, did not influence the length of stay in the post-anesthesia care unit. Magnesium sulfate, although not significantly affecting the incidence of delirium, was associated with alleviation of postoperative symptoms such as pain and insomnia in adult patients. Ketamine, while commonly used for analgesic therapy, did not demonstrate a consistent association with delirium prevention and, in some studies, was associated with increased neuropsychiatric events. Further research is required to more precisely define optimal perioperative delirium prevention protocols. Full article

Background/Objectives: Cirrhosis significantly alters physiological function and drug metabolism, particularly for medications primarily metabolized by CYP2C19 and CYP3A4. This study aims to establish a physiologically based pharmacokinetic (PBPK) modelling framework capable of predicting pharmacokinetic changes across different stages of cirrhosis, and to determine optimal dosing regimens that achieve drug exposure levels comparable to those in healthy individuals. Methods: We constructed a physiologically based pharmacokinetic (PBPK) model that incorporates six drugs, including omeprazole, lansoprazole, midazolam, ondansetron, verapamil, and alfentanil, which are metabolized primarily by CYP2C19 or CYP3A4. The pharmacokinetics of these drugs following oral or injectable administration were simulated in 1000 virtual healthy subjects, and the PBPK model was validated using clinical data. The model was further adapted to account for physiological changes in cirrhotic patients, extending its application to a population of 1000 virtual patients with liver cirrhosis. Results: Most observed data fell within the 5th and 95th percentiles of the virtual patient simulation results. Additionally, for most simulations, the area under the concentration-time curve (AUC) and peak concentration (C_max) were within 0.5- to 2-fold of the observed values. Sensitivity analysis indicated that the reduced expression of metabolizing enzymes increased plasma concentrations of drugs, which was a major factor contributing to the elevated drug exposure in patients with cirrhosis. The clinical dosing regimens of the CYP2C19 substrate omeprazole and the CYP3A4 substrate ondansetron were optimized for use in cirrhotic patients. Conclusions: The developed PBPK model successfully predicted the pharmacokinetics of CYP2C19 and CYP3A4 substrates in both healthy individuals and cirrhotic patients and can be effectively used for dose optimization in cirrhotic populations. Full article

Background/Objectives: The use of medicines in pediatrics and geriatrics is widespread. However, information on pharmacokinetics of therapeutic drugs mainly comes from healthy adults, and the pharmacokinetic parameters of therapeutic drugs in other age stages, including pediatrics and geriatrics, are limited. The aim of the study was to develop a dynamic age-dependent physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of drugs in humans at different ages. Method: The PBPK models characterizing dynamic age-dependence were developed in adults (20–59 years old) and 1000 virtual individuals were constructed. Four CYP3A substrates, namely midazolam, fentanyl, alfentanil and sufentanil, served as model drugs. Following validation using clinic observations in adult populations, the developed PBPK models were extrapolated to other age populations, such as pediatrics and geriatrics, via replacing their physiological parameters and pharmacokinetic parameters, such as organ volume, organ blood flow, clearance, f_u,b and K_t:p. The simulations were compared with clinic observations in corresponding age populations. Midazolam served as an example, the dose transitions between adult pediatrics and adult geriatrics were visualized using the developed PBPK models. Results: Most of observed plasma concentrations fell within the 5th–95th percentile of the predicted values in the 1000 virtual individuals, and the predicted AUC_0–t and C_max were almost within between 0.5 and 2 times of the observations. The optimization of dosages in pediatrics and geriatrics were further documented. Conclusions: The developed PBPK model may be successfully used to predict the pharmacokinetics of CYP3A4-metabolized drugs in different age groups and to optimize their dosage regiments in pediatrics and geriatrics. Full article

Piperine has been reported to inhibit the enzyme activity of cytochrome P450 (CYP) 3A4. The aim of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model for piperine and to predict potential food–drug interactions (FDIs) between piperine and CYP3A4 substrate drugs using these models. The PBPK model for piperine was successfully developed and validated. Using this model, FDIs with ten CYP3A4 substrate drugs were simulated. The predicted area under the curve (AUC) ratios (with and without piperine, following a 7-day intake of 20 mg/day) for six drugs were found to exceed 1.25, with significant increases in AUC observed for ritonavir (31%), nifedipine (34%), cyclosporine (35%), triazolam (36%), alfentanil (39%), and simvastatin (59%) in humans. These findings suggest that caution should be exercised when consuming amounts of black pepper equivalent to a daily intake of 20 mg piperine during treatment with CYP3A4 substrate drugs, as it may significantly alter their pharmacokinetics. Full article

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression. Full article

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions. Full article

In recent years, remimazolam has gained approval for use in adult procedural sedation in both the United Kingdom and the United States, potentially offering an alternative to conventional sedatives like propofol and midazolam for procedural sedation. However, there is a limited body of literature that systematically reviews the outcomes of a remimazolam-alfentanil combination protocol for routine office-based dental procedures. The primary objective of this pilot study was to assess the occurrence of significant adverse events associated with the use of a remimazolam-alfentanil sedation protocol for adult dental procedures. Secondary outcomes included evaluating physiological responses, sedation effectiveness, patient and clinician satisfaction and the incidence of intraprocedural awareness. Notably, no significant adverse events were reported among the 25 adult subjects who received remimazolam and alfentanil, and all dental procedures were successfully completed. Patients and clinicians expressed high levels of satisfaction, and patients did not report any distressing memories associated with the dental procedure. These findings suggest that in a limited cohort, the remimazolam-alfentanil regimen appears to be well tolerated and effective for office-based dental procedures in adult patients, with a low risk of adverse events, acceptable hemodynamic effects, rapid onset and recovery and minimal intraoperative awareness. This study provides valuable insights into the potential use of the remimazolam-alfentanil combination in dental sedation practice. Full article

Supermicrosurgical lymphaticovenous anastomosis (LVA) is a minimally invasive surgical technique that creates bypasses between lymphatic vessels and veins, thereby improving lymphatic drainage and reducing lymphedema. This retrospective single-center study included 137 patients who underwent non-intubated LVA in southern Taiwan. A total of 119 patients were enrolled and assigned to two study groups: the geriatric (age ≥ 75 years, n = 23) and non-geriatric groups (age < 75 years, n = 96). The primary outcome was to investigate and compare the arousal and maintenance of the propofol effect-site concentration (Ce) using an electroencephalographic density spectral array (EEG DSA) in both groups. The results showed that the geriatric group required less propofol (4.05 [3.73–4.77] mg/kg/h vs. 5.01 [4.34–5.92] mg/kg/h, p = 0.001) and alfentanil (4.67 [2.53–5.82] μg/kg/h vs. 6.68 [3.85–8.77] μg/kg/h, p = 0.047). The median arousal Ce of propofol among the geriatric group (0.6 [0.5–0.7] μg/mL) was significantly lower than that in patients aged ≤ 54 years (1.3 [1.2–1.4] μg/mL, p < 0.001), 55–64 years (0.9 [0.8–1.0] μg/mL, p < 0.001), and <75 years (0.9 [0.8–1.2] μg/mL, p < 0.001). In summary, the combined use of EEG DSA provides the objective and depth of adequate sedation for extensive non-intubated anesthesia in late-elderly patients who undergo LVA without perioperative complications. Full article

The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing’s syndrome, is prone to drug–food interactions (DFIs) and is well known for its strong drug–drug interaction (DDI) potential. Some of ketoconazole’s potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole’s metabolites on its DDI potential. The parent–metabolites model was developed with PK-Sim^® and MoBi^® using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUC_last and DFI C_max ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUC_last and 21/21 DDI C_max ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUC_last and 18/21 DDI C_max ratios were within the success limits. Full article

Intraocular pressure (IOP) is crucial to the well-being of eyes. During anesthesia, the administration of succinylcholine and endotracheal intubation are associated with an increase in IOP, which may be attenuated by short-acting opioids. However, the drug of choice among the commonly used short-acting opioids is unclear. This study aimed to evaluate the effects of fentanyl, sufentanil, alfentanil, and remifentanil on IOP measured after the administration of succinylcholine and after endotracheal intubation in patients undergoing general anesthesia. Five databases were searched. Randomized controlled trials (RCTs) that compared short-acting opioids and reported at least one of the clinical outcomes of interest were included. Nine RCTs with 357 patients were included. Remifentanil (1 μg kg⁻¹) more effectively alleviated the increase in IOP than the placebo after the administration of succinylcholine [mean difference (MD) of IOP, −3.64; confidence interval (CI), −5.47 to −1.81 and after endotracheal intubation (MD, −9.71; CI, −11.91 to −7.51). Remifentanil (1 μg kg⁻¹) ranked the best in terms of both attenuating the increase in IOP after the administration of succinylcholine [surface under the cumulative ranking curve (SUCRA), 0.91; normalized entropy (NE), 0.47; and after endotracheal intubation (SUCRA, 0.89; NE, 0.54) among all of the treatments. Remifentanil (1 μg kg⁻¹) should be considered the drug of choice in the circumstances where increased IOP is a great concern. Full article

Alfentanil is used for chronic pain relief in palliative care. However, there is a dearth of data on its use. For this reason, a decision was made to review the use of alfentanil in palliative care. Retrospective study was carried out in a palliative care service. The files of patients who received alfentanil as an intravenous or subcutaneous continuous infusion for pain relief, between January 2018 and April 2019. In total, 111 patients received alfentanil out of 113 admissions. Of them, 56 were male, and the median age was 70 years. The median number of days on alfentanil was 6 (range 1 to 129). The most frequent primary reasons for switching to alfentanil was uncontrolled pain in 52 (46%) patients and renal impairment in 24 (21%) patients. The median 24-h initial dose of alfentanil was 4 mg (1–20), and the median final 24-h dose of alfentanil was 5 mg (1–60), (p < 0.001). The initial 24-h median number of rescue doses was 2 (0–8), and the final median number of rescue doses was 1 (0 to 8), (p = 0.025). In 56 patients who were on alfentanil for at least 7 days, the dose decreased in 3 (5%), remained stable in 10 (18%) and increased in 43 (77%). The patient on alfentanil for 129 days maintained the same dose throughout that period. Alfentanil can be a useful second-line opioid. The induction of tolerance does not seem to be particularly rapid with alfentanil. Full article