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Clinical Pharmacokinetics Jun 2024
PubMed: 38940903
DOI: 10.1007/s40262-024-01389-w -
Expert Opinion on Drug Metabolism &... Jun 2024Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics...
BACKGROUND
Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug-interaction (DDI) profile of padsevonil.
RESEARCH DESIGN AND METHODS
An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided.
RESULTS
In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed.
CONCLUSIONS
The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing.
CLINICAL TRIAL REGISTRATION
https://www.clinicaltrials.gov/identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.
PubMed: 38932723
DOI: 10.1080/17425255.2024.2373108 -
Pharmaceutics Jun 2024Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical...
Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly ( < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY.
PubMed: 38931941
DOI: 10.3390/pharmaceutics16060820 -
Pharmaceutics May 2024Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of...
Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine's Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes.
Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ's nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus. The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ's nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC ratio was 0.49 (slightly outside of the two-fold range). CBZ's nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.
PubMed: 38931859
DOI: 10.3390/pharmaceutics16060737 -
Evaluating the Quality of Systematic Reviews on Pediatric Sedation in Dentistry: An Umbrella Review.Journal of Clinical Medicine Jun 2024Sedation is a depression of a patient's state of consciousness, induced by medications, that can reach different levels of intensity during a medical procedure.... (Review)
Review
Sedation is a depression of a patient's state of consciousness, induced by medications, that can reach different levels of intensity during a medical procedure. Conscious sedation produces a minimally depressed level of consciousness without impairment of the ability to maintain an open airway, of protective reflexes or of responses to verbal and physical stimulation. This umbrella review is aimed at critically assessing the available systematic reviews (SRs) and meta-analyses (MA) on sedation in children/adolescents. An electronic database search was conducted that included Pubmed-Medline, Web of Science, Cochrane, Scopus, Scielo, Embase, LILACS and TRIP and the scope of which extended until January 2023. The risk of bias (RoB) of SRs was analyzed using the Measurement Tool to Assess SRs criteria 2 (AMSTAR2). Of 998 entries, 37 SRs were included. In terms of methodological quality, eight studies were assessed as having critically low quality, four studies had low quality, nine studies had moderate quality, and sixteen were considered to be of high quality. Based on the current guidelines, the most employed drugs in pediatric dentistry for sedation are nitrous oxide and midazolam; however, the available evidence supporting their use is insufficient and of low/critically low quality. The combined technique is recommended (nitrous oxide (30-50%) + midazolam). The optimal dose of oral midazolam is 0.75 mg/kg. The level of methodological quality of SRs is expected to increase according to the results and future directions of this umbrella review.
PubMed: 38930074
DOI: 10.3390/jcm13123544 -
Children (Basel, Switzerland) Jun 2024Off-label drug use is prevalent in the pediatric population and represents a patient safety concern. We aimed to identify factors for off-label drug use in our pediatric...
UNLABELLED
Off-label drug use is prevalent in the pediatric population and represents a patient safety concern. We aimed to identify factors for off-label drug use in our pediatric emergency department (PED).
METHODS
We performed a retrospective data analysis. All patients aged 0-18 referred to PED from 1 September to 1 October 2022, were included. Further analysis was performed when respiratory tract infections were diagnosed.
DATA COLLECTED
gender, age, triage group, chronic diseases, vital signs, and PED-prescribed treatment (medications, dosages, methods of administration). Statistical analysis used SPSS 28.0, with significance at < 0.05.
RESULTS
Data from 473 patients were analyzed, median age 3.5 years. Chronic diseases were present in 17.1% of children. 387 medications were prescribed, 47.5% being off-label. Off-label treatment was common for external otitis, acute laryngitis, and acute bronchitis ( < 0.001). There was incorrect administration of tobramycin with dexamethasone for otitis ( = 16, 100%) and inappropriate use of salbutamol inhalations by age (34.8%, = 16). Some medications were given orally instead of injections (ondansetron = 5, 62.5%; dexamethasone = 82, 98.7%) or intranasally instead of intravenously (IV) (midazolam = 7, 87.5%). IV adrenalin was prescribed for inhalations ( = 46). Younger children were more likely to receive off-label treatment ( < 0.001).
CONCLUSION
Our study highlights the widespread issue of off-label and unlicensed drug prescribing in pediatric emergency care. Further research is necessary, because this reliance on off-label prescribing raises concerns about patient safety and compliance, especially given the limited clinical trials and therapeutic options available.
PubMed: 38929314
DOI: 10.3390/children11060735 -
International Journal of Molecular... Jun 2024Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar...
Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.
Topics: Midazolam; Animals; TOR Serine-Threonine Kinases; Mice; Signal Transduction; Brain; Male; Hypnotics and Sedatives; Behavior, Animal; Female; Mice, Inbred C57BL; Maze Learning; Animals, Newborn
PubMed: 38928447
DOI: 10.3390/ijms25126743 -
Neurological Research and Practice Jun 2024This review specifically investigates ketamine's role in SRSE management. (Review)
Review
OBJECTIVE
This review specifically investigates ketamine's role in SRSE management.
METHODS
PubMed, EMBASE, and Google Scholar databases were searched from inception to May 1st, 2023, for English-language literature. Inclusion criteria encompassed studies on SRSE in humans of all ages and genders treated with ketamine.
RESULTS
In this systematic review encompassing 19 studies with 336 participants, age ranged from 9 months to 86 years. Infections, anoxia, and metabolic issues emerged as the common causes of SRSE, while some cases had unknown origins, termed as NORSE (New Onset RSE) or FIRESs (Febrile Infection-Related Epilepsy Syndrome). Most studies categorized SRSE cases into convulsive (N = 105) and non-convulsive (N = 197). Ketamine was used after failed antiepileptics and anesthetics in 17 studies, while in others, it was a first or second line of treatment. Dosages varied from 0.5 mg/kg (bolus) and 0.2-15 mg/kg/hour (maintenance) in adults and 1-3 mg/kg (bolus) and 0.5-3 mg/kg/hour (maintenance) in pediatrics, lasting one to 30 days. Ketamine was concurrently used with other drugs in 40-100% of cases, most frequently propofol and midazolam. Seizure resolution rate varied from 53.3 to 91% and 40-100% in larger (N = 42-68) and smaller case series (N = 5-20) respectively. Seizure resolution occurred in every case of case report except in one in which the patient died. Burst suppression in EEG was reported in 12 patients from two case series and two case reports. Recurrence was reported in 11 patients from five studies. The reported all-cause mortality varied from 38.8 to 59.5% and 0-36.4% in larger and smaller case series., unrelated directly to ketamine dosage or duration.
SIGNIFICANCE
Ketamine demonstrates safety and effectiveness in SRSE, offering advantages over GABAergic drugs by acting on NMDA receptors, providing neuroprotection, and reducing vasopressor requirement.
PubMed: 38926769
DOI: 10.1186/s42466-024-00322-7 -
BMC Pulmonary Medicine Jun 2024Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Dexmedetomidine-ketamine combination versus fentanyl-midazolam for patient sedation during flexible bronchoscopy: a prospective, single-blind, randomized controlled trial.
BACKGROUND
Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the procedure are achieved. Nevertheless, the optimal sedation method for FB has yet to be established. This study aimed to compare the standard recommended combination of midazolam-fentanyl (MF) with that of dexmedetomidine-ketamine (DK) for patient sedation during FB.
METHODS
Patients subjected to FB were randomly assigned to a DK (n = 25) and an MF group (n = 25). The primary outcome was the rate of critical desaturation events (arterial oxygen saturation < 80% with nasal oxygen supply 2 L/min). Secondary outcomes included sedation depth, hemodynamic complications, adverse events, and patient and bronchoscopist satisfaction.
RESULTS
The incidence rates of critical desaturation events were similar between the two groups (DK: 12% vs. MF: 28%, p = 0.289). DK achieved deeper maximum sedation levels (higher Ramsay - lower Riker scale; p < 0.001) and was associated with longer recovery times (p < 0.001). Both groups had comparable rates of hemodynamic and other complications. Patient satisfaction was similar between the two groups, but bronchoscopist satisfaction was higher with the DK combination (p = 0.033).
CONCLUSION
DK demonstrated a good safety profile in patients subjected to FB and achieved more profound sedation and better bronchoscopist satisfaction than the standard MF combination without increasing the rate of adverse events.
Topics: Humans; Dexmedetomidine; Bronchoscopy; Fentanyl; Male; Midazolam; Ketamine; Female; Middle Aged; Prospective Studies; Hypnotics and Sedatives; Single-Blind Method; Aged; Patient Satisfaction; Adult; Conscious Sedation
PubMed: 38926768
DOI: 10.1186/s12890-024-02988-w -
The Journal of Veterinary Medical... Jun 2024Laparoscopic ovariectomy under general anesthesia was planned in a 10-year-old, 146 kg, apparently healthy female African lion (Panthera leo). The lion was immobilized...
Laparoscopic ovariectomy under general anesthesia was planned in a 10-year-old, 146 kg, apparently healthy female African lion (Panthera leo). The lion was immobilized via intramuscular darts containing midazolam (0.033 mg/kg), medetomidine (50 µg/kg) and ketamine (2.5 mg/kg), and intubated using an endotracheal tube (16 mm internal diameter). The anesthesia was maintained using sevoflurane (0.9-2.1% end-tidal concentration), in combination with remifentanil (0.1 µg/kg/min) and ketamine (11 µg/kg/min) at a constant rate infusion (CRI), with Hartmann's solution (5 mL/kg/hr). Surgery was conducted with stable vital signs, but hypotension (mean arterial blood pressure 55 mmHg) developed, requiring dobutamine treatment. The hypotension was effectively controlled by adjusting dobutamine from 5 µg/kg/min to 0.2 to 0.3 µg/kg/min. This case suggests possibilities that dosages in this range can be clinically useful for peri-anesthetic hypotension in lions.
PubMed: 38925983
DOI: 10.1292/jvms.23-0436