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Drugs in R&D Mar 2020The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years.
BACKGROUND
The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years.
OBJECTIVES
The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evaluate the suitability of the models to predict drug clearance in children aged ≤ 2 years (preterm, term, and infants).
METHODS
Ten drugs were included in this study and administered intravenously: alfentanil, amikacin, busulfan, cefetamet, meperidine, oxycodone, propofol, sufentanil, theophylline, and tobramycin. These drugs were selected according to the availability of individual subjects' weight, age, and clearance data (concentration-time data for these drugs were not available to the author). The chosen drugs are eliminated by extensive metabolism by either the renal route or both the renal and hepatic routes. The six empirical models were (1) age and body weight-dependent sigmoidal maximum possible effect (E) maturation model, (2) body weight-dependent sigmoidal E model, (3) uridine 5'-diphospho [body weight-dependent allometric exponent model (BDE)], (4) age-dependent allometric exponent model (ADE), (5) a semi-physiological model, and (6) an allometric model developed from children aged > 2 years to adults. The model-predicted clearance values were compared with observed clearance values in an individual child. In this analysis, a prediction error of ≤ 50% for mean or individual clearance values was considered acceptable.
RESULTS
Across all age groups and the ten drugs, data for 282 children were compared between observed and model-predicted clearance values. The validation data consisted of 33 observations (sum of different age groups for ten drugs). Only three of the six models (body weight-dependent sigmoidal E model, ADE, and semi-physiological model) provided reasonably accurate predictions of clearance (> 80% observation with ≤ 50% prediction error) in children aged ≤ 2 years. In most instances, individual predicted clearance values were erratic (as indicated by % error) and were not in agreement with the observed clearance values.
CONCLUSIONS
The study indicated that simple empirical models can provide more accurate results than complex empirical models.
Topics: Adult; Alfentanil; Amikacin; Busulfan; Ceftizoxime; Child, Preschool; Humans; Infant; Injections, Intravenous; Meperidine; Metabolic Clearance Rate; Models, Biological; Oxycodone; Propofol; Sufentanil; Theophylline; Tobramycin
PubMed: 31820365
DOI: 10.1007/s40268-019-00291-2 -
Journal of Pain and Symptom Management Jul 2020Hospital palliative care is an essential part of the COVID-19 response but data are lacking. We identified symptom burden, management, response to treatment, and...
Hospital palliative care is an essential part of the COVID-19 response but data are lacking. We identified symptom burden, management, response to treatment, and outcomes for a case series of 101 inpatients with confirmed COVID-19 referred to hospital palliative care. Patients (64 men, median [interquartile range {IQR}] age 82 [72-89] years, Elixhauser Comorbidity Index 6 [2-10], Australian-modified Karnofsky Performance Status 20 [10-20]) were most frequently referred for end-of-life care or symptom control. Median [IQR] days from hospital admission to referral was 4 [1-12] days. Most prevalent symptoms (n) were breathlessness (67), agitation (43), drowsiness (36), pain (23), and delirium (24). Fifty-eight patients were prescribed a subcutaneous infusion. Frequently used medicines (median [range] dose/24 hours) were opioids (morphine, 10 [5-30] mg; fentanyl, 100 [100-200] mcg; alfentanil, 500 [150-1000] mcg) and midazolam (10 [5-20] mg). Infusions were assessed as at least partially effective for 40/58 patients, while 13 patients died before review. Patients spent a median [IQR] of 2 [1-4] days under the palliative care team, who made 3 [2-5] contacts across patient, family, and clinicians. At March 30, 2020, 75 patients had died; 13 been discharged back to team, home, or hospice; and 13 continued to receive inpatient palliative care. Palliative care is an essential component to the COVID-19 response, and teams must rapidly adapt with new ways of working. Breathlessness and agitation are common but respond well to opioids and benzodiazepines. Availability of subcutaneous infusion pumps is essential. An international minimum data set for palliative care would accelerate finding answers to new questions as the COVID-19 pandemic develops.
Topics: Aged; Aged, 80 and over; COVID-19; Coronavirus Infections; Disease Management; Female; Hospice Care; Hospitalization; Humans; Male; Palliative Care; Pandemics; Pneumonia, Viral; Referral and Consultation; Treatment Outcome
PubMed: 32325167
DOI: 10.1016/j.jpainsymman.2020.04.015 -
Journal of Thoracic Disease Jan 2023
PubMed: 36794143
DOI: 10.21037/jtd-22-1460 -
BMC Anesthesiology May 2024Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90%... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90% effective dose (ED90) of remimazolam to inhibit responses to insertion of a duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP).
METHODS
A dose-response study was carried out undergoing ERCP who received remimazolam-alfentanil anesthesia using 10 µg/kg of alfentanil between September 2021 and November 2021. The initial dose of remimazolam was 0.2 mg/kg. The dose was then decided based on the responses of earlier patients by exploiting the sequential ascend and descend according to a 9: 1 biased coin design. Upon failure, the dose of remimazolam was increased by 0.025 mg/kg in the next patient. When the insertion was successful, the succeeding patient was randomized to an identical dose or a dose that was lower by 0.025 mg/kg.The ED90 of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP was calculated. Adverse events and complications of remimazolam were recorded.
RESULTS
A total of 55 elderly patients (age > 65) were included in the study. 45 successfully anesthetized patients, and 10 unsuccessfully. The ED90 of remimazolam was 0.300 mg/kg (95% CI = 0.287-0.320). ED95 was 0.315 (95% CI = 0.312-0.323) and ED99 was 0.323 (95% CI = 0.323-0.325). Among the patients, 9 patients developed hypotension, 2 patients developed bradycardia and 1 patient developed tachycardia, and hypoxia occurred in 2 patients.
CONCLUSIONS
A loading dose of 0.300 mg / kg of remimazolam for elderly patients undergoing ERCP can safely, effectively, and quickly induce patients to fall asleep and inhibit responses to the insertion of a duodenoscope.
TRIAL REGISTRATION
The study protocol was registered at the website ClinicalTrials.gov on 22/09/2021(NCT05053763).
Topics: Humans; Cholangiopancreatography, Endoscopic Retrograde; Male; Female; Hypnotics and Sedatives; Duodenoscopes; Dose-Response Relationship, Drug; Aged; Alfentanil; Middle Aged; Benzodiazepines
PubMed: 38745175
DOI: 10.1186/s12871-024-02554-1 -
Pharmacogenomics and Personalized... 2024The polymorphism of the gene coding mu-opioid receptor () is one of the factors contributing to the variability in the response to opioid analgesics in children. The...
INTRODUCTION
The polymorphism of the gene coding mu-opioid receptor () is one of the factors contributing to the variability in the response to opioid analgesics in children. The goal of this study is to investigate its role in association with postoperative acute pain in children of various ages.
METHODS
This prospective study analyzed 110 pediatric patients, after plastic or orthopedic surgery, who were genotyped and randomly assigned to receive fentanyl or alfentanil. Postoperative pain was rated using Numerical Rating Scale (0-10). All the patients were genotyped for () gene polymorphism.
RESULTS
School children under the age of 11 with the genotype were shown to have a higher BMI (p<0.05). Children over the age of 12 carrying G allele , had increased postoperative pain sensitivity and intensity (3.28±1.95 vs 4.91±2.17; p<0.05), as compared to allele carriers.
DISCUSSION
polymorphism may explain the variation in the perception of postoperative pain in children over the age of 12 and may be a useful predictor for adjusting the dose of analgesics, but the dose is relative to the patient's needs regardless of his genetic characteristics. In younger children, carriers of polymorphic allele may be protected from obesity, due to diminished expression.
PubMed: 38313794
DOI: 10.2147/PGPM.S443035