Adverse drug reactions in the ambulatory internal patients at the emergency department: Focus on causality assessment and drug-drug interactions.

A non-interventional retrospective study in ambulatory patients was conducted at the emergency department of the Division of internal medicine. In 2 months, 266 suspected adverse drug reactions (ADRs) were identified in 224/3453 patients (6.5 %). In 158/3453 patients (4.6 %), an ADR was the reason for emergency department visit and in 49 patients (1.4 %), ADRs led to hospitalisation. A causality assessment algorithm was developed, which included Naranjo algorithm and levels of ADR recognition by the treating physician and the investigators. Using this algorithm, 63/266 ADRs (23.7 %) were classified as "certain", whereas using solely the Naranjo score calculation, only 19/266 ADRs (7.1 %) were assessed as "probable" or "certain", and the rest of ADRs (namely, 247/266 = 92.9 %) were assessed as "possible". There were 116/266 (43.6 %) ADRs related to potential drug-drug interactions (DDIs), stated in at least one of the literature sources used. Based on the causality relationship, the rate of the clinically expressed DDIs was 19.0 %, or 12/63 "certain" ADR cases. Of these, 10 cases presented serious DDI-related ADRs. In summary, ADR causality assessment based exclusively on Naranjo algorithm demonstrated low sensitivity at an ambulatory emergency setting. Additional clinical judgment, including the opinion of the treating physician, proved necessary to avoid under-rating of the causality relationship, and enabled the determination of clinically expressed DDIs.

External validation of population pharmacokinetic models of gentamicin in paediatric population from preterm newborns to adolescents.

The aim of this study was to externally validate the predictive performance of published population pharmacokinetic models of gentamicin in all paediatric age groups, from preterm newborns to adolescents. We first selected published population pharmacokinetic models of gentamicin developed in the paediatric population with a wide age range. The parameters of the literature models were then re-estimated using the PRIOR subroutine in NONMEM®. The predictive ability of the literature and the tweaked models was evaluated. Retrospectively collected data from a routine clinical practice (512 concentrations from 308 patients) were used for validation. The models with covariates characterising developmental changes in clearance and volume of distribution had better predictive performance, which improved further after re-estimation. The tweaked model by Wang 2019 performed best, with suitable accuracy and precision across the complete paediatric population. For patients treated in the intensive care unit, a lower proportion of patients would be expected to reach the target trough concentration at standard dosing. The selected model could be used for model-informed precision dosing in clinical settings where the entire paediatric population is treated. However, for use in clinical practice, the next step should include additional analysis of the impact of intensive care treatment on gentamicin pharmacokinetics, followed by prospective validation.

Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis.

PURPOSE: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. METHODS: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. RESULTS: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. CONCLUSIONS: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.

Repeated Treatments with Chitosan in Combination with Antibiotics Completely Eradicate Uropathogenic Escherichia coli From Infected Mouse Urinary Bladders.

Uropathogenic Escherichia coli (UPEC), the primary causative agents of urinary tract infections, colonize and invade the epithelial cells of the bladder urothelium. Infection of immature urothelial cells can result in the formation of persistent intracellular reservoirs that are refractory to antibiotic treatments. Previously, we defined a novel therapeutic strategy that used the bladder cell exfoliant chitosan to deplete UPEC reservoirs. However, although a single treatment of chitosan followed by ciprofloxacin administration had a marked effect on reducing UPEC titers within the bladder, this treatment failed to prevent relapsing bacteriuria. We show here that repeated use of chitosan in conjunction with the antibiotic ciprofloxacin completely eradicates UPEC from the urinary tract and prevents the development of relapsing bouts of bacteriuria. In addition, microscopy revealed rapid restoration of bladder integrity following chitosan treatment, indicating that chitosan can be used to effectively combat recalcitrant bladder infections without causing lasting harm to the urothelium.

A nonlinear mixed effects modelling analysis of topiramate pharmacokinetics in patients with epilepsy.

Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.

Heparin decreases permeability of pig urinary bladder wall preliminarily enhanced by chitosan.

Chitosan significantly increases the permeability of the isolated pig urinary bladder wall by causing urothelial desquamation, the extent of which depends also on the concentration of the polymer. By desquamation permeability barriers of the urothelium are removed. To gain additional insight into the mechanism by which chitosan acts an absorption enhancer into urinary bladder mucosa, we evaluated the influence of a polysaccharide heparin on the permeability of isolated pig urinary bladder wall preliminarily treated with chitosan. Moreover, we aimed to establish whether the effect of heparin depends on its concentration and on the degree of urothelial desquamation caused by chitosan. In the permeability studies performed by the use of diffusion cells, transport of a model drug, pipemidic acid, into the isolated pig urinary bladder wall was determined. Heparin did not have a significant effect on the permeability of the intact urothelium. When applied to the urinary bladder wall, whose permeability was preliminarily enhanced by 0.005% or 0.001% w/v chitosan, heparin decreased the permeation of pipemidic acid into the bladder wall to a level not significantly different from the intact tissue. However, the effect of heparin was not significant at the highest concentration of chitosan tested, where the damage to the urothelium was much more intense compared with that found at lower concentrations of the polymer. The formation of complexes between pipemidic acid and heparin cannot be excluded completely, but it seems that they are not the main reason for the decreased permeation of pipemidic acid in the presence of heparin. By application on the urothelium, damaged by chitosan, heparin is supposed to form a layer on the surface of the urothelium that prevents the transport of the model drug into the bladder wall. In this way heparin probably restores the impermeability properties of the urinary bladder wall to a degree dependent on the urothelial damage.

Permeability of pig urinary bladder wall: time and concentration dependent effect of chitosan.

Chitosan in 0.5% w/v concentration enhanced the permeability of the isolated pig urinary bladder wall by desquamation of the urothelium as ascertained in our previous study. The aim of the present work was to determine the time and concentration dependence of chitosan's effect on the permeation of a model drug into the bladder wall and to establish if the mechanism of permeation enhancement depends on the concentration of chitosan used. In the permeability studies performed by the use of diffusion cells, transport of a model drug moxifloxacin into the isolated pig urinary bladder wall was determined. For morphological observations of the urothelium in response to chitosan treatment scanning and transmission electron microscopy were applied. Within 90 min the effect of chitosan on the tissue amounts of moxifloxacin gradually increased and approached its plateau. In one hour even 0.0005% w/v dispersion of chitosan significantly enhanced the permeability of the pig urinary bladder wall for the model drug and at 0.001% w/v concentration the maximal effect on the tissue permeability was achieved. All concentrations of chitosan that significantly enhanced the permeability of the bladder wall triggered necrosis of superficial cells or desquamation of the urothelium. However, at lower concentrations and shorter exposure times the damage of the urothelium was limited to the changes in tight junctions. Chitosan was ascertained to increase the permeation of moxifloxacin into the urinary bladder wall in a time and concentration dependent manner.