Effectiveness of pharmacist-led medication reconciliation on medication errors at hospital discharge and healthcare utilization in the next 30 days: a pragmatic clinical trial.

Transitions of care often lead to medication errors and unnecessary healthcare utilization. Medication reconciliation has been repeatedly shown to reduce this risk. However, the great majority of evidence is limited to the provision of medication reconciliation within clinical trials and countries with well-established clinical pharmacy. Thus, this pragmatic, prospective, controlled trial evaluated the effectiveness of routine pharmacist-led medication reconciliation compared to standard care on medication errors and unplanned healthcare utilization in adult general medical patients hospitalized in a teaching hospital in Slovenia. All patients hospitalized in a ward where medication reconciliation was integrated into routine clinical practice were included in the intervention group and received admission and discharge medication reconciliation, coupled with patient counselling. The control group consisted of randomly selected patients from the remaining medical wards. The primary study outcome was unplanned healthcare utilization within 30 days of discharge, and the secondary outcomes were clinically important medication errors at hospital discharge and serious unplanned healthcare utilization within 30 days of discharge. Overall, 414 patients (53.4% male, median 71 years) were included-225 in the intervention group and 189 in the control group. In the intervention group, the number of patients with clinically important medication errors at discharge was significantly lower (intervention vs control group: 9.3% vs 61.9%). Multiple logistic regression revealed that medication reconciliation reduced the likelihood of a clinically important medication error by 20-fold, while a higher number of medications on admission was associated with an increased likelihood. However, no significant differences were noted in any and serious unplanned healthcare utilization (intervention vs control group: 33.9% vs 27.8% and 20.3% vs 14.6%, respectively). The likelihood of serious healthcare utilization increased with the age of the patient, the number of medications on admission and being hospitalized for an acute medical condition. Our pragmatic trial confirmed that medication reconciliation, even when performed as part of routine clinical practice, led to a substantial reduction in the risk of clinically important medication errors at hospital discharge but not to a reduction in healthcare utilization. Medication reconciliation is a fundamental, albeit not sufficient, element to ensure patient safety after hospital discharge. Clinical Trial Registration: https://clinicaltrials.gov/search?id=NCT06207500, identifier NCT06207500.

Sex-Dependent Differences in Blood-Urine Barrier Are Subtle but Significant in Healthy and Chronically Inflamed Mouse Bladders.

The urothelium is a vital permeability barrier that prevents the uncontrolled flow of urinary components into and out of the bladder interstitium. Our study addressed the question of possible sex-specific variations in the urothelium of healthy mice and their impact on chronic bladder inflammation. We found that healthy female bladders have a less robust barrier function than male bladders, as indicated by significant differences in transepithelial electrical resistance (TEER) values. These differences could be attributed to detected higher claudin 2 mRNA expression and a less pronounced glycocalyx in females than in males. In addition, TEER measurements showed delayed barrier recovery in chronically inflamed female bladders. We found subtle differences in the expressions of genes involved in the regulation of the actin cytoskeleton between the sexes, as well as pronounced urothelial hyperplasia in females compensating for attenuated barrier function. The identified genetic variations in glycosylation pathways may also contribute to this divergence. Our findings add to the growing body of literature on the intricate sex-specific nuances of urothelial permeability function and their implications for chronic bladder inflammation. Understanding these differences could lead to tailored diagnostic and therapeutic approaches in the treatment of bladder disorders in the future.

Deprescribing proton pump inhibitors: A study in hospitalized patients in Slovenia.

OBJECTIVE: To evaluate the possibility of deprescribing proton pump inhibitors in adult inpatients hospitalized in a teaching hospital in Slovenia. MATERIALS AND METHODS: We conducted a prospective observational clinical study in 120 patients taking a proton pump inhibitor. Data were obtained from hospital medical records and patient interviews. First, treatment compliance with relevant guidelines was assessed, and then the possibility of deprescribing was considered. RESULTS: Treatment with a proton pump inhibitor was in accordance with guidelines in only 39% of the 120 patients. In 24% of patients, the indication for proton pump inhibitor use was invalid, and 22% and 15% of patients were taking a proton pump inhibitor at a higher dose or for a longer period than recommended, respectively. Deprescribing could be undertaken in 61% of patients, as discontinuation in 38%, and dose reduction in 23%. A deprescribing possibility was noted more frequently in patients prescribed proton pump inhibitors for peptic ulcer disease, Helicobacter pylori infection, or without a valid indication (p < 0.001), as well as in patients taking a double or higher dose of a proton pump inhibitor (p < 0.001). CONCLUSION: Deprescribing of proton pump inhibitors could be undertaken in nearly 2/3 of our cohort of adult hospitalized patients. Hospitalization may serve as an opportunity to deprescribe proton pump inhibitors.

Adverse drug events during transitions of care : Randomized clinical trial of medication reconciliation at hospital admission.

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.

Incidence and control of steroid-induced hyperglycaemia in hospitalised patients at a tertiary care centre for lung diseases.

BACKGROUND: The aim of this study was to determine the incidence of steroid-induced hyperglycaemia (SIH) in patients hospitalised at the tertiary centre for lung diseases, to assess glycaemic control during hospitalisation, and to determine the factors associated with the control of SIH. METHODS: A 4-month retrospective study was conducted. All patients who received systemic glucocorticoids for ≥ 2 days during hospitalisation, with ≥ 2 elevated blood glucose (BG) readings, were included in the analysis. SIH control was determined by mean BG levels, the number and proportion of elevated and pronouncedly elevated BG readings, and the number of hypoglycaemic events. RESULTS: 60 of 283 patients (21.2%) developed SIH, of which 55 patients were included in further analysis. Mean fasting and daytime BG levels were 7.8 ± 2.9 mmol/l and 10.9 ± 2.2 mmol/l, respectively. 41/55 patients (74.5%) had elevated average BG levels. 45/55 patients (81.8%) had > 5 readings or > 20% of all readings exceeding hyperglycaemia threshold, and 33/55 patients (60.0%) had pronouncedly elevated BG levels on more than one occasion. 6/55 patients (10.9%) experienced more than one hypoglycaemic event or a severe hypoglycaemia. Only 9/55 patients (16.4%) achieved adequate SIH control according to all defined criteria. Pre-existing diabetes and longer duration of hospital treatment with low glucocorticoid dose were significantly associated with poorer glycaemic control (p < 0.001 and p = 0.003, respectively). CONCLUSIONS: Appropriate SIH management was demonstrated to be challenging. According to the defined criteria, adequate glycaemic control during hospitalisation was not achieved in the large majority of patients with SIH.

Does the Urothelium of Old Mice Regenerate after Chitosan Injury as Quickly as the Urothelium of Young Mice?

The aging of organisms leads to a decreased ability of tissue to regenerate after injury. The regeneration of the bladder urothelium after induced desquamation with biopolymer chitosan has been studied in young mice but not in old mice. Chitosan is a suitable inducer of urothelial desquamation because it is known to be non-toxic. We used chitosan for desquamation of urothelial cells in order to compare the dynamics of urothelial regeneration after injury between young and old mice. Our aim was to determine whether the urothelial function and structure of old mice is restored as fast as in young mice, and to evaluate the inflammatory response due to chitosan treatment. We discovered that the urothelial function restored comparably fast in both age groups and that the urothelium of young and old mice recovered within 5 days after injury, although the onset of proliferation and differentiation appeared later in old mice. Acute inflammation markers showed some differences in the inflammatory response in young versus old mice, but in both age groups, chitosan caused short-term acute inflammation. In conclusion, the restoration of urothelial function is not impaired in old mice, but the regeneration of the urothelial structure in old mice slightly lags behind the regeneration in young mice.

Sensitivity of Different In Vitro Performance Tests and Their In Vivo Relevance for Calcipotriol/Betamethasone Ointment.

PURPOSE: We compared results of in vitro performance testing with results of therapeutic equivalence study for calcipotriol/betamethasone ointment, to evaluate their sensitivity and in vivo relevance. METHODS: Different in vitro methods were used to evaluate drug release and permeation from the test and reference ointment. Moreover, 444 psoriasis patients were randomized in the therapeutic equivalence study and the parameters of efficacy and safety were compared with in vitro results. RESULTS: In vitro release and permeation rate of calcipotriol and betamethasone from the test formulation was higher than from the reference product for all methods used (p ≤ 0.05 for calcipotriol and p < 0.01 for betamethasone). Observed batch-to-batch variability of reference product confirmed high sensitivity and discriminatory power of in vitro methods. Higher release and permeation rate of calcipotriol and betamethasone from test product was reflected in the efficacy assessment (mean response difference 4.78 mPASI percentage points), but the observed difference was within the equivalence margins. Systemic exposure to calcipotriol and betamethasone was similar in both treatment groups. CONCLUSION: The results of in vitro experiments rank orderly correlated with the results of clinical study. In vitro methods are more sensitive and highly discriminatory when compared to in vivo performance.

Efficacy of Calcipotriol-Betamethasone Ointment in Patients with Mild to Moderate Plaque Psoriasis: Subgroup Analyses.

BACKGROUND: Several factors have been shown to affect psoriasis pathogenesis, clinical presentation and treatment response. OBJECTIVES: The aim of this study was to investigate the potential relationship between patients' baseline characteristics and the efficacy of calcipotriol-betamethasone ointment in patients with mild to moderate plaque psoriasis and to evaluate whether the efficacy is consistent across subgroups. METHOD: Using data from the therapeutic equivalence study on patients with plaque psoriasis, post hoc analyses were performed to evaluate the impact of baseline demographic and disease characteristics, habits and comorbidities on the response to treatment with calcipotriol-betamethasone ointment. RESULTS: Body mass index (BMI) and obesity were each independently associated (univariate analysis, p < 0.05) with reduction in modified Psoriasis Area and Severity Index (mPASI) and PASI75 (≥75% improvement in mPASI from baseline). Increased body weight is more common in patients with late-onset psoriasis. There was a significant trend for lower response rates with increasing BMI (p = 0.007) and obesity (p = 0.003). The odds of achieving PASI75 is 2.3 times lower for obese compared to normal-weight subjects.If patients with obesity or hypertension were treated with calcipotriol-betamethasone, they were still more likely to achieve PASI75 after 4-week treatment compared to vehicle (p < 0.001). CONCLUSION: Increased BMI and obesity present risk factors for reduced treatment effectiveness. Importantly, the efficacy of calcipotriol-betamethasone ointment was consistent in all subgroups.

Poly-L-lysine as an Effective and Safe Desquamation Inducer of Urinary Bladder Epithelium.

Induced desquamation of urinary bladder epithelial cells, also called urothelial cells, is frequently used in studies of bladder epithelial regeneration and also in treating recurrent bacterial cystitis. Positively charged polymer chitosan is known to cause large-scale desquamation of terminally differentiated urothelial cells called umbrella cells. Aiming to compare the desquamation ability of another polycation poly-L-lysine, we studied the effect of this polymer on the functional and structural integrity of the urothelium in ex vivo and in vivo experiments. The urothelium was analyzed by measuring transepithelial electrical resistance, and the structural changes of its luminal surface were analyzed with scanning electron microscopy. The results revealed a selective and concentration-dependent desquamation effect of poly-L-lysine on superficial urothelial cells followed by quick regeneration of the urothelium, which functionally and structurally recovers in 2 to 3 h after poly-L-lysine-induced injury. Poly-L-lysine was thus proven to be a promising polymer to be used when desquamation of urothelial cells is required in basic and potentially clinical studies.

A review of population pharmacokinetic models of gentamicin in paediatric patients.

WHAT IS KNOWN AND OBJECTIVES: Gentamicin is often used for the treatment of Gram-negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. METHODS: The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. RESULTS AND DISCUSSION: In most of the studies, one- or two-compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. WHAT IS NEW AND CONCLUSION: Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat-free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.

Bisoprolol pharmacokinetics and body composition in patients with chronic heart failure: a longitudinal study.

PURPOSE: We investigated bisoprolol pharmacokinetics, including longitudinal changes and importance of patient characteristics in chronic heart failure. METHODS: Forty-six patients with chronic heart failure (57 % male, NYHA class I/II/III = 2/36/8) were followed for an average of 8 ± 2 months. At baseline and follow-up, plasma bisoprolol concentrations were determined and body composition was measured using dual-energy X-ray absorptiometry. A bisoprolol pharmacokinetic model was built with non-linear mixed-effects modeling to analyze the association with various parameters of body composition. RESULTS: Mean bisoprolol clearance (10.2 L/h) was 30 % lower than in healthy individuals and correlated with MDRD4-estimated renal function. The mean volume of distribution (230 L) was similar to healthy population and was associated with total body mass and skeletal muscle index (SMI). During follow-up, we observed minor changes in the absorption rate constant (2.83 vs. 2.27 h(-1), P = 0.030) and volume of distribution (227 vs. 250 L, P = 0.004), which are not clinically relevant. CONCLUSIONS: In patients with chronic heart failure, bisoprolol clearance was associated with estimated renal function; thus, in moderately and severely decreased renal function, patients may need to have their dose adjusted. Patients with low body weight or low SMI have greater fluctuations and higher maximal plasma concentrations of bisoprolol because of the lower volume of distribution. Longitudinal changes of bisoprolol pharmacokinetics were not associated with changes in body composition.

Influence of cancer cachexia on drug liver metabolism and renal elimination in rats.

BACKGROUND: Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats. METHODS: Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5-D5), and when rats were severely cachectic (Day 10-D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters. RESULTS: All three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam and propranolol CL and midazolam Vd significantly decreased from baseline (-80.5%, -79.8%, and -72.0%, respectively, P < 0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r = 0.837, P = 0.019). CONCLUSIONS: Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.

Iohexol clearance is superior to creatinine-based renal function estimating equations in detecting short-term renal function decline in chronic heart failure.

AIM: To compare the performance of iohexol plasma clearance and creatinine-based renal function estimating equations in monitoring longitudinal renal function changes in chronic heart failure (CHF) patients, and to assess the effects of body composition on the equation performance. METHODS: Iohexol plasma clearance was measured in 43 CHF patients at baseline and after at least 6 months. Simultaneously, renal function was estimated with five creatinine-based equations (four- and six-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Cockcroft-Gault adjusted for lean body mass, Chronic Kidney Disease Epidemiology Collaboration equation) and body composition was assessed using bioimpedance and dual-energy x-ray absorptiometry. RESULTS: Over a median follow-up of 7.5 months (range 6-17 months), iohexol clearance significantly declined (52.8 vs 44.4 mL/[min ×1.73 m2], P=0.001). This decline was significantly higher in patients receiving mineralocorticoid receptor antagonists at baseline (mean decline -22% of baseline value vs -3%, P=0.037). Mean serum creatinine concentration did not change significantly during follow-up and no creatinine-based renal function estimating equation was able to detect the significant longitudinal decline of renal function determined by iohexol clearance. After accounting for body composition, the accuracy of the equations improved, but not their ability to detect renal function decline. CONCLUSIONS: Renal function measured with iohexol plasma clearance showed relevant decline in CHF patients, particularly in those treated with mineralocorticoid receptor antagonists. None of the equations for renal function estimation was able to detect these changes. ClinicalTrials.gov registration number: NCT01829880.

Liquid chromatography-tandem mass spectrometry method for simultaneous quantification of bisoprolol, ramiprilat, propranolol and midazolam in rat dried blood spots.

Dried blood spot (DBS) sampling represents a suitable method for pharmacokinetic studies in rats, particularly if serial sampling is needed. To study the pharmacokinetics of drugs in a rat heart failure (HF) model, we developed and validated a method for the simultaneous determination of bisoprolol, ramiprilat, propranolol and midazolam in DBS samples. Bisoprolol and ramipril are widely used in the treatment of HF, and midazolam and propranolol are markers of hepatic metabolism, which can be altered in HF. A 20µL sample of rat blood was pipetted onto Whatman 903 Protein Saver Card and allowed to dry. The whole spot was excised and 300µL of solvent (methanol with 10% ultrapure water and 0.1% formic acid) was added. After mixing and incubating the sample in an ultrasonic bath, a mixture of isotopically labeled internal standards was added. After centrifugation, the extracts were cleaned on an Ostro™ plate and analyzed using liquid chromatography-tandem mass spectroscopy. The method was successfully validated. No significant interference was observed in the retention times of analytes or internal standards. The intraday and interday accuracy and precision were within a ±15% interval. The method was linear in the range 5-250µg/L and the lower limit of quantification was 5µg/L for all four analytes. The absolute matrix effect ranged from 98.7% for midazolam to 121% for ramiprilat. The recovery was lowest for ramiprilat and highest for propranolol. Samples were stable at all tested temperatures. The method has been used successfully in a real-time pharmacokinetic study in rats.

Pharmacokinetics of drugs in cachectic patients: a systematic review.

Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

Correlative study of functional and structural regeneration of urothelium after chitosan-induced injury.

High transepithelial electrical resistance (TEER) demonstrates a functional permeability barrier of the normal urothelium, which is maintained by a layer of highly differentiated superficial cells. When the barrier is challenged, a quick regeneration is induced. We used side-by-side diffusion chambers as an ex vivo system to determine the time course of functional and structural urothelial regeneration after chitosan-induced injury. The exposure of the urothelium to chitosan caused a 60 % decrease in TEER, the exposure of undifferentiated urothelial cells to the luminal surface and leaky tight junctions. During the regeneration period (350 min), TEER recovered to control values after approximately 200 min, while structural regeneration continued until 350 min after injury. The tight junctions are the earliest and predominant component of the barrier to appear, while complete barrier regeneration is achieved by delayed superficial cell terminal differentiation. The barrier function and the structure of untreated urothelium were unaffected in side-by-side diffusion chambers for at least 6 h. The urinary bladder tissue excised from an animal thus retains the ability to maintain and restore the transepithelial barrier and cellular ultrastructure for a sufficient period to allow for studies of regeneration in ex vivo conditions.

Rapid differentiation of superficial urothelial cells after chitosan-induced desquamation.

Superficial cell desquamation followed by differentiation of newly exposed superficial cells induces regeneration of the urinary bladder epithelium, urothelium. In the present work, chitosan was evaluated as a new inducer of urothelial cell desquamation, in order to study the regeneration of mouse urothelial cells in vivo. Intravesical application of chitosan dispersion caused complete removal of only the superficial layer of cells within 20 min of treatment. Differentiation of the new superficial layer was followed by the appearance and distribution of three urothelial differentiation markers, tight junction protein ZO1, cytokeratin 20 and the maturation of the apical plasma membrane. The arrangement of ZO1 into continuous lines in individual cells of the intermediate layer was already found after 10 min of chitosan application, when desquamation had just started. The appearance of the apical membrane changed from microvillar to typically scalloped within 20 min of regeneration, while complete arrangement of the cytokeratin 20 network took 60 min. These findings provide a new perspective on the rate of the differentiation process in the urothelium and make chitosan a new and a very controllable tool for studies on urothelial regeneration.