Determination of remifentanil in neonatal dried blood spots by liquid chromatography-tandem mass spectrometry.

Remifentanil is an ultra-short-acting synthetic opioid-class analgesic which might be increasingly used "off-label" as pain management during labour. Side effects in parturients during labour, and in the infant at birth are of particular concern, especially respiratory depression which is concentration-dependent, and can occur at levels as low as 3-5 ng mL-1. The safety of such use, particularly in newborns due to remifentanil placental transfer, has not been fully demonstrated yet, partly due to the lack of a suitable non-invasive analytical method. The aim of our work was to develop a sensitive method to monitor the levels of remifentanil in neonates by a non-invasive sampling of umbi lical cord blood to support efficacy and safety trials. The presented LC-MS method is sensitive enough to reliably quantify remifentanil in just 20 µL of blood at only 0.3 ng mL-1. The dried blood spot sample preparation included solvent extraction with subsequent solid-phase extraction. The method was validated in terms of accuracy, precision, recovery, matrix effect, and stability, and was successfully applied to a small pilot study. The estimated arterial blood concentrations at the time of delivery ranged from 0.2 to 0.3, and up to 0.9 ng mL-1 in neonatal, and maternal samples, respectively.

Potential Drug-Drug Interactions among Patients with Schizophrenia Spectrum Disorders: Prevalence, Association with Risk Factors, and Replicate Analysis in 2021.

Background and Objectives: Patients with schizophrenia are often exposed to polypharmacotherapy, which may lead to drug-drug interactions. The aim of the study was to investigate the prevalence of potential drug-drug interactions (pDDIs) in hospitalized patients with schizophrenia spectrum disorders and to identify factors associated with pDDIs and manifested symptoms and signs. Materials and Methods: This cross-sectional observational study included 311 inpatients admitted to a psychiatric hospital. The LexiComp drug interaction program was used to identify pDDIs in 2014. Factors associated with the prevalence of pDDIs and factors related to clinically observed symptoms and signs were assessed using multivariable regression. In addition, replicate analysis of pDDI was performed using 2021 program updates. Results: The prevalence of pDDIs was 88.7%. Our study showed that more than half of the patients received at least one drug combination that should be avoided. The most common pDDIs involved combinations of two antipsychotics or combinations of antipsychotics and benzodiazepines, which can lead to cardio-respiratory depression, sedation, arrhythmias, anticholinergic effects, and neuroleptic malignant syndrome. The number of prescribed drugs was a risk factor for pDDIs (OR 2.85; 95% CI 1.84-5.73). All groups of clinically observed symptoms and signs were associated with the number of drugs. In addition, symptoms and signs characteristic of the nervous system and psychiatric disorders were associated with antipsychotic dosage (IRR 1.33; 95% CI 1.12-1.58), which could contribute to the development of extrapyramidal syndrome, insomnia, anxiety, agitation, and bipolar mania. The 2021 version of the drug interaction program showed a shift in drug interactions toward a lower risk rating, implying less severe patient management and possibly less alert fatigue. Conclusions: Patients with schizophrenia spectrum disorders are at high risk of developing drug-drug interactions. Optimization of drug therapy, patient monitoring, and use of drug interaction programs could help to prevent pDDIs and subsequent adverse drug events.

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.

Impact of clinical pharmacist's interventions on pharmacotherapy management in elderly patients on polypharmacy with mental health problems including quality of life: A prospective non-randomized study.

Mental health problems (MHPs) are very common in the elderly and can have an important influence on their quality of life (QoL). There is almost no data on the impact of clinical pharmacists' (CPs) interventions on the QoL including elderly patients and MHPs. The main aim of this study was to determinate the impact of (CP's) interventions on the QoL and quality of pharmacotherapy. A prospective non-randomized pre-post study was designed which included residents of a nursing home aged 65 age or more with at least one MHP. Each patient also filled out the EQ-5D questionnaire. The medical review MR included drug-related problems (DRPs) and potentially drug-drug interactions (pDDIs), as well as potentially inappropriate medications (PIMs). After 2 months, the participants were interviewed again. The mean number of medications before the intervention was 12,2 ± 3,1 per patient and decreased to 10,3 ± 3,0 medications per patient (p < 0,05) (n = 24). The total number of PIMs and pDDIs was also reduced and QoL was also significantly higher (p < 0,05). A collaborative care approach with a CP led to a decrease of DRPs, pDDIs, PIMs, the total number of medications and to an improvement in the patients' QoL.

Fast and Simple LC-MS/MS Method for Rifampicin Quantification in Human Plasma.

A simple, fast, and cost-effective LC-MS/MS method for quantification of rifampicin in human plasma was developed and fully validated. The plasma samples containing rifampicin and isotopically labelled internal standard rifampicin D8, were cleaned up using a Captiva ND Lipids filtration plate. Chromatographic separation was achieved on an 1290 Infinity liquid chromatograph coupled to 6460 Triple Quadrupole operated in positive mode on a core-shell Kinetex C18 column (50 × 2.1 mm, 2.6 µm) by gradient elution using 0.1% formic acid in water and acetonitrile as a mobile phase. The proposed method is the fastest method published by now, both in terms of sample preparation (approximately one minute per sample) and chromatographic analysis (total run time 2.4 min). Another key benefit is the outstanding sensitivity and wide analytical range (5-40000 µg/L) with good linearity, accuracy, and precision. The method showed almost complete recovery (92%) and absence of any significant matrix effect as demonstrated by uniform responses from QC samples prepared in blood plasma from 6 volunteers (RSD <5%). The proposed method was successfully applied to rifampicin quantification in 340 patients' plasma samples, thus demonstrating its suitability for both therapeutic drug monitoring and pharmacokinetic analysis.

Impact of drugs on venous thromboembolism risk in surgical patients.

PURPOSE: This review focuses on the most common drugs administered to surgical patients during the perioperative period that affect the risk of venous thromboembolism (VTE). RESULTS: Among analgesics, the risk of VTE is increased in patients treated with diclofenac, ibuprofen, and rofecoxib, but not naproxen, while metamizole can confer a protective effect. The relationship between sedatives and VTE has not been sufficiently studied. Tricyclic antidepressants, low-potency serotonin reuptake inhibitors, and antipsychotics have been associated with increased risk of VTE. The use of diuretics in the perioperative period is poorly researched; however, hyponatremia is considered a risk factor. Other factors that may influence the risk of VTE include bridging anticoagulation, allogeneic transfusion, and hemostatic management before surgery. Pharmacotherapy for HIV or cancer may also increase VTE risk. CONCLUSION: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.

Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study.

PURPOSE: Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects. METHODS: Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects. RESULTS: A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration. CONCLUSIONS: We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.

Prescribing patterns for inpatients with schizophrenia spectrum disorders in a psychiatric hospital in Slovenia: Results of 16-month prospective, non-interventional clinical research.

BACKGROUND: In Slovenia, there has been no evidence about the prescribing patterns for inpatients with psychotic disorders. The research aims to analyze drug utilization patterns for inpatients with psychotic disorder that are coded as F20-F29 according to International Classification of Diseases (ICD) 10th revision (schizophrenia spectrum disorders). SUBJECTS AND METHODS: Prospective research was conducted at the Psychiatric Hospital Idrija. The medical records of the inpatients admitted over a 12-month period were collected from the beginning to the end of their hospitalization. RESULTS: A total of 311 inpatients with 446 hospitalizations were included, producing a total of 3954 medication prescriptions. Medications prescribed pro re nata (the use of as needed) were also taken into account. Antipsychotics (N=1149, 43% of prescriptions) were the most often prescribed medications, followed by anxiolytics, antiparkinsonians, antidepressants, mood stabilizers and cardiovascular drugs. A total of 256 (82%) inpatients received at least one pro re nata medication. It was observed that the studied population was treated with one antipsychotic on 27 percent of prescriptions. CONCLUSIONS: Inpatients with schizophrenia spectrum disorders were exposed to a large number of different drugs. They were not received only psychotropic drugs but also other medications. With the knowledge about medications the implementation of clinical pharmacy services to the psychiatrists would significantly improve medication of inpatients with psychotic disorders and polypharmacotherapy.

Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

PURPOSE: Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. METHODS: A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. RESULTS: Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. CONCLUSION: DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

Polypharmacotherapy and blood products as risk factors for venous thromboembolism in postsurgical patients: a case-control study.

Background After surgical procedures, patients are at high risk of developing venous thromboembolism, clinically manifested as deep vein thrombosis (DVT) or pulmonary embolism (PE). Objective To evaluate the influence of polypharmacotherapy, comorbidity, drug treatments, packed red blood cells application, adequacy of thromboprophylaxis, and patient characteristics on the occurrence of DVT or PE in postsurgical patients. Setting The surgical department at Murska Sobota General Hospital, Slovenia. Methods In this retrospective case control study, the records of 286 surgical patients were analysed: DVT or PE group (n = 144) and control group (n = 142). The number of prescribed drugs and drug-drug interactions were reviewed, together with prescription of low-molecular-weight heparins. The odds ratios (OR) of risk factors for DVT or PE were calculated using a multivariable logistic regression model. Main outcome measure Risk factors assessment for the occurrence of DVT or PE in surgical patients. Results Polypharmacotherapy (OR 2.02, 95% CI 1.03-3.96, p = 0.040) and packed red blood cells application (OR 3.44, 95% CI 1.46-8.10, p = 0.005) were associated with an increased risk of PE or DVT after surgery. Inadequate thromboprophylaxis with low-molecular-weight heparins significantly increased the likelihood of DVT or PE (OR 2.50, 95% CI 1.41-4.43, p = 0.002). There were no differences between the groups concerning the treatment with nonsteroidal anti-inflammatory drugs, benzodiazepines or antipsychotics. Conclusions Patients with polypharmacotherapy and patients receiving red blood cells should be monitored more closely after surgery as they are more likely to develop DVT or PE.

Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome.

AIMS: Pharmacokinetic (PK) studies suggest that there is a room for improvement in clinical use of rituximab through more individualized treatment. The objective of this study was to characterize rituximab PK in 29 newly diagnosed patients with diffuse large B-cell lymphoma treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine and methylprednisolone every 3 weeks. We also evaluated the association of rituximab PK with clinical outcome. METHODS: Rituximab serum levels were determined by enzyme-linked immunosorbent assay and evaluated by a population PK analysis applying nonlinear mixed effects modelling. RESULTS: The data were best described by a two-compartment model comprising linear nonspecific clearance of 0.252 [95% confidence interval (CI): 0.227-0.279] l day-1 and time-varying specific clearance of 0.278 (95% CI: 0.181-0.390) l day-1 , corresponding to target-mediated drug disposition of rituximab. Nonspecific clearance was lower in older patients and those with lower body weight. Additionally, volume of the central compartment was higher in males. A clear association of clinical response with rituximab PK has been observed. Rate constant of specific clearance decay was 0.143 day-1 (95% CI: 0.0478-0.418) in patients with no disease progression, while in patients with disease progression it was 82.2% lower (95% CI: 33.4-95.0). CONCLUSIONS: This finding indicates that time-changes in clearance could serve as a predictive marker of response to rituximab. Our report demonstrates the rationale for studies evaluating higher doses of rituximab in selected patients.

Original research paper. Switching antipsychotics: Results of 16-month non-interventional, prospective, observational clinical research of inpatients with schizophrenia spectrum disorders.

The study aims to identify prescribing and switching patterns of antipsychotics in clinical practice. A 16-month, prospective study was conducted at the Psychiatric Hospital Idrija, Slovenia. Inpatients (N = 311) with schizophrenia spectrum disorders were observed. The causes for switching antipsychotics and switching strategies were analyzed. Analyzing a total of 3954 prescriptions, the collected data confirmed that treatment strategies in this psychiatric hospital are very complex. It was found that 37 percent of inpatients had at least one switch. Moreover, switches that included three or more antipsychotics were detected. The most common causes for switching antipsychotics were adverse reactions and inefficacy or lack of efficacy. Among switching options, abrupt switch was recorded several times. As some patients are receiving several antipsychotics at the same time, it is possible that unusual switching occurs in clinical practice. It seems that the choice of switching strategy is also affected by the cause and urgency for switching an antipsychotic.

Influence of Prescribed Blood Products on the Incidence of Deep Vein Thrombosis and Pulmonary Embolism in Surgical Patients.

Deep vein thrombosis (DVT) and pulmonary embolisms (PEs) are common complications after surgical procedures. The influence of prescribed blood products on the occurrence of DVT and PE was evaluated in postsurgical patients in this retrospective case-control study. The records of 286 surgical patients were analyzed: DVT (n = 52), PE (n = 92), and a control group (n = 142). The amounts of prescribed blood, blood products, and vitamin K were reviewed, together with appropriate prescribing of low-molecular-weight heparins. The influence of prescribed blood products on the occurrence of DVT or PE was analyzed using multinomial logistic regression. We demonstrated a significant difference between the test and control groups ( P < .05) in relation to receiving packed red blood cells. Treatment with red blood cells was associated with an increased risk of PE but not DVT. Patients who developed PE after surgery were hospitalized for longer (median 10 days) than patients with DVT (median 6 days). There was no difference between the test and control groups concerning treatment with fresh frozen plasma. Inadequate thromboprophylaxis significantly increased the likelihood of DVT. There is a connection between receiving packed red blood cells and occurrence of postoperative PE in surgical patients. Thus, patients receiving red blood cells should be monitored more closely after surgery, as they are more likely to develop PE postoperatively.

Therapy modifications during hospitalization in patients with chronic heart failure.

BACKGROUND: Guidelines on suggested pharmacological treatments for heart failure (HF) are not optimally implemented in clinical practice and whether pharmacotherapy adjustment actually happens in daily practice is largely unknown. We aimed to investigate pharmacotherapy modifications during hospitalization. METHODS: This was a prospective observational survey where all admissions were screened for HF; 210 patients were included. The guideline adherence index (GAI) and modified GAI (mGAI, if ≥50% of target dose) were used to grade the pharmacotherapy. RESULTS: Among 198 patients discharged alive (mean age 77years, 51% male), 49% had preserved left ventricular ejection fraction (PLVEF) and 30% had left ventricular systolic dysfunction (LVSD); the echocardiography report was unavailable for 21%. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists were prescribed to 78%, 58% and 20% of patients on admission and 72%, 65% and 23% at discharge, respectively. Overall, 14% of patients met GAI-3, but at discharge only 7% met mGAI-3. One of the key drugs was stopped or down-titrated in 27%. During follow-up, 21% of patients died (25% with LVSD). Patients with LVSD discharged with at least one HF drug had a lower risk of death than patients with none (HR=0.142, 95% CI=0.029-0.683, p=0.015). Patients with PLVEF had better prognosis than LVSD patients when no HF drugs were prescribed at discharge (HR=0.075, 95% CI=0.009-0.627, p=0.017). CONCLUSIONS: The pharmacotherapy of HF patients did not improve significantly during hospitalization, remaining suboptimal. Treatment with key drugs was terminated or reduced in a significant proportion of patients, mostly without specific written justification.

A simple dried blood spot method for clinical pharmacological analyses of etoposide in cancer patients using liquid chromatography and fluorescence detection.

BACKGROUND: Therapeutic drug monitoring of etoposide is not part of the routine clinical practice, however, measuring etoposide plasma concentration may be useful to prevent chemotherapy related adverse drug reactions. This paper describes the development and validation of a dried blood spot (DBS) assay for the determination of etoposide in blood samples of lung cancer patients. METHODS: The whole blood spot was cut out of the DBS card followed by sonication assisted liquid drug extraction. Extraction solution was evaporated and re-dissolved. A high-performance-liquid-chromatography method with fluorimetric detection ( λex=230nm; λem=330nm) was used. RESULTS: Method met the validation criteria in terms of selectivity, linearity (0.5-20.0µg/mL), accuracy (≥96.1%), precision (≤10.1%) and stability (long term 4weeks at room temperature and 40°C). Haematocrit did not influence DBS etoposide concentration. Good correlation between measured plasma and DBS concentrations was observed. The equation considering only haematocrit value was used for conversion of DBS to plasma concentration. CONCLUSIONS: DBS sampling method showed comparable results to plasma samples. Therefore, it can be concluded that the developed and validated DBS method, which is more patient-friendly and requires less sample handling, is a reliable alternative to conventional plasma methods for measuring etoposide concentration in clinical pharmacological analyses.

Efflux and uptake transporters involved in the disposition of bazedoxifene.

Bazedoxifene, a novel selective estrogen receptor modulator, has complex pharmacokinetics with rapid absorption, high metabolic clearance, low oral bioavailability (6.25 %) and a slow elimination phase. Our hypothesis is that drug uptake and efflux transporters may play an important role in its disposition. To adequately cover all aspects of bazedoxifene transport, several approaches were undertaken: PAMPA assay, ATPase assay, membrane inside-out vesicles and Caco-2 and CHO cell lines. The results obtained from PAMPA experiments showed moderate passive permeability of bazedoxifene (P app ≈ 2 × 10(-6)cm/s), suggesting the existence of an active transport during the rapid absorption phase. The Caco-2 transport assay showed large and significant changes in the measured efflux ratios of bazedoxifene when selective transporter inhibitors were applied: verapamil (a Pgp inhibitor), MK571 (an MRP inhibitor), Ko143 (a BCRP inhibitor) and DIDS (an OATP inhibitor). Additionally, membrane preparation experiments demonstrated the interaction of bazedoxifene with P-gp, MRP2 and BCRP. CHO experiments did not show any interactions of bazedoxifene with OATP1B1 or OATP1B3; therefore, bazedoxifene may be a substrate of other OATP isoform(s). The comprehensive in vitro study indicates a strong involvement of Pgp, MRP, BCRP and OATP in bazedoxifene disposition.

Clinical-pharmacist intervention reduces clinically relevant drug-drug interactions in patients with heart failure: A randomized, double-blind, controlled trial.

BACKGROUND: Incidence of drug-drug interactions (DDIs) increases with complexity of treatment and comorbidities, as in heart failure (HF). This randomized, double-blind study evaluated the intervention of the pharmacist on prevalence of clinically relevant DDIs (NCT01855165). METHODS: Patients admitted with HF were screened for clinically relevant DDIs, and randomized to control or intervention. All attending physicians received standard advice about pharmacological therapy; those in the intervention group also received alerts about clinically relevant DDIs. Primary endpoint was DDI at discharge and secondary were re-hospitalization or death during follow-up. RESULTS: Of 213 patients, 51 (mean age, 79 ± 6 years; male, 47%) showed 66 clinically relevant DDIs and were randomized. For intervention (n=26) versus control (n=25), the number of patients with and the number of DDIs were significantly lower at discharge: 8 vs. 18 and 10 vs. 31; p=0.003 and 0.0049, respectively. Over a 6 month follow-up period, 11 control and 9 intervention patients were re-hospitalized or died (p>0.2 for all). No significant differences were seen between control and intervention for patients with eGFR <60 mL/min/1.73 m(2) (78%) for re-hospitalization or death (10 vs. 7; p=0.74). CONCLUSIONS: Pharmacist intervention significantly reduces the number of patients with clinically relevant DDIs, but not clinical endpoints 6 months from discharge.

Febrile neutropenia in chemotherapy treated small-cell lung cancer patients.

BACKGROUND: Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients. METHODS: The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored. RESULTS: Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia. CONCLUSIONS: Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.

Assessment of surveys for the management of hospital clinical pharmacy services.

OBJECTIVE: Survey data sets are important sources of data, and their successful exploitation is of key importance for informed policy decision-making. We present how a survey analysis approach initially developed for customer satisfaction research in marketing can be adapted for an introduction of clinical pharmacy services into a hospital. METHODS AND MATERIAL: We use a data mining analytical approach to extract relevant managerial consequences. We evaluate the importance of competences for users of a clinical pharmacy with the OrdEval algorithm and determine their nature according to the users' expectations. For this, we need substantially fewer questions than are required by the Kano approach. RESULTS: From 52 clinical pharmacy activities we were able to identify seven activities with a substantial negative impact (i.e., negative reinforcement) on the overall satisfaction of clinical pharmacy services, and two activities with a strong positive impact (upward reinforcement). Using analysis of individual feature values, we identified six performance, 10 excitement, and one basic clinical pharmacists' activity. CONCLUSIONS: We show how the OrdEval algorithm can exploit the information hidden in the ordering of class and attribute values, and their inherent correlation using a small sample of highly relevant respondents. The visualization of the outputs turns out highly useful in our clinical pharmacy research case study.