Game-based training to improve the compliance of hospital pharmacy operators with handwashing guidelines.

INTRODUCTION: Good hand hygiene techniques (HHTs), like those of the World Health Organization (WHO), prevent microbial contamination of aseptic preparations. The objective of this study was to assess the efficacy of a game-based training (GBT) tool (the Handtastic Box) to improve the compliance of hospital pharmacy operators (HPOs) with handwashing guidelines. METHODS: A camera recorded handwashing by HPOs for 1 month before the training day, for 1 month after the training day (M1), and between month 1 and month 3 (M2&3). Movements were scored as fully executed, partially executed or not executed. Compliance rates of each HPO with HHTs were compared between observation periods. During 1-h training sessions, pairs of HPO trainees watched handwashing videos and noted which of five guideline steps was missing. They examined wooden hands with areas stained with fluorescein under ultraviolet light to find the hand showing the matching contamination. RESULTS: The mean compliance score for nine HPOs increased from 44.6% (before training, N=32 videos) to 86.7% (M1, N=40) to 82.5% (M2&3, N=45). Compliance with every step improved from before training to M1 and generally stabilized in M2&3, except for the fingertip washing step which dropped significantly in M2&3. DISCUSSION: To the authors' knowledge, this is the first study to assess the efficacy of a GBT tool to improve HPO compliance with the WHO HHTs. The tool improved handwashing scores significantly, and maintained them at the same level for 3 months after training. The separate results for each step highlight the need to train every movement. CONCLUSION: This GBT tool successfully improved compliance with the WHO HHTs for 3 months. This training could be used for other healthcare professionals.

Development and application of a liquid chromatography coupled to mass spectrometry method for the simultaneous determination of 23 antineoplastic drugs at trace levels.

The goal of this study was to develop a method for the simultaneous quantification of 23 commonly used antineoplastic drugs in a hospital pharmacy, using ultra-high pressure liquid chromatography separation coupled to tandem mass spectrometry detection (UHPLC-MS/MS). The following drugs were investigated: 5-fluorouracil, cytarabine, ganciclovir, gemcitabine, dacarbazine, methotrexate, pemetrexed, busulfan, topotecan, rentitrexed, ifosfamide, cyclophosphamide, etoposide, irinotecan, doxorubicin/epirubicin, vincristine, docetaxel, paclitaxel, daunorubicin, idarubicin, vinblastine, oxaliplatin and carboplatin. The chromatographic separation was performed on a phenyl-hexyl column (2.1 ×100 mm, 1.7 µm) with a gradient elution of methanol and water containing 10 mM ammonium formate adjusted to pH 4.9. All compounds were analyzed in less than 13 min and detected with a triple quadrupole mass spectrometer operating in MRM mode. Limits of detection (LODs) and limits of quantification (LOQs) were comprised between 0.01 and 5 ng.mL-1, and between 0.5 and 5 ng.mL-1, respectively. Accuracies ranged between 117% and 83% at the LOQ, intermediate and upper LOQ concentrations, with relative standard deviations (RSD) inferior to 8%, for all the antineoplastic drugs. Finally, the UHPLC-MS/MS method was successfully applied to the analysis of surface samples to evaluate the chemical contamination by these highly toxic compounds in a chemotherapy preparation unit in a hospital pharmacy with the purpose of monitoring the exposure of health care professionals.

Prevention of potentially inappropriate medication in internal medicine patients: A prospective study using the electronic application PIM-Check.

WHAT IS KNOWN: Potentially inappropriate medication (PIM) is a risk factor for drug-related problems (DRPs) and an important inpatient safety issue. PIM-Check is a screening tool designed to detect PIM in internal medicine patients. OBJECTIVE: This study aimed to determine whether PIM-Check could help to identify and reduce DRPs. METHOD: Prospective interventional study conducted on patients admitted to internal medicine wards in a university hospital between 1 September 2015 and 30 October 2015. Adult patients were included if they were hospitalized for more than 48 hours. Patients received either usual care (period 1 = control) or usual care plus medication screening by the wards' chief residents using PIM-Check (period 2 = intervention). An expert panel, composed of a clinical pharmacist, a clinical pharmacologist and two attending physicians in internal medicine, blinded to patient groups, identified DRPs. RESULTS: A total of 297 patients were included (intervention: 109). The groups' demographic parameters were similar. The expert panel identified 909 DRPs (598: control; 311: intervention). The mean number of DRPs per patient was similar in the control (3.2; 95% CI: 2.9-3.5) and intervention groups (2.9; 95% CI: 2.4-3.3) (P = .12). PIM-Check displayed 33.4% of the 311 DRPs identified in the intervention group. WHAT IS NEW AND CONCLUSION: In this study, PIM-Check had limited value, as the average number of DRPs per person was similar in both groups. Although one-third of DRPs counted in intervention group had been identified by PIM-Check, this did not lead to a reduction in DRPs. This lack of impact of PIM-Check on drug prescription may be explained by the number of alerts displayed by the application and hospital physicians' reluctance to modify the treatments for chronic conditions previously prescribed by general practitioners.

A cross-sectional comparison between the perception of physicians and pharmacists concerning the role of the pharmacist in physician training.

OBJECTIVES: This study aimed to identify and compare physician-pharmacist perceptions concerning drug teaching to physicians by pharmacists in Swiss hospital settings. MATERIAL AND METHODS: Questionnaires were emailed to all French-speaking physicians (survey A) and pharmacists (survey B) working in Swiss hospitals where medical directors/chief-pharmacists had approved the study. Questions were developed based on previous physician interviews. Most questions used four Likert-type response alternatives. A Mann-Whitney U test was used to compare answers to survey A and B. RESULTS: Fourteen out of 18 medical directors and 16/16 chief-pharmacists gave permission for the study. In total, 244 (11%) physicians answered survey A, and 115 (74%) pharmacists answered survey B. Nearly all participants agreed that pharmacists should take part in both medical student and physician postgraduate training. Most physicians answered wanting additional training and pharmacists are unaware of this need. Only two thirds of physicians reported having acquired knowledge about drugs thanks to pharmacists; document diffusion and direct answers to their questions having contributed the most to their training. Participants agreed that physician training by pharmacists needs a clearer delineation regarding the type of training, its aim, its targeted public, when and what pharmaceutical benefits are used. Physicians' priority-training topics are high-risk drugs, novelties and areas in which they consider their basic training was insufficient. Methods preferred for training are: case studies; exercises with individual corrections; and group work. CONCLUSION: Improved resources and planning are needed to meet physicians' expectations. Training is often carried out implicitly, through activities with various other aims, and needs to be better defined and formalized collaboratively.

Younger age and in situ duration of peripheral intravenous catheters were risk factors for extravasation in a retrospective paediatric study.

AIM: Epidemiological data on the incidence and risk factors of extravasation of peripheral intravenous catheters (PIVC) in neonates and children are scarce and that is what this study explored. METHODS: This was a one-year retrospective study of all neonates and paediatric intensive care patients with at least one recorded PIVC at the Geneva University Hospitals, Switzerland, in 2013. The extravasation rate was determined for all patients, including neonates below 28 days, and for all PIVCs. Multivariate analysis of the associated risk factors was performed. RESULTS: We analysed 1300 PIVC in 695 paediatric patients with a median age of 1.5 years. The overall extravasation incidence was 17.6% for all patients and 11.7% for PIVC. The overall incidence rate of PIVC extravasation was 4.5 per 100 catheters days, and the risk was highest in the 201 neonates, at 28.4%. The incidence rate four days after insertion of the PIVC was around three times higher than on day one. Neonates and the in situ duration of PIVCs were associated risk factors (p < 0.001). CONCLUSION: Extravasation was frequent and neonates were particularly at risk. Younger age and longer in situ PIVC duration were independent risk factors for extravasation.

A comparison of two tools to screen potentially inappropriate medication in internal medicine patients.

WHAT IS KNOWN: Potentially inappropriate medication (PIM) is an important issue for inpatient management; it has been associated with safety problems, such as increases in adverse drugs events, and with longer hospital stays and higher healthcare costs. OBJECTIVE: To compare two PIM-screening tools-STOPP/START and PIM-Check-applied to internal medicine patients. A second objective was to compare the use of PIMs in readmitted and non-readmitted patients. METHOD: A retrospective observational study, in the general internal medicine ward of a Swiss non-university hospital. We analysed a random sample of 50 patients, hospitalized in 2013, whose readmission within 30 days of discharge had been potentially preventable, and compared them to a sample of 50 sex- and age-matched patients who were not readmitted. PIMs were screened using the STOPP/START tool, developed for geriatric patients, and the PIM-Check tool, developed for internal medicine patients. The time needed to perform each patient's analysis was measured. A clinical pharmacist counted and evaluated each PIM detected, based on its clinical relevance to the individual patient's case. The rates of screened and validated PIMs involving readmitted and non-readmitted patients were compared. RESULTS: Across the whole population, PIM-Check and STOPP/START detected 1348 and 537 PIMs, respectively, representing 13.5 and 5.4 PIMs/patient. Screening time was substantially shorter with PIM-Check than with STOPP/START (4 vs 10 minutes, respectively). The clinical pharmacist judged that 45% and 42% of the PIMs detected using PIM-Check and STOPP/START, respectively, were clinically relevant to individual patients' cases. No significant differences in the rates of detected and clinically relevant PIM were found between readmitted and non-readmitted patients. WHAT IS NEW AND CONCLUSION: Internal medicine patients are frequently prescribed PIMs. PIM-Check's PIM detection rate was three times higher than STOPP/START's, and its screening time was shorter thanks to its electronic interface. Nearly half of the PIMs detected were judged to be non-clinically relevant, however, potentially overalerting the prescriber. These tools can, nevertheless, be considered useful in daily practice. Furthermore, the relevance of any PIM detected by these tools should always be carefully evaluated within the clinical context surrounding the individual patient.

Drug information leaflets improve parental knowledge of their child's treatment at paediatric emergency department discharge.

BACKGROUND: Hospital discharge is a complex multidisciplinary process that can lead to non-compliance and drugs-related problems. Crucial issue for children is parental knowledge of discharge treatments, especially in the time-limited and stressful environment of an emergency department (ED). OBJECTIVE: To compare parental correct knowledge of treatment with and without supply of customised drug information leaflets for the 10 most commonly prescribed drugs. METHOD: Inclusion criteria: paediatric patients (0-16 years) with French-speaking parents discharged from ED of the paediatric department of Geneva University Hospitals before (phase A) and after (phase B) intervention. INTERVENTION: Supply and brief comment of drug information leaflets focusing on specific information not available in official drugs information documents. Follow-up Semi-structured phone interview within 72 h after discharge to evaluate the percentage of parents with correct knowledge of dose, frequency, duration and indication of drugs. Multivariate analysis to identify factors associated with correct knowledge (phases A/B, drugs collection at usual pharmacy, drugs categories). RESULTS: 125 patients were included (phase A: 56; phase B: 69). Drug information leaflets were given to 63/69 ED patients (91%), covering 96/138 prescribed drugs (70%). Parental knowledge was significantly improved in phase B (dose: 62.3% to 89.1%; frequency: 57.9% to 85.5%; duration: 34.2% to 66.7%; indication: 70.2% to 94.9%; p<0.0001). Phase B and collection of drugs at usual pharmacy were significant factors associated with correct knowledge. CONCLUSIONS: Drug information leaflets significantly improved treatment knowledge of French-speaking parents after paediatric ED discharge. Leaflets are now available online for general population.

Identification and weighting of the most critical "real-life" drug-drug interactions with acenocoumarol in a tertiary care hospital.

PURPOSE: The objective of this study was to identify the most clinically relevant drug-drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. METHODS: We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system (n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994-2007) (n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. RESULTS: One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. CONCLUSION: Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drugs.

Chemical contamination during the preparation of cytotoxics: validation protocol for operators in hospital pharmacies.

BACKGROUND AND OBJECTIVES: The chemical contamination during the preparation of cytotoxics remains a serious problem in hospital pharmacies and the operators could contribute to this risk during their manipulations. A validation protocol was developed using a non-toxic, highly detectable tracer, quinine dihydrochloride. METHOD: Further, a method for a high recovery extraction and quantification of this marker, and a protocol covering the critical operations of cytotoxic preparation, was developed and validated. Various devices were used to fill the syringes and perfusion bags. All the filled containers and used materials were collected at the end of the protocol and the tracer was extracted in water. The contaminated water was analyzed by fluorimetry. The number of spots on the working pads was counted under ultraviolet light. During a total of 28 sessions, the procedure was applied by 20 different operators. RESULTS: The mean cumulated quantities of contamination were 6.2 µL (0.6-23.8) and >10 spots (0-20), which was considered as high. No correlation was observed between the contamination rate and the operator's experience. CONCLUSION: This validation protocol facilitates controlling the operators' working 'cleanliness' and helps to improve the initial and continuing training. This simple test presents an effective answer for the important issue of the chemical safety of operators.

[Comparison of four drug interaction screening programs]. / Quel programme informatique de détection des interactions médicamenteuses néfastes?

Adverse drug events (ADE) are a major public health issue, with drug-drug interactions (DDI) being one of well-recognized causes of ADE that could be preventable by the use of DDI screening software. We compared the ability of four programs to detect clinically important DDI. We tested 62 drug pairs with and 12 drug pairs without clinically important DDI. Lexi-Interact and Epocrates were the most sensitive (95%) compared to the Compendium and Theriaque (80 and 73%, respectively). The Compendium and Theriaque also showed the lowest negative predictive value. All programs showed high specificity and positive predictive value. The qualitative assessment showed the best performances for Compendium and Lexi-Interact. The last one seems to be the best screening program, but the Compendium is in French and is freely available.

Reliable low-cost capillary electrophoresis device for drug quality control and counterfeit medicines.

The proportion of counterfeit medicines is dramatically increasing these last few years. According to numerous official sources, in some pharmaceutical wholesalers in African countries, the proportion has reached 80%. Unfortunately, this situation is far to be improved due to lack of suitable analytical equipment allowing rapid actions of the Regulatory Agencies based on scientific consideration, at affordable cost and all over the drug supply chain. For that purpose, a network group considered that mater by building a low-cost original capillary electrophoresis (CE) equipment equipped with a new deep UV detector based on LED technology. The generic conditions for analysis were investigated: capillary zone electrophoresis (CZE) performed at acidic pH for basic drug molecules (i.e., quinine, highly used as the last antimalarial rampart), basic pH for compounds such as furosemide (a common diuretic drug) and at neutral pH for a well known antibiotic combination, trimethoprim/sulfamethoxazol. To evaluate the ability of the CE equipment for quantification, a full validation and a method comparison study were carried out for the CZE method dedicated to quinine determination. The validation involved the use of accuracy profile and total error concept to monitor the adequacy of the results obtained by the new prototype. The method comparison was based on the Bland and Altman approach by comparing results obtained by the low-cost CE and a conventional set-up. Subsequent validation studies were realized with neutral and acidic drug molecules, each focusing on a single concentration level calibration curve in order to maintain as low as possible the expenses due to reagents and thus the cost of analysis, as important advantages of CE for drug quality control.

Drug selection errors in relation to medication labels: a simulation study.

The aim of this study was to assess the impact of differences in drug label information on injectable drug selection errors. Differences in the display of drug strength information were assessed in a randomised controlled trial involving ward nurses, intensive care nurses, nurse anaesthetists, ward physicians, and anaesthetists. A set of 24 on-screen tasks were constructed. For each task, a label corresponding to an instruction consisting of two from three possible pieces of information (concentration, quantity, volume) had to be selected from a list of 10 items. The set was presented three times to participants using three different label formats. Format A provided two pieces of strength information different from those in the instruction. Format B and C provided all three pieces in a random and a fixed sequence, respectively. The frequency of errors was statistically higher with formats A and B than with format C, and greater in nurses than in anaesthetists. Regulatory bodies should therefore implement a standard requiring that the concentration (expressed in 'mg x ml(-1)'), the amount and the volume of drug be displayed on medication labels in fixed locations.

Measuring human-error probabilities in drug preparation: a pilot simulation study.

OBJECTIVES: Designing a safe medication process requires the ability to model its reliability using methods such as probabilistic risk assessment (PRA). However, lack of data, especially on human-error probabilities (HEPs), limits its use. To assess whether small-scale simulations could help generate HEP data, a pilot study was conducted among nurses and anaesthetists. It focused on two core activities, namely, the manual preparation of medications and the arithmetic necessary to prepare drugs. Its specific objectives were to evaluate whether HEPs could be high enough to be measurable and to determine whether these HEPs could be sensitive to individuals and task details. These would give some insight into the level of detail required by PRA analysis. METHODS: Thirty nurse and 28 anaesthetist volunteers were involved in the experiment. Nurses and anaesthetists had to prepare medications for 20 patients and 22 syringes of various drugs, respectively. Both groups had to perform 22 calculations relating to the preparation of drugs. HEPs, distribution of HEPs and dependency of HEPs on individuals and task details were assessed. RESULTS: In the preparation tasks, overall HEP was 3.0% for nurses and 6.5% for anaesthetists. In the arithmetic tasks, overall HEP was 23.8% for nurses and 8.9% for anaesthetists. A statistically significant difference was noted between the two groups. In both preparation and arithmetic tasks, HEPs were dependent on individual nurses but not on individual anaesthetists. In every instance, HEPs were dependent on task details. CONCLUSION: Our study illustrates that small-scale simulations represent an interesting way of generating HEPs. HEPs are, indeed, in the range of 10(-2) and 10(-1). But in most cases, HEPs depend heavily on operators and task details. This dependency means that the influence of these parameters must be determined before advanced PRA analysis. There is therefore an urgent need to develop experimental research into assessing this influence by means of randomised controlled trials.

Guarantying the quality of chemotherapy: from the order to the administration.

Ensuring the quality and security when prescribing drugs like chemotherapies is a complex task if one wants to cover the whole chain from the prescribing physician to the administrant nurse. At the University hospitals of Geneva, new applications covering the whole chain from the prescription up to and including the fabrication of the products have been developed in three phases and are being used in a production stage. In order to cover the "last yard" at the bed level, a fourth phase has been started with a pilot study based on labels containing RFID chips for preparations and for patients. The last phase will make use of all traceability data acquired from the prescription to the preparation to validate that the right product is administered to the right patient, and to record who is administrating it.

Use of a systematic risk analysis method to improve safety in the production of paediatric parenteral nutrition solutions.

BACKGROUND: Until recently, the preparation of paediatric parenteral nutrition formulations in our institution included re-transcription and manual compounding of the mixture. Although no significant clinical problems have occurred, re-engineering of this high risk activity was undertaken to improve its safety. Several changes have been implemented including new prescription software, direct recording on a server, automatic printing of the labels, and creation of a file used to pilot a BAXA MM 12 automatic compounder. The objectives of this study were to compare the risks associated with the old and new processes, to quantify the improved safety with the new process, and to identify the major residual risks. METHODS: A failure modes, effects, and criticality analysis (FMECA) was performed by a multidisciplinary team. A cause-effect diagram was built, the failure modes were defined, and the criticality index (CI) was determined for each of them on the basis of the likelihood of occurrence, the severity of the potential effect, and the detection probability. The CIs for each failure mode were compared for the old and new processes and the risk reduction was quantified. RESULTS: The sum of the CIs of all 18 identified failure modes was 3415 for the old process and 1397 for the new (reduction of 59%). The new process reduced the CIs of the different failure modes by a mean factor of 7. The CI was smaller with the new process for 15 failure modes, unchanged for two, and slightly increased for one. The greatest reduction (by a factor of 36) concerned re-transcription errors, followed by readability problems (by a factor of 30) and chemical cross contamination (by a factor of 10). The most critical steps in the new process were labelling mistakes (CI 315, maximum 810), failure to detect a dosage or product mistake (CI 288), failure to detect a typing error during the prescription (CI 175), and microbial contamination (CI 126). CONCLUSIONS: Modification of the process resulted in a significant risk reduction as shown by risk analysis. Residual failure opportunities were also quantified, allowing additional actions to be taken to reduce the risk of labelling mistakes. This study illustrates the usefulness of prospective risk analysis methods in healthcare processes. More systematic use of risk analysis is needed to guide continuous safety improvement of high risk activities.

Sterility validity period of vials after multiple sampling under vertical laminar airflow hood.

STUDY OBJECTIVES: The aim of this study is to validate the sterility period of vials after multiple sampling under Grade A vertical laminar airflow hood. METHODS: Vials filled aseptically with a sterile culture medium have been sampled with syringes three times a week over one month under Grade A vertical laminar airflow hood and in the mean-while, keeping the vials out of the laminar airflow hoods. RESULTS: No microbial growth has been observed. On the basis of these results, it has been decided to modify our standard operating procedures, to allow keeping the vials for two weeks in a box out of the laminar airflow hoods (ambient temperature Grade B) or any controlled environment (under refrigeration). CONCLUSIONS: This study validates the multiple use of vials of small to large volumes (5-100 mL), to simplify handling and to reduce the costs in centralized cytostatic reconstitution units in hospital pharmacies, with no microbial risk.

Quantitative drug interactions prediction system (Q-DIPS): a dynamic computer-based method to assist in the choice of clinically relevant in vivo studies.

Metabolic drug interactions are a major source of clinical problems, but their investigation during drug development is often incomplete and poorly specific. In vitro studies give very accurate data on the interactions of drugs with selective cytochrome P450 (CYP) isozymes, but their interpretation in the clinical context is difficult. On the other hand, the design of in vivo studies is sometimes poor (choice of prototype substrate, doses, schedule of administration, number of volunteers), with the risk of minimising the real potential for interaction. To link in vitro and in vivo studies, several authors have suggested using extrapolation techniques, based on the comparison of in vitro inhibition data with the active in vivo concentrations of the inhibitor. However, the lack of knowledge of one or several important parameters (role of metabolites, intrahepatocyte accumulation) often limits the possibility for safe and accurate predictions. In consequence, these methods are useful to complement in vitro studies and help design clinically relevant in vivo studies, but they will not totally replace in vivo investigation in the future. We have developed a computerised application, the quantitative drug interactions prediction system (Q-DIPS), to make both qualitative deductions and quantitative predictions on the basis of a database containing updated information on CYP substrates, inhibitors and inducers, as well as pharmacokinetic parameters. We also propose a global approach to drug interactions problems--'good interactions practice--to help design rational drug interaction investigations, sequentially associating in vitro studies, in vitrolin vivo extrapolation and finally well-designed in vivo clinical studies.

Quantitative drug interactions prediction system (Q-DIPS): a computer-based prediction and management support system for drug metabolism interactions.

OBJECTIVE: Drug biotransformation and interactions are a major source of variability in the response to drugs. The superfamily of cytochromes P450 plays a key role in this phenomenon but, because of the complexity of interactions between drugs and isozymes, it becomes more and more difficult for clinicians to master the knowledge required to predict the occurrence of such drug interactions. To predict and help manage the occurrence of cytochrome P450-dependent interactions, we developed an original computer application: Q-DIPS (quantitative drug interactions prediction system). METHODS: A multidisciplinary work team was created, associating clinical pharmacologists, pharmacists and a computer scientist. Major steps of investigation were: (1) the creation of a database to collect qualitative and quantitative data describing substrates, inhibitors and inducers of specific cytochrome P450 isozymes, with quality assessments; (2) the development of multi-access to these data and (3) their incorporation into extrapolation systems allowing the prediction of in vivo drug interactions on the basis of in vitro data. As an example, prediction and validation studies of CYP3A4 inhibition by ketoconazole and fluconazole will be discussed. RESULTS: Q-DIPS gives up-to-date information, in dynamic tables, describing which specific P450 isozymes metabolise a given drug, as well as which drugs may inhibit or induce a given isozyme. To better answer common clinical questions and help to rapidly evaluate the risk of interactions, it is possible to obtain an overview of substances causing interactions with a specific drug or to focus on drugs taken by a patient ("clinical case"). For each question, key references, relevant quantitative data and quality indices are easily accessible. Two modules allowing input with commercial names and the anatomical therapeutic chemical classification were also included. On the basis of enzymatic and pharmacokinetic data generated in vitro or collected in vivo, the extrapolation module integrates quantitative models to predict the impact of a treatment on enzymatic activities. The simplest model predicted a strong but fluctuating inhibition of CYP3A4 by ketoconazole, whereas the impact of fluconazole was lower. Validations with published in vivo data suggested an appropriate prediction of the risk. CONCLUSION: The current Q-DIPS prototype shows promising potential for helping to improve the management of drug interactions involving metabolism. Validation of extrapolation techniques need to be completed, in view of including important factors such as intrahepatocyte drug accumulation, contribution of metabolites to inhibition as well as in vitro non-specific binding to microsomal proteins. The final goal will be to help select the most judicious clinical studies to be performed so as to avoid useless, expensive and unethical investigations in man.

Stereoselective interaction between piroxicam and acenocoumarol.

1. An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2. Eight healthy male volunteers received an oral dose of 4 mg rac-acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3. The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P < 0.05; AUC(0, 24 h)+47.2% (21.5), P < 0.005; and t1/2 +38.0% (34.5), P < 0.01. A concomitant decrease of CL/F was observed: -30.8% (10.0), P < 0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): + 15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: -9.8% (20.5). V/F remained unchanged for both enantiomers. 4. Piroxicam plasma AUC(0, 24 h) correlated closely with R- and S-acenocoumarol AUCs on day 1 (r = 0.901, P < 0.005 and r = 0.797, P < 0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol (r = 0.903, P < 0.001) and S-acenocoumarol (r = 0.711, P < 0.05). 5. Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.