Biomedical subjects

P Bonnabry

Publications and source records attributed to P Bonnabry.

10 recordsLinked to original sources

PubMed2006

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.

Drug Therapy↗

PubMed2005

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.

Child↗

PubMed2005

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.

Bacteria, Aerobic↗

PubMed2001

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.

Computers↗

PubMed1999

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.

Antifungal Agents↗

PubMed1996

Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam.

OBJECTIVE: The nature of the enzyme(s) catalysing the biotransformation of lornoxicam to one of its major metabolites, 5'-hydroxy-lornoxicam, has been investigated in human liver microsomes. The reaction kinetics were characterised, the affinity of lornoxicam for three major human drug metabolising cytochrome P-450 isozymes (CYP2C9, CYP2D6 and CYP3A4) was determined, and inhibition of the reaction by known substrates (diclofenac, ibuprofen, mefenamic acid, phenytoin, tolbutamide and warfarin) and the prototype inhibitor (sulphaphenazole) of CYP2C9 was investigated. RESULTS: Lornoxicam 5'-hydroxylation displayed single enzyme Michaelis-Menten kinetics, with a KM of 3.6 mu mol center dot l-1 and a Vmax of 2.6 nmol center dot h-1 center dot mg-1 microsomal protein. The apparent affinity of lornoxicam was high for CYP2C9, but negligible for CYP3A4 and CYP2D6. Inhibition of lornoxicam 5'-hydroxylation by CYP2C9 substrates and sulphaphenazole competitively and completely inhibited lornoxicam 5'-hydroxylation (Ki = 0.31 mu mol center dot l-1 as well as lornoxicam clearance (Ki = 0.33 mu mol center dot l-1), partial metabolic clearance (fm) = 0.95). CONCLUSION: 5'-Hydroxylation appears to be the only cytochrome P-450 catalysed metabolic reaction of lornoxicam by human liver microsomes and this major in vivo biotransformation pathway is catalysed virtually exclusively by CYP2C9.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

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.

Acenocoumarol↗

PubMed1994

Selective inhibition of major drug metabolizing cytochrome P450 isozymes in human liver microsomes by carbon monoxide.

The selectivity of carbon monoxide binding to specific human cytochrome P450 isozymes was investigated by studying its inhibition of prototype reactions for 3 major drug metabolizing P450s in liver microsomes: dextromethorphan O-demethylation and (+)-bufuralol 1'-hydroxylation (P450DB1, CYP2D6), diclofenac 4'-hydroxylation (P450TB, CYP2C subfamily), and midazolam 1'-hydroxylation (P450NF, CYP3A subfamily). The affinity of carbon monoxide is different for each P450 isozyme. Warburg partition coefficients were 0.35, 1.1 and 3.9 microM for P450DB1, P450TB and P450NF, respectively. Differential inhibition by carbon monoxide may be a useful tool to identify specific human cytochrome P450 isozymes in the early screening of drug biotransformation catalysts. Further studies involving other P450 isozymes and substrates should extend our understanding of the phenomena and their implications.

Carbon Monoxide↗

PubMed1993

A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal antiinflammatory drugs.

Most non-steroidal antiinflammatory drugs (NSAIDs) are extensively metabolized by liver oxidation with broad interindividual variability, but little is known about the nature of the enzyme(s) catalysing these reactions. The role of specific cytochrome P450 isozymes in the formation of the major oxidized metabolites of phenylacetic acid (diclofenac), propionic acid (ibuprofen), fenamate (mefenamic acid) and oxicam (piroxicam and tenoxicam) derivatives was studied in human liver microsomes using mostly selective inhibition by known substrates and inhibitors of specific cytochrome P450 monooxygenases. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathways of these NSAIDs. The authors have also determined, in two in vitro models of P450TB activity, the affinity for this isozyme of other NSAIDs (acetylsalicylic acid, indomethacin, pirprofen). The NSAIDs tested displayed a high affinity (5-500 microM): diclofenac approximately mefenamic acid > ibuprofen approximately indomethacin approximately piroxicam approximately tenoxicam > acetylsalicylic acid approximately pirprofen. Cytochrome P450TB therefore plays a key role in the oxidation by human liver of major NSAIDs from various chemical classes. Inhibition data and chemical structure similarities suggest that many other NSAIDs may be substrates of this isozyme as well. P450TB appears to be a common site both for the control of interindividual differences in the capacity to oxidize major NSAIDs and for interactions involving NSAIDs as well as other known substrates (oral anticoagulants, hypoglycaemic sulfonylureas, phenytoin) or inhibitors (antifungals, antibacterial sulfonamides, calcium channel blockers) of P450TB. Consequently this P450 isozyme is likely to be a major determinant of NSAIDs action.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1992

[The biotransformation of NSAIDs: a common elimination site and drug interactions].

Many NSAIDs are eliminated predominantly through hepatic biotransformation in man. We have studied, in human hepatic microsomes, the role of specific cytochrome P450 isozymes in the formation of the major metabolites of oxicam (piroxicam and tenoxicam), phenylacetic (diclofenac) and propionic acid (ibuprofen) derivatives. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathway of these NSAIDs. We have also determined, in two in vitro models of P450TB, the affinity for this isozyme of NSAIDs from other chemical classes (acetylsalicylic acid, mefenamic acid and indomethacin). All NSAIDs tested displayed a high affinity (3-300 microM) for cytochrome P450TB. Cytochrome P450TB plays a major role in the elimination of several NSAIDs with different chemical structures. NSAIDs are substrates as well as potential inhibitors of cytochrome P450TB. Their elimination can therefore be reduced by concomitant administration of known inhibitors of P450TB (antifungals, antibacterial sulfonamides, calcium channel blockers).

Anti-Inflammatory Agents, Non-Steroidal↗