Docking study: PPARs interaction with the selected alternative plasticizers to di(2-ethylhexyl) phthalate.

Phthalates, used in medical devices (MDs), have been identified as reproductive and developmental toxicants. Their toxicity varies somewhat depending on the specific phthalate and is in part linked to the activation of Peroxisome Proliferating-Activated Receptors (PPARs). So, the use of MDs containing targeted phthalates such as di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/EC. Therefore, MDs manufacturers were forced to quickly find replacement plasticizers. However, very little toxicological and epidemiological studies are available on human health. So, we proceeded to dock these chemicals in order to identify compounds that are likely to interact with PPARs binding sites. The results obtained are generally very mixed on the harmlessness of these alternatives. Moreover, no data exist on the biological effects of their possible metabolites. As DEHP toxicity resulted mainly from its major metabolites, generalizing the use of these plasticizers without conducting extensive studies on the possible effects on human health of their metabolites seems inconceivable.

Pharmacokinetic evaluation of a novel benzopyridooxathiazepine derivative as a potential anticancer agent.

BACKGROUND/AIMS: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. METHODS: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. RESULTS: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 µg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. CONCLUSION: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

Adverse drug events with hyperkalaemia during inpatient stays: evaluation of an automated method for retrospective detection in hospital databases.

BACKGROUND: Adverse drug reactions and adverse drug events (ADEs) are major public health issues. Many different prospective tools for the automated detection of ADEs in hospital databases have been developed and evaluated. The objective of the present study was to evaluate an automated method for the retrospective detection of ADEs with hyperkalaemia during inpatient stays. METHODS: We used a set of complex detection rules to take account of the patient's clinical and biological context and the chronological relationship between the causes and the expected outcome. The dataset consisted of 3,444 inpatient stays in a French general hospital. An automated review was performed for all data and the results were compared with those of an expert chart review. The complex detection rules' analytical quality was evaluated for ADEs. RESULTS: In terms of recall, 89.5% of ADEs with hyperkalaemia "with or without an abnormal symptom" were automatically identified (including all three serious ADEs). In terms of precision, 63.7% of the automatically identified ADEs with hyperkalaemia were true ADEs. CONCLUSIONS: The use of context-sensitive rules appears to improve the automated detection of ADEs with hyperkalaemia. This type of tool may have an important role in pharmacoepidemiology via the routine analysis of large inter-hospital databases.

Clinical evaluation of the ADE scorecards as a decision support tool for adverse drug event analysis and medication safety management.

AIMS: The prevention of adverse drug events (ADEs) demands co-ordination of different health care professionals. ADE scorecards are a novel approach to raise the team awareness regarding ADE risks and causes. It makes information on numbers and on possible causes of possible ADE cases available to the clinical team. The aim of the study was to investigate the usage and acceptance of ADE scorecards by healthcare professionals and their impact on rates of possible ADEs. METHODS: ADE scorecards were introduced in three departments of a French hospital. A controlled time series analysis of ADE data was conducted to assess the impact of the ADE scorecards. In addition, qualitative interviews and a standardized survey with all participating staff members were performed. RESULTS: Physicians, nurses and pharmacists found ADE scorecards effective to increase medication safety and recommended future usage. The time-series analysis did not show changes in rates of possible ADEs. CONCLUSION: ADE scorecards appear to be useful to raise awareness of ADE-related issues among professionals. Although the evaluation did not show significant reductions of ADE rates, the participating physicians, nurses and pharmacists believed that the ADE scorecards could contribute to increased patient safety and to a reduction in ADE rates. Strategies need to be designed to integrate ADE scorecards better into the clinical routine and to increase the precision of ADE detection.

Scorecards: a new method to prevent adverse drug events? Preliminary results from a clinical field study.

In the field of the detection and prevention of preventable ADEs, several methods have been explored to decrease the rate of ADEs due to monitoring errors. This paper describes an innovative method that aims at improving patient safety by increasing ADEs' awareness of healthcare professionals. To this end, ADE-scorecards that provide healthcare professionals with retrospective data about ADEs' causes and rates have been developed. In order to evaluate the impact of this method on the ADE rate, in-field clinical tests have been set up. Data were collected by both qualitative (semi-structured interviews) and quantitative methods (log analysis and ADE rate calculation). Preliminary results reveal that ADE-scorecards are well-accepted by most of the healthcare professionals who intend to use them as discussion supports and/or learning tools. Thus, ADE-scorecards seem to be a relevant method to improve patient safety by increasing ADE-awareness of healthcare professionals.

Medication related computerized decision support system (CDSS): make it a clinicians' partner!

Medication related Computerized Decision Support System (CDSS) are known to have a positive impact on Adverse Drug Events (ADE) prevention but they face acceptance problems due to over alerting and usability issues. We present here a Human factors approach to the design of these Clinical Decision Support (CDS) functions and to their integration into different Electronic Health Record (EHR) / Computerized Physicians Order Entry (CPOE) systems, so that the resulting CDSS corresponds to the users needs and fits clinical workflows and cognitive processes. We used ethnographic observations completed with semi-structured interviews to analyse existing work situations and work processes. These were then described in detail using the SHEL (Software, Hardware, Environment & Liveware) formalism, which enables a structured description of the work system and provides an appropriate classification of human errors potentially leading to ADEs. We then propose a Unified Modelling Language (UML) model supporting the characterization by the CDSS of the drug monitoring and clinical context of patients at risk of ADE. This model combines the status of the lab test orders on the one hand with the validity and normality of the lab results on the other hand. This makes the system able to catch the context of the monitoring of the drugs through their corresponding lab tests and lab results (e.g. kalemia for potassium) and also part of the context of the clinical status of the patient (actual lab values, but also diseases and other pathologies that are identified as potential causes of the ADE e.g. renal insufficiency and potassium). We show that making the system able to catch the monitoring and clinical contexts opens interesting opportunities for the design of the CDS information content and display mode. Implementing this model would allow the CDSS to take into account the actions already engaged by the healthcare team and to adapt the information delivered to the monitoring and clinical context, thus making the CDSS a partner to the clinicians, nurses and pharmacists.

Comparison of the in vitro effects of amoxicillin and ampicillin on the polymorphonuclear neutrophil respiratory burst.

OBJECTIVES: The aim was to compare the in vitro effects of amoxicillin and ampicillin on the oxidative metabolism of polymorphonuclear neutrophils (PMNs). METHODS: Superoxide radical anion production by PMNs, stimulated or not by various exogenous stimulants and in contact with increasing antibiotic concentrations, was measured using spectrophotometric methods. RESULTS: Whereas a pro-oxidative action of amoxicillin on PMNs was obtained without exogenous stimulation or with opsonized zymosan (OZ), the O(2)(-) production by PMNs incubated with ampicillin did not increase significantly. CONCLUSIONS: This amoxicillin pro-oxidative effect could be due to the activation of the PMN NADPH oxidase, to its induction by a membrane effect or via the OZ pathway. It probably reinforces amoxicillin intrinsic bactericidal action and might partly explain the severe rashes sometimes occurring with amoxicillin treatment.

Contribution of human factors for the review of automatically detected ADE.

The European project PSIP (Patient Safety through Intelligent Procedures in Medication) aims at semi-automatically identifying and preventing ADE. Automatically detected Adverse Drug Events have to be reviewed and validated by human experts. Existing methods usually have the experts review the cases and document their rating in a structured form. One of the limitations of these methods is their poor ability to analyze and clear the disagreements between the experts and the system. This paper presents an innovative Human Factors based method to support the review by clinicians and pharmacologists of these automatically detected ADE. We use think aloud methods and portable labs to track and record the experts reasoning and their reviewing cognitive procedures. We present preliminary results obtained with this method, which allows identifying the key data and information used to characterize the ADE. This method provides useful feedbacks allowing a continuous refinement and improvement of the automated detection system.

Hospital-Acquired Hyperkalemia Events in Older Patients Are Mostly Due to Avoidable, Multifactorial, Adverse Drug Reactions.

Drug-induced hyperkalemia is a frequent and severe complication in the hospital setting. Other risk factors may also induce hyperkalemia but the combination of drugs and precipitating factors has not been extensively studied. The aim was to identify drug-induced hyperkalemia events in hospitalized older patients and to describe their combinations with precipitating factors. Two experts independently analyzed retrospective data of patients aged 75 years or more. Experts identified 471 hyperkalemia events and concluded that 379 (80.5%) were induced by drugs. The cause was multifactorial (i.e., at least one drug with a precipitating factor) in 300 (79.2%) of the 379 drug-induced hyperkalemia. Most of the drug-induced hyperkalemia events were avoidable (79.9%)-mainly because of the multifactorial cause (e.g., dosage adaptation during acute kidney injury). Drug-induced hyperkalemia events are frequently combined with precipitating factors in hospitalized older patients and their prevention should focus on these combinations.

Community-Acquired Acute Kidney Injury Induced By Drugs In Older Patients: A Multifactorial Event.

PURPOSE: Community-acquired acute kidney injury (CA-AKI) is a frequent and severe adverse drug reaction (ADR) among older patients. The combination of drugs and other CA-AKI risk factors was barely evaluated. The objectives of our study were to both accurately identify CA-AKI induced by drugs in older patients, and to describe their combination with other risk factors. PATIENTS AND METHODS: We conducted a retrospective, single-center study in a general hospital over a two-year period. An automated detection identified CA-AKI according to KDIGO criteria, amongst 4,767 eligible inpatient stays among patients aged 75 years or older. Two independent experts reviewed all CA-AKI events to adjudicate drug involvement (Naranjo scale), identify inappropriate prescriptions (STOPP criteria), evaluate avoidability (Hallas criteria) and identify combined risk factors. RESULTS: An expert review confirmed 713 CA-AKI (15.0% of inpatient stays) and determined that 419 (58.8%) CA-AKI were induced by drugs. A multifactorial cause (i.e., at least one drug with a precipitating factor) was found in 63.2% of drug-induced CA-AKI. Most of the drug-induced events were avoidable (66.8%), mainly in relation to a multifactorial cause. CONCLUSION: Drug-induced CA-AKI were frequent, multifactorial events in hospitalized older patients and their prevention should focus on combinations with precipitating factors.

Antioxidative effect of Bacteroides thetaiotaomicron extracts: superoxide dismutase identification.

Bacteroides thetaiotaomicron, a bowel anaerobic commensal, seems to release enzymes detoxifying reactive oxygen species according to our recent work. This opportunistic pathogen would be beneficial in the case of an inflammatory process. To explore its role after an oxidative or nutritive stress, six to seven separate experiments were performed. The bacteria were grown on media restricted in growth factors or supplemented with bile. Their viability was checked after surface protein extraction. The extracts underwent 2D electrophoresis. Gel images were statistically analysed to construct "master" gels. Proteins were identified (peptide-mass fingerprinting technique). The effect of each extract on superoxide anions was evaluated (spectrophotometric method). Superoxide dismutase was identified and a major superoxide anion inhibition was shown by extracts obtained after a nutritive and oxidative stress without significant bacterial death. So, a therapeutic antioxidant potential is firmly hoped for. [figure: see text]

Molecular modelling of phthalates - PPARs interactions.

Di(2-ethylhexyl) phthalate (DEHP) is the most widely plasticizer for polyvinyl chloride (PVC) that is used in plastic tubes, in medical and paramedical devices as well as in food storage packaging. The toxicological profile of DEHP has been evaluated in a number of experimental animal models and has been extensively documented. Its toxicity is in part linked to the activation of the peroxisome proliferator-activated receptor alpha (PPAR(alpha)). As a response, an intensive research for a new, biologically inert plasticizer has been initiated. Among the alternative studied, tri(2-ethylhexyl) trimellitate (TEHTM) or trioctyl trimellitate (TOTM) has attracted increasing interest. However, very little information is available on their biological effects. We proceeded to dock TOTM, DEHP and its metabolites in order to identify compounds that are likely to interact with PPAR(alpha) and PPAR(gamma) binding sites. The results obtained hint that TOTM is not able to bind to PPARs and should therefore be safer than DEHP.

Evaluation of a Computer Application for Retrospective Detection of Vitamin K Antagonist Treatment Imbalance.

OBJECTIVE: Management of vitamin K antagonists (VKAs) is difficult, and overdoses can have dramatic hemorrhagic consequences. The adverse drug event (ADE) scorecards is a tool intended for the detection and description of adverse drug reaction/ADE developed during a European computerized medical data processing project. It is used in a quality assurance process. Our objective was to evaluate the performance of the ADE scorecards in the detection of the contributing factors for VKA overdoses, among the cases where a VKA overdose is observed. METHODS: Twenty-eight rules allow the detection of VKA treatment overdose related to drug or a clinical situation. They were applied on 14,748 electronic medical records from a community hospital. Among 582 records including a VKA prescription, 59 cases of VKA overdoses (international normalized ratio ≥ 5) during the hospital stay have been identified. The ADE scorecards detected 49 of them. We evaluated the positive predictive value and sensitivity of these rules, by an expert review of the cases. RESULTS: The expert review confirmed the contribution of a detected risk factor to the VKA overdose in 11 cases. Therefore, the precision of the rules is 22.4%. The sensitivity is 84.6%. The risk factors were mainly infection and amiodarone introduction. The 4 cases of clinical injury related to a drug were properly designated by the rules. CONCLUSIONS: Our study shows the great potential of the ADE scorecards for detecting cofactors of VKA overdoses and gives an argument to include complex rules in the knowledge bases used for the detection and identification of ADEs in large medical databases.

Inappropriate anticholinergic drugs prescriptions in older patients: analysing a hospital database.

Background Although many anticholinergics are inappropriate in older patients, the prescription of these drugs in a hospital setting has not been extensively studied. Objective To describe prescriptions of anticholinergic drugs in terms of frequency, at risk situations and constipation in hospitalized, older adults. Setting Using a database from a French general hospital (period 2009-2013), we extracted information on 14,090 hospital stays by patients aged 75 and over. Methods Anticholinergic drug prescriptions were automatically detected, with a focus on prescriptions in three well-known at-risk situations: falls, dementia, and benign prostatic hyperplasia. Cases of constipation that might have been causally related to the administration of anticholinergic drugs were screened for and reviewed. Main outcome measure Prescriptions with a high associated risk of anticholinergic related adverse reactions. Results Administration of an anticholinergic drug was detected in 1412 (10.0%) of the hospital stays by older patients. At-risk situations were identified in 413 (36.5%) of these stays: 137 (9.7%) for falls, 243 (17.2%) for dementia, and 114 (8.1%) for benign prostatic hyperplasia; 78 (18.9%) of these 413 stays featured a combination of two or three at-risk situations. Cases of constipation induced by anticholinergic drug administration were identified in 188 (13.3%) patient stays by using validated adjudication rules for adverse drug reactions: 85 and 103 cases were respectively evaluated as "possible" or "probable" adverse drug reactions. Conclusions Anticholinergic drugs prescription was found in 10.0% of hospitalized, older patients. More than one third of these prescriptions occurred in at-risk situations and more than one in ten prescriptions induced constipation.

Underuse of Oral Anticoagulants and Inappropriate Prescription of Antiplatelet Therapy in Older Inpatients with Atrial Fibrillation.

BACKGROUND: Several studies have shown that the prescription of antiplatelet therapy (APT) is associated with an increased risk of oral anticoagulant (OAC) underuse in patients aged 75 years and over with atrial fibrillation (AF). An associated atheromatous disease may be the underlying reason for APT prescription. The objective of the study was to determine whether the association between underuse of OAC and APT prescription was explained by the presence of an atheromatous disease. METHODS AND RESULTS: We performed a retrospective, observational, single-centre study between 2009 and 2013 based on administrative data. Patients aged 75 years and over with non-valvular AF were identified in a database of 72,090 hospital stays. Prescriptions of anti-thrombotic medications and their association with the presence of atheromatous disease were evaluated by the mean of a logistic regression. A total of 2034 hospital stays were included (mean age 84.3 ± 5.2 years). The overall prevalence of known atheromatous disease was 25.9%. OAC underuse was observed in 58.5% of the stays. In multivariable analysis, the prescription of an APT was associated with an increased risk of OAC underuse [odds ratio (OR) 6.85; 95% confidence interval (CI) 5.50-8.58], independently of the presence of a concomitant known atheromatous disease (OR 0.78; 95% CI 0.60-1.01). Among the 692 stays with APT monotherapy (34.0%), 232 (33.5%) displayed an atheromatous disease. CONCLUSIONS: The underuse of OAC is associated with the prescription of APT in older patients with AF, regardless of the presence or absence of known atheromatous disease. Our results suggest that APT is often inappropriately prescribed instead of OAC.

Evaluation of compliance with recommendations of prevention of thromboembolism in atrial fibrillation in the elderly, by data reuse of electronic health records.

Under-prescription of anticoagulants in the elderly with atrial fibrillation (AF) has been described in several studies, showing that only 15 to 44% of them receive anticoagulants. However, the European Society of Cardiology recommendations state that anticoagulants should be systematically prescribed. In case of refusal of the treatment by the patient, a platelet aggregation inhibitor should be prescribed in monotherapy or bitherapy according to the HAS-BLED bleeding risk score. In all the cases the patient should receive an antithrombotic treatment. In this work we observe the adequacy of prescription practices to the recommendations for AF in the elderly by data reuse on a monocentric observational retrospective cohort. Data of a 222 beds French community hospital were extracted for the year 2013. The patients aged over 75 years and presenting AF were selected. The HAS-BLED score was calculated and the consistency of the prescriptions with the recommendations of the European Society of Cardiology was verified. Then the compliance rate to the recommendations was calculated. The rules detected 433 patients with AF and aged over 75 years. From those patients, 45% received an anticoagulant, 32.1% received platelet aggregation inhibitors and 22.9% did not receive any antithrombotic treatment. When a platelet aggregation inhibitor was prescribed the recommendation for bitherapy was not followed in 97% of the cases. The compliance rate to the recommendations was 47.8%. This work highlights a major problem of quality of the prescriptions in the hospital field and shows how data reuse can help describing this type of issues.

Investigations of new lead structures for the design of novel cyclooxygenase-2 inhibitors.

On the basis of molecular modelling studies, five new compounds were synthesised and studied in an attempt to design new lead structures as selective COX-2 inhibitors.

Effects of a caffeine-free Cola nitida nuts extract on elastase/alpha-1-proteinase inhibitor balance.

In an infection, polymorphonuclear neutrophils (PMN) become activated and they produce oxidizing compounds and elastase in the extracellular medium. Alpha-1-proteinase inhibitor (alpha1PI), a protease inhibitor which is inactivated by oxidants, is the main endogenous inhibitor of elastase helping to limit excessive elastase activity. This study evaluates the ability of a plant extract, Cola nitida nuts, to protect alpha1PI from inactivation by oxidizing compounds as reactive oxygen species. On the one hand, we have evaluated the direct effect of cola nut extract on neutrophil elastase, and on the H(2)O(2) and myeloperoxidase (MPO)-H(2)O(2) system via cell-free systems. Results showed that cola nut extract scavenges H(2)O(2) and therefore protects alpha1PI from HOCl which is produced from the MPO-H(2)O(2) system. Experiments also showed that cola extract has the capacity to limit elastase activity. On the other hand, we have worked on cellular systems including isolated PMN with the aim to study the effect of cola extract on PMN metabolism. PMN were stimulated with PMA, calcium ionophore or fMLP. Each stimulant possesses its own stimulation pathway. According to the inhibitory concentration obtained at 50%, the results on cellular systems led to the conclusion that cola extract can reduce elastase liberation from PMN. It can then be concluded that cola nut extract can protect alpha1PI from inactivation, and has an effect both on elastase liberation and elastase activity. The cola nut extract effect is rather biased towards a reduction in elastase release, thus limiting the injurious effects caused by this enzyme.

In vitro and ex vivo antioxidant activities of labetalol on rabbit neutrophil respiratory burst.

The beta-adrenoreceptor blocker labetalol has demonstrated important antioxidant properties in vitro that inhibit superoxide anion production during normal leukocyte oxidative metabolism. This study investigated the in vitro and ex vivo effects of labetalol on respiratory burst in rabbit neutrophils. The production of superoxide anions was examined in activated purified rabbit neutrophils after intravenous administration of labetalol (4.0 mg/kg of body weight). At a concentration up to 200 mg/L, labetalol did not demonstrate any cytotoxic effects on neutrophils, as determined by enzyme lactate dehydrogenase activity. In the cell-free system, labetalol demonstrated no significant activity, but in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rabbit neutrophils, labetalol demonstrated concentration-dependent antioxidant activity. The in vitro 50% inhibitory concentration (IC50) with the fMLP stimulus was 16.5+/-0.21 mg/L in the rabbit neutrophils and 13.2+/-0.16 mg/L in the human neutrophils. In the fMLP-stimulated rabbit polymorphonuclear leukocytes, labetalol demonstrated its peak inhibitory activity (47%) 3 hours after administration. The mechanism by which labetalol acts in the treatment of hypertension may occur from an interaction in the signaling pathway of protein kinase C activation. The antioxidant properties demonstrated in this mechanism contribute to the drug's antihypertensive action and thus, may reduce the risk of injuries inflicted by reactive oxygen species involved in the pathogenesis of hypertension.

Pharmacokinetics and dialysability of naltrexone in patients undergoing hemodialysis.

The disposition of naltrexone (NLT) (REVIA), an opioid antagonist intended for patients with impaired renal function and with severe intractable itching refractory to regular antipruritic therapy, was characterized. Hemodialysis effects on both efficacy and elimination of NLT also were assessed. We developed a simple, sensitive and selective reverse-phase high-performance liquid chromatographic (HPLC) method for measuring NLT plasma concentration in hemodialysis patients treated to relieve pruritus. NLT and the internal standard, naloxone (NLX) were extracted from plasma using a solid-phase extraction method with sep-pack C18 cartridge. The method was employed to determine both naltrexone pharmacokinetics and dialysability parameters during 4-h in dialyzed patients with chronic renal impairment. Thus, seven patients (2 men, 5 women) with end-stage renal disease and pruritus on regular hemodialysis were included. They received one tablet of NLT (Revia, 50 mg) orally prior dialysis session. The Cmax at the inlet and at the outlet the dialyzer were higher (255+/-117 ng/mL and 206+/-137 ng/ml respectively) in comparison with healthy subjects (9 - 44 ng/mL). The decrease hepatic first-pass metabolism of NLT consecutive to end-stage renal disease and the renal impairment could explain the increased levels of the drug in plasma. Tmax before and after dialysis plates remain unchanged as healthy subjects (approximately 1h). With regard to dialysability, a high dialyzer extraction ratio averating 30 % was found with a low dialysis clearance of 58.70+/-17 mL/min. The amount removed by dialysis is only 1.27 mg. We concluded that hemodialysis has little effect on NLT blood levels, and consequently on drug pharmacokinetics, when the drug is delivered to dialyzed patients following oral route. Thus, dosage adjustement is not required in the presence of advanced dialysis-dependant renal failure. In patients with end-stage renal disease, hemodialysis does not result in clinically significant alterations in the disposition of NLT. Post-dialysis supplementation is not required. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but in view of NLT plasma concentration levels in the patients, a clinician could determine whether dosage adjustment are necessary and, if so, make the required calculations accurately.