[Identification of knowledge deficits of pharmacy students at the beginning of the fifth year of pharmacy practice experience: Proposals to change the content of academic programs]. / Identification des lacunes de connaissances des étudiants en filière officine débutant le stage de 5(e) année : propositions pour modifier le contenu de l'enseignement.

INTRODUCTION: In France, community pharmacy students performed a hospital pharmacy practice experience during the 5th year of the university curriculum. The purpose of a part of the content of the academic teaching program delivered before this practice experience is to prepare the students for their future hospital activities. It should enable them for the practical use of knowledge in order to improve pharmacotherapy, laboratory diagnosis and monitoring of patients' care. The aim of this study was to show if there are gaps in this program. METHODS: Fourteen students performing their clerkship in a teaching hospital were invited to highlight these gaps when they were gradually immersed in the pharmaceutical care. They did so under the careful observation of hospital pharmacist preceptors. These practitioners referred to professional guidelines, documentary tools used in daily clinical practice and publications supporting their pharmaceutical care practices. RESULTS: Shortcomings and gaps identified were: how to communicate with other healthcare professionals and the content of verbal exchanges, how to conduct a patient-centered consultation, documentation tools required for relevant pharmacist' interventions, codification of pharmacist's interventions, risks related to drug packaging and benefit risk assessment of health information technologies. DISCUSSION: These gaps represent a handicap by delaying the process that led to move from student to healthcare professional. Hospital pharmacist preceptors have to fill in these gaps before engaging students in pharmaceutical care. CONCLUSION: These results invite to revise partly the content of the academic teaching program delivered before the 5th year hospital pharmacy practice experience.

High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine.

OBJECTIVE: Aminosalicylates are widely used with azathioprine in the treatment of IBD. The association results in an increase in 6-TGN levels in adults with IBD with a difference in the occurrence of myelotoxic effects. Scarce data are available in pediatric population. We proposed to investigate the effect of the coadministration of aminosalicylates on thiopurine concentrations in pediatric IBD patients. MATERIALS AND METHODS: Data from 71 patients treated for at least 1 y by azathioprine and aminosalicylates were recorded. 6-TGN and 6-MeMPN concentrations, blood cell counts and liver function tests were compared between patients taking and those not taking aminosalicylates. RESULTS: Aminosalicylate therapy was associated with a significant increase in mean 6-TGN but also 6-MeMPN concentrations. In patients in remission, 6-TGN level was related to aminosalicylate dosage (r = 0.561, p = 0.010). Lymphopenia rate was higher in patients receiving combined therapy compared to monotherapy whereas a slight rise in leucopenia was found. CONCLUSIONS: This observation suggests that the higher frequency of lymphopenia may be associated with the elevated 6-TGN concentrations recovered in patients treated with aminosalicylates. This combination does not improve remission rate but could increase adverse effects especially lymphopenia.

Evaluation of the estimation of midazolam concentrations and pharmacokinetic parameters in intensive care patients using a bayesian pharmacokinetic software (PKS) according to sparse sampling approach.

The aim of the study was to assess the performance of a bayesian program (PKS System, Abbott) for predicting midazolam concentrations and pharmacokinetic parameters in intensive care patients by comparing the pharmacokinetic parameters estimated by PKS to those calculated according to rich data. The study involved 42 patients receiving midazolam infusion for two hours or for several days. The program was used to predict plasma midazolam concentrations after feedback of 1, 2 or 3 concentrations. High correlation between observed and estimated concentrations was shown (r(2) > 0.992). Mean prediction error, mean absolute prediction error and root mean squared error were low for the patients of the reference and validation groups. From two or three feedback concentrations, midazolam pharmacokinetic parameters estimated by PKS were statistically comparable with those obtained using a rich pharmacokinetic analysis (P > 0.05 paired Wilcoxon test). Thus, PKS is useful for predicting midazolam concentrations and pharmacokinetic parameters when at least two feedback concentrations are known. This software seems to be appropriate for providing significant help to the clinician for midazolam dosage adjustment, according to midazolam concentrations and clinical sedation.

Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury.

BACKGROUND: Ketamine is used as an anaesthetic agent for short surgical procedures, and as a sedative and analgesic in intensive care patients. Intensive care patients with brain or spinal cord injury may have physiological changes that could alter the pharmacokinetics of ketamine. The pharmacokinetics of ketamine have been studied in healthy volunteers and in patients undergoing different types of surgery, but no data are available in intensive care patients. METHODS: We determined the pharmacokinetics of ketamine and its active metabolites, norketamine and dehydronorketamine, in 12 intensive care patients with brain or spinal cord injury. The effect of ketamine on haemodynamic variables was also investigated. RESULTS: The total clearance of ketamine, mean (SD), was 36.0 (13.3) ml min(-1) kg(-1), the volume of distribution (Vbeta) was 16.0 (8.6) litre kg(-1), and the elimination half-life was 4.9 (1.6) h. Ketamine did not alter any haemodynamic variables in the patients studied. CONCLUSIONS: Pharmacokinetic variables of ketamine in intensive care patients are greater than in healthy volunteers and in surgical patients. The increase in the volume of distribution is greater than the increase in clearance, resulting in a longer estimated half-life of ketamine in this patient group.

[Use of midazolam in postoperative sedation of patients with multiple organ failure treated with hemodiafiltration. Clinical study and pharmacokinetics]. / Utilisation du midazolam en sédation postopératoire chez des patients en défaillance polyviscérale, traités par hémodiafiltration. Etude clinique et pharmacocinétique.

OBJECTIVES: Evaluate the risk of accumulation of midazolam and conjugated 1-hydroxy-midazolam in high-risk ICU patients treated by continuous veno-venous haemofiltration. STUDY DESIGN: A prospective pharmocokinetic and clinical evaluation in 11 patients, with hepatic and renal failure. METHODS: Midazolam and metabolites were dosed in plasma and ultratiltration liquid by chromatography. Sedation was assessed by a simplified Ramsay score (EDS) with 4 levels. RESULTS: The mean duration of continuous infusion was 11 +/- 6 days. Peak plasma levels were over 150 ng ml-1 during the first 3 days, but normalized after that, only by drug adjustment based on scoring and clinical observation. There was no progressive accumulation of OH-midazolam, in spite of high levels (> 1000 ng ml-1). The Sieving coefficient (S) was 0.11 +/- 0.10 and 0.44 +/- 0.15 for midazolam and conjugated OH-midazolam respectively. A significant clearance (9.6 +/- 1.9 ml min-1) was observed for the conjugated products. T 1/2 beta was 11 h and was correlated with the mean time of recovery. A significant correlation was found between sedation score and both midazolam (r = 0.47) and OH-midazolam (r = 0.32). CONCLUSION: OH-midazolam risk of accumulation and significant clearance by haemodiafiltration should be taken into account in the drug adjustment in patients treated by continuous veno-venous haemofiltration.

[Sedation induced by midazolam in intensive care: pharmacologic and pharmacokinetic aspects]. / Sédation par le midazolam en réanimation: aspects pharmacologiques et pharmacocinétiques.

OBJECTIVE: Review on midazolam in order to optimize drug utilisation and therapeutic monitoring. DATA SOURCES: Research of English or French articles published until August 2001, using Medline database. The key words were: midazolam, pharmacokinetics, pharmacodynamic, sedation, drug interaction. STUDY SELECTION: Original articles, clinical cases and letters to the Editor were selected. Animal studies were excluded. DATA EXTRACTION: The articles were analysed according to their interest in midazolam clinical practice. DATA SYNTHESIS: Midazolam is a benzodiazepine widely used in intensive care unit, as a sedative, anxiety-relieving, and amnesic drug. Midazolam could be used in patients with cardiac, or respiratory failure, and in neurosurgery. A great interindividual variability on pharmacokinetic and pharmacodynamic response was observed. In intensive care patients, elimination half-life is known to be widely increased. Midazolam is metabolised by hepatic microsomes. The major metabolite is the 1-hydroxymidazolam, which is pharmacologically active. A prolonged sedation due to an accumulation of conjugated metabolite was observed in renal failure patients. Enzymatic inductors or inhibitors could influence pharmacokinetics and pharmacodynamic effects of midazolam. CONCLUSION: According to midazolam pharmacokinetic and pharmacodynamic variability, an individual dosage adjustment is essential for long-term sedation. Target controlled sedation could be a mean to limit the variability and to reach quickly the pharmacodynamic effect.

Propofol metabolites in man following propofol induction and maintenance.

BACKGROUND: The pharmacokinetics of propofol in man is characterized by a rapid metabolic clearance linked to glucuronidation of the parent drug to form the propofol-glucuronide (PG) and sulfo- and glucuro-conjugation of hydroxylated metabolite via cytochrome P450 to produce three other conjugates. The purpose of this study was to assess the urine metabolite profile of propofol following i.v. propofol anaesthesia in a Caucasian population. METHODS: The extent of phase I and phase II metabolism of propofol was studied in 18 female and 17 male patients after an anaesthesia induced and maintained for at least 4 h with propofol. The infusion rates (mg kg(-1) h(-1)) of propofol were (mean (SD)) 4.1 (1.0) and 4.5 (1.3) for males and females, respectively. Urine was collected from each patient for the periods 0-4, 4-8, 8-12, and 12-24 h after the start of propofol administration. In a preliminary study, the three main glucuro-conjugated metabolites were isolated from urine and characterized by magnetic resonance spectroscopy. The quantification of these metabolites for the different collection periods was then performed by a HPLC-UV assay. RESULTS: Total recovery of propofol in the metabolites studied amounts to 38%, of which 62% was via the PG metabolite and 38% via cytochrome P-450. This percentage is significantly higher than that previously reported from patients after a bolus dose of propofol. Extreme values for PG (0-24 h period) were included from 73 to 49%. There was no significant difference between female and male patients in the metabolite ratio. CONCLUSIONS: We conclude that the extent of hydroxylation in propofol metabolism was higher than in previous findings after administration of anaesthetic doses of propofol. Moreover, the ratio between hydroxylation and glucuronidation of propofol is subject to an inter-patient variability but this does not correlate with the dose of propofol. However, the variation of the metabolite profile observed in the present report does not seem to indicate an extended role of metabolism in pharmacokinetic variability.

Stability of sufentanil in human plasma samples.

The stability of sufentanil in human plasma kept under various storage conditions was investigated. Extraction was performed using solid phase extraction with new mixed-mode cation exchange Oasis MCX columns; quantification was carried out using gas chromatography equipped with a mass spectrometry detector. When plasma was left at 4 degrees C in nonsilanized tubes, concentrations of sufentanil decreased significantly during the first hour. In plasma samples kept at -25 degrees C for 8 hours in nonsilanized glass tubes, a significant decrease of sufentanil concentrations was found, with an average loss of 10.1% of the initial concentration. A significant decrease occurred when plasma was kept in silanized glass tubes for 12 hours at -25 degrees C. The current study emphasizes the importance of sampling and storage conditions for an accurate determination of sufentanil concentration in plasma.

Midazolam disposition in patients undergoing continuous venovenous hemodialysis.

The aim of the study was to investigate the pharmacokinetics and removal of midazolam and unconjugated and glucuronidated 1-hydroxy-midazolam in 4 intensive care patients on continuous venovenous hemodialysis. Plasma midazolam and its metabolites were assessed by HPLC from blood samples collected during continuous infusion and after the end of infusion. Additional samples from the arterial and venous bloodlines and ultrafiltrate were drawn to calculate sieving coefficient and clearance of ultrafiltration. The elimination half-life of midazolam ranged from 7.6 to 22.8 hours. The clearance of ultrafiltration was between 0.13 and 4.7 ml/min and reached approximately 11% of the total clearance. The range of sieving coefficient was from 0.006 to 0.26, with an average fraction removal of 0.2%. 1-Hydroxy-midazolam glucuronide was removed by continuous hemodialysis (sieving 0.36 to 0.63), with a clearance of ultrafiltration ranging from 7.8 to 12.0 ml/min. These preliminary results showed that midazolam is not removed efficiently, and approximately half of the 1-hydroxy-midazolam glucuronide was removed by dialysis.

Detection of new propofol metabolites in human urine using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry techniques.

Using hyphenated analytical techniques, gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a study on minor propofol metabolites in human urine was conducted. These techniques allowed identification of two new phase I metabolites (2-(omega-propanol)-6-isopropylphenol and 2-(omega-propanol)-6-isopropyl-1,4-quinol). In addition, their four corresponding conjugates (three glucuronides and one sulphate) were detected. Thus in human urine at least eight conjugate metabolites are produced, derived from four different aglycones (propofol; 2, 6-diisopropyl-1,4-quinol; 2-(omega-propanol)-6-isopropylphenol and 2-(omega-propanol)-6-isopropyl-1,4-quinol).

High-performance liquid chromatographic assay to detect hydroxylate and conjugate metabolites of propofol in human urine.

This paper describes a HPLC method for the simultaneous detection of phase I (2,6-diisopropyl-1-4-quinol and 2,6-diisopropyl-1-4-quinone) and phase II (4-(2,6-diisopropyl-1-4-quinol)-sulphate, 1-(2,6-diisopropyl-1-4-quinol)-glucuronide, 4-(2,6-diisopropyl-1-4-quinol)-glucuronide, and propofol-glucuronide) metabolites of propofol in human urine samples. Separation was based on a simple mobile phase and a reversed-phase chromatographic column. Metabolite identification was performed by UV spectrum on a diode-array detector and by LC-APCI-MS. The identification was also carried out using in vitro incubation mixtures (cytosol and microsomes prepared from liver) from several species: human, rat and rabbit. This assay was performed using UV, fluorescence and electrochemical detection modes. Each of these was analyzed and discussed.

Pyrolysis-gas-liquid chromatography with atomic emission detection for the identification of Corynebacterium species.

We report here the application of pyrolysis-gas chromatography followed by atomic emission detection (AED) for the characterisation of microorganisms. AED measured the quantity of carbon, sulfur and nitrogen in the molecules separated chromatographically. Twenty-three strains, representing eight Corynebacterium species, were tested in this preliminary study. Co-ordinate principal analysis grouped 11 strains in their respective species group. Most of the other strains appear randomly distributed, perhaps because these strains require additional nutrients. These preliminary results show that the method could be used as a tool for the taxonomic and perhaps the epidemiologic characterisation of bacteria.

Implementation of a quality system in a therapeutic drug monitoring laboratory.

The concept of quality assurance is emerging in public and private clinical laboratories in France following the introduction of decrees on Hospital Accreditation procedure. We report here the methodology used for the implementation of a quality system in a Therapeutic Drug Monitoring laboratory. The quality manual, which represents the basis of the quality system, was drafted according to the following methodology: Step 1--study of the requirements of ISO 9001 Standard; Step 2--analysis and synthesis of the European EN 45001 Standard and French regulation GBEA system respectively, compared with the 20 headings of the ISO 9001 Standard; Step 3--elaboration of the quality manual on the basis of steps 1 and 2 and relating to: laboratory and staff organization, quality document management, quality planning relating to specific activities relevant to projects or contracts on drug monitoring and pharmacokinetic studies, and operating procedures. The implementation of a quality system in a public hospital laboratory may be considered as a means of improving the laboratory organization and management.

Identification of 6-methylmercaptopurine derivative formed during acid hydrolysis of thiopurine nucleotides in erythrocytes, using liquid chromatography-mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance assay.

6-Thioguanine and 6-methylmercaptopurine (Me6-MP) nucleotides are the two major thiopurine metabolites of azathioprine found in erythrocytes. During the acid hydrolysis required for the conversion of thiopurine nucleotides into their free bases, Me6-MP was converted into a compound that could be analyzed on a Purospher RP18-e column with dihydrogen phosphate-methanol buffer as eluent. The pH of the acid extract strongly influenced the conversion of Me6-MP into its derivative. The Me6-MP derivative was identified using liquid chromatography-mass spectrometry and infrared and nuclear magnetic resonance spectrometric methods. During the acid hydrolysis of thiopurine nucleotides in erythrocytes, Me6-MP undergoes degradation, leading to 4-amino-5-(methylthio)carbonyl imidazole.