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Resume Introduction Le contenu de l’enseignement dispense au cours des etudes de pharmacie doit permettre l’utilisation pratique des connaissances acquises, dans un souci d’amelioration du soin medicamenteux. L’objectif de ce travail a ete de mettre en lumiere les lacunes que presentent les etudiants de la filiere officine debutant leur stage hospitalier de 5 e annee. Methode Quatorze etudiants en stage de 5 e annee accompli dans un CHU ont ete invites a mettre en lumiere ces lacunes au fur et a mesure de leur immersion dans le soin medicamenteux. Ils l’ont fait sous l’observation attentive des praticiens hospitaliers les encadrant. Ces praticiens se sont appuyes sur des referentiels metiers, des outils documentaires employes en routine clinique et des publications leur ayant servi a asseoir leurs pratiques de soins pharmaceutiques. Resultats Les insuffisances ou lacunes identifiees ont ete : la forme et le contenu de la communication avec d’autres professionnels de sante, la forme de la communication avec les patients, la faible appropriation des outils documentaires indispensables a une pratique clinique pertinente, la meconnaissance de la codification des interventions pharmaceutiques, les risques lies au conditionnement des medicaments et les avancees et dangers lies aux technologies de l’information. Discussion Ces lacunes constituent un handicap retardant le processus qui conduit a passer du stade d’etudiant au stade de professionnel de sante. Il revient aux praticiens hospitaliers la necessite de combler ces lacunes avant immersion totale en situation de soin. Conclusion Ces resultats invitent a reviser partiellement le contenu du programme d’enseignement dispense avant la 5 e annee.

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.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.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.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.These results invite to revise partly the content of the academic teaching program delivered before the 5th year hospital pharmacy practice experience.

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.

International audience; 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).

This study aimed at assessing the effects of midazolam (MDZ) sedation on auditory brainstem (BAEP) and middle latency (MLAEP) evoked potentials in intensive care conditions. Ten ventilated comatose patients were receiving an intravenous MDZ bolus dose (0.2 mg/kg) followed by a 2 h continuous infusion (0.1 mg/kg/h). MLAEPs and BAEPs elicited by clicks (90 dB HL + masking) were simultaneously and continuously monitored during the first 6 h and for 30 min the next morning. We found no effect of MDZ sedation on BAEPs. Only MLAEP components were modified. However, none of the patients presented any total abolition of the MLAEPs. Bolus injection led to very early alteration of cortical responses, beginning after 5 min and lasting almost 1 h (maximum Pa latency increase, 3.1 ms; maximum Pa-Nb amplitude decrease, 46%). During continuous infusion, MLAEPs remained slightly, although significantly, altered (Pa latency, +1.3 ms; Pa-Nb amplitude, 27%). The Nb wave seemed to be modified earlier and to return to normality later than the Pa wave. These findings incite a careful interpretation of MLAEP tracings acquired during the first hour following MDZ bolus injection. If possible, MDZ should be administered as continuous infusion for reliable interpretation of evoked potential changes in intensive care unit, or during surgery.

A sample treatment procedure for the determination of thiopurine and ganciclovir nucleotides in human tissues was developed. Owing to the lack of suitable standards for most of the active nucleotide analogues, the procedure was based on two steps: (1) perchloric acid homogenization and deproteinization of the tissue specimen and (2) conversion of purine nucleotides into parent drug or free bases by enzymatic or acid hydrolysis. The parent drug or purine bases formed were then analysed on a Hypersil ODS column using isocratic elution with dihydrogenphosphate buffer for ganciclovir nucleotides or the gradient elution mode with dihydrogenphosphate buffer-methanol for thiopurine nucleotides. The sample treatment procedure was evaluated using guanosine triphosphate (GTP), 6-thioinosinic acid (6TIMP) and 6-thioguanosine monophosphate (6TGMP) as standards. Mean analytical recoveries determined by adding known concentrations of standards to the tissue specimen before sample processing were higher than 97%. The sample preparation described is simple and represents a suitable method for the investigation of active nucleotide pool in tissues.

A method for the analysis of thiopurine nucleotides in human transbronchial lung biopsy was developed. The sample treatment procedure is based on perchloric acid homogenisation and deproteinisation with dithiothreitol and hydrolysis of thiopurine nucleotides into their free bases by heating of the acid extract. Then, the free bases were analyzed in the gradient elution mode on a Hypersil ODS, 3-μm column using dihydrogenphosphate buffer-methanol as eluent. Mean analytical recoveries for 6-thioguanosine monophosphate and 6-thionosinic acid from lung tissue were 97.0 ± 2.0 and 98.0 ± 1.8% at a concentration of 3.0 nmol/ml and the minimum detectable amounts were 3.5 and 2 pmol, respectively. The procedure described is simple and represents a suitable method for the investigation of thiopurine nucleotides in tissues.

A method for the analysis of ganciclovir nucleotides in myocardial tissues was developed. The antiviral effect of ganciclovir is attributed to intracellular ganciclovir nucleotides. The procedure is based on perchloric acid deproteinization and enzymatic hydrolysis of the ganciclovir nucleotides to ganciclovir. Then, the parent drug was analyzed on a Hypersil ODS column using potassium dihydrogenphosphate buffer as mobile phase. The mean analytical recovery of ganciclovir from myocardial tissue was 101 ± 2% and the detection limit was 2 pmol. The sample treatment procedure described is simple and presents a suitable analytical tool for the investigation of the ganciclovir nucleotides pool in tissues.

A rapid, selective and sensitive isocratic reversed-phase high-performance liquid chromatographic method for the determination of ganciclovir in plasma samples was developed. This method, which was applied to the analysis of plasma ganciclovir from heart transplant patients under ganciclovir therapy for cytomegalovirus infections, represents a suitable analytical tool for drug monitoring and pharmacokinetic investigations.

A rapid solid-phase extraction method for the determination of diltiazem and its metabolites from plasma was compared to a conventional liquid-liquid extraction procedure we have described previously. Analytical recovery for all compounds was greater than 90 % for solid-phase extraction whereas for liquid-liquid extraction, mean recovery ranged from 67 to 82 %. The increase of extraction efficiency was closely related to an improvement of the detection limit for the metabolites. Solid phase extraction procedure was found to be more convenient, rapid and sensitive than liquid-liquid extraction and represents a useful analytical tool for the monitoring of diltiazem and its metabolites in clinical investigations.

In this high performance liquid chromatographic method described for the analysis of diltiazem and its metabolites, the compounds of interest are separated with high efficiency and selectivity on a Nucleosil C18 column, 3 μm particle size. Stability assay shows a significant degradation of diltiazem and its metabolites in blood samples and only a significant degradation of the major metabolite, N-demethyldiltiazem in plasma when samples are kept at room temperature. This observation shows the necessity of observing rigorous conditions during collection, transport and treatment of blood samples. This method is applied to the analysis of plasma samples from patients under diltiazem therapy.

A capillary electrophoretic (CE) method for the determination of hypoxanthine and xanthine in urine was developed to diagnose xanthinuria. The linearity was excellent up to 200 μmol l−1 for the two compounds and the limit of quantitation was 2 μmol 1−1. A comparison o the results obtained using CE was made with those obtained by the high-performance liquid chromatographic (HPLC) technique described previously. With regard to specificity, sensitivity and reproducibility, the results are similar but CE is more rapid than HPLC.

Evaluate the risk of accumulation of midazolam and conjugated 1-hydroxy-midazolam in high-risk ICU patients treated by continuous veno-venous haemofiltration.A prospective pharmocokinetic and clinical evaluation in 11 patients, with hepatic and renal failure.Midazolam and metabolites were dosed in plasma and ultratiltration liquid by chromatography. Sedation was assessed by a simplified Ramsay score (EDS) with 4 levels.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).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.

Review on midazolam in order to optimize drug utilisation and therapeutic monitoring.Research of English or French articles published until August 2001, using Medline database. The key words were: midazolam, pharmacokinetics, pharmacodynamic, sedation, drug interaction.Original articles, clinical cases and letters to the Editor were selected. Animal studies were excluded.The articles were analysed according to their interest in midazolam clinical practice.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.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.

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.

The pharmacokinetics of midazolam and of its main metabolite, 1-hydroxymidazolam, were investigated in intensive care patients after intravenous bolus of 0.2 mg/kg followed by a 0.1 mg/kg/h intravenous infusion of midazolam over 2 hours. A wide interpatient variability of the main pharmacokinetic parameters of midazolam was found. The mean values of elimination half life and volume of distribution, 4.5 +/- 5.4 h and 1.7 +/- 0.7 l/kg respectively, were higher than those reported in healthy subjects. Total plasma clearance was significantly increased in patients taking drugs that induce hepatic metabolism. Significant concentrations of the unconjugated form of 1-hydroxymidazolam were recovered in plasma. The volume of distribution and the elimination half life of the metabolite were higher than those of the parent drug. These results show that 1-hydroxymidazolam might contribute to the pharmacodynamic effect of midazolam and consequently must be taken into account during pharmacokinetic and pharmacodynamic studies.

Using HPLC methods, we measured the concentrations of nucleosides and nucleotides for a patient with no purine nucleoside phosphorylase (PNP; EC 2.4.2.1) enzymatic activity. Concentrations of inosine and guanosine were abnormally high in urine and plasma, whereas guanosine diphosphate (GDP) and guanosine triphosphate (GTP) concentrations in erythrocytes were depleted. The unusual presence of deoxyribonucleosides (deoxyinosine and deoxyguanosine) and deoxyribonucleotides (dGDP and dGTP) was also notable. Thus, HPLC represents an accurate and useful tool for the study of purine metabolic disorders.

A selective and sensitive high-performance liquid chromatographic method for the analysis of midazolam and its unconjugated 1-hydroxy metabolite in plasma samples was developed. The compounds were extracted from plasma by a liquid-liquid extraction procedure with diethyl ether. Mean analytical recoveries were 87% and 86% at a concentration of 300 ng/ml for midazolam and 1-hydroxymidazolam, respectively, and the quantification limit was 2 ng/ml for a plasma volume of 1 ml. The separation of midazolam, 1-hydroxymidazolam and flurazepam (internal standard) was achieved on a Spherisorb 5 CN column using methanol-2-propanol (75:25, v/v) containing 0.015% perchloric acid at a flow-rate of 1.5 ml/min. The method is sensitive enough for monitoring midazolam and also the unconjugated form of the active metabolite in plasma during pharmacokinetic studies.

Calcium-channel inhibitors are widely used in therapeutics. Many patients administered calcium channel inhibitors undergo surgical procedures and the cardiologists or the anaesthesiologists are concerned with pharmacological interactions with anaesthetic agents such as halogenated gases. The combination of calcium channel inhibitors and halogenated anaesthetics may exert an additive effect on myocardial depression, conduction disturbances and arterial vasodilatation. The continuation of oral calcium channel inhibitors until the day of surgery is recommended provided the use of enflurane is restrained. Calcium-channel inhibitors such as dihydropyridines are currently administered intravenously to control intra and postoperative arterial hypertension while verapamil and diltiazem are used to treat supraventricular arrhythmias and myocardial ischaemic episodes. In patients with cardiac disease, haemodynamic monitoring may allow to anticipate or to treat episodes of cardiac dysfunction associated with I.V. calcium-channel inhibitors during the perioperative period.

Preoperative oral administration of calcium channel blocking agents has been found ineffective to prevent perioperative myocardial ischaemia. Our hypothesis was that low plasma concentrations may account for this inefficiency. Twenty-three male patients, scheduled for surgical myocardial revascularisation, were administered their usual anti-anginal treatment, including 180 to 360 mg of diltiazem since more than one week. The usual dosage was given at 8.00 p.m. on the day before surgery. On the morning of surgery, after withdrawal of a first blood sample, 60 mg of diltiazem were administered per month before the induction of anaesthesia. The anaesthesia was obtained with fentanyl, midazolam or flunitrazepam, pancuronium and isoflurane as required. The cardiopulmonary bypass (CPB) was associated with total haemodilution with Ringer's Lactate and a membrane oxygenator. A second blood sample was withdrawn after CPB. Plasma concentrations of diltiazem and its two active metabolites, N-monodemethyldiltiazem (MA) and desacetyldiltiazem (M1), were assessed by HPLC. Plasma diltiazem concentrations decreased from 78 +/- 66 (mean +/- SD) to 51 +/- 42 micrograms.l-1 (p0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before (p0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before induction and in 22 patients after CPB. The metabolite/diltiazem ratios remained constant. A dosage-plasma concentration relationship was observed preoperatively with diltiazem and MA. It is concluded that plasma concentrations of diltiazem should be optimized preoperatively in order to prevent myocardial ischaemia.

Using the rapid and sensitive high-performance liquid chromatographic (HPLC) method previously described for the analysis of ganciclovir in plasma, we have observed an interfering peak which co-elutes with the peak of ganciclovir in plasma samples from heart-transplant patients with severe renal insufficiency. A slight modification of this method allows the separation of the two peaks. The modified HPLC method, presented in this paper, is suitable for the accurate determination of ganciclovir in plasma from patients with severe renal impairment.

The effect of polyethylene glycol-adenosine deaminase (PEG-ADA) therapy on biochemical, immunological and clinical abnormalities in an ADA-deficit child with severe combined immunodeficiency has been studied. Following PEG-ADA therapy, total lymphocytes, lymphocyte subsets (CD3, CD4 and CD8) and the response of lymphocytes to non specific mitogens increase significantly. The improvement of immunological functions is closely related to a decrease of erythrocyte deoxyadenosine triphosphate (dATP) concentrations. This study shows that PEG-ADA therapy is sufficiently effective to reduce and to maintain erythrocyte dATP levels at values compatible with normal immune functions. PEG-ADA represents an important progress for the treatment of ADA deficiency associated with severe combined immunodeficiency disease.

The pharmacokinetics of methohexital after intravenous bolus administration was studied during cardiovascular surgery with cardiopulmonary bypass. The effect of body temperature (normothermia and hypothermia) during cardiopulmonary bypass on methohexital pharmacokinetics was investigated. The pharmacokinetic data obtained were compared with those from vascular surgery without cardiopulmonary bypass. A marked decrease in plasma methohexital concentrations and therefore in area under curve and a significant increase in clearance and in volume of distribution were observed in the cardiopulmonary bypass groups compared to the vascular surgery group without cardiopulmonary bypass. However, the elimination half-life and the mean residence time were similar in the 2 groups. Furthermore, the study shows that body temperature during cardiopulmonary bypass does not influence methohexital pharmacokinetics.

The effect of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy on biochemical abnormalities, clinical status, and immunologic function in an adenosine deaminase-deficient child was investigated. After red cell transfusions, erythrocyte deoxyadenosine triphosphate (dATP) concentrations decreased about 95% and were closely related to adenosine deaminase activities; deoxyadenosine diphosphate concentrations decreased only approximately 30%. The evolution of dATP levels was also closely related to the improvement in clinical status of the patient. However, immune function was not restored. After polyethylene glycol-modified adenosine deaminase therapy, the concentration of erythrocyte dATP decreased to undetectable levels correlated with an increase of T lymphocyte counts and an increase of lymphocyte responses to mitogens. Immune functions were restored only when dATP levels were below 15 mumols/L. It appears that red cell transfusion therapy is not sufficiently effective to reduce and maintain erythrocyte dATP levels at values compatible with normal immune function. On the contrary, polyethylene glycol-modified adenosine deaminase therapy is a suitable treatment to reduce dATP levels to near undetectable values, allowing the immune function to be restored, dATP measurement is a very useful tool for monitoring and evaluating the degree of efficiency of therapy in adenosine deaminase deficiency.

Data is scarce concerning ganciclovir, used in CMV-related diseases in transplant patient with renal failure, especially when dialysis is necessary.Prospective trial.Intensive care unit in a university hospital, and pharmacy laboratory.pharmacokinetics were obtained in 3 patients undergoing continuous veno-venous hemodialysis (CVVHD) (PAN 69).HPLC measurements of plasmatic and ultrafiltrated ganciclovir were determined at 17 times intervals after a 5 mg/kg every 48 h dosage.Peak and trough concentrations were respectively 16.1 +/- 2.4 and 5.5 +/- 0.5 mg/l, sieving coefficient 0.75-0.95, and volume of distribution at steady state 0.64 +/- 0.09 l/kg, half life (beta phase) 18.6 +/- 1.8 h. No direct toxicity, or CMV-related death occurred.Plasma concentrations were higher than the ID 90. A dosage of 5 mg/kg/48 h of ganciclovir could be used during CVVHD, and ideally adjusted to monitoring of plasma drug levels.

In this anion-exchange "high-performance" liquid-chromatographic method of analysis for purine nucleotides, the nucleotides are separated with high efficiency and selectivity on a weak anion exchanger (Hypersil APS 2, 3-micron particle size) by elution with a gradient of eluent pH and concentration. Applying this method to analysis for these compounds in human blood cells, we determined them in a patient with adenosine deaminase deficiency who was treated with a bone-marrow transplantation, finding that the transplantation did not entirely correct the patient's abnormalities of purine metabolism.

A procedure is presented for the simultaneous measurement of concentrations of labeled and non labeled hypoxanthine by HPLC in order to study hypoxanthine transport in erythrocytes. A radioactivity detector connected on-line to the high performance liquid chromatograph in series with a UV detector provides on-line quantitative monitoring of hypoxanthine in erythrocytes or incubation medium. The procedure provides a rapid, sensitive and convenient means for the study of hypoxanthine transport.

Triethyltin intoxication induces, in vivo, a significant increase of malondialdehyde concentration in rat brain. After treatment with a Ginkgo biloba extract, an extract known to possess antiedematous and radical scavenging properties, the malondialdehyde level in the brain is significantly decreased. This suggests that a lipid peroxidation process is associated with cerebral oedema induced by triethyltin.

A rapid and selective reversed-phase high-performance liquid chromatographic method for the simultaneous determination of hypoxanthine and xanthine in biological fluids was developed. The identification of hypoxanthine and xanthine was confirmed by xanthine oxidase reaction. This method was applied to the investigation of purine metabolism in subjects with xanthine oxidase deficiency or gout. Hypoxanthine concentrations three to ten times higher than those determined in plasma were found in erythrocyte samples from normal subjects and from patients with xanthine oxidase deficiency or hyperuricemia under allopurinol therapy.