A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

How to minimize toxic exposure to pyridine during continuous infusion of ceftazidime in patients with cystic fibrosis?

Ceftazidime is particularly efficient against Pseudomonas aeruginosa in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. Our aim was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4°C, 22°C, or 33°C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, we administered 12 g of ceftazidime infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Samples were collected at 0 h and then every 4 and 2 h after the shaping of portable infusion pumps in models 1 and 2, respectively. Both ceftazidime and pyridine were analyzed using an ultraviolet high-performance liquid chromatograph. Production of pyridine is highly depending on the temperature. The in situ production of pyridine per day of treatment decreases at a ratio close to 1/6 and 1/3 between 33°C and 4°C in models 1 and 2, respectively. Regardless of the conditions, the production of pyridine is significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4°C and 33°C compared to that in model 1. According to a the precautionary principle, these findings lead to three major recommendations: (i) exposing a solution of ceftazidime to over 22°C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 h instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

[Raman spectroscopy applied to analytical quality control of injectable drugs: analytical evaluation and comparative economic versus HPLC and UV / visible-FTIR]. / La spectroscopie Raman appliquée au contrôle de qualité analytique des médicaments injectables: évaluation analytique et économique comparative versus CLHP et uv/visible-iRTF.

In France, central IV admixture of chemotherapy (CT) treatments at the hospital is now required by law. We have previously shown that the shaping of Therapeutic Objects (TOs) could profit from an Analytical Quality Assurance (AQA), closely linked to the batch release, for the three key parameters: identity, purity, and initial concentration of the compound of interest. In the course of recent and diversified works, we showed the technical superiority of non-intrusive Raman Spectroscopy (RS) vs. any other analytical option and, especially for both HPLC and vibrational method using a UV/visible-FTIR coupling. An interconnected qualitative and economic assessment strongly helps to enrich these relevant works. The study compares in operational situation, the performance of three analytical methods used for the AQC of TOs. We used: a) a set of evaluation criteria, b) the depreciation tables of the machinery, c) the cost of disposables, d) the weight of equipment and technical installations, e) the basic accounting unit (unit of work) and its composite costs (Euros), which vary according to the technical options, the weight of both human resources and disposables; finally, different combinations are described. So, the unit of work can take 12 different values between 1 and 5.5 Euros, and we provide various recommendations. A qualitative evaluation grid constantly places the SR technology as superior or equal to the 2 other techniques currently available. Our results demonstrated: a) the major interest of the non-intrusive AQC performed by RS, especially when it is not possible to analyze a TO with existing methods e.g. elastomeric portable pumps, and b) the high potential for this technique to be a strong contributor to the security of the medication circuit, and to fight the iatrogenic effects of drugs especially in the hospital. It also contributes to the protection of all actors in healthcare and of their working environment.

[Antibiotic treatment of appendicular peritonitis in children: is the oral route done?]. / Antibiothérapie dans les péritonites appendiculaires de l'enfant : le relais par voie orale est-il effectué ?

The use of intravenously administered antibiotics has several disadvantages including hospitalization costs, infectious risk, and patient discomfort. The objective of this study was to estimate the proportion of children receiving intravenous antibiotic therapy (IV), for whom there was a switch to an oral route conforming to the criteria established by the American Pediatric Surgical Association (APSA). A cohort of 100 children hospitalized for acute appendicitis with generalized peritonitis or abscess were analyzed. In this study, we compared the criteria of switching to an oral route as recommended by the APSA (disappearance of the pain, normalization of white blood cells, afebrile for 48 hours, return to bowel function) and by reports from the literature (afebrile, tolerating regular diet). In 47.5% of the children, there was a switch to an oral route conforming to the APSA recommendations. In children having a late switch, the average duration of the IV treatment was of 7.6 ± 3.6 days associated with 62 days of avoidable IV antibiotics. The duration of hospitalization and antibiotic treatment was significantly higher in children having a late switch (P=0.04; P=0.01, respectively). Concerning the criteria reported in the literature, 14.5% of children were not switched to an oral route. Meeting the criteria from the literature would have resulted in 199 days of avoidable IV antibiotics. A significant number of days of IV antibiotics could have been avoided. However, the large number of exclusion criteria in the APSA analysis suggests that practitioners do not follow these recommendations or objective criteria. The criteria proposed in the literature could decrease the duration of IV antibiotics and the associated hospitalization costs.

[The Raman Spectroscopy (RS): A new tool for the analytical quality control of injectable in health settings. Comparison of RS technique versus HPLC and UV/Vis-FTIR, applied to anthracyclines as anticancer drugs]. / La Spectroscopie Raman (SR) : un nouvel outil adapté au contrôle de qualité analytique des préparations injectables en milieu de soins. Comparaison de la SR aux techniques CLHP et UV/visible-IRTF appliquée à la classe des anthracyclines en cancérologie.

The study compares the performances of three analytical methods devoted to Analytical Quality Control (AQC) of therapeutic solutions formed into care environment, we are talking about Therapeutics Objects(TN) (TOs(TN)). We explored the pharmacological model of two widely used anthracyclines i.e. adriamycin and epirubicin. We compared the performance of the HPLC versus two vibrational spectroscopic techniques: a tandem UV/Vis-FTIR on one hand and Raman Spectroscopy (RS) on the other. The three methods give good results for the key criteria of repeatability, of reproducibility and, of accuracy. A Spearman and a Kendall correlation test confirms the noninferiority of the vibrational techniques as an alternative to the reference method (HPLC). The selection of bands for characterization and quantification by RS is the results of a gradual process adjustment, at the intercept of matrix effects. From the perspective of a AQC associated to release of TOs, RS displays various advantages: (a) to decide quickly (~2min), simultaneously and without intrusion or withdrawal on both the nature of a packaging than on a solvant and this, regardless of the compound of interest; it is the founder asset of the method, (b) to explore qualitatively and quantitatively any kinds of TOs, (c) operator safety is guaranteed during production and in the laboratory, (d) the suppression of analytical releases or waste contribute to protects the environment, (e) the suppression.of consumables, (f) a negligible costs of maintenance, (g) a small budget of technicians training. These results already show that the SR technology is potentially a strong contributor to the safety of the medication cycle and fight against the iatrogenic effects of drugs.

Safety and quality assurance of chemotherapeutic preparations in a hospital production unit: acceptance sampling plan and economic impact.

OBJECTIVE: The opportunity to apply a sampling plan was evaluated. Costs were computed by a microcosting study. SETTING: In 2003, a sampling plan was defined to reduce the number of chemotherapy quality controls while preserving the same level of quality. Recent qualitative and quantitative changes led us to define a second sampling plan supplemented by an economic evaluation to determine the cost and cost-savings of quality control. METHODS: The study considers preparation produced during four semesters classified into three groups. The first one includes drugs produced below 200 batches a semester. Group 2, those for which the lot of preparation lots would have been rejected twice among these four semesters. Group 3, those would have been accepted (≥3 'acceptable lot'). A single sampling plan by attributes was applied to this group with an acceptance quality level of 1.65% and a lot tolerance percent defective below 5%. A micro-costing study was conducted on quality control, from the sampling to the validation of the results. RESULTS: Among 39 cytotoxic drugs, 11 were sampled which enabled to avoid a mean of 17,512 control assays per year. Each batch of the 28 non-sampled drugs was however analyzed. Costs were estimated at 2.98€ and 5.25€ for control assays depending of the analytical method. The savings from the application of the sampling plans was 153,207€ in 6 years. CONCLUSION: The sampling plan allowed maintaining constancy in number of controls and the level of quality with significant costsavings, despite a substantial increase in drugs to assay and in the number of preparations produced.

Evaluation of the pharmacokinetic profile and analgesic efficacy of oral morphine after total hip arthroplasty.

BACKGROUND AND OBJECTIVE: Oral morphine may be useful for postoperative pain relief, but few studies have tested its use after in-hospital surgery. METHODS: We evaluated clinical efficacy and the pharmacokinetic parameters of oral morphine after total hip arthroplasty. We recruited 60 patients who had total hip arthroplasty under general anaesthesia. The patients were randomized to receive placebo, 10 mg morphine sulphate or 20 mg morphine sulphate orally every 4 h for 24 h. The oral administration was started 3 h after the morphine-loading dose in the Post Anaesthesia Care Unit and then patients used intravenous morphine patient-controlled analgesia for 24 h. Pain score at rest (scored by patients on a visual analogue scale), sedation, nausea, vomiting and urinary retention were monitored. In 11 additional total hip arthroplasty patients, we determined the pharmacokinetics of morphine and its metabolites after oral administration of 20 mg morphine sulphate every 4 h for 16 h. RESULTS: The amount of morphine administered via patient-controlled analgesia over 24 h was reduced in the 20-mg group compared with that in the placebo group (19.0 +/- 2.7 mg vs. 33.0 +/- 5.5 mg; P = 0.03). No significant morphine-sparing effect was observed in the 10-mg group. Pain scores and side-effects were similar in all groups. The pharmacokinetic study revealed a limited and slow absorption of morphine. CONCLUSION: Despite a limited absorption of oral morphine postoperatively, high doses of oral morphine have a significant analgesic effect after total hip arthroplasty.

Near infrared spectroscopy and process analytical technology to master the process of busulfan paediatric capsules in a university hospital.

The prescription of unlicensed oral medicines in paediatrics leads the hospital pharmacists to compound hard capsules, such as busulfan, an alkylating agent prescribed in preparative regimens for bone marrow transplantation. In this study, we have investigated how the general principle of process analytical technology (PAT) can be implemented at the small size of our hospital pharmacy manufacturing unit. Near infrared spectroscopy (NIRS) was calibrated for raw material identification, blend uniformity analysis and final content uniformity of busulfan hard capsules of 11 different strengths. Measurements were performed on capsules from 2 to 40 mg (n=440). After optimisation, accuracy and linearity of the NIRS quantitative method was demonstrated after comparison with a previously validated quantitative high performance thin layer chromatography (HPTLC) method. Such a comparison led to attractive NIRS precision: +/-0.7 to +/-1.0 mg for capsules from 2 to 40 mg, respectively. As NIRS is a rapid and non-destructive technique, the individual control of a whole batch of busulfan paediatric capsules intended to be administrated is possible. Actually, mastering the process of busulfan paediatric capsules with the NIRS integrated into the notion of PAT is a powerful analytical tool to assess the process quality and to perform content uniformity of at least 5mg busulfan-containing capsules.

[Shelf-lives of morphine and pethidine solutions stored in patient-controlled analgesia devices: physico-chemical and microbiological stability study]. / Durée de péremption des solutions de morphine et de la péthidine présentées dans des dispositifs pour analgésie autocontrôlée: étude de stabilité physicochimique et microbiologique.

Morphine and meperidine in Patient-Controlled Analgesic devices are commonly used to treat chronic pain patients. These devices deliver a programmed amount of drug and allow self-administration by the patient depending on the pain. In our department of pharmacy, 300 devices were manufactured in 2003. The aim of this study was to assess their shelf-life. The devices were filled aseptically and without preservatives with 1 and 40 mg/ml morphine solution and 5 and 20 mg/ml meperidine and stored over 30 days at room temperature and protected from light. Culture assay of the solutions showed that they remained sterile for 30 days. No turbidity of any solutions from samples collected twice a week was noticed. pH and osmolarity remained constant. Drug concentrations were determined using stability indicating HPLC method, as we showed that degradation products can be separated from the drugs. Little loss of meperidine occurred within 21 days (<5%) and morphine concentration, which increased, because of solvent evaporation, remained lower than 5% within 21 days but increased up to 10% after 30 days. No traces of degradation products (pseudomorphine or pethidic acid) were detected. The physicochemical and microbiological stability of morphine and meperidine hydrochlorides stored in such devices has been established for 21 days at room temperature and protected from light.

Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance.

BACKGROUND: The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan. PATIENTS AND METHODS: Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m(2)), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m(2)). IPCH was carried out with the abdomen open, for 30 min at 43 degrees C, with 2 l/m(2) of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of oxaliplatin and irinotecan. RESULTS: Irinotecan concentration in tumoral tissue increased until 400 mg/m(2) and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%. CONCLUSION: Intraperitoneal heated oxaliplatin (460 mg/m(2)) plus irinotecan (400 mg/m(2)) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.

Identification and quantitation of antineoplastic compounds in chemotherapeutic infusion bags by use of HPTLC: application to the vinca-alkaloids.

An instrumental quantitative high-performance thin-layer chromatographic (HPTLC) method has been developed for the determination of vinca-alkaloids (antineoplastic compounds) in chemotherapeutic infusion bags prepared in a hospital pharmacy. The method uses automated band application onto silica gel plates containing a fluorescent indicator and scanning densitometry of fluorescence-quenched zones of samples and standards. Samples were analyzed to check the content of the active substance against the label declaration of the preparation. The four compounds were separated using the following solvent system CH(2)Cl(2)-CH(3)OH (93:7, v/v). Vincristine (VCR) and vinorelbine (NVB) were assessed in the same run whilst vinblastine (VLB) and vindesine (VDS) were analyzed in a second run. HPTLC allows the identification and the quantitation of more than 20 samples in the same chromatographic run. The analysis of the samples requires 30 min compared with more than 2 h using a typical HPLC method. Moreover, there is no need for a conditioning step, as with HPLC, and each analysis by HPTLC is less expensive.

Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly hypotonic solutions after complete resection of peritoneal carcinomatosis.

PURPOSE: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions. METHODS: Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied. RESULTS: Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. SAFETY: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups. CONCLUSION: Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

[Pharmaceutical traceability integrated with the patient file. Development of a computerized hospital application]. / Traçabilité pharmaceutique intégrée au dossier patient. Développement d'une application informatique hospitalière.

The Clinical Pharmacy Department (CPD) of the Gustave Roussy Institute, has developed a traceability software package that is integrated with the patient file. The Traceability & Medical Devices Functional Unit manages the Blood Derivative Medicinal Product traceability circuits, the circuits of over 400 Sterile Medical Devices and, generally speaking, those for all pharmaceutical goods for which traceability is imperative. The SIMBAD-TRACE software package has been developed in situ and was first open for access in March 1999. It enables pharmaceutical traceability data to be accessed from 500 networked workstations. The references tracked generated about 10,000 movements per year. In terms of performance, the system achieves three complementary objectives: 1) reporting traceability scores which reflect the ability of CPD and the establishment to pertinently respond to a complex regulatory requirement on a daily basis; 2) the contribution of the tool to cost containment with respect to allocating rare goods; the contribution of the software package to the implementation of medical device vigilance inquiries, particularly descending inquiries. Finally, SIMBAD-TRACE is one of the pillars of our Quality Assurance Program (QAP).

Application of high-performance, thin-layer chromatography to quality control of antimetabolite analogue infusion bags.

A global postproduction quality program was developed to secure chemotherapy infusion at the Gustave Roussy Institute. Despite rigorous procedures and computerized prescriptions, an analytical check was necessary to improve the quality of ready-to-use solutions of cytotoxic drugs in our Centralized Antineoplastics Reconstitution Unit. High-performance, thin-layer chromatography was selected as the analytical tool to assay 12 anticancer drugs. One of the analytical methods can separate 4 antimetabolite substances, i.e., fludarabine (FDB), cytarabine (CTB), gemcitabine (GTB), and fluorouracil (5 FU). For all infusion bags manufactured, up to 26 samples could be assayed per series using a double standard calibration (GTB and 5 FU).

[Role and functional spectrum of HPTLC in a hospital pharmaceutical quality control program]. / Place et spectre fonctionnel de l'HPTLC dans un programme d'assurance qualité pharmaceutique hospitalier.

As part of the development of a quality assurance program (QAP), a high performance thin layer chromatography (HPTLC) analysis unit was installed in the pharmacy department at Gustave-Roussy. The HPTLC-CAMAG consists of: 1) an HPTLC-Vario development chamber for optimization of the mobile phases; 2) TLC Sampler III automated sample applicators; 3) solid teflon migration chambers, i.e., horizontal tanks that enable separation to be carried out either in sandwich or in saturation mode; 4) a TLC Scanner 3 densitometer controlled by CATS 4 software; and 5) a Pentium MMX 233 MHz personal computer with an external backup unit. HPTLC quantitative and qualitative analysis has now reached a remarkably high level of development and performance. The samples (aqueous or non-aqueous solutions) that are to be processed are automatically applied by spraying (50-300 nl) in calibrated bands of a few mm (with up to 64 3-mm bands per 10 x 20 cm plate) on high-performance stationary phases and of wide technological diversity. The chromatogram is obtained in 10 min, and run over a migration pathway of 5-6 cm. The plates are read by absorption-reflection or fluorescence-reflection at an ad hoc wavelength (190-800 nm), then the peak areas which have been scanned are calculated by the trapezoid method. The calibration curves are generated by Michaelis-Menten non-linear regression, and validated by internal quality control. The analytical yield is high, i.e., up to 50 assays and 250 determinations per day. HPTLC analysis covers a wide functional range, and can be used in the following ways: 1) as a teaching tool for separative analysis and GLP; 2) it is an invaluable method for the optimization of mobile phases and for the determination of absorption spectra and absorption maxima, with a view to developing HPLC methods in complex matrices; 3) it provides major support for post-production quality control of prescribed hospital preparations of all types, e.g., those connected with parenteral nutrition, chemotherapy, synthetic narcotic analgesia; and it can also be used for dry dosage analysis; 4) it is useful in pharmaceutical assessment, e.g., in studies on the physico-chemical characteristics of various substances, such as their identity, purity, concentration, stability and compatibility, particularly with regard to generic products; 5) it can contribute to monitoring the safety of medical apparatus and equipment via the analysis of container-content interactions; 6) it provides a qualification system for personnel and procedures for within- and between-center validation of GMP. Setting up such an HPTLC quality control unit requires a basic investment of about 0.9 MF or 70,000 US dollars for a cost of no more than 10 F or 1.5 US dollars (including tax) per routine assay. After 18 months in operation and 16,500 assays, the HPTLC analysis unit has become one of the mainstays of the Gustave-Roussy QAP.

Clinical pharmacokinetics of ciprofloxacin in patients with major burns.

OBJECTIVE: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects. METHODS: Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree burns was 31.8 +/- 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental method was used for kinetic and graphic analysis of concentration-time pairs. RESULTS: No adverse effects were noted. Trough concentrations measured on day 3 (mean +/- SD) were above the minimum inhibitory concentration (MIC) for the organism responsible for infection; i.e., 2.0 +/- 1.2 microg. ml(-1), and maximum concentrations were high 9. 9 +/- 3.4 microg. ml(-1). An area under the concentration-time curve (AUC)/MIC ratio above 125 SIT(-1) (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in 11 patients with a MIC of 0.5 microg. ml(-1). There was a statistically significant difference between C(min) and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased. CONCLUSION: The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF, i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy.

[Pharmacokinetics of fusidic acid in patients with seriously infected burns]. / Pharmacocinétique de l'acide fusidique administré au sujet gravement brûlé infecté.

The pharmacokinetics of fusidic acid (FA) were studied in 10 infected severe burns patients (35 +/- 5 yrs, 81 +/- 17 kg) i.e. 43 +/- 10% in 3rd degree. Treatment was given at the dose of 500 mg/8 hours (2-hour infusion). The kinetics of FA were evaluated on D1 (1st infusion) and at steady state on D4 (10th infusion), each sequence involving 9 whole blood samples. Samples were assayed by high-performance liquid chromatography. Data were analysed by a non-compartmental method. Mean duration of treatment, considered effective in all cases, was 5.9 +/- 2.1 days. The systemic safety of FA was felt to be good. Kinetic analysis revealed the existence of significant differences between D1 and D4 concerning the parameters Cmax, Cmin, AUC, Cl and Vss. These events are attributable to the non-linear nature of the human kinetics of FA. Accumulation ratios R1 and R2 did not differ i.e. 1.51 +/- 0.25 and R2 = 2.44 +/- 0.68. Kinetic modelling based upon the experimental tracing obtained on D1 revealed good coincidence of the predictive tracing in relation to data determined on D4. The dosage algorithm of 500 mg/8 hours was microbiologically satisfactory with Cmin measured on D1 and at steady state constantly greater than the MIC of the main organisms concerned (< to 2 micrograms/ml). Reduction in the parameters Cmax and AUC in comparison with a group of healthy subjects ultimately led to shortening of the mean T1/2 of FA. In the absence of impaired liver function, this is attributable to the known increase in hepatic clearances in burns patients and, to a certain extent, to the existence of translesional extra-hepatic clearance, which could contribute to the success of treatment.