[Research ethics: French regulations and applications in radiation oncology]. / Éthique de la recherche : réglementations françaises et applications en oncologie radiothérapie.

French regulations about research ethics are based on the so-called Jardé law, which defines researches involving human beings. Researches involving human beings require the submission of research protocols to a committee for protection of persons with a precise list of documents to submit for a favourable opinion. This law describes different categories of researches and determines the ethical procedures to apply before setting up a research protocol. This issue of categorisation is central and must be taken into account by researchers from the beginning of the research process. Researches considered as not involving human beings also require a set of ethical precautions focused on patients' information and the collection of their non-opposition (due to the application of the General Data Protection Regulation adopted by the European Parliament). Thus, many regulations exist and they require a real work for researchers to meet these requirements in research ethics. This article aims to summarise French regulations. Selected examples are specifically taken into the field of radiation oncology research.

Pharmacokinetics of free ertapenem in critically ill septic patients: intermittent versus continuous infusion.

BACKGROUND: The aim of this paper was to compare the pharmacokinetic and pharmacodynamic (PK/PD) parameters of continuous (CI) and intermittent infusion (ITI) of ertapenem into critically ill patients with severe abdominal infections. METHODS: Twenty septic patients hospitalized in a university hospital intensive care unit were enrolled in the study. Half of the patients received ertapenem as an ITI 1 g bolus once daily, and the other half of the patients received the same dose via CI over 24 h following a 1-g loading dose. Blood was drawn 1, 12 and 24 h after terminating ITI or on days 2, 3 and 5 after starting CI for each patient. After centrifugation, the drawn blood was frozen at -80 °C until being examined by high-performance liquid-chromatography analysis. RESULTS: Median serum-free ertapenem concentrations were as follows: ƒCmax = 98.9 mg/L and ƒCmin = 2.5 mg/L for ITI, and ƒCss=15.9 mg/L for CI. The ITI and CI median total clearance and volumes of distribution were 2.2 L/h vs. 2.5 L/h and 15.4 L vs. 21.0 L, respectively. The ertapenem MIC ranges were as follows: Escherichia coli (0.006 to 0.5 mg/L), Enterobacter cloacae (0.023 to 0.5 mg/L), Klebsiella oxytoca (0.023 to 0.5 mg/L), Staphylococcus aureus (0.38 to 3 mg/L), Streptococcus viridians (0.38 to 3 mg/L) and Enterococcus faecalis (0.38 to 3 mg/L). ITI and CI provided steady-state serum-free ertapenem concentrations constantly above the MIC for all bacteria. CONCLUSION: Ertapenem exhibited satisfactory PK/PD parameters and achieved serum-free concentrations 100% of the time, above even the high MIC of extracellular pathogens normally encountered during severe abdominal infections. CI administration resulted in equally effective PK/PD parameters as ITI in normal weight, good renal-function patients.

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C.

BACKGROUND: The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated. AIM: To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin. PATIENTS AND METHODS: Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment. RESULTS: At week 4, a strong correlation was found between HCV-RNA and C(min) of ribavirin plasma level (r = -0.376, P = 0.002) and AUC(0-->12h) of ribavirin plasma level (r = -0.277, P = 0.018). At week 12, a strong correlation was found between HCV-RNA and C(min) of ribavirin plasma level (r = -0.384, P < 0.0001) and AUC(0-->12h) of ribavirin plasma level (r = -0.257, P = 0.002). In genotype 1 patients, AUC(0-->12h) ribavirin and C(min) were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12. CONCLUSION: C(min) of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.

Quantitative and qualitative control of cytotoxic preparations by HPLC-UV in a centralized parenteral preparations unit.

The constantly growing incidence of cancer and long-term treatment are leading to an increasing number of cytotoxic preparations in hospital pharmacies. Security and quality standards of cytotoxic preparations are essential to assure treatment efficiency and limit iatrogenic toxicity. In order to secure the process of cytotoxic preparations; we decided to install a quantitative and qualitative High Performance Liquid Chromatography (HPLC) control of cytotoxic preparations carried inside our pharmacotechnic unit. A 100 microl sample of each preparation was assayed by HPLC with ultraviolet/visible-diode array detection, which enabled the identification of all cytotoxic agents thanks to their characteristic UV spectra. We developed rapid and specific HPLC assays that determined qualitatively and quantitatively the presence of 21 different cytotoxic agents in less than 3.5 min. A fifteen per cent tolerance from the theoretical concentration was chosen in agreement with preparation and dosage bias, and a first period control of more than 4400 preparations revealed that around 7.7% preparations did not conform. The main objective of these controls was to avoid the administration of defective chemotherapies to patients and finally to use their results to identify error factors; as a result we will take corrective measures in order to reduce error frequency.

Diffusion of ertapenem into bone and synovial tissues.

OBJECTIVES: The degree of penetration of an antibiotic into the infected site is an important criterion for therapeutic success. Ertapenem is a new carbapenem, exhibiting activity against most Gram-positive and Gram-negative aerobic and anaerobic bacteria commonly recovered from community-acquired infections. However, no studies concerning its diffusion into bone and synovial tissue are available. Our objective was to quantify ertapenem bone and synovial tissue penetration and to compare our data with the MIC(90)s for causative pathogens. PATIENTS AND METHODS: In an open-label study, 18 patients who were undergoing elective total hip replacement received a single, parenteral, 1 g dose of ertapenem. One serum, one cortical and cancellous bone and one synovial tissue sample was collected per patient a median [interquartile range (IQR)] of 1.6 (1.5-1.7), 12.4 (11.9-13.1) or 23.8 h (22.6-25.2) later and analysed by HPLC. RESULTS: The median (IQR) serum concentrations of ertapenem were 70.1 (56.1-75.9), 10.0 (9.1-11.2) and 2.6 mg/L (2.3-3.0), respectively, at the different time points. The median (IQR) cancellous bone tissue concentrations were 13.2 (10.2-14.8), 1.9 (1.7-2.1) and 0.6 microg/g (0.4-0.6) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.19 (0.18-0.23). The median (IQR) cortical bone tissue concentrations were 8.0 (6.5-9.5), 1.3 (1.2-1.3) and 0.3 microg/g (0.3-0.4) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.13 (0.12-0.14). The median (IQR) synovial tissue concentrations were 26.2 microg/g (22.7-28.4), 4.0 mg/L (3.7-4.4) and 1.0 mg/L (0.9-1.2) at the different time points, corresponding to a median (IQR) tissue/serum penetration ratio of 0.41 (0.39-0.42). CONCLUSIONS: The concentrations after an ertapenem 1 g dose achieved in cancellous and cortical bone tissue and in synovial tissue were greater than the MIC(90)s for most aerobic organisms for 24 h, and for 12 to 24 h for anaerobic bacteria in healthy volunteers undergoing total hip replacement.

Diffusion of levofloxacin into bone and synovial tissues.

OBJECTIVES: The degree of penetration of an antibiotic into the infected site is an important determinant of therapeutic success. Levofloxacin is widely used in the treatment of serious infections. However, there are only few studies concerning its diffusion into bone tissue and none concerning its diffusion into synovial tissue. Our objective was to quantify levofloxacin bone and synovial tissue penetration and to compare our data with the breakpoint for susceptible organisms. PATIENTS AND METHODS: In an open-label study, 12 subjects who were undergoing elective total hip replacement received a single, parenteral, 500 mg dose of levofloxacin. Plasma, cortical and cancellous bone, and synovial tissue samples were collected a mean of 1.2 h later and analysed by a validated HPLC method. RESULTS: The mean +/- S.D. plasma concentration of levofloxacin at the time of bone removal was 7.5 +/- 1.3 mg/L. The levofloxacin concentrations were 7.4 +/- 2.2 mg/kg in cancellous bone tissue and 3.9 +/- 1.2 mg/kg in cortical bone tissue. The levofloxacin concentration was 8.9 +/- 2.1 mg/kg in synovial tissue. The mean +/- S.D. ratios of levofloxacin concentration in bone and plasma (bone/plasma) were 1.0 +/- 0.4 for cancellous bone tissue and 0.5 +/- 0.1 for cortical bone tissue. The ratio of levofloxacin concentration in synovial tissue and plasma (synovial tissue/plasma) was 1.2 +/- 0.4. CONCLUSIONS: The concentrations of levofloxacin achieved in cancellous and cortical bone tissue and in synovial tissue are greater than the breakpoint for susceptible organisms, which is < or =2 mg/L.

Determination of levofloxacin in plasma, bronchoalveolar lavage and bone tissues by high-performance liquid chromatography with ultraviolet detection using a fully automated extraction method.

The aim of this study was to develop a specific and sensitive high-performance liquid chromatographic (HPLC) assay for the determination of levofloxacin in human plasma, bronchoalveolar lavage and bone tissues. The sample extraction was based on a fully automated liquid-solid extraction with an OASIS cartridge. The method used ultraviolet detection set at a wavelength of 299 nm and a separation with a Supelcosil ABZ+ column. The assay has been found linear over the concentration range 0.25-25 microg/ml for levofloxacin in plasma, 1-6 microg/ml in bronchoalveolar lavage and 0.5-10 microg/g for bone tissues and it provided good validation data for accuracy and precision. The assay will be applied to determine the penetration of levofloxacin in human bronchoalveolar lavage (BAL) and bone tissues during pharmacokinetic steady state.

Diffusion of cefepime into cancellous and cortical bone tissue.

The degree of penetration of an antibiotic into the infection site is an important factor in its therapeutic efficacy, particularly in bone and joint infections. In the present study, we examined the bone tissue penetration of cefepime at a dose of 2 g, and the results were correlated to microbiological data to estimate the clinical efficacy of cefepime in bone infections. In this open-label, single-arm, noncomparative study, subjects of similar age, body weight, height and creatinine clearance who were undergoing elective total hip replacement received a single, parenteral 2 g dose of cefepime. Plasma samples were collected simultaneously with bone tissue samples 1.5 hours later, on average, and analyzed by a validated high performance liquid chromatography assay. Ten patients (7 women and 3 men; mean age, 78 years; mean body weight, 57 Kg; mean creatinine clearance, 56 mL/min) were enrolled. The mean +/- SD plasma concentration of cefepime at the time of bone removal was 72.9 +/- 24.4 microg/mL. The mean +/- SD cefepime concentrations were 73.5 +/- 16.2 microg/mL in cancellous bone tissue and 67.7 +/- 17.0 microg/mL in cortical bone tissue. The mean +/- SD ratios of cefepime concentration in bone and plasma (bone/plasma) were 1.06 +/- 0.23 for cancellous bone tissue and 0.87 +/- 0.37 for cortical bone tissue. Cefepime exhibits an excellent diffusion into bone tissue, with concentrations achieved in both cancellous and cortical bone tissue greater than the minimum concentrations required to inhibit the growth of 90% of strains (MIC90) of most of the susceptible pathogens commonly involved in bone infections.

Diffusion of oral and intravenous 400 mg once-daily moxifloxacin into lung tissue at pharmacokinetic steady-state.

The degree of penetration of an antibiotic into the infection site is an important factor for its therapeutic efficacy, particularly in respiratory tract infections. In the present study, we examined the lung tissue diffusion of moxifloxacin at a dose of 400 mg administered intravenously or orally once-daily, and the results were correlated to microbiological data to estimate the clinical efficacy of moxifloxacin in lower community-acquired respiratory infections. This was a prospective, randomized, parallel-group trial, open-label, single-center study. Patients undergoing lung surgery for bronchial cancer which necessitates the removal of an anatomical piece of lung tissue were randomized into twelve treatment groups, dependent upon the time of surgery and the moxifloxacin formulation, i.v. or oral, administered. During surgery, one blood sample was taken at the time of tissue collection to determine moxifloxacin plasma concentration. At the same time, tissue samples were taken by pulmonary exeresis. A validated new high performance liquid chromatography assay was used to determine moxifloxacin concentrations in plasma and lung tissue. A total of 49 patients (25 for i.v. administration, 24 for oral administration, 44 men and 5 women, mean age, 61 years, mean body weight, 72 kg, mean creatinine clearance was 84 ml/min/1.73 m2) were enrolled. The mean +/- SD steady-state moxifloxacin ratios between lung and plasma concentrations were respectively: 3.53 +/- 1.89 and 4.36 +/- 1.48 for i.v. and oral administration. The mean steady-state moxifloxacin maximal lung concentrations (Cmax) were respectively 12.37 microg/g and 16.21 microg/g for i.v. and oral administration. Moxifloxacin both intravenously and orally exhibits high penetration in lung tissue, with tissue concentrations far above the MIC90s for most of the susceptible pathogens commonly involved, thus underlining its suitability for the treatment of community-acquired, lower respiratory tract infections.

[Neurosurgical and endovascular treatment of intracranial aneurysms: a cost analysis of two different strategies at the University Hospital of Bordeaux (France)]. / Traitement neurochirurgical et endovasculaire des anévrismes intracrâniens. Approche économique de deux alternatives thérapeutiques sur le CHU de Bordeaux.

BACKGROUND: Rupture of intracranial aneurysms causes major mortality and morbidity. Moreover, treatment of this vascular malformation generates high medical costs. We compared the cost of two different strategies employed at the University of Bordeaux to prevent aneurysms from rebleeding: a classical neurosurgical technique consisting in clipping the neck of the aneurysm and a new less invasive neuroradiological technique based on embolization using platinum coils. METHOD: A micro-cost study was carried out retrospectively from May 1998 to June 2000) comparing data from 44 patients admitted for ruptured intracranial aneurysm: 22 operated patients and 22 patients treated with an endovascular approach. Each operated patient was matched with an embolized patient for clinical status at admission (World Federation of Neurological Surgeons Scale) and complications resulting from cerebral hemorrhage (hydrocephalus, vasospasm, rebleeding). RESULTS AND CONCLUSION: Our results showed the same cost for the same efficiency . Expenditures are however made differently. The endovascular technique allows a shorter hospital stay (8 days less), balancing the high cost of single use medical supplies (coils, microcatheters.). The endovascular technique has many advantages for the patients, but cannot be successful in all types of intracranial aneurysms. Both techniques remain indispensable.

Diffusion of isepamicin into cancellous and cortical bone tissue.

The degree of penetration of an antibiotic into the infection site is an important factor in its therapeutic efficacy, particularly in bone and joint infections. In the present study, we examined the bone tissue penetration of isepamicin at a dose of 15 mg/Kg, and the results were correlated to microbiologic data to estimate the clinical efficacy of isepamicin in bone infections. In this open-label, single-arm, noncomparative study, subjects of similar age, body weight, height and creatinine clearance who were undergoing elective total hip replacement received a single, parenteral 15 mg/Kg dose of isepamicin. Plasma and bone tissue samples were collected a mean 1.3 hours later and analyzed by a high-pressure liquid chromatography method. Twelve patients (3 men and 9 women; mean age, 73.5 years; mean body weight, 53.5 Kg, mean creatinine clearance, 58.5 mL/min) were enrolled. The mean +/- SD plasma concentration of isepamicin at the time of bone removal was 43.0 +/- 10.4 microg/mL. The mean +/- SD isepamicin concentrations were 11.6 +/- 7.1 microg/mL in cancellous bone tissue and 12.0 +/- 7.3 microg/mL in cortical bone tissue. The mean +/- SD ratios of isepamicin concentration in bone and plasma (bone/plasma) were 0.28 +/- 0.14 for cancellous bone tissue and 0.31 +/- 0.20 for cortical bone tissue. The concentrations achieved in both cancellous and cortical bone tissue were greater than the minimum concentrations required to inhibit the growth of 90% of strains (MIC90) of most of the susceptible pathogens commonly involved in bone infections.

Population pharmacokinetics of cisapride in neonates.

OBJECTIVES: We conducted a population pharmacokinetic analysis of cisapride in neonates to study whether metabolic immaturity in this population may lead to increased concentrations. METHODS: Cisapride was administered orally in 91 neonates at the dose of 0.2 mg/kg four times a day. Plasma concentrations were measured using a validated HPLC method. A one-compartment model with first-order absorption was fitted to the data using NONMEM software. RESULTS: One to seven plasma samples were obtained from neonates aged 7-123 days. Cisapride concentrations ranged from 5.5 ng/mL to 172 ng/mL and were not higher than those reported in adults. The absorption constant rate was fixed to 2.5 h-1. Clearance (CL/F) and volume of distribution (V/F) both significantly correlated to weight (WT), but addition of this covariate in V/F did not improve the objective function after it was added in the CL/F covariate model. Prematurity, postnatal age, or coadministered drugs did not affect cisapride clearance. Final population pharmacokinetic parameters (interindividual variability) were: V/F=17,200 mL (90.4%) and CL/F=3.91 x WT(3/4) mL/h (36.3%). CONCLUSIONS: Our finding that cisapride clearance is primarily influenced by weight is in agreement with current recommendations of weight-adjusted doses. This study indicates that no clinically relevant maturational changes in cisapride clearance have to be considered during the first quadrimester of life.

Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro.

The synthetic pentasaccharide, fondaparinux, is the first of a new antithrombotic class: selective factor Xa inhibitors. Comparative clinical trials of fondaparinux versus heparins in prevention and treatment of venous thromboembolism are ongoing. Little is known about fondaparinux during pregnancy, as women of child-bearing potential were excluded from clinical trials. No particular safety issue, for either mother or fetus, has been reported for heparins. The objective of this study was to compare in vitro the steady state placental transfer of fondaparinux and enoxaparin at the plasma concentrations reached during acute treatment of venous thromboembolism (1.75 microg/mL and 1 anti-Xa IU/mL respectively), using antipyrine (20 mg/L) as reference. No biological activity was detectable in the fetal venous effluent during perfusion of enoxaparin-antipyrine, fondaparinux-antipyrine or control media. Furthermore, fetal venous samples did not differ significantly from fetal arterial samples. This apparent absence of placental transfer supports further evaluation of fondaparinux in pregnant women.

Pharmacokinetic parameters of ciprofloxacin (500 mg/5 mL) oral suspension in critically ill patients with severe bacterial pneumonia: a comparison of two dosages.

The authors determined the pharmacokinetic parameters of a new immediate-release ciprofloxacin suspension in tube-fed intensive care patients with bacterial pneumonia, to compare two dosage regimens: 500 mg b.i.d and 750 mg b.i.d. in this prospective clinical trial. The 20 patients were critically ill and on mechanical ventilation and enteral feeding with bacterial pneumonia. They were randomized to receive two different ciprofloxacin dosages: 500 mg b.i.d (group 1) versus 750 mg b.i.d. (group 2). Blood samples were collected from these patients after reaching steady-state and the pharmacokinetic parameters were determined. The mean (range) serum steady-state concentration at 2 h after enteral administration was: C(max 500) = 2.6 (1.2-4.3) mg/L in group 1 and C(max 750) = 3.5 (1.5-5.9) mg/L in group 2. The mean (range) calculated 12-h area under the serum concentration was high in both groups: AUC(0-12 (500)) = 24.7 (12.9-36.2) mg.h/L in group 1 and AUC(0-12 (750)) = 28.9 (18.3-47.5) mg.h/L in group 2. In conclusion, ciprofloxacin oral suspension was well absorbed via nasogastric route in intensive care patients with severe pneumonia, achieving reliable pharmacokinetic parameters for most of the pathogens and important cost reduction compared to intravenous delivery. However, with less susceptible pathogens such as Staphylococcus aureus or Pseudomonas aeruginosa, higher dosages than 750 mg b.i.d. should be given.

Penetration of piperacillin/tazobactam (4 g/500 mg) into synovial tissue.

The degree of penetration of an antibiotic into the infected site is an important criterion for therapeutic success. This is particularly true for bone and joint infections. The association of piperacillin and tazobactam has been widely used in the treatment of serious infections including bone infections, but no study has been devoted to the subject of its diffusion into synovial tissue. Our objective was to quantify piperacillin/tazobactam synovial tissue penetration and to estimate the efficacy of the association against the microorganisms usually encountered in joint infections. In an open-label study, 6 subjects with similar age, weight, height and creatinine clearance, who were undergoing elective total hip replacement, received a single, parenteral, 4 g/500 mg dose of piperacillin/tazobactam. Plasma and synovial tissue samples were collected and analyzed by a validated HPLC method. The mean concentrations of piperacillin and tazobactam 1.5 h after the initiation of infusion were 69.9 +/- 4.9 microg/mL and 7.7 +/- 0.3 microg/mL, respectively, in plasma and 37.1 +/- 2.1 microg/g and 2.8 +/- 0.4 microg/g, respectively, in synovial tissue. The synovial tissue/plasma ratios were 0.5 +/- 0.0 for piperacillin and 0.4 +/- 0.0 for tazobactam. The piperacillin/tazobactam ratios were 9.1:1 in plasma and 13.5:1 in synovial tissue. The concentrations achieved in synovial tissue are above the MICs of most of the susceptible pathogens usually involved in joint infections, which suggests that the piperacillin/tazobactam combination should be effective in the treatment of most joint infections caused by susceptible microorganisms.

High-performance liquid chromatographic separation of fluoroquinolone enantiomers: a review.

Fluoroquinolones are antibacterial agents widely used clinically. In recent years, there has been an important development of new derivatives, and more than 7000 analogues have been described today. Different fluoroquinolones (FQ) have one or two chiral centers in their chemical structure and are available as racemates, diastereoisomers, or pure enantiomers. The clinical and pharmaceutical uses of these compounds need effective analytical procedures for quality control and pharmacodynamic and pharmacokinetic studies. This review article focuses on the high-performance liquid chromatographic separation of fluoroquinolone stereoisomers by the use of derivatization methods and ligand exchange (LE) or chiral liquid chromatography.

Placental transfer of SR49059 in the human dually perfused cotyledon in vitro.

SR49059 is an antagonist of vasopressin V(1a)receptors currently developed as a tocolytic drug. We investigated the transplacental transfer of SR49059 in vitro using the single pass dually perfused human cotyledon model. Thirteen placentae were collected from normal term pregnancies immediately after delivery. The placental transfer of SR49059 was tested at steady state at three different concentrations (100 ng/ml, 200 ng/ml and 500 ng/ml) along with that of antipyrine 20 mg/l as a reference substance. Concentrations were assayed by liquid chromatography with UV (antipyrine) or mass spectrometry (SR49059) detection. At steady state, the mean+/-s.d. fetal transfer rate of SR49059 was 10.80+/-4.33 per cent, 9.34+/-4.41 per cent, and 11.78+/-3.26 per cent at 100 ng/ml, 200 ng/ml and 500 ng/ml, respectively. The corresponding clearance indices were 0.29+/-0.14, 0.25+/-0.08, and 0.31+/-0.06, respectively. The absence of saturation kinetics is consistent with a passive mechanism of transfer. Moderate amounts of SR49059 are transferred from the maternal to the fetal circulation. The clearance index of SR49059 appeared to be very similar to that of ritodrine, which is currently used as a tocolytic.

Pharmacokinetics and resistance mutations affect virologic response to ritonavir/saquinavir-containing regimens.

The authors assessed the impact of protease and reverse transcription (RT) mutations and individual pharmacokinetic parameters on virologic response to a four-drug regimen including ritonavir/saquinavir. Treatment was given at the start of the study (M0) to 22 HIV-1 protease inhibitor-naive or pretreated patients. Protease and RT genes were sequenced at M0, at the time of virologic failure, or at the end of the follow-up. Plasma ritonavir and saquinavir peak C(max), C(min), and area under the curve (AUC) were determined based on samples taken 0, 1, 2, 3, 4, 6, 8, and 12 hours after administration. HIV-1 RNA decreased to less than 50 copies/mL in 11 patients (group 1). At M0, five of them had no RT mutation and 10 had three or fewer secondary protease mutations with no new mutation during follow-up. Ritonavir and saquinavir pharmacokinetics showed wide interindividual variability. Treatment failed in 11 patients (group 2): 9 had three to eight protease mutations and a mean of 5.8 RT mutations at M0, with emergence of new mutations during follow-up. Pharmacokinetics was similar to those of group 1. The other two patients with virologic failure showed no baseline primary mutation but were the only patients with insufficient saquinavir and ritonavir AUC. The authors showed the complementarity between drug-resistance genotype and individual pharmacokinetics and the potential utility of AUC and Cmax to manage treatment.

A randomized study comparing blood glucose control and risk of severe hypoglycemia achieved by non-programmable versus programmable external insulin pumps.

OBJECTIVE: To compare a non-programmable and a programmable insulin external pump using regular insulin on glycemic stability, the risk of severe hypoglycemia and metabolic control in type 1 diabetic patients. MATERIAL AND METHODS: Ten type 1 diabetic patients were involved in a randomized, crossover study comparing two periods of 3 months with continuous subcutaneous insulin infusion (CSII) either with a non-programmable insulin pump or a programmable insulin pump. Comparisons were made among mean blood glucose values before and after meals, at bedtime and at 2: 00 a.m.; the risk of severe hypoglycemia assessed by the low blood glucose index (LBGI); and HbA1c. RESULTS: Mean average blood glucose (BG) measurements were significantly lower with the programmable in comparison with the non-programmable insulin pump (respectively 157+/-78 vs. 165+/-79, p=0.034). While postprandial values for BG were not different between the two pumps, the use of the programmable pump resulted in a significant decrease in mean preprandial BG levels (140+/-68 vs. 150+/-73 mg/dl p=0.039). Conversely mean BG level was lower at 2 a.m. with the non-prgrammable pump (125+/-81 vs. 134 +/-93 mg/dl, p=0.02) but with a higher incidence of hypoglycemia. Mean LBGI was comparable with the two pumps (3.1+/-8.6 vs. 2.8+/-6.9, p=0.1). There was a 0.2% decrease in HbA1c during the programmable pump period that did not reach statistical significance (p=0.37). CONCLUSIONS: The present study suggests that programmable external insulin pumps, although more complex and more expensive than non-programmable insulin pumps, significantly reduce fasting glycemia during the day without increasing the risk of severe hypoglycemia and are safer during the night.

Uptake of quinolones by in-vitro human monocyte derived macrophages.

We have developed an in-vitro model of monocyte-derived macrophage (MDMphi) to compare fluoroquinolone uptake in monocytes and derived macrophages. Monocyte-derived macrophages were obtained in-vitro by cultivating freshly isolated monocytes for seven days in RPMI 1640 medium, containing foetal calf serum and Rhu granulocyte-macrophage colony stimulating factor. Final suspensions contained 95% viable cells and 63% macrophages. Intramacrophagic accumulation of ciprofloxacin, ofloxacin or sparfloxacin was measured at equilibrium after 30-min incubation in the presence of 16-18 microg mL(-1) antibiotic. The results revealed low intracellular accumulation of ofloxacin in MDMphi (intracellular/extracellular ratio: IC/EC = 1.7). Ciprofloxacin and sparfloxacin uptake was significantly higher. The IC/EC ratios were only slightly increased in macrophages when compared with monocytes under the same experimental conditions. These results suggest that maturation of monocyte to macrophage has only a limited effect on basal quinolone uptake. Monocytic maturation cannot explain the important differences between fluoroquinolone accumulation in monocytes and tissue macrophages. Cell activation may be a greater determinant.