A new pharmacokinetic model for 90Y-ibritumomab tiuxetan based on 3-dimensional dosimetry.

Monoclonal antibodies (mAbs) are key components in several therapies for cancer and inflammatory diseases but current knowledge of their clinical pharmacokinetics and distribution in human tissues remains incomplete. Consequently, optimal dosing and scheduling in clinics are affected. With sequential radiolabeled mAb-based imaging, radiation dosing in tissues/organs can be calculated to provide a better assessment of mAb concentrations in tissues. This is the first pharmacokinetic model of 90Y-Ibritumomab tiuxetan (90Y-IT) in humans to be described, based on three-dimensional (3D) dosimetry using single-photon emission computed-tomography coupled with computed-tomography. 19 patients with follicular lymphoma were treated initially with 90Y-IT in the FIZZ trial. Based on a compartmental approach individualising the vascular compartment within studied organs, this study proposes a reliable pharmacokinetic (PK) five-compartment model replacing the currently used two-compartment model and constitutes a new direction for further research. This model provides exchange constants between the different tissues, Area Under the Curve of 111In-IT in blood (AUC) and Mean Residence Time (MRT) that have not been reported so far for IT. Finally, the elimination process appears to occur in a compartment other than the liver or the spleen and suggests the metabolism of mAbs may take place mainly on the vascular compartment level.

Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid.

Ibrutinib is an orally administered first-in-class irreversible Bruton's tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 × 2.1 mm; 1.7 µm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 µL·min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng·mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng·mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% α-risk (ß = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at ±25% for the LLOQ and ±15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples.

Prospective assessment of patients' knowledge and informational needs and of surgeon-to-patient information transfer before and after knee or hip arthroplasty.

BACKGROUND: Patients are playing an increasingly large role in their own management and must therefore receive clear, complete, and comprehensible information. In the field of hip and knee arthroplasty, little is known about the level of patient knowledge and effectiveness of surgeon-to-patient information transfer. We therefore designed a prospective observational study with the objective of assessing four factors: patient knowledge during management, quality of information transfer, informational needs, and factors associated with the level of knowledge. HYPOTHESIS: The level of patient knowledge changes during the management process. PATIENTS AND METHODS: A prospective single-centre study was conducted between January 2014 and March 2015 during the outpatient visits and inpatient stays of 63 patients who underwent arthroplasty of the hip (n=36) or knee (n=27). A single observer attended all patient visits and recorded the information provided by the surgeon. Each patient completed a self-questionnaire after the outpatient visit (T1), at admission (T2), and at discharge after surgery (T3). Semi-quantitative scores were used to assess knowledge and informational needs. The effectiveness of information transfer was evaluated by comparing the information provided by the surgeon to the replies made by the patients. RESULTS: The mean overall knowledge score (on a 0-42 scale) increased from 17.22±6.33 at T1 to 19.44±6.89 at T3 (P=0.0028). In contrast, knowledge about complications was better at T1 than at T3 (2.67±1.98 vs. 2.19±1.91; P<0.05). Agreement between information given by the surgeon and replies made by patients varied across items from 23% to 100%. The mean informational needs score (on a scale from 0 to 21) ranged from 3.67 to 4.83 and was higher at T3 than at T2 (4.83±3.77 vs. 3.67±4.86; P=0.03). The proportion of patients who wanted written information was higher at T3. Most patients sought information before the outpatient visit. At each step of the management process, the main areas about which the patients wanted information were the surgical procedure, the rehabilitation programme, and the prosthesis. Several socio-demographic or management-related factors influenced the level of knowledge. Thus, older age and lower educational attainment were associated with lower knowledge scores, whereas previous lower-limb orthopaedic surgery and amount of information provided by the surgeon were associated with higher knowledge scores. Knowledge scores were not associated with being employed vs. retired, gender, replacement of a hip vs. a knee, the surgeon, or being accompanied by another person. DISCUSSION: Our study is original in that we assessed changes in patient knowledge during the management process for hip or knee arthroplasty. The level of patient knowledge was fairly low and varied considerably across individuals and time points in the management process. These data highlight the importance of providing patients with information throughout their management and particularly at discharge, when the desire for information seems greatest. LEVEL OF EVIDENCE: IV, prospective observational study with no control group.

Evaluation of Pentravan®, Pentravan® Plus, Phytobase®, Lipovan® and Pluronic Lecithin Organogel for the transdermal administration of antiemetic drugs to treat chemotherapy-induced nausea and vomiting at the hospital.

The objective of this study was to evaluate five commercial ready-to-use transdermal vehicles (Phytobase®, Lipovan®, Pentravan®, Pentravan® Plus and Pluronic Lecithin Organogel (PLO)), for the compounding of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) and their administration in combination to treat chemotherapy-induced nausea and vomiting (CINV) at the hospital. Drugs were individually formulated in these vehicles and in mixture in Pentravan® Plus using different penetration enhancers. Quality control of the forms has demonstrated that formulation process was mastered and convenient for the hospital (time required: 20min). Diffusion experiments through synthetic membranes and pig ear epidermis performed using Franz-type diffusion cells, have shown that the release and permeation process were greater for ondansetron than for dexamethasone and aprepitant, with a release step not limiting. As permeation of aprepitant was too low, it was discarded of the study. When ondansetron and dexamethasone were compounded in combination in Pentravan® Plus, the most efficient vehicle, a permeation decrease was observed. Finally, the use of tween 20 instead of EtOH as chemical enhancer has led to 2-fold factor increase in the flux of dexamethasone, resulting in fluxes convenient for transdermal administration of ondansetron to a child, but insufficient for an adult and for dexamethasone.

[Preliminary assessment of the use of portable hydrogen peroxide detectors in a centralized cytotoxic preparation unit]. / Évaluation préliminaire de l'utilisation de détecteurs individuels portatifs de peroxyde d'hydrogène au sein d'une unité de préparation centralisée de médicaments cytotoxiques.

INTRODUCTION: For 1 year, our unit has been equipped with portable H2O2 Dräger detectors contributing to protect the staff from a possible exposure to this odourless and toxic gas. This work shows the current available data about H2O2 toxicity, describes the organization of the implementation and the analysis of the values measured over 12 months. MATERIAL AND METHODS: Data about H2O2 toxicity have been obtained through a literature review. The measured values are presented in instantaneous value and occupational exposure limit (OEL) over 8 h. RESULTS: Over six technicians, the average percentage, of detected values superior to zero reached 1.06% in August. The detected maximum instantaneous value reached 2.2 ppm in May. These isolated exposures have little incidence when related to the 8-h exposure with an occupational exposure limit (OEL) of 0.072 ppm over 12 months. DISCUSSION AND CONCLUSION: The implementation of this tool has allowed to highlight a technical problem of the sterilization airlock that could be resolved. This measuring device of H2O2 concentration in the air in real time allows to secure everyday working conditions and to alert the staff of a possible technical failure. However, literature data regarding chronic toxicity are limited and restrict the analysis of the measured values.

[Major haemodynamic incident during continuous norepinephrine infusion: Beware of the infusion line. An avoidable postoperative hypertensive peak?]. / Incident hémodynamique majeur pendant une perfusion continue de noradrénaline : attention à la ligne de perfusion. Un pic hypertensif postopératoire évitable ?

The restoration of patients' mean arterial pressure after ineffective fluid resuscitation is obtained by vasopressive treatment such as norepinephrine. However, no guidelines exist concerning a norepinephrine infusion method: whether it be the norepinephrine concentration in the syringe, single or double pump administration via a carrier such as an isotonic saline solution, or use of minimized dead-volume extension sets. We present the case of a female patient requiring norepinephrine treatment, who quickly suffers a major haemodynamic incident (a sudden rise in systolic blood pressure above 220 mmHg associated with tachycardia up to 189 b/min). The main causes of this incident are discussed and infusion parameters considered with a view to developing an optimal infusion method for a drug with a specific therapeutic index.

Chronic dialysis-associated anaemia in end-stage renal disease: analysis of management in two French centres.

BACKGROUND: Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients. METHODS: Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other. RESULTS: A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs. CONCLUSION: The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary.

Gemtuzumab ozogamicin-induced sinusoidal obstructive syndrome treated with defibrotide: a case report.

New treatments for relapse of acute myeloid leukaemia (AML), include gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody. We describe a second case of GO-induced sinusoidal obstructive syndrome (SOS) effectively treated with defibrotide (DF). No stem-cell transplantation was involved. On day 23 after the first GO dose, a patient presented with ascites, weight gain, liver enlargement and pain in the right upper quadrant. Sudden hepatic cytolysis (transaminases at six times the normal range: grade 3) and cholestasis [alkaline phosphatase ALP and gamma-glutamyltransferase (GGT) respectively at four and eight times the normal range: grade 2] were observed but there was no evidence of increase serum bilirubin. Treatment with DF (Prociclide), Crinos; 10 mg/kg/day, or 200 mg, q.i.d.) improved the hepatic abnormality within a few days (serum transaminases decreased from 312 to 103 IU/L for aspartate aminotransferase (AST) and from 141 to 80 IU/L for alanine aminotransferase (ALT) within 3 days ALP increased from 253 to 383 IU/L and gamma-GT from 238 to 417 IU/L 4 days after administration of DF. The clinical and biological features of our case suggest a direct involvement of GO in causing SOS, even when used as monotherapy, without allogenic stem-cell transplantation. Low dose DF (10 mg/kg/day) given early during the development of SOS associated with GO was effective. Unfortunately, in our case the patient eventually died of multi-organ failure probably because of failure of GO.

[Spontaneously acquired haemophilia: report of a patient with prostatic adenoma]. / Hémophilie A acquise secondaire à un adénome prostatique.

We report the case of a 86-year-old man admitted in a local hospital with spontaneous haematoma, an isolated prolonged activated partial prothrombin time (114/32 seconds; ratio = 3.6), an anemia and a normal platelet count. Two diagnosis were suspected: a coagulation factor defect, or the presence of a lupus anticoagulant or of anti-factor antibodies. An acquired haemophilia A was confirmed with a factor VIII activity level < 1 U/dL associated with the presence of an anti-factor VIII inhibitor. The factor VIII inhibitor titer reached 195 Bethesda U/mL. A prostatic adenocarcinoma was suspected: a 5 cm prostatic tumour was found and the PSA level was 113 ng/mL. The patient was treated with recombinant factor VIIa: Novoseven (90 microg/kg). None immunosuppressive agents were prescribed in this elderly patient. The patient's disease was identified as a spontaneously acquired haemophilia A associated with prostatic adenocarcinoma.

Omeprazole-induced leukopenia. A case report.

BACKGROUND: Omeprazole has been marketed in France since 1989, for the healing of peptic ulcers, erosive reflux oesophagitis, and the Zollinger-Ellison syndrome. However, the drug has been associated with serious adverse reactions, including haemolytic anaemia and acute interstitial nephritis. More recently, an autoimmune syndrome induced by omeprazole has been described. OBJECTIVE: We present here a clinical history and an in vitro test of cytotoxicity linking leukopenia to omeprazole. RESULTS: A 37-year-old woman was hospitalized in the intensive care unit of our hospital with acute pulmonary insufficiency secondary to pneumonia. 72 h after starting omeprazole treatment, a decrease in leucocyte count was observed. The leukopenia was maximal on day 22: total white cell count was 2. 1x109/l, and neutrophil count was less than 0.75x109/l. In order to find the cause of this leukopenia, an in vitro cytotoxicity test was performed. The test was positive only when patient neutrophils and patient serum were in the presence of omeprazole. This cytotoxicity seems to be complement-dependent, as in the presence of heated serum, the omeprazole toxic effect was substantially reduced. CONCLUSION: This case report suggests that the leukopenia was associated with omeprazole.