The efficacy of fluticasone furoate administered in the morning or evening is comparable in patients with persistent asthma.

BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) is efficacious as a once-daily treatment for the management of asthma. Asthma is associated with circadian changes, with worsening lung function at night. We compared the efficacy of once-daily FF in the morning or evening for the treatment of asthma. METHODS: Adults with persistent bronchial asthma were enrolled into this randomised, repeat-dose, double-blind, double-dummy, placebo-controlled, three-way crossover study. After a 14-day run-in period, patients received either: FF 100 µg in the morning (AM); FF 100 µg in the evening (PM); or placebo, via the ELLIPTA(®) dry powder inhaler. Patients received all three treatments (14 ± 2 day duration) separated by a 14- to 21-day washout period. The primary endpoint was 24-h weighted mean forced expiratory volume in 1 s (FEV1) measured at the end of each 14-day treatment. RESULTS: A total of 28 patients aged between 19 and 67 years were randomised and 21 (75%) completed all three study arms. Once-daily administration of FF 100 µg resulted in an increased 24-hour weighted mean FEV1; differences between the adjusted means for AM and PM FF dosing versus placebo were 0.077 L (90% confidence interval [CI]: 0.001, 0.152) and 0.105 L (90% CI: 0.029, 0.180), respectively (adjusted mean difference: -0.028 L [90% CI: -0.102, 0.045]). AM or PM doses had comparable incidences of adverse events (AEs; 18/23 versus 18/24, respectively), no serious AEs occurred. CONCLUSION: AM and PM doses of once-daily FF 100 µg produced comparable improvements in lung function relative to placebo.

Mid-dilution: the perfect balance between convection and diffusion.

Although hemodiafiltration (HDF) offers the advantage of increased convective clearance for middle molecules, there is still controversy as to whether reinfusion should occur pre- or post-filter. Mid-dilution hemodiafiltration (MD HDF) is a new HDF technique that uses a special dialyzer, MD190, which allows both pre- and post-reinfusion. While externally the dialyzer looks similar to conventional hemodialyzers, the internal fibers are divided into two bundles by a special annular header that first lets the blood pass through the peripheral bundle in post-dilution, mix with the reinfusion fluid at the opposite end of the dialyzer and then proceed (after pre-dilution) to the dialyzer blood exit. The dialyzer is able to support substantially higher reinfusion rates (10-12 l/h). We have compared the removal characteristics of several small solutes and larger middle-molecular-weight toxins by examining instantaneous clearance at 45 min, the dialysis reduction ratio and total mass removal (by spilling) in a three-center prospective cross-over study. Twenty patients were randomized to a treatment sequence of one-week high-flux bicarbonate hemodialysis (HD) followed by MD HDF, or vice versa. The parameters evaluated included urea, creatinine, beta2-microglobulin, angiogenin, leptin, retinol-binding protein, and the effects on sodium, potassium, bicarbonate and calcium. Blood flow rates ranged between 300-450 ml/min (mean 359 +/- 44 HD, 367 +/- 35 MD HDF). The mean reinfusion for MD HDF was 166 +/-17 ml/min. MD HDF had a significantly better instantaneous clearance for urea (328 +/- 28 vs 277 +/- 40); creatinine (292 +/- 32 vs. 212 +/- 66); phosphate (324 +/- 38 vs. 242 +/- 63); beta2-microglobulin (249 +/- 27 vs. 100 +/- 24); angiogenin (173 +/- 27 vs. 28 +/- 32); and leptin (202 +/- 29 vs. 63 +/- 43). Treatments were well tolerated with no adverse reactions occurring during any of the treatments. The MD HDF filter's unique configuration is designed to deliver high-efficiency HDF with a significant improvement in small and middle molecule removal. MD HDF supports substantially higher ultrafiltration rates, and as such, results in a higher removal of middle-molecular-weight toxins.

Bradykinin and nitric oxide generation by dialysis membranes can be blunted by alkaline rinsing solutions.

BACKGROUND: Bradykinin (BK) generation following the first contact of blood with the dialysis materials is thought to enhance hypersensitivity reactions (HSRs). Some of the effects of BK are mediated by nitric oxide (NO). We have recently reported that the pH of diluted blood modulates the kinin system. The present study was aimed to investigate the role of the pH of culture media and filter-washing solutions and BK and NO generation, either in vitro and ex vivo. METHODS: BK was measured by a specific enzyme-linked immunosorbent assay (ELISA), and NO synthase (NOS) activity by 3H-citrulline production after incubation with 3H-arginine and nitrites by using the Griess reagent. In in vitro experiments, NOS activity was detected in endothelial cells (ECs) cultured with graded BK concentrations at various pH values. Blood from 30 patients in regular dialysis was ex vivo circulated in one single passage through minifilters prerinsed with pH 7 or pH 8 phosphate buffer (PB) solutions. The out-flowing blood was tested for BK and nitrite content and was incubated with cultured ECs to evaluate its capacity to modulate NOS activity. RESULTS: BK induced in vitro a dose-dependent increase in NOS activity of ECs, which was mediated by tyrosine kinase phosphorylation. NO generation was enhanced at pH 7.2, which remained unchanged at pH 7.6. In ex vivo experiments, blood out-flowing after one passage on filters washed with pH 7 PB solutions had increased BK levels (P < 0.0001), increased nitrites (P < 0.05), and enhanced EC NOS activity (P < 0. 05) in comparison to data found when filters were washed with pH 8 PB. Only when the filters were rinsed with a solution at pH 7 did PAN DX and AN69 membranes show a distinct BK generation capability, and cuprophane a peculiar capability to enhance NOS. Such effects were prevented when dialyzers were prerinsed with pH 8 PB. Multiple regression analysis showed that the pH of the uremic blood was the driving factor for BK and NOS activation (r = 0.54, P < 0.02). CONCLUSIONS: BK and NO generation are modulated by environmental pH. Rinsing the blood and dialysate compartments of filters with an alkaline solution prior to use may mitigate the activation of mediators likely to be involved in some HSRs.

Activation of the kallikrein-kinin system in hemodialysis: role of membrane electronegativity, blood dilution, and pH.

BACKGROUND: The kallikrein-kinin system activation by contact with a negatively charged surface has been promulgated to be responsible for hypersensitivity reactions. However, to explain the low frequency and heterogeneity of hypersensitivity reactions, we hypothesized that not only the electronegativity of the membrane, but also other physicochemical parameters could influence the activation of the contact phase system of plasma assessed by the measurement of kallikrein activity and bradykinin concentration. METHODS: Plasma kallikrein activity using chromogenic substrate (S2302) and plasma bradykinin concentration (enzyme immuno assay) were measured during the perfusion of human plasma (2.5 ml/min) through minidialyzers mounted with six different membranes [polyacrylonitrile (PAN) from Asahi (PANDX) and from Hospal (AN69), polymethylmethacrylate (PMMA) from Toray, cellulose triacetate (CT) from Baxter, cuprophane (CUP) from Akzo and polysulfone (PS) from Fresenius]. RESULTS: A direct relationship was shown between the electronegativity of the membrane assessed by its zeta potential and the activation of plasma during the first five minutes of plasma circulation. With the AN69 membrane, the detection of a kallikrein activity in diluted plasma but not in undiluted samples confirmed the importance of a protease-antiprotease imbalance leading to bradykinin release during the first five minutes of dialysis. With PAN membranes, the use of citrated versus heparinized plasma and the use of various rinsing solutions clearly show a dramatic effect of pH on the kallikrein activity and the bradykinin concentration measured in plasma. Finally, increasing the zeta potential of the membrane leads to a significant increase of plasma kallikrein activity and bradykinin concentration. CONCLUSIONS: Our in vitro experimental approach evidences the importance of the control of these physicochemical factors to decrease the activation of the contact system.

Low concentrations of glucose degradation products in peritoneal dialysis fluids and their impact on biocompatibility parameters: prospective cross-over study with a three-compartment bag.

The side effects of glucose degradation products (GDPs) in conventional peritoneal dialysis (PD) fluids are well described. Using the three-compartment bag concept--that is, in situ preparation of concentrated glucose solution into a standard ionic solution--a GDP-free solution can be processed. To investigate the possible impact of this product on biological and clinical parameters, we carried out a prospective cross-over study with 31 patients, comparing the short-term effects of conventional PD and GDP-free PD solutions. Classical peritoneal parameters and ultrafiltration rate did not change during the study. After three months and after six months with the three-compartment bag, cancer antigen 125 (CA125) concentration in overnight fluid increased significantly (p < 0.001) from 24.4 IU/mL to 44.4 IU/mL and 41.1 IU/mL respectively. CA125 decreased significantly (p < 0.01) to 21.7 IU/mL after three months with the conventional solution. No change in hyaluronan concentration was observed. A slight increase of procollagen III N-terminal peptide in overnight effluent with the GDP-free solution was followed by a significant reduction after three months with standard solution. In summary, our data show that the GDP-free PD fluid improves mesothelial cell mass and turnover even after a short-term period of three months. A better quality of PD solution is obtained by using the three-compartment bag.

Evaluation of haemodialysis membrane biocompatibility by parallel assessment in an ex vivo model in healthy volunteers.

BACKGROUND: Precise evaluation of the haemocompatibility of prototype membranes, flow configurations and anticoagulant regimens is an essential step in the development of dialysis systems minimizing blood activation. An ex vivo model in humans currently employed in our laboratory has recently been adapted to allow the parallel evaluation of two minimodule dialysers with blood from a single donor, thus eliminating differences due to donor variability in the comparison of test and control dialysis modules. METHODS: The ex vivo flow system is designed to reproduce the haemodynamic conditions of clinical dialysis on a 1/50 scale. A blood line from the forearm vein of the volunteer donor is divided at a Y-shaped junction, two roller pumps assure equivalent blood flow (5 ml/min) in the branches leading to two minimodule dialysers and heparin (0.1 IU/ml final concentration) is injected into each branch immediately after the Y junction. Samples for analysis of blood activation markers are collected at the exits of the two minimodules over a test period of 27 min. In the present series of tests, a new polyacrylonitrile membrane (PAN) was evaluated relative to standard commercial polysulphone (PS), acrylonitrile copolymer (AN 69) and cuprophan (CUP) membranes. RESULTS: A steady minimal level of anticoagulation corresponding to a slightly less than two-fold prolongation of APTT (activated partial thromboplastin time) was maintained throughout testing in both branches of the ex vivo flow system. Time curves for the accumulation of activation markers (thrombin-antithrombin III complexes, prothrombin fragment 1 + 2, platelet beta-thromboglobulin, and complement fragment C3a) showed all four types of minimodule dialyser to induce comparable low levels of activation of coagulation parameters and platelets, together with similar mild activation of complement for AN 69, PAN, and PS dialysers as compared to stronger activation for CUP modules. Overall results thus confirmed the acceptable haemocompatibility of the prototype polyacrylonitrile (PAN) membrane. CONCLUSIONS: Among current methods for evaluation of the biocompatibility of haemodialysis systems, ex vivo flow models in humans avoid problems arising from species differences and may be designed to closely reproduce the conditions of clinical dialysis. A parallel configuration eliminates artefacts due to individual variations in donor response. This not only facilitates the direct comparison of test and control membranes under close to identical experimental conditions, but also provides a model particularly well adapted to studies of the effects of different anticoagulation regimens, flow configurations, and dialysates, or alternative methods of sterilization, rinsing, and priming of the dialysers.

Piperacillin-tazobactam treatment for severe intra-abdominal infections.

In this limited series of 23 patients suffering from severe or life-threatening intra-abdominal infection, piperacillin + tazobactam, together with adequate surgical drainage and resections, cured 78% of our patients and eradicated almost all the pathogens. Side effects included essentially eosinophilia and elevation of transaminases but was never severe. Piperacillin + tazobactam seem thus to be an acceptable treatment, associated with correct surgical drainage. This regimen has to be compared in appropriate trial versus gold standard therapy, such as imipenem, a beta-lactam with aminoglucoside and imidazole or clindamycin or with broad spectrum beta-lactam and other inhibitors or beta-lactamases, but our rate of cure is impressive in such a population.

Minimodule dialyser for quantitative ex vivo evaluation of membrane haemocompatibility in humans: comparison of acrylonitrile copolymer, cuprophan and polysulphone hollow fibres.

Minimodule hollow fibre dialysers, representing clinical dialysis modules on a scale of 1/25, enable quantitative evaluation of the haemocompatibility of hollow fibre membranes in an ex vivo flow system in humans. On line heparinization, adjusted for donor sensitivity, is maintained at a minimal level (approximately 0.14 units/ml). Blood samples collected at the minimodule exit over 30 min are analysed for heparin (anti-Xa activity), activated partial thromboplastin time, fibrinopeptide A, platelet count and beta-thromboglobulin, complement fragment C3a, leucocyte count and polymorphonuclear neutrophil elastase. Initial experiments were performed using well-characterized reference materials: acrylonitrile copolymer (AN 69 HF), polysulphone and cuprophan (CUP). Activation of coagulation and platelets was low for AN 69 HF, intermediate for CUP and greatest for polysulphone, while complement activation was negligible in the presence of AN 69 HF, moderate for polysulphone and most important for CUP. Future applications will be directed towards haemocompatibility screening of prototype membranes with the aim of developing clinical dialysers with improved biocompatibility.

[A phase III trial comparing the antiemetic activity of tetracosactide with dexamethasone in combination with metoclopramide, diphenhydramine and clorazepate during chemotherapy including cisplatin]. / Essai phase III comparant l'activité anti-émétique du tétracosactide à la dexaméthasone employés en association avec le metoclopramide, la diphénhydramine et le clorazépate au cours de chimiothérapies comportant du cisplatine.

In order to compare the safety and the antiemetic effectiveness of tetracosactide (TCS) or beta 1,24 ACTH with those of dexamethasone (DXM) as an adjunct to high-dose metoclopramide, diphenhydramine and clorazepate, 33 patients receiving cisplatin based cancer chemotherapy were enrolled in a double-blind cross-over clinical trial. TCS and DXM were given intravenously, respectively at a dose of 2 mg and 20 mg, and concurrently to the cisplatin infusion. No statistically significant difference was noted between the two drugs with regard to efficacy or side effects. We conclude that TCS can serve as a substitute for DXM in combination antiemetic regimens for management of cisplatin-induced nausea and vomiting.

Randomized study of minocycline + gentamicin compared with metronidazole + gentamicin for prophylaxis or treatment of mixed infections in abdominal surgery.

Seventy patients admitted for abdominal surgery requiring short-term perioperative prophylaxis were randomized to receive minocycline + gentamicin or metronidazole + gentamicin. Thirty patients were considered to be infected at the time of surgery and were treated with the same regimen. In the prophylactic cohort, one patient from each group developed postoperative fever. One patient receiving minocycline developed a wound infection. The overall infection rate was 2.6%. In the treatment cohort, it appeared that the patients receiving metronidazole had more severe underlying diseases than those receiving minocycline. Consequently, more postoperative non-infectious complications were observed in the former. Minocycline + gentamicin appeared at least as effective than metronidazole + gentamicin in preventing postoperative infectious complications associated with abdominal surgery or in treating intra-abdominal infections.

Cis platine (CDDP) in continuous intravenous ambulatory infusion: a new method of administration.

Twenty-three patients with metastatic tumors received multiple chemotherapy regimens which included CIS platine (CDDP) by continuous ambulatory infusion for 4 successive days at a rate of 25 mg/m2/day repeated every 4 weeks. Continuous infusion was provided by an external disposable pump, the "Infusor," which delivers the drug in a volume of 48 ml at a constant rate of 2 ml/hour, in conjunction with oral hydration and antiemetics. No incident detrimental to the patient was recorded. The average duration of the infusions was 23 hr. Only 22% of the patients had minor nausea and vomiting, and 1 case of functional renal insufficiency (4%) was easily corrected by simple intravenous hydration. A randomized study is ongoing to compare continuous perfusion with standard infusion for efficiency, side effects and response rate. Patients with "Infusor" are treated at home under Minitel supervision.

Plasma thrombospondin in patients with chronic renal failure, liver disease and splenectomy.

Thrombospondin (TSP), is a major constituent of human blood platelet alpha-granules. Stimulation of platelets causes the release of TSP in parallel with other alpha-granule constituents such as beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) but the thrombospondin plasma in vivo half life is significantly greater than beta-TG and PF4. The aim of this study was to assay TSP levels in plasma of patients with chronic renal failure (CRF), liver disease (LD) and following splenectomy. The TSP values were then compared to the patients plasma levels of two traditional markers of platelet activation, beta-TG and PF4, and to fibronectin (FN) and von Willebrand factor (VIII:vWF). Plasma TSP levels (67.6 +/- 16.9 ng/ml) assayed in 14 CRF patients were significantly higher (p less than 0.05) than those measured in 28 donors (55.5 +/- 11.7 ng/ml). No correlation was observed, in CRF patients, between the TSP level and PF4 (2.5 +/- 1.5 ng/ml), beta-TG (131.1 +/- 21 ng/ml), FVIII:vWF (252 +/- 85%), or FN (102 +/- 33%) plasma levels. The TSP plasma level in CRF patients was significantly correlated (p less than 0.02) with that of fibrinopeptide A (4.1 +/- 1.9 ng/ml). Although the beta-TG (23.5 +/- 6.9 ng/ml) and PF4 (2.9 +/- 2 ng/ml) plasma levels in six LD patients were normal, the TSP levels (82.5 +/- 39.1 ng/ml) were significantly increased (p less than 0.01). Thrombospondin plasma levels (77.1 +/- 20.1 ng/ml) in 14 patients having undergone splenectomy were significantly increased (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Chemotherapy by ambulatory continuous infusion using a portable pump: a feasibility trial]. / Chimiothérapie en perfusion continue ambulatoire par pompe portable: essai de faisabilité.

43 metastatic cancer patients received 190 portable infusors over 24 hours or more. This portable infusor is a disposable material made by Travenol which operates without outside energy. The drug in an elastomere balloon reservoir is injected about 24 hours at a rate of 2 ml/hour. We used various drugs: CDDP, bleomycin, 5 fluorouracil, aracytine, velbe, voltarene. The patients were under hospital observation and received their treatment without any incident due to the pump itself. The patients who had already been perfused with the usual technique greatly appreciated the comfort of this light portable device. Our next step will permit us to estimate the use of these infusors by patients at home.