Variable viral clearance despite adequate ganciclovir plasma levels during valganciclovir treatment for cytomegalovirus disease in D+/R- transplant recipients.

ABSTRACT: BACKGROUND: Valganciclovir, the oral prodrug of ganciclovir, has been demonstrated equivalent to iv ganciclovir for CMV disease treatment in solid organ transplant recipients. Variability in ganciclovir exposure achieved with valganciclovir could be implicated as a contributing factor for explaining variations in the therapeutic response. This prospective observational study aimed to correlate clinical and cytomegalovirus (CMV) viral load response (DNAemia) with ganciclovir plasma concentrations in patients treated with valganciclovir for CMV infection/disease. METHODS: Seven CMV D+/R- transplant recipients (4 kidney, 2 liver and 1 heart) were treated with valganciclovir (initial dose was 900-1800 mg/day for 3-6.5 weeks, followed by 450-900 mg/day for 2-9 weeks). DNAemia was monitored by real time quantitative PCR and ganciclovir plasma concentration was measured at trough (Ctrough) and 3 h after drug administration (C3h) by HPLC. RESULTS: Four patients presented with CMV syndrome, two had CMV tissue-invasive disease after prophylaxis discontinuation, and one liver recipient was treated pre-emptively for asymptomatic rising CMV viral load 5 weeks post-transplantation in the absence of prophylaxis. CMV DNAemia decreased during the first week of treatment in all recipients except in one patient (median decrease: -1.2 log copies/mL, range: -1.8 to 0) despite satisfactory ganciclovir exposure (AUC0-12 = 48 mg.h/L, range for the 7 patients: 40-118 mg.h/L). Viral clearance was obtained in five patients after a median of time of 34 days (range: 28-82 days). Two patients had recurrent CMV disease despite adequate ganciclovir exposure (65 mg.h/L, range: 44-118 mg.h/L). CONCLUSIONS: Valganciclovir treatment for CMV infection/disease in D+/R- transplant recipients can thus result in variable viral clearance despite adequate ganciclovir plasma concentrations, probably correlating inversely with anti-CMV immune responses after primary infection.

Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNF-alpha single-chain antibody, upon topical administration to the rabbit eye.

PURPOSE: The purpose of this study was to characterize local distribution and systemic absorption of the tumor necrosis factor (TNF)-alpha inhibitory single-chain antibody fragment (scFv) ESBA105 following topical administration to the eye in vivo. METHODS: Rabbits received ESBA105 as topical eye drops in two dosing regimens. First, pharmacokinetics after the topical route of administration was compared to the intravenous (i.v.) route by means of applying the identical cumulative daily dose of ESBA105. In a second study rabbits received five eye drops daily for six consecutive days in a lower frequency topical dosing regimen. Kinetics and biodistribution of ESBA105 in ocular tissues and fluids as well as in sera were determined in all animals. RESULTS: After topical administration to the eye, ESBA105 quickly reaches therapeutic concentrations in all ocular compartments. Systemic exposure after topical administration is 25,000-fold lower than exposure after i.v. injection of the identical cumulative daily dose. ESBA105 levels in vitreous humor and neuroretina are significantly higher on topical administration than after i.v. injection. Absolute and relative intraocular biodistribution of ESBA105 is different with topical and systemic delivery routes. Compared to its terminal half-life in circulation (7 hours), the vitreal half-life of ESBA105 is significantly enhanced (16-24 hours). CONCLUSIONS: On topical administration, ESBA105 is efficiently absorbed and distributed to all compartments of the eye, whereby systemic drug exposure is very low. Based on its unique intraocular biodistribution and pharmacokinetics and the absolute intraocular levels reached, topical ESBA105 appears highly attractive for treatment of various ophthalmological disorders.

Anti-TNF Therapy in the Swiss Inflammatory Bowel Disease G8 Cohort

Background: A nti-TNF d rugs (Infliximab (IFX), Adalimumab (ADA), Certolizumab pegol (CZP)) are effective in inducing and maintaining response a nd remission in i nflammatory bowel disease (IBD). Insufficient response or side effects may lead to a switch o f the anti-TNF d rug. W e aimed to e valuate the frequency and reasons for anti-TNF switches. Methods: Analysis of data from the Swiss Inflammatory Bowel Disease Cohort (SIBDCS). Eighty percent of included patients were recruited in hospitals and 20% from private practice. Results: From 2,058 patients ( 1,172 with Crohn's disease (CD), 842 with ulcerative colitis (UC) and 44 with indeterminate colitis (IC)), 772 received at least one anti-TNF. Forty-eight % of patients w ith CD, 23% with U C, a nd 30% with IC w ere ever treated with an anti-TNF drug. There was no gender difference with respect to the frequency of a nti-TNF treatment. A total of 584 patients (76%) were treated with one, 142 (18%) with two, and 46 (6%) with three anti-TNF (of which 32 were female). A total of 89% patients were treated with IFX, 28% ADA and 13% with CZP. Overall response rate (defined as drop in CDAI >100 points) to anti-TNF was 50%, with best response rates for the first used anti-TNF. Reasons t o switch t he anti-TNF w ere in 11% a primary non-response, in 38% a loss of response and in 36% anti-TNF s ide effects o r intolerance ( reasons for 15% of treatment failures not documented). Conclusion: A nti-TNF d rugs were used in h alf of the CD patients a nd in o ne quarter of U C patients. Anti-TNF d rug switch d ue to insufficient response a nd/or side effects w as necessary in one quarter of IBD patients. IFX was mainly used as first-line therapy. Best response rates were observed for the first used anti-TNF. Following analyses will identify risk median treatment duration as well as risk factors for anti-TNF switch.

CHO expression of a novel human recombinant IgG1 anti-RhD antibody isolated by phage display.

Replacement of the hyperimmune anti-Rhesus (Rh) D immunoglobulin, currently used to prevent haemolytic disease of the newborn, by fully recombinant human anti-RhD antibodies would solve the current logistic problems associated with supply and demand. The combination of phage display repertoire cloning with precise selection procedures enables isolation of specific genes that can then be inserted into mammalian expression systems allowing production of large quantities of recombinant human proteins. With the aim of selecting high-affinity anti-RhD antibodies, two human Fab libraries were constructed from a hyperimmune donor. Use of a new phage panning procedure involving bromelin-treated red blood cells enabled the isolation of two high-affinity Fab-expressing phage clones. LD-6-3 and LD-6-33, specific for RhD. These showed a novel reaction pattern by recognizing the D variants D(III), D(IVa), D(IVb), D(Va), D(VI) types I and II. D(VII), Rh33 and DFR. Full-length immunoglobulin molecules were constructed by cloning the variable regions into expression vectors containing genomic DNA encoding the immunoglobulin constant regions. We describe the first, stable, suspension growth-adapted Chinese hamster ovary (CHO) cell line producing a high affinity recombinant human IgG1 anti-RhD antibody adapted to pilot-scale production. Evaluation of the Fc region of this recombinant antibody by either chemiluminescence or antibody-dependent cell cytotoxicity (ADCC) assays demonstrated macrophage activation and lysis of red blood cells by human lymphocytes. A consistent source of recombinant human anti-RhD immunoglobulin produced by CHO cells is expected to meet the stringent safety and regulatory requirements for prophylactic application.

Dispositius nanoplasmònics basats en polaritons anti-simètrics per apliacacions biosensores i nanofotòniques

Presentem un estudi teòric comparatiu de les sensibilitats en volum dels sensors d’índex de refracció basats en polaritó de plasmó superficial (SPP) i en ressonància localitzada de plasmó superficial (LSPR). Els resultats demostren que el sensor SPP, àmpliament conegut i comercialitzat, ofereix una major sensibilitat en volum comparada amb la del sensor LSPR, estant aquest últim basat en l’ús de nanorods d’or. A més, la figura de mèrit del sensor LSPR, emprada per a analitzar la seva capacitat sensora, exhibeix una regió sensora òptima quan la longitud d’ona de ressonància es troba propera a 700 nm.

Synthesis and characterization of a new class of anti-angiogenic agents based on ruthenium clusters.

New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.

Pulmonary biology of anti-interleukin 5 antibodies

Interleukin 5 (IL-5) is a critical cytokine for the maturation of eosinophil precursors to eosinophils in the bone marrow and those eosinophils then accumulate in the lungs during asthma. We have studied anti IL-5 antibodies on allergic responses in mice, guinea pigs and monkeys and are extending this experiment into humans with a humanized antibody. In a monkey model of pulmonary inflammation and airway hyperreactivity, we found that the TRFK-5 antibody blocked both responses for three months following a single dose of 0.3 mg/kg, i.v. This antibody also blocked lung eosinophilia in mice by inhibiting release from the bone marrow. To facilitate multiple dosing and to reduce immunogenicity in humans, we prepared Sch 55700, a humanized antibody against IL-5. Sch 55700 was also active against lung eosinophilia in allergic monkeys and mice and against pulmonary eosinophilia and airway hyperresponsiveness in guinea pigs. Furthermore, as opposed to steroids, Sch 55700 did not cause immunosuppression in guinea pigs. Studies with this antibody in humans will be critical to establishing the therapeutic potential of IL-5 inhibition.

Approximation algorithms for two-state anti-ferromagnetic spin systems on bounded degree graphs

In a seminal paper [10], Weitz gave a deterministic fully polynomial approximation scheme for counting exponentially weighted independent sets (which is the same as approximating the partition function of the hard-core model from statistical physics) in graphs of degree at most d, up to the critical activity for the uniqueness of the Gibbs measure on the innite d-regular tree. ore recently Sly [8] (see also [1]) showed that this is optimal in the sense that if here is an FPRAS for the hard-core partition function on graphs of maximum egree d for activities larger than the critical activity on the innite d-regular ree then NP = RP. In this paper we extend Weitz's approach to derive a deterministic fully polynomial approximation scheme for the partition function of general two-state anti-ferromagnetic spin systems on graphs of maximum degree d, up to the corresponding critical point on the d-regular tree. The main ingredient of our result is a proof that for two-state anti-ferromagnetic spin systems on the d-regular tree, weak spatial mixing implies strong spatial mixing. his in turn uses a message-decay argument which extends a similar approach proposed recently for the hard-core model by Restrepo et al [7] to the case of general two-state anti-ferromagnetic spin systems.

Recommandations pour la prise en charge des formes oligoarticulaire et polyarticulaires (en dehors de la polyarthrite rhumatoïde) d'arthrite juvénile idiopathique [Guidelines for diagnosis and treatment of oligoarticular and polyarticular juvenile idiopathic arthritis].

A guideline group of pediatric rheumatologist experts elaborated guidelines related to the management of idiopathic juvenile arthritis in association with the Haute Autorité de santé (HAS). A systematic search of the literature published between 1998 and August 2008 and indexed in Pubmed was undertaken. Here, we present the guidelines for diagnosis and treatment in oligoarticular and polyarticular juvenile idiopathic arthritis (except for spondylarthropathy and rheumatoid arthritis).

Impacto de la utilización de hígados de donantes anti-HBc positivo en pacientes trasplantados por hepatitis B

El nostre objectiu és avaluar l’impacte de la utilització de fetges de donants anti-HBc positius en pacients trasplantats per hepatitis B, els quals van ser revisats de manera retrospectiva. La probabilitat acumulada d’hepatitis B post-trasplantament al 1er, 5é i 10é any va ésser del 3,7%, 8,3% i 8,3% en els receptors d’un empelt anti-HBc+ en comparació amb el 2,7%, 9,8% i 9,8% en els que varen rebre un empelt anti-HBc- (p=0,99). La probabilitat de supervivència al 1er, 5é i 10é any dels receptors d’un òrgan anti-HBc+ va ésser del 87%, 82% i 58% front al 87%, 82% i 74% en els que varen rebre un anti-HBc- (p=0,73). La utilització de donants anti-HBc positius no afecta ni a la supervivència ni al desenvolupament de hepatitis B en pacients trasplantats per VHB.