Biases affecting injected doses of an experimental drug during clinical trials.

During clinical trials, researchers rarely question nominal doses specified on labels of investigational products, overlooking the potential for inaccuracies that may result when calculating pharmacokinetic and pharmacodynamic parameters. This study evaluated the disparity between nominal doses and the doses actually administered in two Phase I trials of a biosimilar drug. In Trial A, 12 healthy volunteers received various doses of an interferon β-1a biosimilar via either subcutaneous or intravenous injection, prepared by partially emptying 0.53 ml syringes supplied by the manufacturer. In Trial B, 12 volunteers received three different formulations of the drug via intravenous injection (biosimilar with and without albumin and a comparator), followed by multiple subcutaneous injections. In both trials, the dose administered was calculated as D = C × V - losses, where C is the drug concentration assessed using ELISA, V is the volume administered calculated using syringe weighing and losses are deduced from in-vitro experiments. Interferon binding to added albumin and infusion lines was evaluated using a (125)I-interferon tracer with gel-filtration chromatography. In Trial A, measured concentrations were close to the nominal strength indicated by the manufacturer (median bias: -6 %), whereas in Trial B they differed significantly for all three formulations (median biases: +67 %, +73 % and +31 % for the biosimilar with albumin, the biosimilar without albumin and the comparator, respectively). In Trial A, the doses actually administered showed large variability and biases, especially at the lowest doses. Indeed, actually injected volumes differed by as much as 74 % from theoretical volumes - a phenomenon mainly attributed to unnoticed fluid re-aspiration through the syringe needle. This was corrected in Trial B. Interferon was not significantly adsorbed on the infusion lines used for intravenous administration. Its binding to albumin was slow, reaching 50 % after a 16 h incubation. These examples illustrate the importance of assessing the actual doses administered in clinical trials, to ensure accuracy in the determination of clearance, distribution volume, bioavailability and dose-response relationships. Clinicaltrials.gov NCT02515695 (Trial A) and NCT02517788 (Trial B). Registered on 24 July and 5 August 2015, respectively

Disposition of valganciclovir during continuous renal replacement therapy in two lung transplant recipients

Objectives To determine whether valganciclovir 450 mg every 48 h for cytomegalovirus (CMV) prophylaxis provides appropriate ganciclovir exposure in solid organ transplant recipients during continuous renal replacement therapy (CRRT). Patients and methods Ganciclovir pharmacokinetics was intensively studied in two lung transplant recipients under valganciclovir 450 mg every 48 h over one dosing interval. In vitro experiments using blank whole blood spiked with ganciclovir further investigated exchanges between plasma and erythrocytes. Results Ganciclovir disposition was characterized by apparent total body clearance of 3.3 and 5.8 L/h, terminal half-life of 16.9 and 14.1 h, and apparent volume of distribution of 60.3 and 104.9 L in Patients 1 and 2, respectively. The observed sieving coefficient was 1.05 and 0.96, and the haemofiltration clearance was 3.3 and 3.1 L/h. In vitro experiments confirmed rapid efflux of ganciclovir from red blood cells into plasma, increasing the apparent efficacy of haemofiltration. Conclusions A valganciclovir dosage of 450 mg every 48 h appears adequate for patients under CRRT requiring prophylaxis for CMV infection, providing concentration levels in the range reported for 900 mg once daily dosing outside renal failur

New nonrenormalization theorems for anomalous three point functions

Nonrenormalization theorems involving the transverse, i.e. non anomalous, part of the correlator in perturbative QCD are proven. Some of their consequences and questions they raise are discussed.Comment: 14 pages. People added in the acknowledgements. Minor changes to match version to appear in journa

Two--Loop Electroweak Corrections to the Muon g-2: a new class of Hadronic Contributions

We discuss, within the framework of the Standard Model, the calculation of the two-loop electroweak contributions to the anomalous magnetic moment of the muon involving triangle fermionic loops of leptons and quarks. Because of the large ratios of masses involved, these contributions are rather large. The result we obtain differs from a previous estimate reported in the literature. The discrepancy originates in the cancellation of anomalies in $SU(3)_c\times SU(2)_L\times U(1)_Y$, a cancellation that requires the consideration of both leptons {\it and} quarks within each generation and that had been previously overlooked.Comment: 9 pages, 5 figs., sign error corrected, numerical result changes slightly, note added referring to some recent related wor

Analyticity, crossing and the absorptive parts of the one-loop contributions to the quark-quark-gluon gauge boson four-point function

Starting from the known one-loop result for the $e^{+}e^{-}$-annihilation process $e^{+}e^{-}\stackrel{\gamma,Z} {\longrightarrow} q\bar{q}g$ with massless quarks we employ analyticity and crossing to determine the absorptive parts of the corresponding one-loop contributions in Deep Inelastic Scattering (DIS) and in the Drell-Yan process (DY). Whereas the ${\cal O}(\alpha_s^2)$ absorptive parts generate a non-measurable phase factor in the $e^{+}e^{-}$-annihilation channel one obtains measurable phase effects from the one-loop contributions in the deep inelastic and in the Drell-Yan case. We compare our results with the results of previous calculations where the absorptive parts in DIS and in the DY process were calculated directly in the respective channels. We also present some new results on the dispersive and absorptive contributions of the triangle anomaly graph to the DIS process.Comment: 23 pages, 5 figures, typos corrected. Version to appear in Phys. Rev.

Structure analysis of the virtual Compton scattering amplitude at low energies

We analyze virtual Compton scattering off the nucleon at low energies in a covariant, model-independent formalism. We define a set of invariant functions which, once the irregular nucleon pole terms have been subtracted in a gauge-invariant fashion, is free of poles and kinematical zeros. The covariant treatment naturally allows one to implement the constraints due to Lorentz and gauge invariance, crossing symmetry, and the discrete symmetries. In particular, when applied to the $ep\to e'p'\gamma$ reaction, charge-conjugation symmetry in combination with nucleon crossing generates four relations among the ten originally proposed generalized polarizabilities of the nucleon.Comment: 19 pages, LaTeX2e/RevTeX, no figures, original sections IV.-VI. removed, to be discussed in a separate publication, none of the conclusions change

Hadronic light-by-light scattering contribution to the muon g-2: an effective field theory approach

The hadronic light-by-light contribution to a_{mu}, the anomalous magnetic moment of the muon, is discussed from the point of view of an effective low-energy theory. As an application, the coefficient of the leading logarithm arising from the two-loop graphs involving two anomalous vertices is computed, and found to be positive. This corresponds to a positive sign for the pion-pole contribution to the hadronic light-by-light correction to a_{mu}, and to a sizeable reduction of the discrepancy between the present experimental value of a_{mu} and its theoretical counterpart in the standard model.Comment: 4 pages, 1 figure. v2: published versio

Contactless power and information transmission

In some applications, contacts between two devices are the first cause of dysfunctions. The aim of this paper is to transfer contactless power energy to add new functions to a tool (e.g., drill machine). A bidirectional communication is also needed. This is realized with an ironless high-frequency transformer for both power and information transmission. Different coil geometries have been studied to reduce mutual inductance between power and information coils. This new solution enables to build low-cost and smart energy transfer systems including communication

Étude des biais sur la dose parentérale d'un nouveau médicament lors d'un essai clinique avec profil cinétique.

Introduction et objectif: Lors d'essais cliniques, le pharmacien est responsable de la préparation et de la dispensation des médicaments à évaluer. Un article récent a toutefois montré que les aspects pharmaceutiques liés au contrôle de la dose administrée in fine étaient souvent mal contrôlés. Il peut exister une différence entre la dose nominale fournie par le certificat d'analyse du fabricant et la dose réellement administrée au sujet, biais qui se reporte en cascade sur l'estimation des paramètres pharmaco¬cinétiques (PK), comme la clairance ou le volume de distribution. Ce travail visait à évaluer les biais entachant la quantité de médicament réellement injectée (iv/sc) aux volontaires d'un essai clinique étudiant la PK et la relation dose-réponse d'un nouveau produit biotechnologique. Méthode: La dose de médicament administrée lors de l'essai clinique (D) a été calculée de la manière suivante: D = C ? V - pertes. La concentration du produit (C; titre nominal du fabricant) a été vérifiée par immuno-essai. Le volume de médicament injecté (V) a été déterminé pour chaque injection par pesée (n=72), en utilisant la masse de la seringue avant et après injection et la densité du produit. Enfin, une analyse in vitro a permis d'évaluer les pertes liées à l'adsorption du produit dans les lignes de perfusion et de choisir le dispositif adéquat in vivo. Résultats: La concentration du médicament s'est révélée proche du titre nominal (96 ± 7%), et a été utilisée comme référence. Le volume injecté était quant à lui entaché d'un biais systématique par rapport à la valeur théorique correspondant à 0.03 mL pour la dose minimale (i.e. 75% du volume à injecter à cette dose). Une analyse complémentaire a montré que cela s'expliquait par une réaspiration partielle de la solution médica-menteuse avant le retrait de la seringue après injection sc, due à l'élasticité du piston. En iv, le biais était par contre provoqué par une réaspiration du soluté de perfusion co-administré. Enfin, la mesure des quantités de médicament récupérées après injection dans le dispositif de perfusion a démontré des pertes minimales par adsorption. Discussion-conclusion: Cette étude confirme l'existence de biais inversement corrélés au volume et à la concentration du médicament administré, pouvant provoquer des erreurs importantes sur les paramètres PK. Ce problème est négligé ou insuffisamment considéré dans les protocoles de Phase I et nécessiterait une planification rigoureuse. Les procédures opératoires devraient attirer l'attention sur ce point crucial