Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

New formulation of vasoactive intestinal peptide using liposomes in hyaluronic acid gel for uveitis.

We evaluated the benefits of a novel formulation of vasoactive intestinal peptide (VIP) based on the incorporation of VIP-loaded rhodamine-conjugated liposomes (VIP-Rh-Lip) within hyaluronic acid (HA) gel (Gel-VIP-Rh-Lip) for the treatment of endotoxin-induced uveitis (EIU) in comparison with VIP-Rh-Lip alone. In vitro release study and rheological analysis showed that interactions between HA chains and liposomes resulted in increased viscosity and reinforced elasticity of the gel. In vivo a single intravitreal injection of Gel-VIP-Rh-Lip was performed in rats 7 days prior to uveitis induction by subcutaneous lipopolysaccharide injection. The maximal ocular inflammation occurs within 16-24 h in controls (VIP-Rh-Lip, unloaded-Rh-Lip). Whereas intraocular injection of VIP-Rh-Lip had no effect on EIU severity compared with controls, Gel-VIP-Rh-Lip reduced significantly the clinical score and number of inflammatory cells infiltrating the eye. The fate of liposomes, VIP and HA in the eyes, regional and inguinal lymph nodes and spleen was analyzed by immunostaining and fluorescence microscopy. Retention of liposomes by HA gel was observed in vitro and in vivo. Inflammation severity seemed to impact on system stability resulting in the delayed release of VIP. Thus, HA gel containing VIP-Rh-Lip is an efficient strategy to obtain a sustained delivery of VIP in ocular and lymph node tissues.

Bromocriptine:old drug, new formulation and new indication

Bromocriptine is an ergot alkaloid dopamine D receptor agonist that has been used extensively in the past to treat hyperprolactinaemia, galactorrhoea and Parkinsonism. It is known that hypothalamic hypodopaminergic states and disturbed circadian rhythm are associated with the development of insulin resistance, obesity and diabetes in animals and humans. When administered in the early morning at the start of the light phase, a new quick release (QR) formulation of bromocriptine appears to act centrally to reset circadian rhythms of hypothalamic dopamine and serotonin and improve insulin resistance and other metabolic abnormalities. Phase II and III clinical studies show that QR-bromocriptine lowers glycated haemoglobin by 0.6-1.2% (7-13 mmol/mol) either as monotherapy or in combination with other antidiabetes medications. Apart from nausea, the drug is well tolerated. The doses used to treat diabetes (up to 4.8 mg daily) are much lower than those used to treat Parkinson's disease and have not been associated with retroperitoneal fibrosis or heart valve abnormalities. QR-bromocriptine (Cycloset™) has recently been approved in the USA for the treatment of type 2 diabetes mellitus (T2DM). Thus, a QR formulation of bromocriptine timed for peak delivery in the early morning may provide a novel neurally mediated approach to the control of hyperglycaemia in T2DM. © 2010 Blackwell Publishing Ltd.

A New Formulation of the Spectral Energy Budget of the Atmosphere, with Application to Two High-Resolution General Circulation Models

International audience

Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/ day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruzi quantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

A new compact linear programming formulation for choice network revenue management

The choice network revenue management model incorporates customer purchase behavioras a function of the offered products, and is the appropriate model for airline and hotel networkrevenue management, dynamic sales of bundles, and dynamic assortment optimization.The optimization problem is a stochastic dynamic program and is intractable. A certainty-equivalencerelaxation of the dynamic program, called the choice deterministic linear program(CDLP) is usually used to generate dyamic controls. Recently, a compact linear programmingformulation of this linear program was given for the multi-segment multinomial-logit (MNL)model of customer choice with non-overlapping consideration sets. Our objective is to obtaina tighter bound than this formulation while retaining the appealing properties of a compactlinear programming representation. To this end, it is natural to consider the affine relaxationof the dynamic program. We first show that the affine relaxation is NP-complete even for asingle-segment MNL model. Nevertheless, by analyzing the affine relaxation we derive a newcompact linear program that approximates the dynamic programming value function betterthan CDLP, provably between the CDLP value and the affine relaxation, and often comingclose to the latter in our numerical experiments. When the segment consideration sets overlap,we show that some strong equalities called product cuts developed for the CDLP remain validfor our new formulation. Finally we perform extensive numerical comparisons on the variousbounds to evaluate their performance.

Evaluating a new LISFLOOD-FP formulation with data from the summer 2007 floods in Tewkesbury, UK

Two-dimensional flood inundation modelling is a widely used tool to aid flood risk management. In urban areas, where asset value and population density are greatest, the model spatial resolution required to represent flows through a typical street network (i.e. < 10m) often results in impractical computational cost at the whole city scale. Explicit diffusive storage cell models become very inefficient at such high resolutions, relative to shallow water models, because the stable time step in such schemes scales as a quadratic of resolution. This paper presents the calibration and evaluation of a recently developed new formulation of the LISFLOOD-FP model, where stability is controlled by the Courant–Freidrichs–Levy condition for the shallow water equations, such that, the stable time step instead scales linearly with resolution. The case study used is based on observations during the summer 2007 floods in Tewkesbury, UK. Aerial photography is available for model evaluation on three separate days from the 24th to the 31st of July. The model covered a 3.6 km by 2 km domain and was calibrated using gauge data from high flows during the previous month. The new formulation was benchmarked against the original version of the model at 20 m and 40 m resolutions, demonstrating equally accurate performance given the available validation data but at 67x faster computation time. The July event was then simulated at the 2 m resolution of the available airborne LiDAR DEM. This resulted in a significantly more accurate simulation of the drying dynamics compared to that simulated by the coarse resolution models, although estimates of peak inundation depth were similar.

Evaluating a new LISFLOOD-FP formulation with data from the summer 2007 floods in Tewkesbury, UK

Two-dimensional flood inundation modelling is a widely used tool to aid flood risk management. In urban areas, the model spatial resolution required to represent flows through a typical street network often results in an impractical computational cost at the city scale. This paper presents the calibration and evaluation of a recently developed formulation of the LISFLOOD-FP model, which is more computationally efficient at these resolutions. Aerial photography was available for model evaluation on 3 days from the 24 to the 31 of July. The new formulation was benchmarked against the original version of the model at 20 and 40 m resolutions, demonstrating equally accurate simulation, given the evaluation data but at a 67 times faster computation time. The July event was then simulated at the 2 m resolution of the available airborne LiDAR DEM. This resulted in more accurate simulation of the floodplain drying dynamics compared with the coarse resolution models, although maximum inundation levels were simulated equally well at all resolutions tested.

Pharmacokinetics of a new long acting endectocide formulation containing 2.25% ivermectin and 1.25% abamectin in cattle

The objective of this study was to determine the kinetic parameters of a new formulation that contained 2.25% ivermectin combined with 1.25% abamectin in bovine plasma. The results for 2.25% ivermectin: C-max (37.11 ng/mL +/- 7.42), T-max (16 days +/- 5.29), T-1/2 (44.62 days +/- 53.89), AUC (928.2 ng.day/mL +/- 153.83) and MRT (36.73 days +/- 33.64), and for 1.25% abamectin: C-max (28.70 ng/mL +/- 9.54), T-max (14 days +/- 4.04), T-1/2 (15.40 days +/- 11.43), AUC (618.05 ng.day/mL +/- 80.27) and MRT (20.79 days +/- 8.43) suggest that this combination of 2.25% ivermectin + 1.25% abamectin possesses properties that give this pharmaceutical formula a longer activity time than two of the commercial products tested (1% ivermectin and 1% abamectin), and showed similarity to 3.15% ivermectin.

A laminated polymer film formulation for enteric delivery of live vaccine and probiotic bacteria

Live bacterial cells (LBC) are administered orally as attenuated vaccines, to deliver biopharmaceutical agents, and as probiotics to improve gastrointestinal health. However, LBC present unique formulation challenges and must survive gastrointestinal antimicrobial defenses including gastric acid after administration. We present a simple new formulation concept, termed Polymer Film Laminate (PFL). LBC are ambient dried onto cast acid-resistant enteric polymer films that are then laminated together to produce a solid oral dosage form. LBC of a model live bacterial vaccine and a probiotic were dried directly onto a cast film of enteric polymer. The effectiveness at protecting dried cells in a simulated gastric fluid (pH 2.0) depended on the composition of enteric polymer film used, with a blend of ethylcellulose plus Eudragit L100 55 providing greater protection from acid than Eudragit alone. However, although PFL made from blended polymers films completely released low molecular weight dye into intestinal conditions (pH 7.0), they failed to release LBC. In contrast, PFL made from Eudragit alone successfully protected dried probiotic or vaccine LBC from simulated gastric fluid for 2h, and subsequently released all viable cells within 60min of transfer into simulated intestinal fluid. Release kinetics could be controlled by modifying the lamination method.

Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hamilton-Jacobi formulation for singular systems with second-order Lagrangians

Recently, the Hamilton-Jacobi formulation for first-order constrained systems has been developed. In such formalism the equations of motion are written as total differential equations in many variables. We generalize the Hamilton-Jacobi formulation for singular systems with second-order Lagrangians and apply this new formulation to Podolsky electrodynamics, comparing with the results obtained through Dirac's method.