Dopexamine and norepinephrine versus epinephrine on gastric perfusion in patients with septic shock: a randomized study [NCT00134212]

INTRODUCTION: Microcirculatory blood flow, and notably gut perfusion, is important in the development of multiple organ failure in septic shock. We compared the effects of dopexamine and norepinephrine (noradrenaline) with those of epinephrine (adrenaline) on gastric mucosal blood flow (GMBF) in patients with septic shock. The effects of these drugs on oxidative stress were also assessed. METHODS: This was a prospective randomized study performed in a surgical intensive care unit among adults fulfilling usual criteria for septic shock. Systemic and pulmonary hemodynamics, GMBF (laser-Doppler) and malondialdehyde were assessed just before catecholamine infusion (T(0)), as soon as mean arterial pressure (MAP) reached 70 to 80 mmHg (T(1)), and 2 hours (T(2)) and 6 hours (T(3)) after T(1). Drugs were titrated from 0.2 μg kg(-1 )min(-1 )with 0.2 μg kg(-1 )min(-1 )increments every 3 minutes for epinephrine and norepinephrine, and from 0.5 μg kg(-1 )min(-1 )with 0.5 μg kg(-1 )min(-1 )increments every 3 minutes for dopexamine. RESULTS: Twenty-two patients were included (10 receiving epinephrine, 12 receiving dopexamine–norepinephrine). There was no significant difference between groups on MAP at T(0), T(1), T(2), and T(3). Heart rate and cardiac output increased significantly more with epinephrine than with dopexamine–norepinephrine, whereas. GMBF increased significantly more with dopexamine–norepinephrine than with epinephrine between T(1 )and T(3 )(median values 106, 137, 133, and 165 versus 76, 91, 90, and 125 units of relative flux at T(0), T(1), T(2 )and T(3), respectively). Malondialdehyde similarly increased in both groups between T(1 )and T(3). CONCLUSION: In septic shock, at doses that induced the same effect on MAP, dopexamine–norepinephrine enhanced GMBF more than epinephrine did. No difference was observed on oxidative stress

Apport de la spectroscopie Raman a l'etude des phases ordonnees et desordonnees de cristaux moleculaires : phase I du fluoroadamantane, phase II du cyanoadamantane

SIGLECNRS T 58956 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Study of the phase transition in lysozyme crystals by Raman spectroscopy

BackgroundRecently, it has been revealed that tetragonal lysozyme crystals show a phase transition at 307 K upon heating. The underlying mechanisms of the phase transition are still not fully understood. Here we focus on the study of high-frequency vibrational modes arising from the protein and their temperature evolution in the vicinity of Tph as well as on the detailed study of crystalline water dynamics near Tph.MethodsRaman experiments have been performed at temperatures 295–323 K including Tph. The low-frequency modes and the modes of fingerprint region, CH- and OH-stretching regions have been analyzed.Results and conclusionsIn spite of the absence of noticeable rearrangements in protein structure, the high-frequency vibrational modes of lysozyme located in the fingerprint region have been found to exhibit the features of critical dynamics near Tph. Pronounced changes in the dynamics of α-helixes and Tyr residues exposed on the protein surface point to the important role of H-bond rearrangements at the phase transition. Additionally the study of temperature evolution of OH-stretching modes has shown an increase in distortions of tertahedral H-bond network of crystalline water above Tph. These changes in water dynamics could play a crucial role in the mechanisms of the phase transition.General significanceThe present results shed light on the mechanisms of the phase transition in lysozyme crystals

A detailed description of the devitrification mechanism of d -mannitol

The devitrification mechanism of d-mannitol was carefully investigated using micro calorimetry experiments and Raman spectroscopy, in order to understand the phase transformation of the undercooled liquid into an apparently amorphous state, called phase X. It was found from micro spectroscopy analyses that the formerly assigned "phase X" observed during the devitrification of undercooled d-mannitol results from a surface crystallization accompanied by a very slow bulk crystallization into the alpha form. Such a phenomenon can be more easily identified by analyzing microscopic samples obtained upon slow heating runs from the glassy state

Analysis of Co-Crystallization Mechanism of Theophylline and Citric Acid from Raman Investigations in Pseudo Polymorphic Forms Obtained by Different Synthesis Methods

Designing co-crystals can be considered as a commonly used strategy to improve the bioavailability of many low molecular weight drug candidates. The present study has revealed the existence of three pseudo polymorphic forms of theophylline–citric acid (TP–CA) co-crystal obtained via different routes of synthesis. These forms are characterized by different degrees of stability in relation with the strength of intermolecular forces responsible for the co-crystalline cohesion. Combining low- and high-frequency Raman investigations made it possible to identify anhydrous and hydrate forms of theophylline–citric acid co-crystals depending on the preparation method. It was shown that the easiest form to synthesize (form 1′), by milling one hydrate with an anhydrous reactant, is very metastable, and transforms into the anhydrous form 1 upon heating or into the hydrated form 2 when it is exposed to humidity. Raman investigations performed in situ during the co-crystallization of forms 1 and 2 have shown that two different types of H-bonding ensure the co-crystalline cohesion depending on the presence of water. In the hydrated form 2, the cohesive forces are related to strong O–H … O H-bonds between water molecules and the reactants. In the anhydrous form 1, the co-crystalline cohesion is ensured by very weak H-bonds between the two anhydrous reactants, interpreted as corresponding to π-H-bonding. The very weak strength of the cohesive forces in form 1 explains the difficulty to directly synthesize the anhydrous co-crystal

Mechanism for Stabilizing an Amorphous Drug Using Amino Acids within Co-Amorphous Blends

Designing co-amorphous formulations is now recognized as a relevant strategy for improving the bioavailability of low-molecular-weight drugs. In order to determine the most suitable low-molecular-weight excipients for stabilizing the drug in the amorphous state, screening methods were developed mostly using amino acids as co-formers. The present study focused on the analysis of the thermal stability of co-amorphous blends prepared by cryo-milling indomethacin with several amino acids in order to understand the stabilization mechanism of the drug in the amorphous state. Combining low- and mid-frequency Raman investigations has provided information on the relation between the physical properties of the blends and those of the H-bond network of the amorphous drug. This study revealed the surprising capabilities of L-arginine to stiffen the H-bond network in amorphous indomethacin and to drastically improve the stability of its amorphous state. As a consequence, this study suggests that amino acids can be considered as stiffeners of the H-bond network of indomethacin, thereby improving the stability of the amorphous state

Co-Amorphous Versus Deep Eutectic Solvents Formulations for Transdermal Administration

Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical stability of amorphous drugs within the formulation. Ibuprofen is commonly used in topical formulations and then was selected as a model drug. Additionally, its low Tg allows easy, unexpected recrystallization at room temperature with negative consequence on skin penetration. In this study, the physical stability of amorphous ibuprofen was investigated in two types of formulations: (i) in terpenes-based deep eutectic solvents (DES) and (ii) in arginine-based co-amorphous blends. The phase diagram of ibuprofen:L-menthol was mainly analyzed by low-frequency Raman spectroscopy, leading to the evidence of ibuprofen recrystallization in a wide range of ibuprofen concentration. By contrast, it was shown that amorphous ibuprofen is stabilized when dissolved in thymol:menthol DES. Forming co-amorphous arginine–ibuprofen blends by melting is another route for stabilizing amorphous ibuprofen, while recrystallization was detected in the same co-amorphous mixtures obtained by cryo-milling. The mechanism of stabilization is discussed from determining Tg and analyzing H-bonding interactions by Raman investigations in the C=O and O–H stretching regions. It was found that recrystallization of ibuprofen was inhibited by the inability to form dimers inherent to the preferential formation of heteromolecular H-bonding, regardless of the glass transition temperatures of the various mixtures. This result should be important for predicting ibuprofen stability within other types of topical formulations

Développement d'environnements automatisés pour des applications dans le domaine de l'optique

LILLE1-BU (590092102) / SudocSudocFranceF

Lyophilized proteins: influence of residual water on stability

International audienc