Loco-regional administration of anticancer agents : isolated lung perfusion with doxorubicin hypoxic abdominal stop-flow perfusion with gemcitabine

SUMMARY Regional drug delivery is an approach designed to improve the selectivity of anticancer chemotherapy. The advantage of regional treatments lies in increasing the drug concentration in the affected organ, while the rest of the organism is spared, thus improving efficacy and limiting treatment toxicity. The goal of this thesis was to assess the distribution throughout the body and the disposition (pharmacokinetics) of two anticancer agents, doxorubicin and gemcitabine, administered by two different regional administration modalities: isolated lung perfusion (ILP) for pulmonary metastases from soft tissue sarcomas and abdominal stop-flow hypoxic perfusion for advanced pancreatic cancers, respectively. For this purpose, two high-performance liquid chromatography methods were developed and validated. The first enabled the determination of doxorubicin in four different biological matrices: serum, reconstituted effluent, tissues with low levels of doxorubicin and tissues with high levels of doxorubicin. The second allows the analysis of gemcitabine and its principal metabolite dFdU in plasma. The administration of doxorubicin by ILP was studied in three preclinical studies (one on pigs and two on rats). It was first shown that, regardless of the administration mode, doxorubicin was not homogeneously distributed throughout the lung and that some regions remained out of reach. Secondly, it was demonstrated that doxorubicin did not adequately reach the tumours despite very high levels found in the lung. Finally, an attempt to enhance the doxorubicin tumoural uptake by pharmacologic modulation using two P-glycoprotein inhibitors, cyclosporin and valspodar, was unsuccessful. The last part of this work involves the administration of gemcitabine by abdominal stop-flow as a part of a phase I clinical trial in patients with advanced pancreatic disease or resistant malignant ascites. The study has demonstrated that the regional exposure to gemcitabine was increased while the exposure of the entire organism was similar to standard intravenous administrations. From a toxicological perspective, the procedure was rather well tolerated. However, even if no clinical response is expected from a phase I study, no hints of clinical responses were unfortunately observed. In conclusion, even if loco-regional therapies may afford the pharmacological advantage of increasing anticancer drug levels at the tumour site, further studies of these investigational treatment modalities are warranted to ascertain whether they can provide a significant improvement of the cancer therapy for patients, in terms of treatment tolerability, improved responses and survival rates. RÉSUMÉ L'administration locorégionale d'agents anticancéreux est une approche destinée à augmenter la sélectivité du traitement. L'avantage des traitements régionaux repose sur le fait que la concentration du médicament cytostatique est augmentée dans l'organe où est localisée la tumeur, alors que le reste de l'organisme est épargné, améliorant ainsi en théorie l'efficacité du traitement et en limitant sa toxicité. Le but de ce travail de thèse avait pour objectif de préciser, la pharmacocinétique au sein de l'organisme de deux agents anticancéreux, la doxorubicine et la gemcitabine, administrés par deux types de perfusions loco-régionales: la perfusion isolée du poumon (ILP) pour les métastases pulmonaires de sarcomes des tissus mous, et la perfusion hypoxique (stop-flow) abdominale pour les cancers avancés du pancréas. Dans cette optique, deux méthodes de chromatographie liquide à haute performance ont été développées et validées. La première permet le dosage de la doxorubicine dans quatre milieux biologiques: le sérum, l'effluent reconstitué, ainsi que des tissus contenant des concentrations faibles et élevées en doxorubicine. La seconde méthode permet le dosage dans le plasma de la gemcitabine et de son principal métabolite, le dFdU. L'administration de doxorubicine par ILP a été étudiée dans trois études précliniques (une chez le porc et deux chez le rat). Il a été montré, dans un premier temps, que la doxorubicine n'était pas distribuée de façon homogène au sein du poumon, quel que soit son mode d'administration. Dans un deuxième temps, il a été démontré que le médicament n'atteignait pas les tumeurs de façon adéquate, malgré des concentrations très élevées au sein du tissu pulmonaire. Finalement, une tentative d'augmenter la pénétration tumorale de la doxorubicine par une modulation pharmacologique de la P-glycoprotéine en utilisant la cyclosporine et le valspodar n'a pas abouti. La dernière partie de ce travail concernait l'administration de gemcitabine par stop-flow abdominal dans le cadre d'une étude clinique de phase I menée auprès de patients atteints de cancers avancés du pancréas ou d'ascites malignes réfractaires. Cette étude a démontré que l'exposition régionale à la gemcitabine était augmentée, alors que l'exposition de l'organisme était similaire à une administration de dose standard par voie intraveineuse. D'un point de vue toxicologique la procédure fut relativement bien tolérée. Cependant, même s'il n'est pas attendu de réponses cliniques dans une étude de phase I, aucun signe de réponse au traitement n'a pu être malheureusement observé. En conclusion, même si les thérapies loco-régionales présentent -en théorie- l'avantage pharmacologique d'augmenter les taux du médicaments anticancéreux sur le site de la tumeur, d'autres études précliniques et cliniques sont nécessaires pour démontrer que ces nouvelles modalités de traitement, de nature investigationelle à présent, apportent une réelle amélioration pour la prise en charge des patients cancéreux, en terme de tolérance au traitement et de l'augmentation des taux de réponses et de survie.

Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies.

Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated animals. The success rate of cornea graft transplantation was 73% in treated animals against 25% for the control group. This result was as good as observed for a systemic CsA treatment in the same animal model. This new formulation has the same efficacy like a systemic treatment but without the serious CsA systemic side effects. Ocular drug levels of transplanted and healthy rat eyes were dosed by UPLC/MS and showed a high CsA value in the cornea (11710 ± 7530 ng(CsA)/g(tissue) and 6470 ± 1730 ng(CsA)/g(tissue), respectively). In conclusion, the applied formulation has the capacity to overcome the ocular surface barriers, the micelles formed a drug reservoir in the cornea from, where a sustained release of CsA can take place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection.

Relevance of cohort studies for the study of transplant infectious diseases.

The debate on the merits of observational studies as compared with randomized trials is ongoing. We will briefly touch on this subject, and demonstrate the role of cohort studies for the description of infectious disease patterns after transplantation. The potential benefits of cohort studies for the clinical management of patients outside of the expected gain in epidemiological knowledge are reviewed. The newly established Swiss Transplantation Cohort Study and in particular the part focusing on infectious diseases will serve as an illustration. A neglected area of research is the indirect value of large, multicenter cohort studies. These benefits can range from a deepened collaboration to the development of common definitions and guidelines. Unfortunately, very few data exist on the role of such indirect effects on improving quality of patient management. This review postulates an important role for cohort studies, which should not be viewed as inferior but complementary to established research tools, in particular randomized trials. Randomized trials remain the least bias-prone method to establish knowledge regarding the significance of diagnostic or therapeutic measures. Cohort studies have the power to reflect a real-world situation and to pinpoint areas of knowledge as well as of uncertainty. Prerequisite is a prospective design requiring a set of inclusive data coupled with the meticulous insistence on data retrieval and quality.

Wildflower areas within revitalized agricultural matrices boost small mammal populations but not breeding Barn Owls

Agro-ecosystems have recently experienced dramatic losses of biodiversity due to more intensive production methods. In order to increase species diversity, agri-environment schemes provide subsidies to farmers who devote a fraction of their land to ecological compensation areas (ECA). Several studies have shown that invertebrate biodiversity is actually higher in ECA than in nearby intensively cultivated farmland. It remains poorly understood, however, to what extent ECA also favour vertebrates, such as small mammals and their predators, which would contribute to restore functioning food chains within revitalized agricultural matrices. We studied small mammal populations among eight habitat types - including wildflower areas, a specific ECA in Switzerland - and habitat selection (radiotracking) by the barn owl Tyto alba, one of their principal predators. Our prediction was that habitats with higher abundances of small mammals would be more visited by foraging Barn owls during the period of chicks' provisioning. Small mammal abundance tended to be higher in wildflower areas than in any other habitat type. Barn owls, however, preferred to forage in cereal fields and grassland. They avoided all types of crops other than cereals, as well as wildflower areas, which suggests that they do not select their hunting habitat primarily with respect to prey density. Instead of prey abundance, prey accessibility may play a more crucial role: wildflower areas have a dense vegetation cover, which may impede access to prey for foraging owls. The exploitation of wildflower areas by the owls might be enhanced by creating open foraging corridors within or around wildflower areas. Wildflower areas managed in that way might contribute to restore functioning food chains within agro-ecosystems.

Epidemiology of biliary tract cancers: an update

BACKGROUND: Biliary tract cancer (BTC) is a rare cancer in Europe and North America, characterized by wide geographic variation, with high incidence in some areas of Latin America and Asia. MATERIALS AND METHODS: BTC mortality and incidence have been updated according to recent data, using joinpoint regression analysis. RESULTS: Since the 1980s, decreasing trends in BTC mortality rates (age-standardized, world standard population) were observed in the European Union as a whole, in Australia, Canada, Hong Kong, Israel, New Zealand, and the United States, and high-risk countries such as Japan and Venezuela. Joinpoint regression analysis indicates that decreasing trends were more favorable over recent calendar periods. High-mortality rates are, however, still evident in central and eastern Europe (4-5/100,000 women), Japan (4/100,000 women), and Chile (16.6/100,000 women). Incidence rates identified other high-risk areas in India (8.5/100,000 women), Korea (5.6/100,000 women), and Shanghai, China (5.2/100,000 women). CONCLUSIONS: The decreasing BTC mortality trends essentially reflect more widespread and earlier adoption of cholecystectomy in several countries, since gallstones are the major risk factor for BTC. There are, however, high-risk areas, mainly from South America and India, where access to gall-bladder surgery remains inadequate.

Development and evaluation of a shaken baby syndrome prevention program.

OBJECTIVE: To evaluate parents' and nurses' opinions regarding the adequacy of an educational program on shaken baby syndrome: the Perinatal Shaken Baby Syndrome Prevention Program (PSBSPP). DESIGN: Qualitative and quantitative assessments in the form of interviews and questionnaires administered in French. SETTING: Two birthing institutions in Montréal, QC, Canada: a university hospital and a regional center. PARTICIPANTS: Two hundred and sixty-three parents (73.8% mothers, 26.2% fathers) received the intervention after the birth of their child, and 69 nurses administered it. METHODS: Parents' and nurses' assessments of the adequacy and relevance of the program and nurses' assessments of the training they received to administer the program were evaluated. RESULTS: Both parents and nurses supported this initiative. Most parents appreciated the usefulness of the information. Nurses believed the program was adequate, and their training to deliver the program was satisfactory. All participants reported that the program was highly relevant, especially for new parents. CONCLUSION: The Perinatal Shaken Baby Syndrome Prevention Program achieves the goals of (a) increasing parents' knowledge about infant crying, anger, and shaken baby syndrome and (b) helping parents identify coping strategies. The relevance of introducing the PSBSPP in all birthing institutions is supported. Future studies should focus on vulnerable and culturally diverse populations, and longitudinal follow-up could help determine if the PSBSPP reduces the incidence of shaken baby syndrome.

Main results of the Monte Carlo studies carried out for nuclear medicine practices within the ORAMED project

The aim of ORAMED work package 4 was the optimization of the medical practices in nuclear medicine during the preparation of radiopharmaceuticals and their administration to the patient. During the project a wide campaign of measurements was performed in the nuclear medicine departments of the collaborating hospitals. Such data were intrinsically characterized by a large variability that depended on the procedure, the employed techniques and the operator's habits. That variability could easily hide some important parameter, for example, the effectiveness of the adopted shielding (for syringe and vial) or the effect of the distances from the source. This information is necessary for a valuable optimization purpose of radiation protection. To this end a sensitivity analysis was carried out through Monte Carlo simulations employing voxel models, representing operator's hand during the considered practices. Such analysis allowed understanding at what extent the range of personal dose equivalent evaluated during measurements can be considered intrinsically related to the procedures. Furthermore, with the Monte Carlo simulations it was possible to study the appropriateness of the shielding usually utilized in these practices.

Spontaneous pre-stimulus fluctuations in the activity of right fronto-parietal areas influence inhibitory control performance.

Inhibitory control refers to the ability to suppress planned or ongoing cognitive or motor processes. Electrophysiological indices of inhibitory control failure have been found to manifest even before the presentation of the stimuli triggering the inhibition, suggesting that pre-stimulus brain-states modulate inhibition performance. However, previous electrophysiological investigations on the state-dependency of inhibitory control were based on averaged event-related potentials (ERPs), a method eliminating the variability in the ongoing brain activity not time-locked to the event of interest. These studies thus left unresolved whether spontaneous variations in the brain-state immediately preceding unpredictable inhibition-triggering stimuli also influence inhibitory control performance. To address this question, we applied single-trial EEG topographic analyses on the time interval immediately preceding NoGo stimuli in conditions where the responses to NoGo trials were correctly inhibited [correct rejection (CR)] vs. committed [false alarms (FAs)] during an auditory spatial Go/NoGo task. We found a specific configuration of the EEG voltage field manifesting more frequently before correctly inhibited responses to NoGo stimuli than before FAs. There was no evidence for an EEG topography occurring more frequently before FAs than before CR. The visualization of distributed electrical source estimations of the EEG topography preceding successful response inhibition suggested that it resulted from the activity of a right fronto-parietal brain network. Our results suggest that the fluctuations in the ongoing brain activity immediately preceding stimulus presentation contribute to the behavioral outcomes during an inhibitory control task. Our results further suggest that the state-dependency of sensory-cognitive processing might not only concern perceptual processes, but also high-order, top-down inhibitory control mechanisms.

Influence de l'administration des preuves sur l'activité mentale menant à la formation du verdict au cours d'un procès pénal

Abstract : The role of order effects has been widely shown and discussed in areas such as memory and social impression formation. This work focuses in a first half on order effects influencing the verdict chosen at the end of a criminal trial. Contrary to impression formation but according to trial's characteristics, it has been hypothesised that a recency effect would influence the verdict's choice. Three groups of students (N = 576) received a mock trial resume with a specific order stemming from the combination of three witnesses, one expert and two ocular witnesses. Results show a recency effect, the last testimony provoking significantly more acquittals if discriminating, and more condemnations if incriminating. The second half of this work starts from Gestalt and sociopsychological researches presenting numerous insights into cognitive organization of perceptions and opinions. It has been postulated that a witness probative value will change according to the emitted verdict, an incriminating witness or expert possessing a higher probative value in a condemning verdict than in an innocenting one, on the other hand a discriminating witness or expert having a higher probative value in an acquittal than in a condemnation. Results using a seven points scale measuring witnesses' probative value confirm this hypothesis. Argumentations written by the subjects to explain their verdict and refering to the accusing expert also show a congruency effect as categories of arguments are identical in case of condemnation or acquittal, the only difference between both types of verdicts residing in the frequency of these categories following the judgement, higher use of incriminating arguments in case of guiltiness and higher use of discriminating ones if the accused is found innocent. Résumé : L'intervention des effets sériels a fait l'objet de nombreuses recherches dans le domaine de la mémoire et de la formation d'impression en psychologie sociale. Ce travail s'intéresse dans une première partie aux effets d'ordre pouvant influencer le choix du verdict à la fin d'un procès pénal. Contrairement aux résultats obtenus en matière de formation d'impression, mais conformément aux caractéristiques d'un procès, l'hypothèse de l'intervention d'un effet de récence a été formulée, affirmant que les derniers témoins influencent le plus le choix du verdict. Trois groupes d'étudiants (N = 576) ont lu le résumé d'un procès fictif présentant trois témoignages, deux témoins visuels à décharge et un expert à charge. Chaque groupe recevait un ordre spécifique de présentation des témoins de sorte que l'expert se trouvait en première, deuxième ou troisième position. Les résultats montrent un effet de récence, le dernier témoin provoquant davantage d'acquittements s'il est disculpant et davantage de condamnations s'il est inculpant. La seconde partie de ce travail émane des recherches effectuées dans le domaine de la théorie de la forme et de la psychologie sociale ayant un intérêt marqué pour l'organisation cognitive de nos perceptions et de nos opinions. L'hypothèse que nous avons posée souligne le lien entretenu entre l'évaluation de la force probante d'un témoin et le verdict émis : un témoignage discriminant possédera plus de poids en cas d'acquittement qu'en cas de condamnation, inversement un témoignage incriminant aura plus de poids en cas de condamnation qu'en cas d'acquittement. L'utilisation d'une échelle en sept points mesurant la force probante des deux types de témoins confirme cette hypothèse, l'estimation de la valeur accordée à un même témoin variant selon le type de verdict choisi. Les argumentations de chaque verdict ont également montré que les catégories d'arguments se référant à l'expert étaient identiques en cas de condamnation ou d'acquittement de l'inculpé, par contre les fréquences de ces catégories entretiennent un lien congruent avec le verdict, celles inculpantes étant majoritairement utilisées pour asseoir la culpabilité mais peu représentées en cas d'acquittement, inversement celles disculpantes apparaissant bien plus lorsqu'il s'agit d'innocenter l'inculpé que pour le condamner.

Temozolomide: a milestone in neuro-oncology and beyond?

Temozolomide (Temodal, Temodar), an imidazol derivative, is a second-generation alkylating agent. The orally available prodrug with the capacity of crossing the blood-brain barrier received accelerated US FDA approval in 1999. Three pivotal Phase II trials showed modest activity in the treatment of recurrent anaplastic astrocytoma glioblastoma. In 2005, the FDA and the European Agency for the Evaluation of Medicinal Products approved temozolomide for use in newly diagnosed glioblastoma, in conjunction with radiotherapy, based on an European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial. The adverse events associated with temozolomide are mild-to-moderate and generally predictable; the most serious are noncumulative and reversible myelosuppression and, in particular, thrombocytopenia, which occurs in less than 5% of patients. Continuous temozolomide administration is associated with profound CD4-selective lymphocytopenia. Molecular studies have suggested that the benefit of temozolomide chemotherapy is restricted to patients whose tumors have a methylated methylguanine methyltransferase gene promotor and are thus unable to repair some of the chemotherapy-induced DNA damage. Temozolomide is under investigation for other disease entities, in particular lower-grade glioma, brain metastases and melanoma.

Isotopic variation across the Audubon's-myrtle warbler hybrid zone.

Differences in seasonal migratory behaviours are thought to be an important component of reproductive isolation in many organisms. Stable isotopes have been used with success in estimating the location and qualities of disjunct breeding and wintering areas. However, few studies have used isotopic data to estimate the movements of hybrid offspring in species that form hybrid zones. Here, we use stable hydrogen to estimate the wintering locations and migratory patterns of two common and widespread migratory birds, Audubon's (Setophaga auduboni) and myrtle (S. coronata) warblers, as well as their hybrids. These two species form a narrow hybrid zone with extensive interbreeding in the Rocky Mountains of British Columbia and Alberta, Canada, which has been studied for over four decades. Isotopes in feathers grown on the wintering grounds or early on migration reveal three important patterns: (1) Audubon's and myrtle warblers from allopatric breeding populations winter in isotopically different environments, consistent with band recovery data and suggesting that there is a narrow migratory transition between the two species, (2) most hybrids appear to overwinter in the south-eastern USA, similar to where myrtle warblers are known to winter, and (3) some hybrid individuals, particularly those along the western edge of the hybrid zone, show Audubon's-like isotopic patterns. These data suggest there is a migratory divide between these two species, but that it is not directly coincident with the centre of the hybrid zone in the breeding range. We interpret these findings and discuss them within the context of previous research on hybrid zones, speciation and migratory divides.

Off-resonance angiography: a new method to depict vessels--phantom and rabbit studies.

PURPOSE: To evaluate the utility of inversion recovery with on-resonant water suppression (IRON) in combination with injection of the long-circulating monocrystalline iron oxide nanoparticle (MION)-47 for contrast material-enhanced magnetic resonance (MR) angiography. MATERIALS AND METhods: Experiments were approved by the institutional animal care committee. Eleven rabbits were imaged at baseline before injection of a contrast agent and then serially 5-30 minutes, 2 hours, 1 day, and 3 days after a single intravenous bolus injection of 80 micromol of MION-47 per kilogram of body weight (n = 6) or 250 micromol/kg MION-47 (n = 5). Conventional T1-weighted MR angiography and IRON MR angiography were performed on a clinical 3.0-T imager. Signal-to-noise and contrast-to-noise ratios were measured in the aorta of rabbits in vivo. Venous blood was obtained from the rabbits before and after MION-47 injection for use in phantom studies. RESULTS: In vitro blood that contained MION-47 appeared signal attenuated on T1-weighted angiograms, while characteristic signal-enhanced dipolar fields were observed on IRON angiograms. In vivo, the vessel lumen was signal attenuated on T1-weighted MR angiograms after MION-47 injection, while IRON supported high intravascular contrast by simultaneously providing positive signal within the vessels and suppressing background tissue (mean contrast-to-noise ratio, 61.9 +/- 12.4 [standard deviation] after injection vs 1.1 +/- 0.4 at baseline, P < .001). Contrast-to-noise ratio was higher on IRON MR angiograms than on conventional T1-weighted MR angiograms (9.0 +/- 2.5, P < .001 vs IRON MR angiography) and persisted up to 24 hours after MION-47 injection (76.2 +/- 15.9, P < .001 vs baseline). CONCLUSION: IRON MR angiography in conjunction with superparamagnetic nanoparticle administration provides high intravascular contrast over a long time and without the need for image subtraction.

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSION: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial.

OBJECTIVE: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS: Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES: Mean change in visual acuity at 1 year. RESULTS: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.