The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

Tolerance of high and low amounts of PLGA microspheres loaded with mineralocorticoid receptor antagonist in retinal target site

Mineralocorticoid receptor (MR)contributes to retinal/choroidal homeostasis. Excess MR activation has been shown to be involved in pathogenesis of central serous chorioretinopathy (CSCR). Systemic administration of MR antagonist (MRA) reduces subretinal fluid and choroidal vasodilation, and improves the visual acuity in CSCR patients. To achieve long term beneficial effects in the eye while avoiding systemic side-effects, we propose the use ofbiodegradable spironolactone-loaded polylactic-co-glycolic acid (PLGA)microspheres (MSs). In this work we have evaluated the ocular tolerance of MSs containing spironolactone in rats’ eyes. As previous step, we have also studied the tolerance of the commercial solution of canrenoate salt, active metabolite of spironolactone. PLGA MSs allowed in vitro sustained release of spironolactone for 30 days. Rat eyes injected with high intravitreous concentration of PLGA MSs (10 mg/mL) unloaded and loaded with spironolactone maintained intact retinal lamination at 1 month. However enhanced glial fibrillary acidic protein immunostaining and activated microglia/macrophages witness retinal stress were observed. ERG also showed impaired photoreceptor function. Intravitreous PLGA MSs concentration of 2 mg/mL unloaded and loaded with spironolactone resulted well tolerated. We observed reduced microglial/macrophage activation in rat retina compared to high concentration of MSs with normal retinal function according to ERG. Spironolactone released from low concentration of MSs was active in the rat retina. Low concentration of spironolactone-loaded PLGA MSs could be a safe therapeutic choice for chorioretinal disorders in which illicit MR activation could be pathogenic

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease

Recent extraction techniques for natural products: microwave-assisted extraction and pressurised solvent extraction

In the last 10 years there has been an increased interest in using techniques involving microwave-assisted extraction and pressurised solvent extraction in analytical laboratories. This review gives a brief overview of both methods, and reports on their application to the extraction of natural products. The influence of parameters such as the nature of the solvent and volume, temperature, time and particle size of the matrix is discussed. Through numerous examples, it is demonstrated that both techniques allow reduced solvent consumption and shorter extraction times, while the extraction yields of the analytes are equivalent to or even higher than those obtained with conventional methods

Parameters affecting microwave-assisted extraction of withanolides

Focused microwave-assisted extraction was applied to the extraction of three main withanolides from airdried leaves of Iochroma gesnerioides, namely, withaferin A, iochromolide and withacnistin. Six extraction variables, i.e. nature and volume of extracting solvent, sample moisture, extraction time, power of irradiation and particle size, were investigated with respect to the recovery of withanolides. The most favourable conditions were obtained by using powdered plant material (< 220 microns), previously impregnated with water for 15 min, and extracted with methanol for 40 s at 25 W. The results obtained using the optimised method were compared to those achievable with Soxhlet extraction

Study of factors influencing pressurised solvent extraction of polar steroids from plant material : application to the recovery of withanolides

Pressurised solvent extraction was applied to the extraction of three withanolides from the leaves of lochroma gesnerioides. A study was carried out of the influence of various parameters on the extraction efficiency and kinetic parameters; these included the nature of the extracting solvent, its flow rate, the pressure and temperature, as well as the particle size of the plant material. The pressurised solvent extraction method compared to a conventional Soxhlet extraction showed similar recoveries and extraction selectivity but the total handling time and solvent volume were dramatically reduced

ReintroducIng CIirculatIons: Historiography and the Project of Global Art History

International audienceWorld art history has gained much attention in recent years, opening many new possibilities for the discussion of the history of art in general. There are myriad ways to approach envisaging a history that is truly global, also meaning universal or comprehensive, an Enlightenment project that may perhaps no longer seem so utopian. This book suggests how a revival of attention to circulations can renew the practice of art history and contribute to the discussion of world, global art history. It proposes that following the transnational circulations of artists, artworks, and styles provides a means not only to escape from the national narratives in which previous approaches had been enmeshed, but also to write a global history of art for a globalized world. We still employ the word " art, " although we recognize that the concept of art may be relativized, that for instance it might be conceived differently in one place than in another, that its meaning changes in time, and that this concept might not even be expressed in certain times and places. We advocate an approach to transnational, global history through the study of circulations for several reasons. In the first place, and most important,global history as we understand it has to include the entire world, and not be the history of oneself and of “others.” Approaches toward the comprehension of circulations appear to us to be the only ones that have so far succeeded in taking into account “others” without shutting them inside the prison of the notion of alterity or dismissing them as peripheral. Attention to the constant operation of circulations indicates that what are usually designated “cultures” in effect result from the ceaseless transformation of the circulations and adaptations of ideas, objects, and images originating elsewhere, notably including regions that a point of view governed by a paradigm of center– periphery relations would deem “peripheral.” Hence, only an understanding of history as a result of the continuing circulation of materials, people, and ideas can escape from the hypostasis of cultural entities such as “Western and non-Western,” which derive from a priori essentialist definitions, and which also supply grist to the mill of politicized interests, themselves perhaps not even consciously articulated

Rapid liquid chromatographic-mass spectrometric analysis of withanolides in crude plant extracts by use of a monolithic column

A rapid analytical method has been developed for the mutual resolution of three steroidal compounds, withaferin A, iochromolide, and withacnistin. Liquid chromatography was performed on a Chromolith analytical column (4.6 mm i.d.×50 mm), made from a cylindrical silica rod, operated at a flow rate of 4 mL min−1 with a simple linear gradient prepared from 0.1% aqueous formic acid and 0.1% formic acid in acetonitrile. Under optimum conditions simultaneous separation of the compounds was achieved in less than 7 min, one eighth the time required for conventional LC separation. The overall analysis time was reduced without sacrificing chromatographic performance—essential for the resolution of positional isomers such as iochromolide and withacnistin. The column was coupled to a single-quadrupole mass spectrometer and the method was characterized by good performance in terms of repeatability, selectivity, linearity, and sensitivity. Detection limits in the single-ion-monitoring mode were 0.15 μg mL−1 or below. Finally, the developed method was successfully applied to the determination of withanolides in extracts fromlochroma gesnerioides obtained by three different processes—traditional Soxhlet extraction and two faster methods, microwave-assisted extraction and pressurized solvent extraction

Influence of plant matrix on microwave-assisted extraction process. The case of diosgenin extracted from fenugreek (Trigonella foenum-graecum L.)

A focused microwave-assisted extraction method was developed for the extraction of diosgenin from fenugreek (Trigonella foenum-graecum) seeds, air-dried and fresh leaves and air-dried roots. Several experimental parameters were studied, including extraction time, microwave power applied and percentage of 2-propanol in the extraction mixture as well as their interactions, in order to optimize the extraction efficiency. The two latter parameters were found to be the most important. Response surface modelling was used to predict the extraction yield of diosgenin in selected matrices. The analysis of diosgenin in crude extracts was carried out by capillary gas chromatography-mass spectrometry (GC-MS)