Étude des possibilités et des limitations des réarrangements photochimiques et thermiques dérivés d'acide hydroxamiques cycliques et synthèse formelle de la géphyrotoxine 287C impliquant le réarrangement photochimique de N-chlorolactame

Cette thèse présente l'étude de la régiosélectivité de la contraction de cycle par migration-[1,2] de N -mésyloxylactames par voie photochimique et le développement de ce même type de réarrangement de N -trifloxylactames, mais par voie thermique, en plus des efforts déployés à développer une méthode de synthèse d'acides hydroxamiques cycliques. Également, one étude préliminaire du piégeage intramoléculaire de l'intermédiaire formé lors du réarrangement photochimique de N -mésyloxylactames, un cation aza-acylium, de même qu'une application en synthèse du réarrangement photochimique de N -chlorolactames sont présentées. Le premier chapitre montre one étude complète de la régiosélectivité lors du réarrangement photochimique de N -mésyloxylactames, à savoir quels facteurs influencent la compétition entre la migration du carbone voisin du carbonyle et la migration du carbone voisin de l'atome d'azote. Dans le second chapitre, l'étude des possibilités et limitations du réarrangement thermique de N -trifloxylactames est présentée. Ce réarrangement thermique donne de meilleurs rendements en produits de migration que le réarrangement photochimique de N -mésyloxylactames pour les substrats ne portant pas de substituants sur les carbones qui migrent. De plus, la base utilisée dans la réaction permet d'obtenir on contrôle sur la régiosélectivité dans certains cas. Le troisième chapitre fait état des efforts qui ont été investis dans le développement d'une méthode de synthèse efficace d'acides hydroxamiques cycliques, molécules utilisées dans la synthèse des substrats nécessaires à l'étude des réarrangements photochimiques et thermiques. Le quatrième chapitre porte sur l'étude préliminaire du piégeage intramoléculaire, par on nucléophile carbone, du cation aza-acylium intermédiaire formé lors du réarrangement photochimique de N -mésyloxylactames. Finalement, le cinquième chapitre démontre l'utilité du réarrangement photochimique de N -chlorolactames en l'appliquant à la synthèse d'on produit naturel. En effet, one stratégie comprenant cette réaction de contraction de cycle comme étape-cle à été utilisée dans one synthèse formelle de la géphyrotoxine 287C

Prospects on Time-Domain Diffuse Optical Tomography Based on Time-Correlated Single Photon Counting for Small Animal Imaging

This paper discusses instrumentation based on multiview parallel high temporal resolution (<50 ps) time-domain (TD) measurements for diffuse optical tomography (DOT) and a prospective view on the steps to undertake as regards such instrumentation to make TD-DOT a viable technology for small animal molecular imaging. TD measurements provide information-richest data, and we briefly review the interaction of light with biological tissues to provide an understanding of this. This data richness is yet to be exploited to its full potential to increase the spatial resolution of DOT imaging and to allow probing, via the fluorescence lifetime, tissue biochemical parameters, and processes that are otherwise not accessible in fluorescence DOT. TD data acquisition time is, however, the main factor that currently compromises the viability of TD-DOT. Current high temporal resolution TD-DOT scanners simply do not integrate sufficient detection channels. Based on our past experience in developing TD-DOT instrumentation, we review and discuss promising technologies to overcome this difficulty. These are single photon avalanche diode (SPAD) detectors and fully parallel highly integrated electronics for time-correlated single photon counting (TCSPC). We present experimental results obtained with such technologies demonstrating the feasibility of next-generation multiview TD-DOT therewith

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Étude des possibilités et des limitations des réarrangements photochimiques et thermiques dérivés d'acide hydroxamiques cycliques et synthèse formelle de la géphyrotoxine 287C impliquant le réarrangement photochimique de N-chlorolactame

Cette thèse présente l'étude de la régiosélectivité de la contraction de cycle par migration-[1,2] de N -mésyloxylactames par voie photochimique et le développement de ce même type de réarrangement de N -trifloxylactames, mais par voie thermique, en plus des efforts déployés à développer une méthode de synthèse d'acides hydroxamiques cycliques. Également, one étude préliminaire du piégeage intramoléculaire de l'intermédiaire formé lors du réarrangement photochimique de N -mésyloxylactames, un cation aza-acylium, de même qu'une application en synthèse du réarrangement photochimique de N -chlorolactames sont présentées. Le premier chapitre montre one étude complète de la régiosélectivité lors du réarrangement photochimique de N -mésyloxylactames, à savoir quels facteurs influencent la compétition entre la migration du carbone voisin du carbonyle et la migration du carbone voisin de l'atome d'azote. Dans le second chapitre, l'étude des possibilités et limitations du réarrangement thermique de N -trifloxylactames est présentée. Ce réarrangement thermique donne de meilleurs rendements en produits de migration que le réarrangement photochimique de N -mésyloxylactames pour les substrats ne portant pas de substituants sur les carbones qui migrent. De plus, la base utilisée dans la réaction permet d'obtenir on contrôle sur la régiosélectivité dans certains cas. Le troisième chapitre fait état des efforts qui ont été investis dans le développement d'une méthode de synthèse efficace d'acides hydroxamiques cycliques, molécules utilisées dans la synthèse des substrats nécessaires à l'étude des réarrangements photochimiques et thermiques. Le quatrième chapitre porte sur l'étude préliminaire du piégeage intramoléculaire, par on nucléophile carbone, du cation aza-acylium intermédiaire formé lors du réarrangement photochimique de N -mésyloxylactames. Finalement, le cinquième chapitre démontre l'utilité du réarrangement photochimique de N -chlorolactames en l'appliquant à la synthèse d'on produit naturel. En effet, one stratégie comprenant cette réaction de contraction de cycle comme étape-cle à été utilisée dans one synthèse formelle de la géphyrotoxine 287C