Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Iron- and copper-catalyzed Chemistry of iminoiodanes as novel synthetic strategies for C−N bond formation

The work in this thesis was undertaken in Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences in Nanyang Technological University from January 2009 to May 2012 under the supervision of Asst. Prof. Philip Wai Hong Chan. The work of this thesis has been directed toward the development of new iron and copper-catalyzed chemistry of nitrogen atom transfer reactions from iminoioddanes to C=C and C−H bonds as efficient synthetic strategies to C−N bond formation. This thesis is divided into three parts: Part I consists of Chapter I, which gives an introduction to iron and copper catalysis and its application to aziridination and amination of C=C and C−H bonds with hypervalent iodine(III) reagents. Part II is aimed at exploring novel nitrogen atom transfer reactions employing inexpensive, less-toxic and biocompatible nature of iron and copper catalysis. Chapter II details the efficient and practical iron-catalyzed synthetic route to acyl sulfonamides based on nitrene/imido insertion into the formylic C−H bond of aldehydes. The methodology is aimed to expand the reaction tolerance toward a structurally diverse set of starting aldehydes and compliment earlier works mediated by Ru(II) and Cu(I) catalysts. Detailed mechanistic studies to delineate this amination process will also be discussed. In chapter III, the intriguing conversion of 2-alkyl substituted 1,3-dicarbonyl compounds to α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives mediated by Cu(OTf)2 and PhI=NTs are described. Complete control of product selectivity in the reaction is shown to be possible through slight modification of the reaction conditions. Chapter IV addresses a highly efficient copper-catalyzed amination of various 1,3-dicarbonyls compounds as a convenient and effective route to ketone substituted α-amino acid derivatives. Chapter V presents the ligand-free iron-catalyzed α-amination of saturated heterocyclic compounds via a nitrogen atom insertion to the α-C−H bond of the substrates. The synthetic utility of this methodology is exemplified by ring-opening of the α-aminated products by various nucleophiles to provide a range of substituted diamine and amino alcohol compounds. Part III contains experimental data (Chapter VI) and references (Chapter VII) pertaining to this thesis.DOCTOR OF PHILOSOPHY (SPMS

Copper(II) Triflate catalyzed amination of 1,3-dicarbonyl compounds

A method to prepare α,α-acyl amino acid derivatives efficiently by Cu(OTf)2+1,10-phenanthroline (1,10-phen)-catalyzed amination of 1,3-dicarbonyl compounds with PhI[DOUBLE BOND]NSO2Ar is described. The mechanism is thought to initially involve aziridination of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, by the putative copper–nitrene/imido species generated from the reaction of the metal catalyst with the iminoiodane source. Subsequent ring opening of the resultant aziridinol adduct under the Lewis acidic conditions then provided the α-aminated product. The utility of this method was exemplified by the enantioselective synthesis of a precursor of 3-styryl-2-benzoyl-l-alanine

Copper(II) triflate catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds

A method to prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives efficiently from Cu(OTf)2 + 1,10-phenanthroline (1,10-phen)-catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhI═NTs is described. By taking advantage of the orthogonal modes of reactivity of the substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the iminoiodane, amination of the allylic C—H bond of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the amount of the nitrogen source from 1.2 to 2–3 equiv was discovered to result in preferential formal aziridination of the C—C bond of the 2-alkyl substituent of the starting material and formation of the aziridine product

Practical copper(I)-catalysed amidation of aldehydes

The direct synthesis of amides by insertion into the C-H bond of aldehydes is shown to be a practical procedure through application of cheap, readily available catalysts generated in situ from copper(I) halides and pyridine

Copper(II) Triflate Catalyzed Amination and Aziridination of 2-Alkyl Substituted 1,3-Dicarbonyl Compounds

A method to prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives efficiently from Cu­(OTf)₂ + 1,10-phenanthroline (1,10-phen)-catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhINTs is described. By taking advantage of the orthogonal modes of reactivity of the substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the iminoiodane, amination of the allylic CH bond of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the amount of the nitrogen source from 1.2 to 2–3 equiv was discovered to result in preferential formal aziridination of the CC bond of the 2-alkyl substituent of the starting material and formation of the aziridine product

Copper(II) Triflate Catalyzed Amination and Aziridination of 2-Alkyl Substituted 1,3-Dicarbonyl Compounds

A method to prepare α-acyl-β-amino acid and 2,2-diacyl aziridine derivatives efficiently from Cu­(OTf)₂ + 1,10-phenanthroline (1,10-phen)-catalyzed amination and aziridination of 2-alkyl substituted 1,3-dicarbonyl compounds with PhINTs is described. By taking advantage of the orthogonal modes of reactivity of the substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. In the presence of 1.2 equiv of the iminoiodane, amination of the allylic CH bond of the enolic form of the substrate, formed in situ through coordination to the Lewis acidic metal catalyst, was found to selectively occur and give the β-aminated adduct. On the other hand, increasing the amount of the nitrogen source from 1.2 to 2–3 equiv was discovered to result in preferential formal aziridination of the CC bond of the 2-alkyl substituent of the starting material and formation of the aziridine product

An observational study of breakthrough SARS-CoV-2 Delta variant infections among vaccinated healthcare workers in Vietnam

Background Data on breakthrough SARS-CoV-2 Delta variant infections in vaccinated individuals are limited. Methods We studied breakthrough infections among Oxford-AstraZeneca vaccinated healthcare workers in an infectious diseases hospital in Vietnam. We collected demographic and clinical data alongside serial PCR testing, measurement of SARS-CoV-2 antibodies, and viral whole-genome sequencing. Findings Between 11th–25th June 2021 (7-8 weeks after the second dose), 69 staff tested positive for SARS-CoV-2. 62 participated in the study. Most were asymptomatic or mildly symptomatic and all recovered. Twenty-two complete-genome sequences were obtained; all were Delta variant and were phylogenetically distinct from contemporary viruses obtained from the community or from hospital patients admitted prior to the outbreak. Viral loads inferred from Ct values were 251 times higher than in cases infected with the original strain in March/April 2020. Median time from diagnosis to negative PCR was 21 days (range 8–33). Neutralizing antibodies (expressed as percentage of inhibition) measured after the second vaccine dose, or at diagnosis, were lower in cases than in uninfected, fully vaccinated controls (median (IQR): 69.4 (50.7-89.1) vs. 91.3 (79.6-94.9), p=0.005 and 59.4 (32.5-73.1) vs. 91.1 (77.3-94.2), p=0.043). There was no correlation between vaccine-induced neutralizing antibody levels and peak viral loads or the development of symptoms. Interpretation Breakthrough Delta variant infections following Oxford-AstraZeneca vaccination may cause asymptomatic or mild disease, but are associated with high viral loads, prolonged PCR positivity and low levels of vaccine-induced neutralizing antibodies. Epidemiological and sequence data suggested ongoing transmission had occurred between fully vaccinated individuals

Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke: AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921