Search

Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death. Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394. Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p Interpretation: A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

The reaction of partially saturated derivatives of 3-aminothieno[2,3-b]pyridine-2-carboxamide with phthalic anhydride in acetic acid or DMF on heating leads to the formation of thieno[2′,3′:5.6]pyrimido[2,1-a]isoindole derivatives fused with a pyridine or quinoline core. One of the obtained compounds shows a pronounced UV fluorescence.

The reaction of N-substituted amides of 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylic acids with ninhydrin in the presence of catalytic amounts of sulfuric acid gave 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-triones. Structure of a number of key compounds was studied using 2D NMR spectroscopy; the bioavailability parameters of the obtained compounds in silico were calculated. In a laboratory experiment, a moderate antidote effect was revealed with respect to the 2,4-D herbicide for one compound.

D-Pantoic acid amide obtained by treatment of D-(–)-pantolactone with ammonia reacted with acetic anhydride in the presence of perchloric acid to give 5-[2-(acetoxy)-1,1-dimethylethyl]-2-methyl-4-oxo- 4,5-dihydro-1,3-oxazolium perchlorate. Reaction of the latter with aromatic aldehydes afforded 2-(2- arylethenyl)-4-oxo-4,5-dihydro-1,3-oxazolium perchlorates which showed no appreciable growth-regulating activity but clearly exhibited antidotal activity against 2,4-dichlorophenoxyacetic acid (2,4-D herbicide).

Aminomethylation of xanthane hydride (5-amino-1,2,4-dithiazole-3-thione) with the RNH2–HCHO system has resulted in the formation of the derivatives of new heterocyclic system (3,7-dihydro-5H-[1,2,4]-dithiazolo[4,3-a][1,3,5]triazine) in low yields. The reaction of xanthane hydride with dicyandiamide has led to thioammeline [4,6-diamino-1,3,5-triazine-2(5Н)-thione]. Some practically important properties of xanthane hydride and its derivatives have been investigated. Xanthane hydride has efficiently exhibited carbon steel corrosion in neutral aqueous media. The prepared compounds have not exhibited growth-regulating or antidote activity to herbicide 2,4-D.

The textbook is devoted to the critical analysis of philosophical and historical concepts of the past and the present - from the philosophy of antiquity to postmodernism. Does history make sense? Is there any progress in history? Is it possible to identify the laws of history and manage it? - these and many other questions are answered by the manual. For students and postgraduates of Humanities faculties, as well as for all those interested in actual problems of philosophy

We report N-alkylation reactions of pyrrolo[1,2-a][1,4]diazepin-6-ones annulated with a benzene ring or thieno[2,3-b]pyridine system. A range of new N5-substituted pyrrolodiazepines were synthesized, including compounds acting as antidotes against the herbicide 2,4-D.

In this paper the asymmetric bipolar membranes modified by functionalized hyperbranched polymers were obtained and the pH correction process of sodium chloride dilute solution in the electrodialyzer with a two-compartment elementary cell formed by the original or modified asymmetric bipolar membranes and a strongly basic anion-exchange membranes was studied. The hyperbranched polymer Boltorn H20 with 16 hydroxyl terminal groups in the molecule was used as a substrate for creation of a functionalized water splitting catalyst. The obtained carboxylated and phosphorylated hyperbranched polymers were analyzed by FTIR and NMR spectroscopy. Modified asymmetric bipolar membranes were characterized by scanning electron microscopy and elemental analysis of membrane cross-sections. The comparison of the current efficiency of the electrodialysis process (pH correction of 0.01 M sodium chloride solution) with studied membranes showed that proposed modification makes it possible to achieve an increase in the effectiveness of electrodialysis. It was established that asymmetric bipolar membranes with cation-exchange layer thickness of 20 μm and modified by active catalysts of water dissociation reaction behave like traditional heterogeneous bipolar membranes with their primary function of Н + and ОН − ions generation during pH correction of dilute solutions.

Triethylammonium salts of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)malononitriles were prepared by reaction of aldehydes with Meldrum's acid and 2-amino-1,1,3-tricyanopropene (malononitrile dimer) in the presence of triethylamine. Upon treatment with alpha-mercaptocarbonyl compounds in the presence of alkali, new thieno[2,3-h][1,6]naphthyridines were prepared in good yields.

The reaction of 4-hydroxy-7,7-dimethyl-7,8-dihydro-6H-chromen-2,5-dione with aldehydes and malononitrile afforded new pyrano[3,2-c]chromenes. Upon treatment of 4-hydroxy-7,7-dimethyl-7,8-dihydro-6H-chromen-2,5-dione with anilines and triethyl orthoformate, new 3-anilinomethylidene 7,8-dihydro-2H-chromen-2,4,5(3H,6H)-triones were synthesized.

A library of new spiro pyrido[3',2':4,5]thieno[3,2-d]pyrimidines was synthesized by reaction of 3-aminothieno[2,3-b]pyridine-2-carboxamides with ninhydrin hydrate. The optimal reaction conditions and mechanism are discussed.

Diazotation of substituted 3-aminopyridines with subsequent substitution of diazo groups with sulfonyl groups in the obtained diazonium chlorides was used to synthesize the corresponding pyridine-3-sulfonyl chlorides. The conditions for this synthesis were optimized by taking into account the detailed understanding of this substitution. The synthesized pyridine-3-sulfonyl chlorides were converted to pyridine-3-sulfonic acids and -sulfonyl amides.

The reaction of D-(–)-pantolactone with ammonia leads to the formation of D-pantoamide, which reacts with Ас2О and HClO4 to give 5-[2-(acetoxy)-1,1-dimethylethyl]-2-methyl-4-oxo-4,5-dihydro-1,3-oxazolium perchlorate. The obtained 2-methyl-1,3-oxazolium perchlorate readily reacts with aromatic aldehydes to afford 2-(2-arylvinyl)-1,3-oxazolium perchlorates. The plant protecting properties of the obtained compounds were studied. We found that 2-(2-arylvinyl)-4-oxo-4,5-dihydro-1,3-oxazolium perchlorates are effective as antidotes towards herbicide 2,4-D but have no plant growth activity.

The mild Radziszewski oxidation of 3-aryl-2-cyanoacrylamides with H2O2–NaOH (or H2O2–Na2CO3) system leads to the formation of oxirane-2,2-dicarboxamides in good yields. The reactions and structure of the obtained products were studied. The aminolysis of the oxirane-2,2-dicarboxamides effected by primary amines occurs in keeping with Krasusky rule to afford 2-(1-R-amino-ethyl)-3-aryl-2-hydroxymalonamides or tartronamide.We found that 3-(4-methoxyphenyl)oxirane-2,2-dicarboxamide exhibited moderate activity both as plant growth regulator and 2,4-D antidote.

The reaction of S-alkyl thiobarbiturates with aromatic aldehydes and malononitrile (or arylmethylidenemalononitrile) leads to hitherto unknown 4Н-pyrano[2,3-d]pyrimidines. Plant growth regulating activity and herbicide antidote activity were studied in the series of the obtained compounds. We found that ethyl {[7-amino-6-cyano-5-(4-methoxyphenyl)-4-oxo-3,5-dihydro-4Н-pyrano[2,3-d]pyrimidin-2-yl)thio}acetic acid revealed moderate activity as 2,4-D antidote.