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

Three new constituents from the stems of <i>Knema globularia</i> and their <i>α</i>-glucosidase inhibitory activity

Three new metabolites (1−3) were isolated from the stems of Knema globularia, along with five known compounds, including kaempferol (4), quercetin (5), isovanillic acid (6), protocatechuic acid (7), and gallic acid (8). Their structures were deduced using NMR spectroscopic, mass spectrometric analyses, and literature data. The absolute configurations of 1−3 were established by electronic circular dichroism (ECD) spectroscopy. α-Glucosidase inhibitory activities of those compounds were evaluated using a spectrophotometric method, compounds 1−3 showed very strong effects towards α-glucosidase with IC50 values 1.59, 0.58 and 1.37 µM, respectively (the positive control, acarbose, IC50 93.63 µM). Simultaneously, enzyme kinetics study indicated that 2 was a mix-type inhibitor. 2 interacted well in the active site of α-glucosidase enzyme, primarily through hydrogen bonds and hydrophobic interactions.</p

Biological Activities of Lichen-Derived Monoaromatic Compounds

Lichen-derived monoaromatic compounds are bioactive compounds, associated with various pharmacological properties: antioxidant, antifungal, antiviral, cytotoxicity, and enzyme inhibition. However, little is known about data regarding alpha-glucosidase inhibition and antimicrobial activity. Very few compounds were reported to have these activities. In this paper, a series of monoaromatic compounds from a lichen source were isolated and structurally elucidated. They are 3,5-dihydroxybenzoic acid (1), 3,5-dihydroxybenzoate methyl (2), 3,5-dihydroxy-4-methylbenzoic acid (3), 3,5-dihydroxy-4-methoxylbenzoic acid (4), 3-hydroxyorcinol (5), atranol (6), and methyl hematommate (7). To obtain more derivatives, available compounds from the previous reports such as methyl &beta;-orsellinate (8), methyl orsellinate (9), and D-montagnetol (10) were selected for bromination. Electrophilic bromination was applied to 8&ndash;10 using NaBr/H2O2 reagents to yield products methyl 5-bromo-&beta;-orsellinate (8a), methyl 3,5-dibromo-orsellinate (9a), 3-bromo-D-montagnetol (10a), and 3,5-dibromo-D-montagnetol (10b). Compounds were evaluated for alpha-glucosidase inhibition and antimicrobial activity against antibiotic-resistant, pathogenic bacteria Enterococcus faecium, Staphylococcus aureus, and Acinetobacter baumannii. Compound 4 showed stronger alpha-glucosidase inhibition than others with an IC50 value of 24.0 &micro;g/mL. Synthetic compound 9a exhibited remarkable activity against Staphylococcus aureus with a MIC value of 4 &micro;g/mL. Molecular docking studies were performed to confirm the consistency between in vitro and in silico studies

&alpha;-Glucosidase Inhibitory and Antimicrobial Benzoylphloroglucinols from Garcinia schomburgakiana Fruits: In Vitro and In Silico Studies

&alpha;-Glucosidase plays a role in hydrolyzing complex carbohydrates into glucose, which is easily absorbed, causing postprandial hyperglycemia. Inhibition of &alpha;-glucosidase is therefore an ideal approach to preventing this condition. A novel polyprenylated benzoylphloroglucinol, which we named schomburgkianone I (1), was isolated from the fruit of Garcinia schomburgkiana, along with an already-reported compound, guttiferone K (2). The structures of the two compounds were determined using NMR and HRESIMS analysis, and comparisons were made with previous studies. Compounds 1 and 2 exhibited potent &alpha;-glucosidase inhibition (IC50s of 21.2 and 34.8 &micro;M, respectively), outperforming the acarbose positive control. Compound 1 produced wide zones of inhibition against Staphylococcus aureus and Enterococcus faecium (of 21 and 20 mm, respectively), compared with the 19 and 20 mm zones of compound 2, at a concentration of 50 &micro;g/mL. The MIC value of compound 1 against S. aureus was 13.32 &micro;M. An in silico molecular docking model suggested that both compounds are potent inhibitors of enzyme &alpha;-glucosidase and are therefore leading candidates as therapies for diabetes mellitus

DP4-Assisted Structure Elucidation of Isodemethylchodatin, a New Norlichexanthone Derivative Meager in H-Atoms, from the Lichen Parmotrema tsavoense

International audienceA phytochemical investigation of the foliose lichen (Krog and Swinscow) Krog and Swinscow (Parmeliaceae) resulted in the isolation of a new trichlorinated xanthone, isodemethylchodatin. The structure elucidation of this new norlichexanthone derivative proved tricky owing to proton deficiency, and to the lack of NMR data of closely related analogues. The structure of this compound was determined based on an integrated interpretation of C-NMR chemical shifts, MS spectra, and DP4-based computational chemistry was also performed to provide an independent and unambiguous validation of the determined structure. Isodemethylchodatin represents the first chlorinated lichexanthone/norlichexanthone derivative bearing a methoxy group at C-5

Potential Antimicrobial and Anticancer Activities of an Ethanol Extract from Bouea macrophylla

Bouea macrophylla is a tree widely grown throughout South East Asia. It is used in folk medicine for the treatment of various illnesses. The present study aimed to identify the chemical constituents and to test the antimicrobial and anticancer activities of an ethanol extract from B. macrophylla leaves. The extract exhibited excellent antibacterial properties against 9 out of 10 target microorganisms. including four Gram-negative bacteria (Escherichia coli, Shigella flexneri, Vibrio cholera, and Pseudomonas aeruginosa) and four Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, and Bacillus cereus), as well as a fungus (Candida albicans). In addition, the extract was also tested on HeLa and human colorectal carcinoma (HCT116) cells to evaluate its cytostatic effects. The ethanol extract was able to inhibit the proliferation of HeLa and HCT116 cells, showing IC50 = 24 &plusmn; 0.8 and 28 &plusmn; 0.9 &micro;g/mL, respectively, whereas the IC50 values of doxorubicin (standard) were 13.6 &plusmn; 1.3 and 15.8 &plusmn; 1.1 &micro;g/mL respectively. Also, we identified various bioactive compounds in the extract such as polyphenols, flavonoids, caryophyllene, phytol, and trans-geranylgeraniol by GC-MS, which could contribute to the extract&rsquo;s biological activities. Therefore, our findings strongly indicate that the constituents of the B. macrophylla ethanol extract could be active against the tested bacteria and fungi as well as cancer cells. Further investigation is needed to understand the mechanisms mediating the antimicrobial and anticancer effects and identify signaling pathways that could be targeted for therapeutic application