Magnolin is a naturally occurring, multi-bioactive lignan molecule with inherent anticancer effects. This study aims to summarize the botanical origins and anticancer properties of magnolin. For ...this, a recent (as of March 2023) literature review was conducted using various academic search engines, including PubMed, Springer Link, Wiley Online, Web of Science, Science Direct, and Google Scholar. All the currently available information about this phytochemical and its role in various cancer types has been gathered and investigated. Magnolin is a compound found in many different plants. It has been demonstrated to have anticancer activity in numerous experimental models by inhibiting the cell cycle (G1 and G2/M phase); inducing apoptosis; and causing antiinvasion, antimetastasis, and antiproliferative effects via the modulation of several pathways. In conclusion, magnolin showed robust anticancer activity against many cancer cell lines by altering several cancer signaling pathways in various non- and pre-clinical experimental models, making it a promising plant-derived chemotherapeutic option for further clinical research.
The indiscriminate use of antimicrobial drugs has increased the spectrum of exposure of these organisms. In our studies, these phenolic compounds were evaluated: gallic acid, caffeic acid and ...pyrogallol. The antibacterial, antifungal and modulatory of antibiotic activities of these compounds were assayed using microdilution method of Minimum Inhibitory Concentration (MIC) to bacteria and Minimum Fungicide Concentration (MFC) to fungi. The modulation was made by comparisons of the MIC and MFC of the compounds alone and combined with drugs against bacteria and fungi respectively, using a sub-inhibitory concentration of 128 μg/mL of substances (MIC/8). All substances not demonstrated clinically relevant antibacterial activity with a MIC above ≥1024 μg/mL. As a result, we observed that the caffeic acid presented a potentiating antibacterial effect over the 3 groups of bacteria studied. Pyrogallol showed a synergistic effect with two of the antibiotics tested, but only against Staphylococcus aureus. In general, caffeic acid was the substance that presented with the greatest number of antibiotics and with the greatest number of bacteria. In relation to the antifungal activity of all the compounds, the verified results were ≥1024 μg/mL, not demonstrating significant activity. Regarding potentiation of the effect of fluconazole, was observed synergistic effect only when assayed against Candida tropicalis, with all substances. Therefore, as can be seen, the compounds presented as substances that can be promising potentiating agents of antimicrobial drugs, even though they do not have direct antibacterial and antifungal action.
•The pyrogallol reduces the concentration necessary to kill all population of Candida albicans.•All substances reduced the concentration necessary to kill all population of Candida tropicalis.•The caffeic acid potentiated the antibiotic activity against all bacterial strains.•The pyrogallol and gallic acid potentiated the antibiotic activity only against Staphylococcus aureus.
Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib ...compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12–17 years) and adults (aged 18–75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index EASI score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis vIGA-AD score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 clear or 1 almost clear with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 70% of 281 patients) and upadacitinib 30 mg (227 80% of 285 patients) groups than the placebo group (46 16% of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% 95% CI 46·4–60·2 for the upadacitinib 15 mg group; 63·4% 57·1–69·8 for the upadacitinib 30 mg group) and Measure Up 2 (166 60% of 276 patients in the upadacitinib 15 mg group and 206 73% of 282 patients in the upadacitinib 30 mg group vs 37 13% of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% 39·9–53·9 for the upadacitinib 15 mg group; 59·6% 53·1–66·2 for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 48% patients) and upadacitinib 30 mg (177 62% patients) groups than the placebo group (24 8% patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% 33·2–46·4 for the upadacitinib 15 mg group; 53·6% 47·2–60·0 for the upadacitinib 30 mg group) and Measure Up 2 (107 39% patients in the upadacitinib 15 mg group and 147 52% patients in the upadacitinib 30 mg group vs 13 5% patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% 27·8–40·2 for the upadacitinib 15 mg group; 47·4% 41·0–53·7 for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 7% of 281 patients in the upadacitinib 15 mg group, 49 17% of 285 patients in the upadacitinib 30 mg group, and six 2% of 281 patients in the placebo group in Measure Up 1; 35 13% of 276 patients in the upadacitinib 15 mg group, 41 15% of 282 patients in the upadacitinib 30 mg group, and six 2% of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 9% patients, 38 13% patients, and 20 7% patients; 19 7% patients, 17 16% patients, and 12 4% patients), nasopharyngitis (22 8% patients, 33 12% patients, and 16 6% patients; 16 6% patients, 18 6% patients, and 13 5% patients), headache (14 5% patients, 19 7% patients, and 12 4% patients; 18 7% patients, 20 7% patients, and 11 4% patients), elevation in creatine phosphokinase levels (16 6% patients, 16 6% patients, and seven 3% patients; nine 3% patients, 12 4% patients, and five 2% patients), and atopic dermatitis (nine 3% patients, four 1% patients, and 26 9% patients; eight 3% patients, four 1% patients, and 26 9% patients).
Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit–risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
AbbVie.
Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement.
To assess the ...safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD.
Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population.
Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week.
The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug.
Of 924 patients screened, 348 (183 men 52.6%; mean SD age, 36.6 14.6 years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men 56.4%; mean SD age, 36.9 14.1 years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean SE, 31.4% 1.7% vs 8.8% 1.8%; P < .001), achievement of EASI75 as early as week 2 (152 43.7% vs 60 17.4%; P < .001), and achievement of EASI100 at week 16 (97 27.9% vs 26 7.6%; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab.
During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals.
ClinicalTrials.gov Identifier: NCT03738397.
Electronic health records have brought valuable improvements to hospital practices by integrating patient information. In fact, the understanding of these data can prevent mistakes that may put ...patients' lives at risk. Nonetheless, to the best of our knowledge, there are no previous studies addressing the automatic detection of outlier prescriptions, regarding dosage and frequency. In this paper, we propose an unsupervised method, called density-distance-centrality (DDC), to detect potential outlier prescriptions. A dataset with 563 thousand prescribed medications was used to assess our proposed approach against different state-of-the-art techniques for outlier detection. In the experiments, our approach achieves better results in the task of overdose and underdose detection in medical prescriptions, compared to other methods applied to this problem. Additionally, most of the false positive instances detected by our algorithm were potential prescriptions errors.
Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions.
We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 ...inhibitor upadacitinib in patients with moderate to severe atopic dermatitis.
In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment.
Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P = .03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% 1 of 40 for placebo).
A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.
The gut microbiome, a crucial component of the human system, is a diverse collection of microbes that belong to the gut of human beings as well as other animals. These microbial communities continue ...to coexist harmoniously with their host organisms and perform various functions that affect the host's general health. Each person's gut microbiota has a unique makeup. The gut microbiota is well acknowledged to have a part in the local as well as systemic inflammation that underlies a number of inflammatory disorders (e.g., atherosclerosis, diabetes mellitus, obesity, and inflammatory bowel disease).The gut microbiota's metabolic products, such as short-chain fatty acids (butyrate, propionate, and acetate) inhibit inflammation by preventing immune system cells like macrophages and neutrophils from producing pro-inflammatory factors, which are triggered by the structural elements of bacteria (like lipopolysaccharide). The review's primary goal is to provide comprehensive and compiled data regarding the contribution of gut microbiota to inflammation and the associated signalling pathways.
•The microbiome components might trigger inflammation with ILCs and other cytokines.•Short-chain fatty acids of bacterial metabolism may suppress the inflammation.•Address the connection between gut microbiota may lead to new therapeutic approaches.
Phytol is a diterpene constituent of chlorophyll and has been shown to have several pharmacological properties, particularly in relation to the management of painful inflammatory diseases. Arthritis ...is one of the most common of these inflammatory diseases, mainly affecting the synovial membrane, cartilage, and bone in joints. Proinflammatory cytokines, such as TNF-α and IL-6, and the NFκB signaling pathway play a pivotal role in arthritis. However, as the mechanisms of action of phytol and its ability to reduce the levels of these cytokines are poorly understood, we decided to investigate its pharmacological effects using a mouse model of complete Freund’s adjuvant (CFA)-induced arthritis. Our results showed that phytol was able to inhibit joint swelling and hyperalgesia throughout the whole treatment period. Moreover, phytol reduced myeloperoxidase (MPO) activity and proinflammatory cytokine release in synovial fluid and decreased IL-6 production as well as the COX-2 immunocontent in the spinal cord. It also downregulated the p38MAPK and NFκB signaling pathways. Therefore, our findings demonstrated that phytol can be an innovative antiarthritic agent due to its capacity to attenuate inflammatory reactions in joints and the spinal cord, mainly through the modulation of mediators that are key to the establishment of arthritic pain.
Salinization in tropical estuarine environments is expected as a result of climate change. The physiological performance of mangrove-associated key macroalgae can negatively be affected by increased ...salinity in such habitats. Thus, we analyzed photobiological and biochemical responses of the closely related red algae
Bostrychia calliptera
and
Bostrychia montagnei
incubated under a range of salinities (5, 11, 18, 37, 47, and 57 S
A
). Effective and maximum quantum yield, relative electron transport rate vs. photon fluence rate curves, photosynthetic parameters, and complementary energy dissipation pathways indicated that both species had lower photosynthetic performance under increased salinity, which was more strongly pronounced in
B. calliptera
. Both species increased their organic osmolyte contents with rising salinity stress. Dulcitol was the main organic osmolyte synthesized by
B. calliptera
, whereas
B. montagnei
synthesized dulcitol and sorbitol. Our results demonstrate that increased salinity in estuaries due to climate change will be detrimental to photosynthesis of both macroalgae, with
B. calliptera
more affected than
B. montagnei
. As
B. montagnei
synthesizes both dulcitol and sorbitol, it is more tolerant to salinity stress compared to
B. calliptera
. Our data document for the first time a new organic osmolyte distribution pattern in
Bostrychia
species, namely the occurrence of dulcitol only.
An Investigator Global Assessment (IGA) is recommended by health agencies for drug registration in atopic dermatitis (AD). Current IGA scales lack standardization.
To develop an IGA scale, training ...module, and clinical certification examination for use in AD trials; establish content validity; and assess reliability.
Expert dermatologists participated in the development of the validated IGA for AD (vIGA-ADTM). Reliability (interrater and intrarater) was assessed by 2 web-based surveys. Clinical certification for investigators consisted of a training module and examination.
Expert consensus was achieved around a 5-point IGA scale including morphologic descriptions, and content validity was established. Survey 1 showed strong interrater reliability (Kendall's coefficient of concordance W Kendall's W, 0.809; intraclass correlation ICC, 0.817) and excellent agreement (weighted kappa, 0.857). Survey 2, completed 5 months after training of dermatologists, showed improvements in scale reliability (Kendall's W, 0.819; ICC, 0.852; weighted kappa, 0.889). In this study, 627 investigators completed vIGA-AD training and certification.
Ratings were assessed on photographs.
A validated IGA scale and training module were developed with the intent of harmonizing assessment of disease severity in AD trials. Strong reliability and excellent agreement between assessments were observed.
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