Mangaba (hancornia speciosa): exploring potent antifungal and antioxidant properties in lyophilised fruit pulp extract through in vitro analysis.

Mangaba is a fruit native to Brazil, rich in bioactive compounds. To evaluate physicochemical composition, bioactive compounds, antioxidant and antifungal activity of mangaba fruit pulp. Moisture, ash, protein, lipid, energy values and phenolic compounds were determined. Antioxidant activity was determined by capture of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Evaluation of antifungal activity was performed by Minimum Inhibitory Concentration, according to protocols M07-A9 and M27-S3, and minimum fungicidal concentration. Freeze-dried mangaba pulp presented high levels of carbohydrates, low levels of lipids, and high energy density. Phenolic analysis demonstrated that chlorogenic acid was found in the highest concentration, followed by p-coumaric acid and ferulic acid. Mangaba extract showed antioxidant activity like BHT. Mangaba extract inhibited the growth of Candida albicans (ATCC 90028), Cryptococcus gattii (AFLP4), Candida guilliermondii (ATCC 6260) and Candida albicans (MYA 2876). Freeze-dried mangaba inhibited fungal activity associated with antioxidant effect due to presence of phenolic compounds.

Compounds from Natural Products Candidates to Drug for Chikungunya Virus Infection: A Systematic Review.

INTRODUCTION: Chikungunya fever is a disease caused by infection with the Chikungunya virus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Despite its self-limited character, more than 60% of patients have chronic recurrent arthralgia with debilitating pain that lasts for years. AIM: The objective of this review was to gather and analyze evidence from the literature on potential therapeutic strategies with molecules from natural products for the treatment of Chikungunya fever. METHODS: A search was performed for clinical trials, observational studies, in vitro or in vivo, without restriction of the year of publication or language in electronic databases (Medline/PubMed, EMBASE, Google Scholar, The Cochrane Library, LILACS (BVS), clinical trial registries (Clinical Trials.gov), digital libraries from CAPES theses and dissertations (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and conference abstracts. A quality assessment of the selected studies was performed using the SYRCLE, RoB2 and SciRAP tools. RESULTS: 42 studies were included, which showed molecules with potential antiviral pharmacological activity or with activity in reducing the joint complications caused by CHIKV infection. CONCLUSIONS: Among the molecules found in the survey of references, regarding the class of secondary metabolites, flavonoids stood out and for this reason, the molecules may be promising candidates for future clinical trials. Overall, evidence from in vitro studies was of acceptable quality; in vivo and intervention studies showed a high risk of bias, which is a limitation of these studies.

Data wobbles in hidradenitis suppurativa clinical trials and potential contributing factors: a retrospective review.

Background: In some hidradenitis suppurativa (HS) clinical trial study arms, there is an unexpected decline in efficacy between the penultimate visit and the prespecified primary endpoint week, which we have termed a "wobble." Objective: We aimed to establish how often study arms in HS programs wobble. Methods: In a retrospective review, we identified HS clinical trials listed on ClinicalTrials.gov testing systemic, nonantibiotic medications that utilized Hidradenitis Suppurativa Clinical Response (HiSCR) as an outcome measure. We identified study arms demonstrating greater improvement in a visit prior to the primary endpoint week. Baseline subject characteristics were compared between studies with HiSCR wobble and no HiSCR wobble. Results: A total of 21 studies (randomized control trial [RCT], n = 14; open-label, n = 7) with 35 study drug arms (RCT, n = 27; open-label, n = 8) and 14 placebo arms were identified. HiSCR wobble occurred significantly more often in RCT compared to open-label study drug arms (11/27 [40.7%] vs 0/8 [0%]). In RCT study arms with HiSCR wobble, baseline draining fistula counts were significantly lower (2.3 vs 3.2), and numerically fewer Hurley stage 3 patients (33.2% vs 42.5%), lower weighted total abscess and nodule counts (12.1 vs 12.6), lower weighted dermatology life quality index scores (12.5 vs 14.5), and a higher proportion of female patients (63.9% vs 58.3%) were observed. Limitations: Include low number of HS clinical trials and insufficient data reported in many studies to assess for wobble, degree of wobble, and to compare all baseline characteristics. Conclusion: Nonlinear improvement in study arm response occurs in some HS RCTs. Potential contributing factors include a higher proportion of less severe patients at baseline and more female patients.

Disease-modifying therapies in systemic lupus erythematosus for extrarenal manifestations.

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Cancer Incidence After Diagnosis of Abdominal Aortic Aneurysm-Brief Report.

BACKGROUND: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors. METHODS: All individuals ≥18 years of age with ≥36 months of continuous coverage between 2008 and 2020 were enrolled. Those with potential Mendelian etiologies of AAA, aortic aneurysm with nonspecific anatomic location, or a cancer diagnosis before the start of follow-up were excluded. A subgroup analysis was performed of individuals having the Health Risk Assessment records including tobacco use and body mass index. The following groups of individuals were compared: (1) with AAA, (2) with non-AAA CVD, and (3) without any CVD. RESULTS: The propensity score-matched cohort included 58 993 individuals with AAA, 117 986 with non-AAA CVD, and 58 993 without CVD. The 5-year cumulative incidence of cancer was 13.1% (12.8%-13.5%) in participants with AAA, 10.1% (9.9%-10.3%) in participants with non-AAA CVD, and 9.6% (9.3%-9.9%) in participants without CVD. Multivariable-adjusted Cox proportional hazards regression models found that patients with AAA exhibited a higher cancer risk than either those with non-AAA CVD (hazard ratio, 1.28 [95% CI, 1.23-1.32]; P<0.001) or those without CVD (hazard ratio, 1.32 [95% CI, 1.26-1.38]; P<0.001). Results remained consistent after excluding common smoking-related cancers and when adjusting for tobacco use and body mass index. CONCLUSIONS: Patients with AAA may have a unique risk of cancer requiring further mechanistic study and investigation of the role of enhanced cancer screening.

Advances in research and utilization of botanical pesticides for agricultural pest management in Inner Mongolia, China.

Traditional Chinese herbal medicines not only cure human diseases, but also play an important role as insecticides. Compared with conventional chemical agents, traditional Chinese herbal medicines are characterized by low toxicity, low residues, and being eco-friendly, and they have become a research hotspot. Traditional Chinese herbal medicines have tremendous flexibility and indefinite potential. Therefore, this paper reviewed the types of insecticides belonging to traditional Chinese herbal medicines in Inner Mongolia, China, including their traditional uses, secondary metabolites, biological activities, action mechanisms, application methods, and development status. In addition, the most relevant issues involved in the development of traditional Chinese herbal medicines was discussed. We believe that traditional Chinese herbal medicines can be better implemented and developed; such that its other advantages, such as an insect repellent, can be promoted. Moreover, this study lays a solid foundation for further research on traditional Chinese herbal medicines in Inner Mongolia, China.

SF-36v2 and FACIT-Fatigue quality of life improvements with organ-specific SELENA-SLEDAI response and belimumab treatment in patients with systemic lupus erythematosus.

OBJECTIVE: Explore organ-specific SLE burden by assessing health-related quality of life (HRQoL) and fatigue changes associated with Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ system response (score improvement) and belimumab treatment. METHODS: Data from four phase III belimumab trials were pooled for post hoc analysis (GSK Study 217382): BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS-SC (NCT01484496) and EMBRACE (NCT01632241). Patients with baseline organ system involvement were classed as organ system responders if SELENA-SLEDAI scores for that organ system decreased at any post-baseline visit. HRQoL (36-Item Short Form Health Survey version 2 (SF-36v2)) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)) changes over 52 weeks were compared between organ system responders and non-responders, and separately between belimumab versus placebo treatment arms among organ system responders. Group-level differences were compared using analysis of variance; differences were interpreted using published group-level minimal important difference (MID). RESULTS: In these post hoc analyses, musculoskeletal and mucocutaneous organ system responders had greater SF-36v2 improvements than non-responders across most SF-36v2 domains, but differences were largely MID), with FACIT-Fatigue also improving >MID for renal responders receiving belimumab. CONCLUSIONS: SLE disease burden differs with the organ system(s) involved. While these analyses are limited by mutual inclusivity of organ system groupings, differing patient numbers between groups and small numbers in some groups, they suggest that mucocutaneous and musculoskeletal organ system response improves SF-36v2 domain scores; cardiovascular and respiratory organ system response may meaningfully improve fatigue; and belimumab may offer additional HRQoL or fatigue benefits beyond standard therapy for musculoskeletal and renal responders.

A survey of severe asthma in Canada: results from the CASCADE practice reflective program.

BACKGROUND: Since the last guidance was published by the Canadian Thoracic Society, there have been several advances in the clinical management of severe asthma. To gain a better understanding of the current standards of care and treatment patterns of patients, the CASCADE practice reflective program was established to conduct a real-world analysis of severe asthma management among specialists in Canada with a goal of identifying areas of opportunity to enhance patient management and outcomes. METHODS: The CASCADE program was a two-part practice reflective and assessment program delivered through an on-line portal for selected specialists (Respirologists and Allergists) in Canada. The program consisted of a one-time overview survey of physician practice to establish overall practice parameters, followed by a review of at least 5 severe asthma patients to establish the current landscape of severe asthma management. RESULTS: The program collected practice overview surveys from 78 specialists (52 Respirologists, 24 Allergists, and 2 General practice physicians with an interest in respiratory disease) in 8 provinces. Practices included a variety of types in both large metropolitan centres and smaller regional settings. There were 503 patients reviewed and included in the program. Most (65%) patients were currently using a biologic treatment, 30% were biologic naive, and 5% had used a biologic treatment in the past. Most patients (53%) were reported to have mixed allergic and eosinophilic phenotypes, despite a perception that allergic, eosinophilic and mixed phenotypes were evenly balanced in the physician practice. Overall, patients currently treated with biologic agents had parameters suggesting higher control and were more satisfied with treatment. However, there was less than optimal treatment satisfaction for more than half of all patients, particularly for those patients not treated with a biologic agent. CONCLUSIONS: Phenotyping is hampered by poor availability for several assessments, and the full range of treatments are not currently fully utilized, partly due to physician familiarity with the agents and partly due to prescribing restrictions. Even when treated with biologic agents, patient satisfaction can still be improved.

Biosimilars production in Africa opportunities & challenges.

The healthcare systems of African nations heavily rely on importing and repackaging biological medicine. More than 70% of the pharmaceutical products consumed in Africa are imported. The localization of biosimilar production can have a positive impact on the availability and cost of these products by reducing the expenses for African governments and making essential healthcare products more accessible to the population. However, it is evident that the developing countries, particularly African nations, face various obstacles and difficulties in localizing biosimilar production. These challenges encompass development, manufacturing, evaluation, and registration processes. In this review, we will highlight the significant hurdles and achievements encountered during the localization process of biosimilars.

Evaluating the real-world effectiveness of belimumab in patients with SLE using SLE-related laboratory values and rheumatoid arthritis-derived disease activity measures: RAPID3, swollen joint count and tender joint count.

OBJECTIVE: To investigate the real-world impact of intravenous belimumab treatment among patients with SLE using rheumatoid arthritis-derived disease activity measures and SLE-related laboratory values. METHODS: This retrospective cohort study used US electronic medical record data from the United Rheumatology Normalised Integrated Community Evidence (UR-NICE) database. Adult patients with SLE who initiated intravenous belimumab between 1 January 2012 and 3 December 2019 (index), had 12 months of pre-index and 24 months of post-index clinical activity, and had ≥6 infusions of belimumab during the 24 months post-index were included. The primary outcome measure was time to first improvement of minimally important difference (MID) for Routine Assessment of Patient Index Data 3 (RAPID3), Patient Pain Index (PPI), swollen joint count, tender joint count (TJC), complement C3 and C4 and anti-double-stranded DNA antibodies during the on-treatment follow-up period of up to 24 months. The secondary outcome measure evaluated the trajectories of these outcome measures for up to 24 months of belimumab treatment. RESULTS: Of 495 patients included, between 21.0% and 52.1% had ≥1 record for each of the disease activity measures or laboratory values in the pre-index and post-index periods and were included in analyses for that measure. The proportion of patients achieving MID for each measure increased rapidly within 3 months, with continued gradual improvement throughout the remaining on-treatment period, up to 24 months. After 6 months, 52.3% and 55.3% of patients had achieved MID in RAPID3 and PPI, respectively. Outcome measure trajectories indicated improved disease activity with belimumab treatment, particularly in RAPID3, TJC and laboratory values. CONCLUSIONS: In this real-world effectiveness study, belimumab therapy for SLE resulted in clinically meaningful improvements in rheumatoid arthritis-derived disease activity measures within 3 months of treatment, with patients who remained on belimumab therapy experiencing improvement even up to 24 months of observation.

Non-Microbiological Mycobacterial Detection Techniques for Quality Control of Biological Products: A Comprehensive Review.

Mycobacteria can be one of the main contaminants of biological products, and their presence can have serious consequences on patients' health. For this reason, the European Pharmacopoeia mandates the specific testing of biological products for mycobacteria, a critical regulatory requirement aimed at ensuring the safety of these products before they are released to the market. The current pharmacopeial reference, i.e., microbial culture method, cannot ensure an exhaustive detection of mycobacteria due to their growth characteristics. Additionally, the method is time consuming and requires a continuous supply of culture media, posing logistical challenges. Thus, to overcome these issues, pharmaceutical industries need to consider alternative non-microbiological techniques to detect these fastidious, slow-growing contaminating agents. This review provides an overview of alternative methods, which could be applied within a quality control environment for biological products and underlines their advantages and limitations. Nucleic acid amplification techniques or direct measurement of mycobacteria stand out as the most suitable alternatives for mycobacterial testing in biological products.

Machine learning-based identification of novel hub genes associated with oxidative stress in lupus nephritis: implications for diagnosis and therapeutic targets.

BACKGROUND: Lupus nephritis (LN) is a complication of SLE characterised by immune dysfunction and oxidative stress (OS). Limited options exist for LN. We aimed to identify LN-related OS, highlighting the need for non-invasive diagnostic and therapeutic approaches. METHODS: LN-differentially expressed genes (DEGs) were extracted from Gene Expression Omnibus datasets (GSE32591, GSE112943 and GSE104948) and Molecular Signatures Database for OS-associated DEGs (OSEGs). Functional enrichment analysis was performed for OSEGs related to LN. Weighted gene co-expression network analysis identified hub genes related to OS-LN. These hub OSEGs were refined as biomarker candidates via least absolute shrinkage and selection operator. The predictive value was validated using receiver operating characteristic (ROC) curves and nomogram for LN prognosis. We evaluated LN immune cell infiltration using single-sample gene set enrichment analysis and CIBERSORT. Additionally, gene set enrichment analysis explored the functional enrichment of hub OSEGs in LN. RESULTS: The study identified four hub genes, namely STAT1, PRODH, TXN2 and SETX, associated with OS related to LN. These genes were validated for their diagnostic potential, and their involvement in LN pathogenesis was elucidated through ROC and nomogram. Additionally, alterations in immune cell composition in LN correlated with hub OSEG expression were observed. Immunohistochemical analysis reveals that the hub gene is most correlated with activated B cells and CD8 T cells. Finally, we uncovered that the enriched pathways of OSEGs were mainly involved in the PI3K-Akt pathway and the Janus kinase-signal transducer and activator of transcription pathway. CONCLUSION: These findings contribute to advancing our understanding of the complex interplay between OS, immune dysregulation and molecular pathways in LN, laying a foundation for the identification of potential diagnostic biomarkers and therapeutic targets.

[Baseline characterization of a cohort of colombian patients with chronic rhinosinusitis with nasal polyps]. / Caracterización clínica y demográfica de pacientes colombianos con rinosinusitis crónica con poliposis nasal.

OBJECTIVE: To present the baseline clinical and demographic characteristics of CRSwNP patients over the age of 18 enrolled in a Patient Support Program (PSP) prior to biologic treatment. METHODS: Descriptive, cross-sectional study performed in a Colombian CRSwNP asthma PSP sponsored by Sanofi from Aug-2021 to Jul-2022. Data was collected from CRSwNP patients, prior to the start of Dupilumab treatment, who consented to the use of their data. The following information was reported: Age, reporting city, treating medical specialty, comorbidities, and persistence of treatment. RESULTS: 339 patients were included, 171 (50,4%) were women and 168 (49,6%) were men. The mean age at Dupilumab treatment initiation was 52,4 years. 62,8% began treatment during adulthood (26-59y), while 34.1% started at elderly (+60y) and 3.1% were young adults (18-25y). Most cases (29,7%) were included in Bogotá, followed by Antioquia (19%), Valle del Cauca (7,3%) and the remaining 44% nationwide. Comorbidities were present in 67,1% of the patients, with diagnosis of allergic rhinitis, atopic dermatitis, asthma, and other non-type 2 inflammatory diseases. Nasal surgical history was present in 89,6% of the patients, most of them with one to three previous surgeries. Continuous treatment was observed in 70,3% of patients for 6 to 12 months, in 21,3% for more than 12 months and in 8,4% for less than six months. The most frequently treating medical specialty was otorhinolaryngology (79,6%), followed by allergology (16%) and other medical professionals (4,4%). CONCLUSIONS: There is concordance with the literature on a higher presentation of the disease in women than in men. There is a large proportion of patients with nasal surgical history and type 2 inflammatory comorbidities by the moment of biologic treatment initiation. The care and identification of CRSwNP colombian patients is mainly provided by otorhinolaryngologists, followed by allergologists.

OBJETIVO: Presentar las características clínicas y demográficas iniciales de los pacientes con RSCcPN, mayores de 18 años, inscritos en un Programa de Soporte al Paciente (PSP), antes del inicio de tratamiento biológico. MÉTODOS: Estudio descriptivo y transversal realizado en un PSP para RSCcPN en Colombia, entre agosto de 2021 y julio de 2022, patrocinado por Sanofi. Los datos se recopilaron de pacientes con RSCcPN, antes de comenzar el tratamiento con Dupilumab, quienes dieron su consentimiento para el uso de sus datos. Se reportó la siguiente información: edad, ciudad de origen, especialidad médica tratante, comorbilidades y persistencia del tratamiento. RESULTADOS: Se incluyeron 339 pacientes, 171 mujeres (50,4%), y 168 hombres (49,6%). La edad promedio al inicio del tratamiento con Dupilumab, fue de 52,4 años. El 62,8% inició tratamiento durante la edad adulta (entre 26 y 59 años), mientras que el 34,1% comenzó en la vejez (+60 años), y el 3,1% entre los 18 y 25 años. La mayoría de los casos (29,7%) se incluyeron en Bogotá, seguidos por Antioquia (19%), Valle del Cauca (7,3%) y el 44% restante en todo el país. Las comorbilidades estuvieron presentes en el 67,1% de los pacientes, con diagnóstico de rinitis alérgica, dermatitis atópica, asma y otras enfermedades no inflamatorias tipo 2. El 89,6% de los pacientes tenía antecedentes de cirugía nasal, la mayoría de ellos con entre una y tres cirugías previas. Se observó tratamiento continuo en el 70,3% de los pacientes durante 6 y 12 meses, en el 21,3%, durante más de 12 meses, y en el 8,4% durante menos de 6 meses. La especialidad médica que trató a los pacientes con más frecuencia fue la otorrinolaringología (79,6%), seguida por la alergología (16%) y otros profesionales médicos (4,4%). CONCLUSIONES: Existe concordancia con la literatura con una mayor presentación de la enfermedad en mujeres que en hombres. Hay una gran proporción de pacientes con antecedentes de cirugía nasal y comorbilidades inflamatorias tipo 2, al inicio del tratamiento biológico. La atención e identificación de los pacientes colombianos con RSCcPN es proporcionada principalmente por otorrinolaringólogos, seguidos por alergólogos.

Therapeutic drug monitoring in patients with inflammatory bowel disease on ustekinumab.

OBJECTIVE: Therapeutic drug monitoring is used clinically to guide anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD), but its use for ustekinumab (UST) remains unclear. This study aimed to determine predictive variables of UST levels. METHODS: In this retrospective cohort of patients with IBD, UST trough levels were drawn at maintenance dosing. Relationships between UST trough levels and demographics, therapy, and outcomes were analyzed. Machine-learning models were used to infer combinatorial traits predictive of UST levels. RESULTS: Altogether 177 patients with IBD on UST had a mean UST trough level of 4.742 µg/mL. The injection schedule correlated significantly (P < 0.001) with UST levels. Naiveté to anti-TNFs correlated with higher UST levels (P = 0.048). Univariate analysis revealed that higher inflammatory biomarkers significantly correlated to lower UST levels and a lower Simple Endoscopic Score to Crohn's Disease to adequate UST levels (P = 0.018). Multivariate analysis identified body mass index (BMI), previous anti-TNF failure, and laboratory flare as predictors of UST levels with an area under the receiver operating characteristic curve (AUROC) of 0.72. The UST cut-off level of 5.77 µg/mL yielded a 0.79 AUROC, 80% sensitivity, and 81% specificity for predicting endoscopic remission of Crohn's disease. For the clinical remission end-point in ulcerative colitis, UST level of 4.73 µg/mL yielded a 0.69 AUROC, 53% sensitivity, and 86% specificity. CONCLUSIONS: Higher UST levels correlated with less disease activity. BMI was an important consideration for UST response as well. Therefore, UST dose adjustments to reach target levels may optimize response.

Adverse Effects of Natural Products in the Oral Mucosa and Face: A Scoping Review.

Objective: This scoping review aimed to map the adverse reactions in the oral mucosa and face caused by the use of natural products. Methodology: This review was performed according to the Joanna Briggs Institute Manual for Evidence Synthesis and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, with a protocol registered in the Open Science Framework (DOI 10.17605/OSF.IO/R57D8). The search was carried out systematically using PubMed, Scopus, Web of Science, Embase, LILACS, and LIVIVO databases, as well as gray literature through Google Scholar and OpenGrey. Reports of clinical cases on the adverse effects of natural products on the oral mucosa or perioral region of the face resulted from inappropriate use or self-medication were included. Data from the included studies were described in a narrative form. Results: Seven hundred and six studies were identified, and after removing duplicates and applying the eligibility criteria, 28 studies were included. The year of publication ranged from 1976 to 2022. The studies were conducted in 19 countries. Fifty patients were mentioned in the included studies and 34 were female (68%). The natural products most related to adverse reactions were propolis (n = 17), with manifestations such as perioral eczema, edema, erosions, erythema, allergic contact dermatitis, and garlic (n = 9), with manifestations such as chemical burn, burning sensation, vesicles and blisters, crusts, and ulcerations. Conclusion: Propolis and garlic were the natural products with the most reported adverse effects on the oral mucosa and perioral region.

Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease.

OBJECTIVE: To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS: A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis. RESULTS: 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting. CONCLUSIONS: Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug's mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.

Policy measures and instruments used in European countries to increase biosimilar uptake: a systematic review.

Introduction: While biosimilar medicines can contribute to the sustainability of healthcare systems, their utilization rate varies across European countries. This study aims to identify and systematize policy measures and instruments used in European countries to increase biosimilar market share. Methods: A systematic review was conducted according to PRISMA 2020 recommendations. Medline-PubMed, Web of Science and ScienceDirect databases were searched using inclusion criteria that required full articles published in English between January 2006 and November 2023. Reviews, letters, reports, editorials and comments or opinion articles were excluded from this study. Results: Of the 1,137 articles, only 13 met the eligibility criteria for analysis, which covered a total of 28 European countries. Pricing regulation measures were found in 27 of these countries with tendering, price-linkage and internal reference price being the most used. Tendering was used by 27 countries to procure biosimilars in inpatient setting. Prescribing guidelines and recommendations were the widely used instrument. Some European countries adopted physician incentives, quotas, and prescription by international non-proprietary name. Conclusion: Automatic substitution was not commonly recommended or applied. Interchangeability and switching will become increasingly relevant issues. It is important that the positive results from some countries serve as an example for the future of these medicines in the European market. Systematic review registration: https://inplasy.com/, Identifier INPLASY2023120032.

A Cross-National Comparison of Biosimilars Pricing in Argentina, Australia, Brazil, and Italy.

BACKGROUND: Biosimilar medicines are defined as biological products highly similar to an already licensed biological product (RP). The market entry of biosimilars is expected to reduce the costs of biological treatments. OBJECTIVE: This study aims to evaluate the range of differences between the prices of biosimilars and the corresponding RP for biologicals approved in four countries. METHOD: This is a cross-national comparison of pricing of biosimilars in Argentina, Australia, Brazil, and Italy. The study examined online price databases provided by the national authorities of the investigated countries. Biosimilar price difference was calculated by subtracting the unit price of the biosimilar by the unit price of the RP, and then dividing it by the unit price of the RP. The results were presented as percentage. RESULTS: Brazil had the highest median price reduction (- 36.3%) in biosimilars price, followed by Italy (- 20.0%) and Argentina (- 18.6%). All the biosimilars in Italy were priced below the RP presenting a minimum reduction of 6.3%, while in Australia, most of the prices of biosimilars were equal to the RP. In Argentina, one infliximab-biosimilar displayed price above the RP (40.7%) while the lower priced brand had a reduction of 14.4%. Brazil had four biosimilars with prices above the respective RP, including isophane insulin (1), insulin glargine (1) and somatropin (2). CONCLUSION: The study revealed a marked dispersion in the price's differences between biosimilars and RP across the studied countries. Governments should evaluate whether their policies have been successful in improving affordability of biological therapies.

Trends in Systemic Glucocorticoid Utilization in the United Kingdom from 1990 to 2019: A Population-Based, Serial Cross-Sectional Analysis.

Purpose: Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs. Patients and Methods: A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥5 years who were registered for ≥1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year. Results: The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics. Conclusion: Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse.

Profiling of endogenous metabolites and changes in intestinal microbiota distribution after GEN-001 (Lactococcus lactis) administration.

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 1011 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5-6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus, and higher levels of the metabolites that have immunogenic properties.