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Dermatology (Basel, Switzerland) 2021Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD.
BACKGROUND
Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD.
OBJECTIVE
This work aims to summarize both label and off-label biologics on AD treatment in phase II and phase III stages, and compile evidence on the efficacy of the most-studied biologics.
METHODS
We conducted a comprehensive literature search through PubMed, EMBASE, and ClinicalTrials.gov to identify all documented biological therapies for AD. The criteria were further refined to focus on those treatments with the highest evidence level for AD with at least one randomized clinical trial supporting their use. Only studies or articles published in English were enrolled in this study.
FINDINGS
Primary searches identified 525 relevant articles and 27 trials. Duplicated articles and papers without a full text were excluded. Only completed trials were enrolled. We included 28 randomized controlled trials, 4 unpublished trials, 2 observational studies, and 1 meta-analysis. Eight kinds of biologics, including IL-4/IL-13 inhibitors, JAK inhibitors, anti-IL-13 antibodies, anti-IL-22 antibodies, anti-IL-33 antibodies, thymic stromal lymphopoietin inhibitor (TSLP), OX40 antibodies, and H4R-antagonists were included in this work. Dupliumab, as the most widely used and investigated biologic, was reported in 1 meta-analysis and 4 trials exploring its long-term use and application in both adults and pediatric patients. Besides dupilumab, four other IL-4/IL-13 inhibitors recruited were all randomized, clinical trials at phase 2-3 stage. Six different kinds of JAK inhibitors were summarized with strong evidence revealing their significant therapeutic effects on AD. There were 3 trials for nemolizumab, an anti-IL-13 antibody, all of which were in the phase 2 clinical trial stage. Results showed nemolizumab could be another alternative therapy for moderate-to-severe AD with long-term efficiency and safety.
CONCLUSION
The biological therapies with the most robust evidence on efficacy and long-term safety for AD treatment include dupilumab, barcitinib, abrocitinib, and delgocitinib. Most of the biologics mentioned in this review were still at the exploratory stage. This review will help practitioners advise patients seeking suitable biological therapies and offer experimental study directions for treatment.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azetidines; Biological Products; Carbamates; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Heterocyclic Compounds, 3-Ring; Humans; Nitriles; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides
PubMed: 33735876
DOI: 10.1159/000514535 -
Pharmacological Research Jan 2023Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely... (Review)
Review
Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely distributed in a variety of plants and mainly isolated from plants in the Cucurbitaceae family. CuB is mostly obtained from the pedicel of Cucumis melo L. Modern pharmacological studies have confirmed that CuB has a broad range of pharmacological activities, with significant therapeutic effects on a variety of diseases including inflammatory diseases, neurodegenerative diseases, diabetes mellitus, and cancers. In this study the PubMed, Web of Science, Science Direct, and China National Knowledge Infrastructure (CNKI) databases were searched from 1986 to 2022. After inclusion and exclusion criteria were applied, 98 out of 2484 articles were selected for a systematic review to comprehensively summarize the pharmacological activity, toxicity, and pharmacokinetic properties of CuB. The results showed that CuB exhibits potent anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer activities mainly via regulating various signaling pathways, such as the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), nuclear factor (NF)-κB, AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt, focal adhesion kinase (FAK), Notch, and Hippo-Yes-associated protein (YAP) pathways. Studies of its toxicity and pharmacokinetic properties showed that CuB has non-specific toxicity and low bioavailability. In addition, derivatives and clinical applications of CuB are discussed in this paper.
Topics: Cucurbitacins; Protein Phosphatase 2; Antioxidants; Phosphatidylinositol 3-Kinases; Triterpenes; NF-kappa B
PubMed: 36460279
DOI: 10.1016/j.phrs.2022.106587 -
Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis.Molecular and Cellular Biochemistry Oct 2022Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an... (Review)
Review
Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1's relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.
Topics: Arginine; Arginine Kinase; Carcinogenesis; Cell Transformation, Neoplastic; Humans; NF-kappa B; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; RNA Splicing Factors; Serine; Transforming Growth Factor beta
PubMed: 35583632
DOI: 10.1007/s11010-022-04456-7 -
American Journal of Cardiovascular... Jan 2024Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent ventricular dilatation and failure. New therapeutic targets are being investigated for their potential roles in improving PAH patients' symptoms and reversing pulmonary vascular pathology.
METHOD
We aimed to address the available knowledge from the published randomized controlled trials (RCTs) regarding the role of Rho-kinase (ROCK) inhibitors, bone morphogenetic protein 2 (BMP2) inhibitors, estrogen inhibitors, and AMP-activated protein kinase (AMPK) activators on the PAH evaluation parameters. This systematic review (SR) was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CDR42022340658) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
Overall, 5092 records were screened from different database and registries; 8 RCTs that met our inclusion criteria were included. The marked difference in the study designs and the variability of the selected outcome measurement tools among the studies made performing a meta-analysis impossible. However, the main findings of this SR relate to the powerful potential of the AMPK activator and the imminent antidiabetic drug metformin, and the BMP2 inhibitor sotatercept as promising PAH-modifying therapies. There is a need for long-term studies to evaluate the effect of the ROCK inhibitor fasudil and the estrogen aromatase inhibitor anastrozole in PAH patients. The role of tacrolimus in PAH is questionable. The discrepancy in the hemodynamic and clinical parameters necessitates defining cut values to predict improvement. The differences in the PAH etiologies render the judgment of the therapeutic potential of the tested drugs challenging.
CONCLUSION
Metformin and sotatercept appear as promising therapeutic drugs for PAH.
CLINICAL TRIALS REGISTRATION
This work was registered in PROSPERO (CDR42022340658).
Topics: Humans; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; AMP-Activated Protein Kinases; Familial Primary Pulmonary Hypertension; Estrogens; Metformin
PubMed: 37945977
DOI: 10.1007/s40256-023-00613-5 -
Clinical Drug Investigation May 2023Janus kinase (JAK) inhibitors are emerging as a therapeutic option for alopecia areata. The risk of potential adverse events is currently debated. In particular, several...
BACKGROUND AND OBJECTIVES
Janus kinase (JAK) inhibitors are emerging as a therapeutic option for alopecia areata. The risk of potential adverse events is currently debated. In particular, several safety data for JAK inhibitors are extrapolated from a single study in elderly patients with rheumatoid arthritis treated with tofacitinib or adalimumab/etanercept as a comparator. The population of patients with alopecia areata is clinically and immunologically different from persons with rheumatoid arthritis and tumor necrosis factor (TNF) inhibitors are not effective in these patients. The objective of this systematic review was to analyze available data on the safety of various JAK inhibitors in patients with alopecia areata.
METHODS
The systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature review was performed by searching PubMed, Scopus and EBSCO databases with the last search on March 13, 2023.
RESULTS
In total, 36 studies were included. The frequency and odds ratio (OR) for most common adverse events versus placebo were: for baricitinib hypercholesterolemia (18.2% vs 10.5%, OR = 1.9) and headache (6.1% vs 5.1%, OR = 1.2), for brepocitinib elevated creatinine level (27.7% vs 4.3%, OR = 8.6) and acne (10.6% vs 4.3%, OR = 2.7), for ritlecitinib acne (10.4% vs 4.3%, OR = 2.6) and headache (12.5% vs 10.6%, OR = 1.2) and for deuruxolitinib headache (21.4% vs 9.1%, OR = 2.7) and acne (13.6% vs 4.5%, OR = 3.3). The respective numbers for upper respiratory infections were: baricitinib (7.3% vs 7.0%, OR = 1.0) and brepocitinib (23.4% vs 10.6%, OR = 2.6); for nasopharyngitis: ritlecitinib (12.5% vs 12.8%, OR = 1.0) and deuruxolitinib (14.6% vs 2.3%, OR = 7.3).
CONCLUSIONS
The most common side effects of JAK inhibitors in patients with alopecia areata were headache and acne. The OR for upper respiratory tract infections varied from over 7-fold increased to comparable to placebo. The risk of serious adverse events was not increased.
Topics: Humans; Aged; Janus Kinase Inhibitors; Alopecia Areata; Protein Kinase Inhibitors; Arthritis, Rheumatoid; Alopecia
PubMed: 37138134
DOI: 10.1007/s40261-023-01260-z -
Frontiers in Immunology 2023Orally administered small-molecule drugs including tyrosine kinase 2 (TYK2) inhibitors and phosphodiesterase 4 (PDE4) inhibitors are new candidates for systemic therapy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Orally administered small-molecule drugs including tyrosine kinase 2 (TYK2) inhibitors and phosphodiesterase 4 (PDE4) inhibitors are new candidates for systemic therapy in plaque psoriasis. However, no previous articles evaluated the benefit and risk profile of TYK2 and PDE4 inhibitors in psoriasis.
OBJECTIVES
The objective of this study was to compare the efficacy and safety of oral small-molecule drugs, including TYK2 and PDE4 inhibitors, in treating moderate-to-severe plaque psoriasis.
METHODS
PubMed, Embase, and Cochrane library were searched for eligible randomized clinical trials (RCTs). Response rates for a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment score of 0 or 1 (PGA 0/1) were used for efficacy assessment. Safety was evaluated with the incidence of adverse events (AEs). A Bayesian multiple treatment network meta-analysis (NMA) was performed.
RESULTS
In total, 13 RCTs (five for TYK2 inhibitors and eight for PDE4 inhibitors) involving 5274 patients were included. The study found that deucravacitinib at any dose (except for 3 mg QOD), ropsacitinib (200 and 400 mg QD), and apremilast (20 and 30 mg BID) had higher PASI and PGA response rates than placebo. In addition, deucravacitinib (3 mg BID, 6 mg QD, 6 mg BID, and 12 mg QD), and ropsacitinib (400 mg QD) showed superior efficacy than apremilast (30 mg BID). In terms of safety, deucravacitinib or ropsacitinib at any dose did not lead to a higher incidence of AEs than apremilast (30 mg BID). The ranking analysis of efficacy revealed that deucravacitinib 12 mg QD and deucravacitinib 3 mg BID had the highest chance of being the most effective oral treatment, followed by deucravacitinib 6 mg BID and ropsacitinib 400 mg QD.
CONCLUSIONS
Oral TYK2 inhibitors demonstrated satisfactory performance in treating psoriasis, surpassing apremilast at certain doses. More large-scale, long-term studies focusing on novel TYK2 inhibitors are needed.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO (ID: CRD42022384859), available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022384859, identifier CRD42022384859.
Topics: Humans; Network Meta-Analysis; Phosphodiesterase 4 Inhibitors; Psoriasis; Severity of Illness Index; TYK2 Kinase
PubMed: 37334353
DOI: 10.3389/fimmu.2023.1180170 -
European Journal of Cancer (Oxford,... Sep 2023The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and ii) whether anthracyclines could be excluded.
METHODS
A systematic literature search in Medline, Embase and Web of Science databases was performed. Studies had to satisfy the following criteria: i) randomised controlled trials (RCTs), ii) enroled patients treated preoperatively for HER2-positive BC (breast cancer), iii) at least one treatment group received an anti-HER2 agent, iv) available information of any efficacy end-point and v) published in English. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR), event-free survival (EFS) and overall survival (OS) were the efficacy end-points of interest, and selected safety end-points were also analysed.
RESULTS
A total of 11,049 patients with HER2-positive BC (46 RCTs) were included in the network meta-analysis, and 32 different regimens were evaluated. Dual anti-HER2-therapy, with pertuzumab or tyrosine kinase inhibitors, combined with chemotherapy was significantly superior to trastuzumab and chemotherapy in terms of pCR, EFS and OS. However, a higher risk of cardiotoxicity was observed with dual anti-HER2-therapy. Anthracycline-based chemotherapy was not associated with better efficacy outcomes in comparison with non-anthracycline-based chemotherapy. In anthracycline-free regimens, the addition of carboplatin presented numerically better efficacy outcomes.
CONCLUSION
Dual HER2 blockade with chemotherapy is the recommended choice as neoadjuvant therapy for HER2-positive breast cancer, preferably by omitting anthracyclines in favour of carboplatin.
Topics: Humans; Female; Neoadjuvant Therapy; Carboplatin; Network Meta-Analysis; Receptor, ErbB-2; Breast Neoplasms; Trastuzumab; Antibiotics, Antineoplastic; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37142539
DOI: 10.1016/j.ejca.2023.03.042 -
Liver Cancer Apr 2022Multikinase inhibitors (MKIs) have been shown to improve survival in patients with hepatocellular carcinoma (HCC) compared with placebo. Distinct from other MKIs,... (Review)
Review
BACKGROUND
Multikinase inhibitors (MKIs) have been shown to improve survival in patients with hepatocellular carcinoma (HCC) compared with placebo. Distinct from other MKIs, cabozantinib has inhibitory activity for both AXL and MET. This review considers the literature elucidating the role of AXL and MET in HCC progression, treatment resistance, and immunomodulation. A systematic search of the PubMed database was conducted on November 16, 2020, and identified a total of 174 search results. A further 36 potentially relevant articles were identified based on the authors' knowledge. After initial screening by title/abstract, 159 underwent full-text screening and we identified 69 original research articles reporting empirical data from in vitro or in vivo models of HCC evaluating the effects of manipulating AXL or MET signaling on tumorigenic behavior.
SUMMARY
AXL expression is highly correlated with HCC progression and outcomes and has been reported to be involved in transforming growth factor-β and the regulation of PI3K/AKT, ERK/MAPK, and CCN proteins. MET protein expression is increased in HCC with the highest histological grade and has been reported to be involved in the regulation of PI3K/AKT, PLCγ/DAG/PKC, and MAPK/ERK signaling. Both AXL and MET are key regulators of sorafenib resistance in HCC. In terms of immunomodulation, there are data to indicate that AXL and MET interact with the immune components of the tumor microenvironment and promote tumorigenesis and treatment resistance. In addition, AXL was found to play a potential role in the development of a protumorigenic neutrophil phenotype in HCC. Combined inhibition of MET and programmed cell death protein resulted in additive reduction of HCC cell growth.
KEY MESSAGES
AXL and MET play key roles in HCC progression, treatment resistance, and immunomodulation. Continued development of drugs that target these receptor tyrosine kinases appears likely to represent a useful strategy to improve outcomes for patients with HCC.
PubMed: 35634427
DOI: 10.1159/000520501 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
Biomedicines Nov 2022The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular... (Review)
Review
BACKGROUND
The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis.
METHODS
A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor.
RESULTS
530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future.
CONCLUSION
The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted.
PubMed: 36359402
DOI: 10.3390/biomedicines10112884