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Future Medicinal Chemistry Oct 2019Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism...
Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.
Topics: Cell Line, Tumor; Humans; Proteasome Endopeptidase Complex; Proteolysis; Recombinant Fusion Proteins; Ubiquitin
PubMed: 31571504
DOI: 10.4155/fmc-2019-0161 -
Dermatologic Therapy Mar 2021Scalp psoriasis represents the most common difficult-to-treat area in psoriasis patients. Its presence is linked to severe discomfort and impairment of quality of life... (Review)
Review
Scalp psoriasis represents the most common difficult-to-treat area in psoriasis patients. Its presence is linked to severe discomfort and impairment of quality of life given the associated symptoms (most of all, scaling and pruritus) and the location in a highly visible area, thus a prompt treatment is required. Its management may be challenging as the scalp is quite sensitive to long-term treatment with topical corticosteroids and usually resistant to topical and systemic agents. Likely, the currently available therapeutic armamentarium has been enriched with biologicals and small molecules that revolutionized psoriasis treatment and that of scalp psoriasis. Nevertheless, the lack of international dedicated guidelines pushed us to perform a comprehensive review on the efficacy and safety of biologics and small molecules on scalp psoriasis with the aim to put the basis for a therapeutic algorithm. After reviewing all the available evidence on the short-term and long-term efficacy of biologics and small molecules on scalp psoriasis the use of the newest biologics (anti-IL-17 and anti-IL-23) seems to be linked to the highest clinical performances in controlling scalp psoriasis. However, head-to-head comparisons between different biologics or biologics and small molecules are lacking. Hence, treatment selection should always be individualized.
Topics: Biological Products; Humans; Psoriasis; Quality of Life; Scalp; Scalp Dermatoses
PubMed: 33559275
DOI: 10.1111/dth.14857 -
Archives of Rheumatology Jun 2022Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as... (Review)
Review
OBJECTIVES
Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as psoriasiform lesions, alopecia, lupus and, vasculitis, which more often affects the skin (small-sized vessels) and eventually other organs. In this review, we describe the clinical profile of patients with vasculitis induced by the main biological agents used in rheumatology.
PATIENTS AND METHODS
We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The PubMed database was used for searching eligible articles. We included case reports, case series, and letter to the editor of patients on anti-tumor necrosis factor-alpha (anti-TNF-a) molecules, as well as tocilizumab, ustekinumab, secukinumab, rituximab, and abatacept, who had vasculitis induced by these agents.
RESULTS
Eighty-one articles were included for final analysis (n=89). Twenty-seven patients were using infliximab, 20 adalimumab, 18 etanercept, seven secukinumab, four certolizumab, four rituximab, three golimumab, three ustekinumab, two abatacept, and one tocilizumab. Unspecific leukocytoclastic vasculitis (LCV) was the most common type of vasculitis (n=37), followed by anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (n=16). The medication was replaced with another biological molecule in 23 cases, with only four relapses. In six cases, the biological was maintained, but vasculitis worsened/persisted in one case, being necessary drug removal.
CONCLUSION
Infections, infusion reaction, cancer, and autoimmune events are well-known side effects of biological therapy. This review demonstrates that vasculitis is another adverse effect of this type of therapy, particularly the anti-TNF-a molecules, and LCV the most reported type of vasculitis.
PubMed: 36017201
DOI: 10.46497/ArchRheumatol.2022.9049 -
Inflammatory Bowel Diseases Apr 2024Patients undergoing organ transplantation are often on immunosuppressing medications to prevent rejection of the transplant. The data on use of concomitant... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients undergoing organ transplantation are often on immunosuppressing medications to prevent rejection of the transplant. The data on use of concomitant immunosuppression for inflammatory bowel disease (IBD) and organ transplant management are limited. This study sought to evaluate the safety of biologic and small molecule therapy for the treatment of IBD among solid organ transplant recipients.
METHODS
Medline, Embase, and Web of Science databases were systematically searched for studies reporting on safety outcomes associated with the use of biologic and small molecule therapy (infliximab, adalimumab, certolizumab, golimumab, vedolizumab, ustekinumab, and tofacitinib) in patients with IBD postsolid organ transplant (eg, liver, kidney, heart, lung, pancreas). The primary outcome was infectious complications. Secondary outcomes included serious infections, colectomy, and discontinuation of biologic therapy.
RESULTS
Seven hundred ninety-seven articles were identified for screening, yielding 16 articles for the meta-analyses with information on 163 patients. Antitumor necrosis factor α (Anti-TNFs; infliximab and adalimumab) were used in 8 studies, vedolizumab in 6 studies, and a combination of ustekinumab or vedolizumab and anti-TNFs in 2 studies. Two studies reported outcomes after kidney and cardiac transplant respectively, whereas the rest of the studies included patients with liver transplants. The rates of all infections and serious infections were 20.09 per 100 person-years (100-PY; 95% CI, 12.23-32.99 per 100-PY, I2 = 54%) and 17.39 per 100-PY (95% CI, 11.73-25.78 per 100-PY, I2 = 21%), respectively. The rates of colectomy and biologic medication discontinuation were 12.62 per 100-PY (95% CI, 6.34-25.11 per 100-PY, I2 = 34%) and 19.68 per 100-PY (95% CI, 9.97-38.84 per 100-PY, I2 = 74%), respectively. No cases of venous thromboembolism or death attributable to biologic use were reported.
CONCLUSION
Biologic therapy is overall well tolerated in patients with solid organ transplant. Long-term studies are needed to better define the role of specific agents in this patient population.
Topics: Humans; Adalimumab; Biological Products; Inflammatory Bowel Diseases; Infliximab; Organ Transplantation; Ustekinumab
PubMed: 37300512
DOI: 10.1093/ibd/izad108 -
European Review For Medical and... Jul 2023The use of biological drugs to treat ulcerative colitis (UC) represents a clear added value; nevertheless, many patients do not have a sustained response to these drugs.... (Meta-Analysis)
Meta-Analysis
The comparative efficacy and safety of biologics and small molecules for treating patients with ulcerative colitis in Portugal: a systematic literature review and network meta-analysis.
OBJECTIVE
The use of biological drugs to treat ulcerative colitis (UC) represents a clear added value; nevertheless, many patients do not have a sustained response to these drugs. Small molecules were recently approved for the treatment of UC in Portugal. This network meta-analysis aimed to compare the efficacy and safety of the different therapies, including biological and small molecules, in patients prior exposed to biological treatment.
MATERIALS AND METHODS
A systematic review of the literature was performed on January 6, 2022, identifying all the relevant reports about the efficacy and safety of biologics (adalimumab, golimumab, infliximab, vedolizumab, ustekinumab) and small molecules (upadacitinib, filgotinib, tofacitinib) in the treatment of UC in Portugal. Network meta-analysis (NMA) was conducted using Bayesian Markov Chain Monte Carlo simulations. Results were presented in median Odds Ratio and Surface Under the Cumulative RAnking (SUCRA) score for each treatment.
RESULTS
Treatment of UC is divided into two phases: induction and maintenance. Upadacitinib 45 mg was the most efficacious therapy in achieving clinical remission and response and endoscopic improvement in the induction phase. Concerning the maintenance phase, upadacitinib 30 mg performed better than ustekinumab formulations in clinical remission and response, and endoscopic improvement. Regarding safety, there were no significant differences between all the drugs included in the analysis.
CONCLUSIONS
This network meta-analysis showed that upadacitinib reflects better efficacy compared to the available treatments for bio-exposed patients with moderate to severe UC. The safety profile is comparable to the other drugs.
Topics: Humans; Colitis, Ulcerative; Ustekinumab; Network Meta-Analysis; Portugal; Bayes Theorem; Biological Factors; Biological Products
PubMed: 37522686
DOI: 10.26355/eurrev_202307_33145 -
BMJ Mental Health Oct 2023This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.
QUESTION
This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.
STUDY SELECTION AND ANALYSIS
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed.
FINDINGS
Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio.
CONCLUSIONS
The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.
Topics: Humans; Acetylcysteine; Amino Acids; Anti-Inflammatory Agents; Antipsychotic Agents; Schizophrenia; Meta-Analysis as Topic; Randomized Controlled Trials as Topic
PubMed: 37852631
DOI: 10.1136/bmjment-2023-300771 -
American Journal of Clinical Dermatology Sep 2022The evidence for adding small-molecule drugs to an ongoing biologic treatment is sparse, but combination therapies appear to be advantageous in appropriately selected...
BACKGROUND
The evidence for adding small-molecule drugs to an ongoing biologic treatment is sparse, but combination therapies appear to be advantageous in appropriately selected patients with psoriasis. To our knowledge, efficacy and safety of combination therapy with apremilast and biologics has not previously been reviewed.
MATERIALS AND METHODS
A literature search was performed on Medline (PubMed), Embase, Web of Science, and the Cochrane Library. Inclusion criteria were a diagnosis of psoriasis, age ≥ 18 years, concomitant treatment with apremilast and a specified biologic agent, and available safety and/or efficacy results. All papers written in English and published from database inception to August 2021 were included. No limit was set regarding study size.
RESULTS
The literature search yielded 447 citations. Of these, 19 studies published from 2015 to 2020 were included in the review. All papers referred to retrospective studies, comprising case reports (n = 9), case series (n = 8), or cohort studies (n = 2). A total of 172 patients with psoriasis were identified. Clinical subtypes included plaque psoriasis (n = 164), palmoplantar pustulosis (n = 7), and acute pustular psoriasis (n = 1). The observation period ranged from 3 weeks to 24 months. Geographical origin of studies was North America (n = 11), Europe (n = 4), and Asia (n = 4). In general, apremilast-biologic combination therapy was reported to be safe; across papers, one serious adverse event was registered (hospitalization due to weight loss). Adverse events (AEs) were otherwise mostly mild and gastrointestinal. No differences in AEs were observed in studies comparing apremilast mono- and combination therapy. In several papers, sufficient information about AEs was not reported or could not be extracted. Clinical response to combination treatment was evaluated at various time points, and only few studies used validated scores. In the remaining papers, efficacy data were descriptive and/or in photographic form, or not available. In total, two patients discontinued therapy due to lack of efficacy.
CONCLUSION
Evidence for combined treatment with apremilast and biologics is limited and restricted to retrospective studies of various quality. Based on available data, apremilast may constitute an efficacious and safe add-on treatment to biologic therapy, but properly conducted clinical investigations are needed.
Topics: Adolescent; Biological Products; Drug Therapy, Combination; Exanthema; Humans; Psoriasis; Retrospective Studies; Thalidomide
PubMed: 35737251
DOI: 10.1007/s40257-022-00703-1 -
Military Medical Research Jan 2024Antimicrobial resistance is a global public health threat, and the World Health Organization (WHO) has announced a priority list of the most threatening pathogens... (Review)
Review
Antimicrobial resistance is a global public health threat, and the World Health Organization (WHO) has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed. The discovery and introduction of novel antibiotics are time-consuming and expensive. According to WHO's report of antibacterial agents in clinical development, only 18 novel antibiotics have been approved since 2014. Therefore, novel antibiotics are critically needed. Artificial intelligence (AI) has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics. Here, we first summarized recently marketed novel antibiotics, and antibiotic candidates in clinical development. In addition, we systematically reviewed the involvement of AI in antibacterial drug development and utilization, including small molecules, antimicrobial peptides, phage therapy, essential oils, as well as resistance mechanism prediction, and antibiotic stewardship.
Topics: Humans; Artificial Intelligence; Anti-Bacterial Agents; Drug Resistance, Bacterial; Public Health
PubMed: 38254241
DOI: 10.1186/s40779-024-00510-1 -
The Journal of Dermatological Treatment Feb 2022Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life.
BACKGROUND
Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life.
OBJECTIVE
Efficacy assessment of biologics and small molecules in scalp psoriasis with reported safety and quality of life.
METHODS
Biological therapies and small molecules licensed for treatment of plaque psoriasis are assessed. Fourteen studies reporting results from RCTs are included. Efficacy assessment is measured through improvement of Psoriasis Scalp Severity Index (PSSI), Scalp Physician Global Assessment (ScPGA) and/or Scalp-Specific Investigator's Global Assessment (ss-IGA).
RESULTS
Among biologics measured by PSSI, brodalumab, secukinumab and in a subgroup ixekizumab showed high efficacy in moderate to severe scalp psoriasis. Both brodalumab and ixekizumab demonstrated rapid response within 2 weeks. Guselkumab was superior to adalimumab and ixekizumab was superior to etanercept. Apremilast showed long-term efficacy. Only few studies reported quality of life in treatment of scalp involvement which showed improvement. All treatments demonstrated acceptable safety profile.
CONCLUSION
Effective treatment of scalp psoriasis is essential for improving the quality of life of psoriasis patients. Both Biologics and small molecules proved efficacy. This review may help choosing the appropriate treatment in cases where scalp psoriasis is the main complaint. A unified measurement tool for scalp psoriasis severity is needed to facilitate comparisons.
Topics: Biological Products; Humans; Psoriasis; Quality of Life; Scalp; Severity of Illness Index; Treatment Outcome
PubMed: 32406275
DOI: 10.1080/09546634.2020.1770167 -
Arthritis Research & Therapy May 2024Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE.
METHODS
Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety.
RESULTS
A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05).
CONCLUSION
Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.
Topics: Humans; Lupus Erythematosus, Systemic; Randomized Controlled Trials as Topic; Treatment Outcome; Azetidines; Purines; Molecular Targeted Therapy; Sulfonamides; Pyrazoles
PubMed: 38730460
DOI: 10.1186/s13075-024-03331-8