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Biomaterials Oct 2023Multi-organ inflammatory diseases are one of the most serious autoimmune diseases worldwide. The regulation of immune responses by immune checkpoint proteins influences...
Multi-organ inflammatory diseases are one of the most serious autoimmune diseases worldwide. The regulation of immune responses by immune checkpoint proteins influences the development and treatment of cancer and autoimmune diseases. In this study, recombinant murine PD-L1 (rmPD-L1) was used for controlling T cell immunity to treat multi-organ inflammation. To enhance the immunosuppressive effect, we incorporated methotrexate, an anti-inflammatory drug, into hybrid nanoparticles (HNPs) and decorated the surface of HNPs with rmPD-L1 to produce immunosuppressive HNPs (IsHNPs). IsHNP treatment effectively targeted PD-1-expressing CD4 and CD8 T cells in the splenocytes; additionally, it promoted the production of Foxp3-expressing regulatory T cells, which suppressed the differentiation of helper T cells. IsHNP treatment also inhibited anti-CD3 antibody-mediated activation of CD4 and CD8 T cells in mice in vivo. This treatment protected mice from multi-organ inflammation induced by the adoptive transfer of naïve T cells to recombination-activating gene 1 knockout mice. The results of this study imply the therapeutic potential of IsHNPs in the treatment of multi-organ inflammation and other inflammatory diseases.
Topics: Mice; Animals; B7-H1 Antigen; Methotrexate; Immunosuppressive Agents; Mice, Knockout; Inflammation; Autoimmune Diseases; Nanoparticles
PubMed: 37393694
DOI: 10.1016/j.biomaterials.2023.122233 -
Biochimica Et Biophysica Acta. General... Mar 2017For decades, methotrexate (MTX; amethopterin) has been known as an antifolate inhibitor of dihydrofolate reductase (DHFR), and it is widely used for the treatment of... (Review)
Review
BACKGROUND
For decades, methotrexate (MTX; amethopterin) has been known as an antifolate inhibitor of dihydrofolate reductase (DHFR), and it is widely used for the treatment of various malignancies and autoimmune diseases. Although the inclusion of MTX in various therapeutic regimens is based on its ability to inhibit DHFR and consequently to suppress the synthesis of pyrimidine and purine precursors, recent studies have shown that MTX is also able to target other intracellular pathways that are independent of folate metabolism.
SCOPE OF REVIEW
The main aim of this review is to summarize the most important, up-to-date findings of studies regarding the non-DHFR-mediated mechanisms of MTX action.
MAJOR CONCLUSIONS
The effectiveness of MTX is undoubtedly caused by its capability to affect various intracellular pathways at many levels. Although the most important therapeutic mechanism of MTX is strongly based on the inhibition of DHFR, many other effects of this compound have been described and new studies bring new insights into the pharmacology of MTX every year.
GENERAL SIGNIFICANCE
Identification of these new targets for MTX is especially important for a better understanding of MTX action in new protocols of combination therapy.
Topics: Animals; Folic Acid; Folic Acid Antagonists; Humans; Methotrexate; Signal Transduction; Tetrahydrofolate Dehydrogenase
PubMed: 27993660
DOI: 10.1016/j.bbagen.2016.12.014 -
Oncology 2020In this review, human methotrexate dosing regimens, as well as their relationship to data from in vitro cell culture and in vivo animal and human studies, are discussed.... (Review)
Review
In this review, human methotrexate dosing regimens, as well as their relationship to data from in vitro cell culture and in vivo animal and human studies, are discussed. Low-dose, intermediate-dose, and high-dose therapies are covered. Since in vitro and in vivo screenings of potential cancer drugs are commonplace in the development of cancer chemotherapy, comparisons of the three criteria for effectiveness are important.
Topics: Adolescent; Adult; Animals; Antimetabolites, Antineoplastic; Child; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Methotrexate; Neoplasms
PubMed: 32369814
DOI: 10.1159/000506705 -
The Journal of Rheumatology May 2019
Topics: Aged; Arthritis, Rheumatoid; Cardiovascular Diseases; Heart; Humans; Methotrexate
PubMed: 31043496
DOI: 10.3899/jrheum.181269 -
The Journal of Dermatological Treatment Dec 2024Methotrexate is an off-label therapy for atopic dermatitis. A lack of consensus on dosing regimens poses a risk of underdosing and ineffective treatment or overdosing... (Review)
Review
Methotrexate is an off-label therapy for atopic dermatitis. A lack of consensus on dosing regimens poses a risk of underdosing and ineffective treatment or overdosing and increased risk of side effects. This systematic review summarizes the available evidence on dosing regimens.A literature search was conducted, screening all randomized controlled trials (RCTs) and guidelines published up to 6 July 2023, in the MEDLINE, Embase, and Cochrane Library databases.Five RCTs and 21 guidelines were included. RCTs compared methotrexate with other treatments rather than different methotrexate dosing regimens. The start and maintenance doses in RCTs varied between 7.5-15 mg/week and 14.5-25 mg/week, respectively. Despite varied dosing, all RCTs demonstrated efficacy in improving atopic dermatitis signs and symptoms. Guidelines exhibited substantial heterogeneity but predominantly proposed starting doses of 5-15 mg/week for adults and 10-15 mg/m/week for children. Maintenance doses suggested were 7.5-25 mg/week for adults and 0.2-0.7 mg/kg/week for children. One guideline suggested a test dose and nearly half advised folic acid supplementation.This systematic review highlights the lack of methotrexate dosing guidelines for atopic dermatitis. It identifies commonly recommended and utilized dosing regimens, serving as a valuable resource for clinicians prescribing methotrexate off-label and providing input for an upcoming consensus study.
Topics: Adult; Child; Humans; Methotrexate; Dermatitis, Atopic
PubMed: 38124505
DOI: 10.1080/09546634.2023.2292962 -
Expert Opinion on Biological Therapy Mar 2019Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of... (Review)
Review
INTRODUCTION
Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation.
AREAS COVERED
Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries. In addition, mogamulizumab (anti-CC chemokine receptor 4 antibody), chidamide (histone deacetylase inhibitor), and forodesine (purine nucleoside phosphorylase inhibitor) have been approved in Asian countries, including China, and Japan. In this review, we have summarized the available data regarding these approved agents and new agents currently under development for PTCL.
EXPERT OPINION
Novel agents will be a promising therapeutic option in selected patients with relapsed/refractory PTCL and will change the daily clinical practice in the treatment of PTCL. However, these are not a curative option when used as a single agent. Further clinical developments are expected, comprising 1) combination therapies of new agents with cytotoxic chemotherapies; 2) 'novel-novel' combinations; 3) immune therapies, including chimeric antigen receptor T-cell therapy; and 4) predictive marker analysis.
Topics: Aminopterin; Aminopyridines; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Brentuximab Vedotin; China; Depsipeptides; Drug Approval; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunoconjugates; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Sulfonamides
PubMed: 30658046
DOI: 10.1080/14712598.2019.1572746 -
Expert Opinion on Drug Safety May 2017Methotrexate (MTX) is one of the most commonly used disease modifying drugs administered for wide spectrum of conditions. Through the expansion of the indications of MTX... (Review)
Review
Methotrexate (MTX) is one of the most commonly used disease modifying drugs administered for wide spectrum of conditions. Through the expansion of the indications of MTX use, an increasing number of patients nowadays attend orthopaedic departments receiving this pharmacological agent. The aim of this manuscript is to present our current understanding on the effect of MTX on bone and wound healing. Areas covered: The authors offer a comprehensive review of the existing literature on the experimental and clinical studies analysing the effect of MTX on bone and wound healing. The authors also analyse the available literature and describe the incidence of complications after elective orthopaedic surgery in patients receiving MTX. Expert opinion: The available experimental data and clinical evidence are rather inadequate to allow any safe scientific conclusions on the effect of MTX on bone healing. Regarding wound healing, in vitro and experimental animal studies suggest that MTX can adversely affect wound healing, whilst the clinical studies show that lose-dose MTX is safe and does not affect the incidence of postoperative wound complications.
Topics: Animals; Bone and Bones; Humans; Immunosuppressive Agents; Methotrexate; Orthopedic Procedures; Postoperative Complications; Wound Healing
PubMed: 28332422
DOI: 10.1080/14740338.2017.1310839 -
The Journal of Rheumatology Mar 2022
Topics: Arthritis, Rheumatoid; Humans; Methotrexate
PubMed: 34654733
DOI: 10.3899/jrheum.210992 -
Drugs Apr 2018Methotrexate is known to be safe and efficacious in the management of rheumatoid arthritis and psoriasis and thus has been used for the management of psoriatic arthritis... (Review)
Review
Methotrexate is known to be safe and efficacious in the management of rheumatoid arthritis and psoriasis and thus has been used for the management of psoriatic arthritis despite a lack of evidence to support efficacy in psoriatic arthritis from randomized controlled trials. Although the largest randomized trial to date did not support its use as a disease-modifying therapy, observational studies have supported its role, and current treatment recommendations approve of its use as a first-line agent for the management of psoriatic arthritis with predominant peripheral arthritis. The first treat-to-target study in psoriatic arthritis, comparing tight control with standard care, has shown the efficacy of methotrexate as monotherapy in the first 12 weeks. This trial demonstrated the effectiveness of methotrexate with improvement in peripheral arthritis, skin and nail disease, enthesitis, and dactylitis over the course of 12 weeks. There is conflicting evidence about the role of combination (concomitant methotrexate and anti-tumor necrosis factor) therapy. However, drug survival and immunogenicity of certain anti-tumor necrosis factors seem to be better when used in combination with methotrexate. This report reviews the available evidence on the efficacy and effectiveness of methotrexate in psoriatic arthritis and its role in treating psoriatic arthritis to target, as well as in combination with biologic agents. Ideally, randomized placebo-controlled clinical trials evaluating methotrexate (using subcutaneous route of delivery) would provide much-needed clarity on the role of methotrexate in the management of psoriatic arthritis; however, issues around using a placebo in patients with active psoriatic arthritis may render such a trial unfeasible.
Topics: Antineoplastic Agents; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate
PubMed: 29616495
DOI: 10.1007/s40265-018-0898-2 -
British Journal of Clinical Pharmacology Oct 2019Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with... (Review)
Review
Methotrexate at low doses (5-25 mg/week) is first-line therapy for rheumatoid arthritis. However, there is inter- and intrapatient variability in response, with contribution of variability in concentrations of active polyglutamate metabolites, associated with clinical efficacy and toxicity. Prescribing remains heterogeneous across population groups, disease states and regimens. This review examines current knowledge of dose-response of oral methotrexate in the setting of rheumatoid arthritis, and how this could help inform dosage regimens.
Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Humans; Methotrexate; Polyglutamic Acid; Practice Patterns, Physicians'
PubMed: 31276602
DOI: 10.1111/bcp.14057