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Evaluation of methotrexate polyglutamates as a biomarker for optimizing methotrexate treatment in Crohn’s diseaseMohan, Ashray 24 November 2021 (has links)
Methotrexate (MTX) is an antagonist of folic acid metabolism that was initially designed to treat malignancies, including childhood leukemia. After its anti-inflammatory properties were discovered, use of MTX became widespread in the treatment algorithms for several autoimmune illnesses, including the inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC). The specific cause(s) of IBD in general, and CD in specific, have not yet been fully elucidated. However, most investigators agree that the pathogenesis is likely due to a combination of genetic vulnerability and precipitating environmental exposures. Some of these identifiable modifiers include adherence to a low fiber diet, vitamin D deficiency, smoking, and an alteration in the diversity of the gut microbiome in response to viral or bacterial illness or antibiotic medications. Disease activity in patients with CD, particularly during clinical trials, is assessed using composite indices, including the Crohn’s Disease Activity Index (CDAI), Crohn’s Disease Endoscopic Index of Severity (CDEIS), and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ).
A wide range of medications is used to induce and maintain long-term remission in patients with active CD. These include corticosteroids, immunosuppressive agents (thiopurines and MTX) and several classes of biologics such as TNF-inhibitors, anti-IL-12/23 and anti-adhesion molecules. TNF-inhibitors are often used as first-line biologic therapies in patients with IBD because they have been in widespread use for over two decades and therefore afford the clinician a more data-driven consideration of risk to benefit ratio when discussing treatment options with their patients.
However, there is a relatively high rate of primary non-response and acquired secondary loss of response to TNF-inhibitors. A secondary loss of response often results from the production of neutralizing antibodies, referred to as Antibodies to Infliximab (ATI). In response, concomitant low-dose oral MTX therapy has been employed by clinicians to reduce the immunogenicity of biologic therapy. In addition, previous studies have also demonstrated the efficacy of MTX monotherapy in maintaining clinical remission in patients with CD when delivered at relatively higher doses. However, there is no consensus on the proper dosing or route of administration (oral or parenteral) of MTX. This knowledge gap has resulted in inconsistent clinical practice across physicians and institutions.
Pharmacologic studies have identified the metabolic pathways underpinning the mechanism of action of MTX. It is generally understood that MTX in its native form is free to move across cell membranes in a bidirectional manner. It is only after MTX has been glutamated (MTX-PG) that it is “caged” within the cell and can exert its effects. MTX can be glutamated on up to five discrete sites, each contributing to its stereospecificity and membrane permeability. A better understanding of this process may inform the development of rational dosing and pharmacokinetic-based treatment algorithms that provide patients with a sufficient MTX (and subsequently MTX-PG) level required to achieve anticipated clinical efficacy but not so high as to contribute undo morbidity to treated patients. Therefore, optimizing MTX/MTX-PG dosing can significantly advance the utility of this immunomodulatory pathway to treat IBD and other autoimmune disorders.
MTX can be administered orally or parenterally, the latter being delivered by either subcutaneous or intramuscular injection. Previous studies have demonstrated increased bioavailability of the drug at higher doses when delivered via the parenteral route. The native form of MTX has a short half-life and is eliminated from the body within 24 hours. Instead, it is the active metabolites of MTX which are retained for more extended periods of time and are ultimately responsible for the anti-inflammatory effects in the body. A MTX molecule can have anywhere from 1 and 5 glutamyl groups attached to it, denoted as MTX-PG1, MTX-PG 2, MTX-PG3, MTX-PG 4, and MTX-PG 5. The mechanism(s) by which MTX-PG moieties contribute anti-inflammatory activity is not fully understood but remains an area of active research.
Several studies have explored the association between disease activity and erythrocyte MTX-PG levels. While initial results were mixed, more recent prospective cohort studies in patients with Rheumatoid Arthritis (RA) found an inverse relationship between intracellular levels of longer-chain MTX-PG (MTX-PG3, MTX-PG4, and MTX-PG5) and disease activity. This finding has raised the possibility that monitoring MTX-PG levels could be used as a clinical tool to optimize MTX therapy for patients. However, several key issues persist, including high interpatient variability in MTX-PG levels. Similar studies in patients with CD have thus far been scarce. More prospective studies are needed to explore the utility of MTX-PG pharmacokinetics as a useful biomarker and clinical tool to develop an individualized approach to managing patients with Crohn’s disease.
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The cellular pharmacology of antifolates in leukaemiaBarnes, Matthew Joseph January 1998 (has links)
No description available.
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Cell death and DNA damage in methotrexate-treated HeLa cellsPrise, Kevin M. January 1985 (has links)
The cancer chemotherapeutic agent methotrexate inhibits the enzyme dihydrofolate reductase leading to a depletion of cellular reduced folates and inhibition of thymidylate synthase. A predicted consequence of this depletion of cellular thymidylate residues is that the nucleotide dUMP may be incorporated into DNA in place of dTMP. The subsequent cycle of uracil removal and reincorporation by an excision-repair pathway may cause DNA damage, a possible contributory factor leading ultimately to cell death. DNA. damage, in the form of single- and double-strand breaks, was -5 detected in HeLa cells treated with high dose (>10 M) methotrexate using the sensitive nucleoid sedimentation technique and alkaline filter elution. The maximum level of DNA damage, in the form of single-strand breaks, was detected after only 1 hour of drug incubation, but breaks were not detectable after this time, presumably because they had been repaired. DNA double-strand breaks were detectable from 18 hours onwards, along with a small level of single-strand breaks. The presence of hypoxanthine together with the irethotrexate to overcome the inhibition of de novo purine biosynthesis led to a similar occurrence of strand breaks, although a greater number of double-strand breaks was detected. The early appearance of single-strand breaks coincided with a substantial decrease in cellular dTTP levels and loss in colony-forming ability of the cells. No significant changes in cell viability, as measured by a dye-exclusion assay, were detected until at least 12 hours drug incubation. The greater level of double-strand breaks in cells grown with methotrexate and hypoxanthine coincided with a greater loss in colony-forming ability in these cells. 6. Changes in chromatin structure in cells treated with drug for 24 hours or longer were detected as a faster sedimentation of nucleoids compared to control cells. These changes were not due to the supercoiled state of the DNA but were related to the protein component of the nucleoid cage structure. 7. The enzyme ADP-ribosyltransferase was found to be stimulated in response to the appearance of single-strand breaks, reaching a maximum stimulation of 2 - 3 fold after 3 hours incubation with methotrexate. With hypoxanthine present no activation was detected, even though single-strand breaks were present. In neither case was there a change in the degradation rate of ADP-ribose protein conjugates nor a significant change in intracellular NAD+ levels. 8. In methotrexate-treated cells, the activation of the transferase led to an increase in the ADP-ribosylation of three specific proteins, probably by the addition of mono (ADP-ribose) residues. 9. The complete inhibition of ADP-ribosyltransferase activity by 3-aminobenzamide, or the prevention by hypoxanthine of its activation by methotrexate, did not have any significant effect on changes in cell number, cell viability or colony-forming ability in cells incubated with methotrexate. Thus ADP-ribosylation of proteins is not an effective component during the cytotoxic action of methotrexate.
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An investigation into the effects of an antimetabolite (Methotrexate) on bone healing /Jones, Robert Hillary Boucat. January 1976 (has links) (PDF)
Thesis (M.D.S.)--Department of Oral Pathology and Oral Surgery, University of Adelaide, 1977.
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The toxicity and therapeutic index of a methotrexate polymeric compound, D-85Visser, Suzaan 12 May 2008 (has links)
Methotrexate (MTX) has been used for many years in the treatment of patients with cancer as a cytotoxic agent and as an anti-inflammatory drug for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). However, because of the side effects associated with MTX, there is a continuous search for drugs with less toxicity and hence a greater therapeutic index. In pursuit of a better and less toxic compound, researchers have coupled MTX to various polymeric drug carriers. The objective of this study was to evaluate methotrexate and a methotrexate polymer (D-85) in in vitro and in vivo systems. It was hypothesized that D-85 would show improved anti-neoplastic and anti-inflammatory properties with decreased toxicity compared to MTX. The in vitro experiments included cell viability assays on cancerous and non-cancerous cell lines in order to compare the effects of the two drugs on normal and cancerous cells. Other in vitro assays were performed to assess the effect of the two compounds on cell cycle and mixed lymphocyte cultures. Finally, the toxic effects of both drugs were studied concentrating on two treatment regimens, namely that of an anti-inflammatory regimen and a chemotherapeutic regimen. The results obtained during this study clearly illustrate the chemotherapeutic and anti-rheumatic activity of the two drugs, MTX and D-85. The methotrexate water-soluble drug D-85, however showed greater toxicity towards normal cells compared to the toxicity of methotrexate. / Thesis (MSc (Pharmacology))--University of Pretoria, 2008. / Pharmacology / unrestricted
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The effects of variable dose methotrexate infusion in the laboratory rat /Dodridge, M. E. January 1987 (has links) (PDF)
Thesis (M.D.S.)--University of Adelaide, 1988. / Includes bibliographical references (leaves 186-211).
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Intoxikationen durch Methotrexat - Eine retrospektive Analyse von 249 Fällen des Giftinformationszentrums-Nord / Intoxications with methotrexate - a retrospective analysis of 249 cases by the Poisons Centre for northern GermanySchulte-Güstenberg, Lina 27 June 2019 (has links)
No description available.
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Intoxikationen durch Methotrexat - Eine retrospektive Analyse von 249 Fällen des Giftinformationszentrums-Nord / Intoxications with methotrexate - a retrospective analysis of 249 cases by the Poisons Centre for northern GermanySchulte-Güstenberg, Lina 27 June 2019 (has links)
No description available.
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Intoxikationen durch Methotrexat - Eine retrospektive Analyse von 249 Fällen des Giftinformationszentrums-Nord / Intoxications with methotrexate - a retrospective analysis of 249 cases by the Poisons Centre for northern GermanySchulte-Güstenberg, Lina 04 July 2019 (has links)
No description available.
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De behandeling van psoriasis met cytostatica. The treatment of psoriasis with cytostatics.Smit, Frederik, January 1900 (has links)
Proefschrift--Utrecht. / Vita. Summary in English. Includes bibliography.
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