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RSC Advances Sep 2023The potentiality of the 6-mercaptopurine (MP) and 6-thioguanine (TG) expired drugs toward the corrosion inhibition of the aluminium (Al) (111) surface was widely...
The potentiality of the 6-mercaptopurine (MP) and 6-thioguanine (TG) expired drugs toward the corrosion inhibition of the aluminium (Al) (111) surface was widely investigated using a series of density functional theory (DFT) calculations. A competition between the anti-corrosive features of the studied drugs in the gas and aqueous phases was conducted on both neutral and protonated forms by means of quantum mechanical descriptors. The results of the electrostatic potential analysis demonstrated the prominent nucleophilic nature of the sulfur and nitrogen atoms over the structures of the examined drugs. The frontier molecular orbital theory findings outlined the higher preferability of TG over MP as a corrosion inhibitor. Upon determining the most beneficial configurations of the MP/TG⋯Al (111) complexes, first-principles molecular dynamics simulations were executed. Interestingly, the competence of the TG drug in the corrosion inhibition process of Al (111) was more extensive than that of the MP one, which was confirmed by the interaction energy values of -1.79 and -1.64 eV, respectively. Upon obtaining the relaxed complexes, the effect of the presence of water solvent on the adsorption process was studied. These findings provide a foundation for developing green anti-corrosive inhibitors for the aluminium surface.
PubMed: 37799306
DOI: 10.1039/d3ra04954j -
Cureus Dec 2023Inflammatory bowel disease (IBD) is an autoimmune disorder marked by chronic inflammation affecting the intestines. Crohn's disease (CD) and ulcerative colitis (UC) fall...
Inflammatory bowel disease (IBD) is an autoimmune disorder marked by chronic inflammation affecting the intestines. Crohn's disease (CD) and ulcerative colitis (UC) fall under the IBD umbrella, necessitating diverse treatments, including steroids, immunomodulators like 6-mercaptopurine (6-MP) and azathioprine (AZA), and biological agents. The prolonged use of immunomodulators, such as AZA, is associated with an elevated risk of developing lymphomas. This case report centers on a 77-year-old gentleman regularly monitored by Gastroenterology, undergoing long-term AZA therapy for CD management. He presented with palate swelling and acute-on-chronic back pain, diagnosed with follicular lymphoma in the palate with metastasis. Palliative radiotherapy was administered for the paraspinal lesion, and the patient is currently stable. In conclusion, this case underscores the importance of recognizing the heightened risk of neoplasms, especially lymphomas, in patients undergoing prolonged immunomodulator therapy. It emphasizes the need for a vigilant and comprehensive approach to patient care, transcending conventional paradigms.
PubMed: 38125685
DOI: 10.7759/cureus.50839 -
RMD Open Jan 2024Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood.
Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review.
BACKGROUND
Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood.
PURPOSE
To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs.
DATA SOURCES
MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources.
DATA EXTRACTION AND SYNTHESIS
Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework.
RESULTS
Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified.
LIMITATIONS
Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors.
CONCLUSIONS
Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring.
PROSPERO REGISTRATION NUMBER
CRD42020208049.
Topics: Humans; Azathioprine; Chemical and Drug Induced Liver Injury; Glucocorticoids; Kidney; Mercaptopurine; Prognosis
PubMed: 38199851
DOI: 10.1136/rmdopen-2023-003588 -
Infliximab: a single-centre, prospective, observational evaluation of TDM data in patients with IBD.European Journal of Hospital Pharmacy :... Dec 2023Therapeutic drug monitoring of infliximab (IFX) is important to optimise treatment of inflammatory bowel disease (IBD). A recent IBD consensus statement recommends... (Observational Study)
Observational Study
OBJECTIVES
Therapeutic drug monitoring of infliximab (IFX) is important to optimise treatment of inflammatory bowel disease (IBD). A recent IBD consensus statement recommends targeting trough serum concentrations of >3 μg/mL, higher than our local recommendation of >1 μg/mL. We therefore investigated the relationship between IFX trough concentrations and C reactive protein (CRP), faecal calprotectin (FCP), clinical outcomes and anti-IFX antibody (AB) development as well as the influence of concomitant thiopurine treatment.
METHODS
Observational data, prospectively collected in a cohort of adult patients with IBD newly initiated on IFX at a single centre.
RESULTS
IFX concentrations >3 μg/mL were associated with a greater reduction in CRP (% change from baseline) and lower FCP; mean (SD) 47 (33.8) % vs 102.3 (136.9) % and 233.9 (505.1) μg/g vs 416.3 (613.5) μg/g, respectively. Lower IFX concentrations were observed in patients who developed AB than those who did not, mean (range) 6.2 (1.1-10) μg/mL vs 0.9 (0.4-4.9) μg/mL, respectively, and also in patients who stopped/switched therapy compared with those who continued, 2.4 (2.9) μg/mL vs 6.5 (2.8) μg/mL; p=0.0002. Patients taking a concomitant thiopurine were found to have higher IFX concentrations; mean (range) 6.4 (0.7-10) μg/mL vs 3.9 (0.4-10) μg/mL.
CONCLUSIONS
IFX concentrations are correlated with biomarkers, clinical response and AB development in patients with IBD. Concomitant thiopurine therapy appears to be associated with higher IFX concentrations and reduced likelihood of AB development.
Topics: Adult; Humans; Infliximab; Gastrointestinal Agents; Prospective Studies; Colitis, Ulcerative; Crohn Disease; Inflammatory Bowel Diseases; C-Reactive Protein
PubMed: 35217509
DOI: 10.1136/ejhpharm-2021-003015 -
Journal of Pharmaceutical Policy and... Dec 2023Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This...
Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann-Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July-December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.
PubMed: 38082299
DOI: 10.1186/s40545-023-00657-7 -
Chemico-biological Interactions Jan 2024Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and...
Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT). Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs. The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques. Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 10 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm). In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients' leukocytes.
Topics: Humans; Child; Mercaptopurine; Thioguanine; Chromatography, Liquid; Metal Nanoparticles; Silver; Tandem Mass Spectrometry; Methyltransferases; Nucleotides; Leukemia; Spectrum Analysis
PubMed: 37944627
DOI: 10.1016/j.cbi.2023.110792 -
Journal of Clinical Medicine Dec 2023Postoperative recurrence (POR) is the rule in patients with Crohn's disease (CD), mitigated with prophylactic therapy. The evidence for therapeutic choice and timing of...
Early Initiation of Adalimumab Significantly Diminishes Postoperative Crohn's Disease Endoscopic Recurrence and Is Superior to 6-Mercaptopurine Therapy: An Open-Label, Randomized Controlled Study.
Postoperative recurrence (POR) is the rule in patients with Crohn's disease (CD), mitigated with prophylactic therapy. The evidence for therapeutic choice and timing of intervention is lacking. We aimed to compare the rates of POR in patients treated early with prophylactic 6-mercaptopurine (6-MP) or adalimumab. We conducted a prospective single-center randomized open-label clinical study in which patients in surgical remission following their first ileocecectomy were randomized to receive early treatment with 6-MP or adalimumab. Patients were followed up clinically every 3 months and underwent endoscopy at weeks 32 and 58 postoperatively. The primary endpoint was endoscopic recurrence (ePOR) at 1 year (week 58), defined as a Rutgeerts score ≥ i2. We enrolled 35 patients (25 males, mean age 35 ± 1.4 years, median disease duration 5 ± 6.1 years) following ileocecectomy. Of these, seven (20%) were current smokers and nine (26%) biologics-experienced. Patients allocated to adalimumab had significantly less ePOR than patients treated with 6MP at week 32 (21% vs. 69%, = 0.004) and 58 (47% vs. 75%), ( = 0.03, HR = 0.39, 95% CI = 0.16-0.93). POR was associated with an increased diameter of the resected small bowel surgical specimen, lower baseline body mass index (BMI), increased week 18 fecal calprotectin, increased week 18 serum alanine aminotransferase and decreased week 18 hemoglobin level. Adalimumab was more effective than 6-MP in preventing ePOR. Increased operative small bowel diameter and lower postoperative BMI were associated with ePOR. At eighteen weeks, serum hemoglobin, ALT and fecal calprotectin levels were predictive of endoscopic disease recurrence. (ClinicalTrials.gov ID NCT01629628).
PubMed: 38137669
DOI: 10.3390/jcm12247600 -
CEN Case Reports Aug 2023Granulocyte colony-stimulating factor (G-CSF) is commonly used to stimulate bone marrow production. G-CSF is usually safe but sometimes causes serious adverse effects...
Granulocyte colony-stimulating factor (G-CSF) is commonly used to stimulate bone marrow production. G-CSF is usually safe but sometimes causes serious adverse effects and, in rare cases, exacerbates glomerulonephritis. We report a case of immunoglobulin A (IgA) nephropathy that was aggravated by G-CSF. A 56-year-old Japanese man with no relevant medical history was admitted to our hospital as a donor of peripheral blood stem cells (PBSCs) for transplantation. To mobilize PBSCs, he received subcutaneous G-CSF (lenograstim), 500 μg for 4 days. Three days after the first dose of lenograstim, gross hematuria appeared, and after administration on the fourth day, renal dysfunction and nephrotic-range proteinuria were observed. Renal biopsy and light microscopic study revealed mild mesangial proliferation with expansion in association with the presence of cellular segmental crescents. Immunofluorescence study revealed diffuse, granular staining in the mesangium for IgA, complement component 3 (C3), and lambda light chains. We diagnosed highly active IgA nephropathy and initiated treatment with prednisolone and azathioprine. Three months later, renal function returned to normal. Screening for hidden chronic glomerulonephritis should be performed when G-CSF is administered, as in PBSC donors. Immunosuppressant therapy, such as prednisolone or azathioprine, is considered for exacerbations of highly active glomerulonephritis.
Topics: Male; Humans; Middle Aged; Glomerulonephritis, IGA; Azathioprine; Lenograstim; Glomerulonephritis; Granulocyte Colony-Stimulating Factor; Prednisolone; Immunoglobulin A
PubMed: 36508113
DOI: 10.1007/s13730-022-00764-5 -
Journal of Clinical Medicine Oct 2023Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity...
Incidence of Myelotoxicity and Other Adverse Effects Related to Thiopurine Starting in Patients with Inflammatory Bowel Disease: Retrospective Observational Study in a Third-Level Hospital.
BACKGROUND AND OBJECTIVES
Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity being the most relevant. This study aims to determine the incidence of AEs related to the starting of thiopurines in our centre.
METHODOLOGY
Retrospective study. The AEs in patients that were started on thiopurines between January 2016 and June 2020 were registered, with a two-year follow-up. The mean and standard deviation were used to describe the quantitative variables, and percentages and confidence intervals were used for the qualitative variables. The statistical significance was set at a -value < 0.05.
RESULTS
98 patients were included, with 64 AEs detected in 48 patients (49%). Most of the AEs appeared in the first 6 months. The most relevant were: 21 neutropenia (21.4%), 19 hypertransaminasemia (19.4%), 13 digestive intolerances (13.2%), 6 acute pancreatitis (6.12%), 3 phototoxicity (3%), and 2 unknown origin fevers (2%). In 29 patients (29.4%) the treatment had to be suspended due to AEs. In 11 cases (11.2%), azathioprine (AZA) was switched to 6-mercaptopurine (6 MP) as 5 showed tolerance and 6 patients needed suspension due to AEs. Eight patients required hospital admission, but none of them needed intensive care unit admission. There were no fatal adverse effects.
CONCLUSIONS
Thiopurines are a safe drug with few AEs, especially after the first months of treatment. These results suggest that periodic analytic follow-up may not be necessary after the initial period of treatment.
PubMed: 37892708
DOI: 10.3390/jcm12206571 -
BMC Neurology Dec 2023Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior...
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) is a recurring inflammatory demyelinating disease that is commonly observed in Asian countries like China. Prior investigations have shown that mycophenolate mofetil (MMF) with better biocompatibility compared to azathioprine (AZA), and can prevent relapses of NMOSD, but the efficacy was controversially reported in different NMOSD cases. We aimed to explore the factors that weaken efficacy of MMF in NMOSD.
METHODS
A total of 34 NMOSD patients treated with MMF were prospectively enrolled and grouped according to the therapeutic efficacy as effective group (EG, n = 23) versus less-effective group (LEG, n = 11). The purine metabolites were profiled in serum samples and gut microbiota was analyzed using 16S rRNA sequencing with stool samples from the same patients.
RESULTS
Purine salvage pathway (PSP) metabolites (inosine, hypoxanthine, xanthine, guanine and uric acid) in the serum of NMOSD patients were elevated in the LEG compared to EG (p < 0.05). Additionally, the richness and microbial diversity of gut microbiota was found to be similar between EG and LEG patients. However, LEG patients had increased presence of Clostridium and Synergistes but decreased abundance of the Coprococcus genus.
CONCLUSIONS
The PSP metabolites and composition of the gut microbiota were changed between patients with or without optimal clinical response after MMF treatment. This may help us to understand the pharmacodynamics of MMF in NMOSD.
Topics: Humans; Mycophenolic Acid; Neuromyelitis Optica; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Treatment Outcome; Azathioprine; Recurrence
PubMed: 38102573
DOI: 10.1186/s12883-023-03500-3